Vol. 2 No.

 2 November 2017
ISSN 2507-8364 (Online)

IN THIS ISSUE:
ORIGINAL ARTICLES
The Effect of Number of Tests, Hemoglobin Level and Working Temperature on the
Specific Gravity of 100 ml Cooper Sulphate Solution in Hemoglobin Screening
Francis Dematera and Linda Tamesis

Proficiency Testing of Clinical Laboratories for Bacteriology in the Philippines, 2009-2015

Melisa Mondoy, Julius Matt Rapanut, Mark Philip Bugayong, Razaele Aguinaldo, Rafael Navarro,
Kristine Jeanne Yap, Ma. Theresa Kapawan, Daryl Joy Almonia, Grace Esparar, Alexander Sadiasa,
Noel Macalalad, Lydia Sombrero, Maria Rosario Capeding, Socorro Lupisan

REVIEW ARTICLE
An Insight into the Histopathology of Oral Neoplasms with Basaloid Morphology and a
Working Classification
Manas Bajpai and Nilesh Pardhe

CASE REPORTS
The Morphologic Profile of Inflammatory Bowel Disease and the Diagnostic Problem of
Crohn’s Disease versus TB Colitis – A Case Series
Maria Lourdes Tilbe, Francia Victoria de los Reyes, Ricka Valentine Cu, Kathleen Jill Perez

AUTOPSY VAULT
Intravascular Large B-Cell Lymphoma: A Continuing Enigma
Raymundo Lo and Ivy Carol Lique

BRIEF COMMUNICATIONS
External Quality Assessment Scheme for Transfusion Transmissible Infections among
Blood Service Facilities in the Philippines, 2016
Kenneth Aristotle Punzalan, Rhoda Yu, Iza Mae Chamen

IMAGES IN PATHOLOGY
Osteolipoma: A Rare Variant of the Common Lipoma
Emilio Villanueva III and Ariel Vergel de Dios

DIAGNOSTIC PERSPECTIVES
Contrast-enhanced Spectral Mammography: A Radiologic-Pathologic Perspective of a
Novel Functional Imaging Modality for Breast Cancer
Ma. Theresa Buenaflor and Francis Moria

Alocilja Magnetic Nanoparticles Efficiently Capture Escherichia coli O157:H7 Isolates

Dodge Lim, Rovi Gem Villame, Gloria June Quiñones, Dave de Vera, Rebecca Notorio, Lilia Fernando,
Evangelyn Alocilja
 Philippine Journal of Pathology
Vol. 2 No. 2 November 2017 | ISSN 2507-8364 (Online)
http://philippinejournalofpathology.org

This journal is OPEN ACCESS, providing immediate access to its content on the principle that making research freely available to the public supports
a greater global exchange of knowledge. The Philippine Journal of Pathology is licensed under a Creative Commons Attribution-NonCommercial-
ShareAlike 4.0 International License, which allows sharing, copying and redistributing the material in any medium or format, and adaptation, in which
the material can be built upon, under strict terms of giving appropriate credit to the authors and this journal, and use for non-commercial purposes.
 PRESIDENT’S MESSAGE 3
EDITORIAL 4

ORIGINAL ARTICLES AMADO O. TANDOC III

The Effect of Number of Tests, Hemoglobin Level and Working 6 Editor-in-Chief
Temperature on the Specific Gravity of 100 ml Cooper Sulphate Solution in FRANCIS G. MORIA
Hemoglobin Screening Vice Editor-in-Chief
Francis Dematera and Linda Tamesis
IVY A. ROSALES
Proficiency Testing of Clinical Laboratories for Bacteriology in the 10 MARICEL REGINO-RIBO
Philippines, 2009-2015 FARRAH KRISTINE FONTILA-SANTIAGO
Melisa Mondoy, Julius Matt Rapanut, Mark Philip Bugayong, Razaele ANN MARGARET V. CHANG
Aguinaldo, Rafael Navarro, Kristine Jeanne Yap, Ma. Theresa Kapawan, FRANCES SAURA-SANCHEZ
Daryl Joy Almonia, Grace Esparar, Alexander Sadiasa, Noel Macalalad, MARIE CHRISTINE F. BERNARDO
Lydia Sombrero, Maria Rosario Capeding, Socorro Lupisan DAPHNE CHUA ANG
MA. LOURDES L. GOCO
REVIEW ARTICLE MARY JANE CARIAS-MARINES
An Insight into the Histopathology of Oral Neoplasms with 20 Associate Editors
Basaloid Morphology and a Working Classification
Manas Bajpai and Nilesh Pardhe Editorial Board
AGUSTINA D. ABELARDO
CASE REPORTS Cytopathology
The Morphologic Profile of Inflammatory Bowel Disease and the 26
Diagnostic Problem of Crohn’s Disease versus TB Colitis – A Case Series JOSE M. CARNATE JR.
Maria Lourdes Tilbe, Francia Victoria de los Reyes, Ricka Valentine Cu, Head & Neck Pathology
Kathleen Jill Perez MA. RIZALINA F. CHUA
Blood Banking
AUTOPSY VAULT
Intravascular Large B-Cell Lymphoma: A Continuing Enigma 31 NELSON T. GERALDINO
Raymundo Lo and Ivy Carol Lique Biochemistry
EVELINA N. LAGAMAYO
BRIEF COMMUNICATIONS Medical Microbiology
External Quality Assessment Scheme for Transfusion Transmissible 36
Infections among Blood Service Facilities in the Philippines, 2016 RAYMUNDO W. LO
Kenneth Aristotle Punzalan, Rhoda Yu, Iza Mae Chameni Immunology & Molecular Pathology
MIGUEL MARTIN N. MORENO II
IMAGES IN PATHOLOGY Biosafety/Biosecurity
Osteolipoma: A Rare Variant of the Common Lipoma 39
Emilio Villanueva III and Ariel Vergel de Dios JANUARIO D. VELOSO
Hematopathology
DIAGNOSTIC PERSPECTIVES SOCORRO C. YAÑEZ
Contrast-enhanced Spectral Mammography: A Radiologic-Pathologic 41 Laboratory Quality Assurance
Perspective of a Novel Functional Imaging Modality for Breast Cancer
Ma. Theresa Buenaflor and Francis Moria ROWEN T. YOLO
Surgical Pathology
Alocilja Magnetic Nanoparticles Efficiently Capture 47
Escherichia coli O157:H7 Isolates Editorial Advisers
Dodge Lim, Rovi Gem Villame, Gloria June Quiñones, Dave de Vera, JOSE MA. C. AVILA
Rebecca Notorio, Lilia Fernando, Evangelyn Alocilja MARISSA A. ORILLAZA
MARITA V.T. REYES
Instructions to Authors 51
Authorship Form 55 Editorial Staff
Patient Consent Form 56
Peer Reviewers 57 MELISSA O. TANDOC
Editorial Coordinator

The Philippine Journal of Pathology (PJP) is an open-access, peer-reviewed, English language, medical science journal
published by the Philippine Society of Pathologists, Inc. Committee on Publications. It shall serve as the official platform for
publication of high quality original articles, case reports or series, feature articles, and editorials covering topics on clinical and
anatomic pathology, laboratory medicine and medical technology, diagnostics, laboratory biosafety and biosecurity, as well as
laboratory quality assurance. The journal’s primary target audience are laboratorians, diagnosticians, laboratory managers,
pathologists, medical technologists, and all other medical and scientific disciplines interfacing with the laboratory. The PJP
follows the ICMJE Recommendations for the Conduct, Reporting, Editing and Publication of Scholarly
Work in Medical Journals, EQUATOR Network Guidelines, and COPE Guidelines. The PJP does not charge any
article processing or submission fees from authors. It does not charge any subscription fees or download fees to access content.
PRESIDENT’S MESSAGE

To all our PJP readers,

It gives me immense pride and enthusiasm that I invite you to

read our third issue and the succeeding issues of the Philippine
Journal of Pathology.

After quite a while, It was only three years ago that we have
resumed the talk on publishing our own society’s journal and
once it was approved even if we knew it will be difficult, we
proceeded with the publication of our journal. Enormous
brain storming and effort was done to come up with this
journal and I believe you now see that effort reflected in each
edition and in the impact it will have on the field of Pathology.

Our journey to the birth of this journal is not smooth considering

the cost of publication plus the difficulty of acquiring articles
to be published. The journal intends to publish case reports,
review articles and most espiecially original research articles.
Our objective is to reach all the pathologists and clinical
practitioners, who are interested in pathology’s interesting
cases, research activities and probably new techniques
which helps us in updating our knowledge.

The PSP together with the PJP’s editorial staff welcome you to
post comments related to the journal by sparing your valuable
time and request you to send articles.

Finally I would like to thank the PJP editorial team headed

by Dr. Mads Tandoc, his technical team, the authors and the
well wishers, who are promoting this journal. We maintain that
the standard policies will be followed and we remain open to
comments and suggestions but most of all, we are most open
to your continued support.

Thank you!

Bernadette R. Espiritu, M.D. FPSP. MMHoA. MIAC

President, Philippine Society of Pathologists, Inc.

http://philippinejournalofpathology.org | Vol. 2 No. 2 November 2017

EDITORIAL
Horror Vacui
Each completed issue of the
PJP is no small feat. The editorial
process is not as simple as
receiving articles, laying them
out and sending them to press.
Additional processes, based
on international standards,
are now in place in between
point of submission and final
publication, to assure quality: a
checklist of requirements and
forms need to be submitted at the outset; a review of
statistical methods, if applicable, need to be hurdled;
a blind peer review system must be completed to help
the editor arrive at a decision to either accept or reject
a submitted manuscript; and then, there is the back
and forth communication between author and editor,
to ensure that suggested changes are discussed and
considered. It does not end there. Between author
resubmission to final publication lie copyediting and
layout, incorporation of digital object identifiers, and
PDF and HTML conversion.
We aim to assure our readers that every article you
have read in the past issues since our journal’s revival,
and those you shall read in this issue and future issues,
is quality controlled.
There exists a large expanse of time and space between
journal issues released only during conventions. We try
to address this vacuum by aiming for a second issue
within the year. While article submissions may be lean
for now, the fact that we have reached a second
issue for 2017 alone is, in itself, already a milestone. It is
something that we should be proud of and hope we
could sustain in 2018 and beyond.
Content-wise, policy-guiding research from two
National Reference Laboratories are included in this
issue. Data generated from the national external
quality assessment of blood service facilities for 2016
reinforce the need for participants to proactively
review their EQAS reports, discuss and implement
corrective actions and opportunities for improvement
with their staff and management. Seven-year data
from 2009 to 2015 of the external quality assurance
scheme for bacteriology show that, although there is,
in general, improvement of the performance of tertiary
clinical laboratories, there are still poorly performing
facilities lacking trained personnel, resources, and
implementation of quality assurance, that need
attention. We hope that the other National Reference
http://philippinejournalofpathology.org | Vol. 2 No. 2 November 2017
Laboratories shall be encouraged to follow suit in the
upcoming issues, as NRL outputs are critical to fill in the
gaps in national laboratory policies.
This second issue now also features representative
articles for the “Review” and “Autopsy Vault” sections.
The article by Bajpai and Pardhe proposes a working
classification for oral neoplasms with basaloid
morphology. The submission by Lo and Lique discusses
a clinical enigma whose rare cause was solved
postmortem. Both provide important learning points
for pathologists and diagnosticians.
Moreover, we are happy to introduce “Diagnostic
Perspectives,” a new type of article for the PJP with
characteristics in between a feature article, a case
report, and images in pathology. Through this, we
aim to feature new technologies and innovations
that improve diagnostics and ultimately, clinical
management. Preliminary findings, proofs-of-concept,
and scientific anecdotes, will find good company
in this new section. In this issue, we feature two such
articles, one on a novel functional imaging modality
for breast cancer correlated with histopathologic
findings, and another, on the use of patented
magnetic nanoparticles for improving sensitivity of
pathogen detection.
Tilbe et al.’s work on cases of inflammatory bowel
disease seen in a local tertiary hospital, and Villanueva
et al.’s report of a rare variant of a commonly seen
pathologic entity, underscore the enduring value of
the case report, as a learning resource. Rounding up
this issue, is the experimental work by Dematera et al.
to provide additional objective data on a classic test
which, although it may already have been superseded
by technology, is still being used in our setting.
“Horror vacui,” (“Nature abhors vacuum,”) so said
Aristotle, in Book IV of his treatise, Physics. In the modern
context, meaning, if there are gaps, something shall
fill them. It is our hope that the Philippine Society of
Pathologists and its members will use the Philippine
Journal of Pathology as an instrument in solidifying the
evidence basis for national laboratory policies and, in
the process, fill the gaps in local data.
Amado O. Tandoc III, MD, FPSP
Editor-in-Chief
https://doi.org/10.21141/PJP.2017.010
 Invitations from the
BioRisk Association of the Philippines, Inc.
For inquiries, pls call +63.9292.660

* This advertisement is a complimentary service of the PJP for member societies/organizations.

OPEN ACCESS – ORIGINAL ARTICLE

The Effect of Number of Tests, Hemoglobin Level

and Working Temperature on the Specific Gravity of
100 ml Copper Sulphate Solution in Hemoglobin Screening
Francis Dematera and Linda Tamesis

Institute of Medicine, Far Eastern University-Nicanor Reyes Medical Foundation

ABSTRACT

Background. The copper sulphate method, being economical, was used for hemoglobin screening in
blood donation. Various references cite different number of tests that can be performed in a 100 mL copper
sulphate solution.

Objective. To determine the effect of the number of tests, hemoglobin level and working temperature on the
specific gravity of 100ml copper sulfate solution.

Methodology. Three groups of samples of known hemoglobin levels (<12 g/dl, 12-14 g/dl, and >14 g/dl) were
tested using a 100 ml copper sulphate solution with specific gravity 1.053 at room temperature and at
temperature of 29-30°C. Specific gravity of the solution was measured after every 5 tests for a total of 50 tests
per experiment.

Result. There was no change in the specific gravity of copper sulphate solution used in 50 tests. There was no
difference in the measured specific gravity across all experiments.

Conclusion. A 100 mL copper sulphate solution can be used for 50 tests using samples of various hemoglobin
levels, at room temperature and at a higher temperature.

Key words: blood, hemoglobin, copper sulphate

INTRODUCTION
ISSN 2507-8364 (Online)
Printed in the Philippines The copper sulphate method for hemoglobin screening in blood
Copyright © 2017 by the PJP. 
donation has been in use for decades. The Far Eastern University-
Received: 30 March 2016. 
Accepted: 22 August 2017.  Nicanor Reyes Medical Foundation (FEU-NRMF) Medical Center,
Published online first: 8 September 2017. a tertiary hospital, previously utilized a colorimetric method using
https://doi.org/10.21141/PJP.2017.011 an automated analyzer for walk-in and mobile blood donation
    for potential blood donors until 2010, when it shifted to copper
Corresponding author: Francis F. Dematera, MD sulphate method to alleviate the cost of hemoglobin screening and
E-mail: francisdematera@yahoo.com
the total cost of blood donor screening. The method is not only
considered to be the most economical in FEU-NRMF and in the
Philippines, but also in other developing countries.1

The copper sulphate method determines the hemoglobin content

in a drop of blood by inference from the specific gravity of the
copper sulphate solution. A drop of blood upon contact with
the solution becomes encased in a sac of copper proteinate. The
dispersion of the drop of blood and any immediate change in the
specific gravity of the solution due to blood's dispersion is prevented
for about 15 seconds.2 The minimum hemoglobin requirement for
blood donation is 12.5 g/dl and with a copper sulphate solution
with specific gravity of 1.053, a drop of blood with hemoglobin of
12.5 g/dl or higher should sink in 10 to 15 seconds while a drop of
blood with hemoglobin level of lower than 12.5 g/dl the drop of
blood should float.3

http://philippinejournalofpathology.org | Vol. 2 No. 2 November 2017

Dematera et al, Specific Gravity of 100 ml Copper Sulphate Solution in Hemoglobin Screening Philippine Journal of Pathology | 7

METHODOLOGY the solution a depth of 3 inches. One drop of blood was one test.
Blood samples in the group were rotated to complete the 50 tests.
An experimental study was conducted by doing experiments of As in the usual use of copper sulphate solution for hemoglobin
adding another 25 drops of blood to a 100-ml copper sulphate screening, the drops of blood in the solution were observed for
solutions that have been used for 25 tests, one drop of blood per 15 seconds if they would sink or float. The specific gravity was
test, using samples of known hemoglobin levels at assigned working 1.053 at the start of each experiment. Twenty-five tests were
temperatures. performed successively with no change in specific gravity of the
solution measured after the twenty-fifth test. To complete the fifty
Subjects were chosen by judgment sampling. Individuals who tests, another 25 tests were performed and the specific gravity
were invited to participate in the study were blood donors who was determined after every 5 tests. The measurement of specific
had undergone hemoglobin screening utilizing microcuvette gravity was conducted by lifting the buoy of the hydrometer above
technology (Hemocue) using capillary blood, and hospital the solution and lowering it into the solution with a light spinning
employees with a recent complete blood count with low motion. Once the buoy has stopped moving, the plane of the
hemoglobin level. Possible subjects were given the option to surface of the solution that intersected the scale on the stem of the
participate or not to participate in the study. The details of the buoy was taken as the specific gravity. Measurement of the specific
study were explained to them and they were given consent forms. gravity was done without any drop of blood touching the buoy
Those who accomplished the consent forms were included in the of the hydrometer. The specific gravity in each measurement was
study. Thirty subjects were chosen. Blood samples were extracted recorded to determine if there would be change.
from the subjects and hemoglobin level of each sample was
determined using a hemoglobin analyzer employing photometry The investigator did not use any statistical test as the data could
as principle. Blood samples were grouped based on hemoglobin be analyzed without calculation. The measured specific gravity at
level, ten samples having hemoglobin level of less than 12 g/dl as the start of experiment, the specific gravity after the first twenty-
one group, ten samples with 12 to 14 g/dl and remaining ten as five tests and every additional five tests to complete fifty tests were
one group with more than 14 g/dl. tabulated per experiment. Experiments 1, 2, and 3 are presented
in Table 1, and experiments 4, 5, and 6 in Table 2.
The experiments in the study were conducted in the following
order: Table 1. Specific gravity per number of test and hemoglobin
1. Blood collection from subjects by a medical technologist level at room temperature in experiments 1, 2 and 3
2. Hemoglobin level determination of blood samples Specific Gravity of 100 mL Copper Sulphate Solution
Number
3. Grouping of blood samples as to three hemoglobin ranges of Test Experiment 1 Experiment 2 Experiment 3
4. Testing (Drops of (<12 g/dL (12 to 14 g/dL (>14 g/dL
Blood) Hemoglobin Level) Hemoglobin Level) Hemoglobin Level)
5. Recording of results
0 1.053 1.053 1.053
25 1.053 1.053 1.053
The copper sulphate solution used in the experiments was 30 1.053 1.053 1.053
prepared by a medical technologist following the standard 35 1.053 1.053 1.053
operating procedure of FEU-NRMF Medical Center which also 40 1.053 1.053 1.053
45 1.053 1.053 1.053
conforms with the procedure stated in the USAID-published 50 1.053 1.053 1.053
Anemia Detection Methods: A Manual for Health Workers. Please
see appendix B and C for the preparation of the copper sulphate
solution. The measurement of specific gravity of copper sulphate Table 2. Specific gravity per number of test and hemoglobin
level at temperature 29-30°C in experiments 4, 5 and 6
solution throughout the conduct of the study was performed by
Number Specific Gravity of 100 mL Copper Sulphate Solution
a medical technologist who did not perform any other part of
of Test Experiment 1 Experiment 2 Experiment 3
the experiment. (Drops of (<12 g/dL (12 to 14 g/dL (>14 g/dL
Blood) Hemoglobin Level) Hemoglobin Level) Hemoglobin Level)
Blood samples were collected by a medical technologist by 0 1.053 1.053 1.053
25 1.053 1.053 1.053
venipuncture from each of the thirty subjects and transferred to
30 1.053 1.053 1.053
tubes with spray-dried EDTA anticoagulant. Hemoglobin level of 35 1.053 1.053 1.053
each blood sample was determined using a hemoglobin analyzer 40 1.053 1.053 1.053
employing photometry as principle. Samples were grouped as to 45 1.053 1.053 1.053
50 1.053 1.053 1.053
the three hemoglobin ranges, ten samples per group. Samples with
hemoglobin level of less than 12 g/dl were assigned in group A,
samples with hemoglobin level of 12 to 14 g/dl in group B and The change in specific gravity as to the number of tests was
samples with hemoglobin level of more than 14 g/dl in group C. determined by observing for any increase in the specific gravity
Each sample in the group was assigned with an accession number. during performance of additional 25 tests in all six experiments.

Six experiments were done. Experiments 1, 2 and 3 made use of
samples from groups A, B and C, respectively and were conducted
at room temperature. Experiments 4, 5 and 6 also made use of
the same samples from groups A, B, and C, respectively, but were
conducted at working temperature of 29 ºC to 30 ºC.
The change in specific gravity as to hemoglobin level of the samples
was determined by making a comparison of the measured specific
gravity between experiments that used samples from groups with
different hemoglobin ranges. Experiments 1 and 2, 2 and 3, 1 and
3, 4 and 5, 5 and 6, and 4 and 6 were compared.

Each experiment was performed using 100 mL copper sulphate The change in specific gravity as to temperature was determined
solution in a glassware with the buoy of the hydrometer that gave by comparing the measured specific gravity between experiments

http://philippinejournalofpathology.org | Vol. 2 No. 2 November 2017

Dematera et al, Specific Gravity of 100 ml Copper Sulphate Solution in Hemoglobin Screening
1 and 4, 2 and 5, and 3 and 6 which used samples belonging
to same hemoglobin range but were conducted at different
working temperatures.
RESULTS
There was no change in the specific gravity of 100 mL copper
sulphate solution used for fifty tests in the six experiments (Tables
1 and 2). There was no difference in the measured specific gravity
between experiments that were compared.
DISCUSSION
To maintain the sensitivity of the test, the United Kingdom
Blood Transfusion and Tissue Transplantation Service, the
World Health Organization in its publication entitled Model
Standard Operating Procedure for Blood Transfusion Service
and the American Association of Blood Banks recommend
changing the solution after it has been used for 25 tests because
the solution is expected to give unreliable results thereafter.3,4,5
However, in the Anemia Detection Methods for Low Resource-
Settings: A Manual for Health Workers published by USAID in
1997, the copper sulphate solution with the same specific gravity
used for male patients in anemia screening recommends that it
can be used for 50 tests.6 The effect on the reliability of the test
was not specified in the above stated publications if it is due to
change in specific gravity secondary to the effect of temperature
to the solution, the effect of hemoglobin content of the blood
being tested or performance of more than 25 tests with one
drop of blood per test. Although the solution changes in color
after performance of several examinations, performance of 50
tests can be done in a 100-ml copper sulphate solution with no
limitation in the visualization of blood dropped in the solution.
Phillips et al., in their article that introduced the copper sulphate
method for hemoglobin screening, mentioned that correction for
temperature is not needed during the testing as the coefficient of
expansion of copper sulphate solution approximate closely those
of blood and plasma but reports have been received by California
Blood Bank Society that the specific gravity of copper sulphate
solution used in screening hemoglobin for potential blood donors
change with temperature.5
The copper sulphate method of estimating hemoglobin has been
thought by many to be an obsolete test due to the advent of new
technologies. But due to the simplicity of the procedure and
lower cost, the technique is still widely used even in the United
Kingdom.3 In the Philippines, the Philippine Blood Center still
uses copper sulphate in donor screening for hemoglobin. Sawant
et al., showed that 29% of potential donors who were deferred
had hemoglobin level of more than 12.5 g/dl in a study involving
400 blood donors.7 However, in the prospective study evaluating
the quality and the cost of four hemoglobin screening methods,
automated analyzer being the standard, done by Tondon et al., in
2009, they found out that the copper sulphate method still stands
the test of time and remains the primary screening method.1
They, however, recommended that to avoid the inappropriate
deferrals, subsequent testing with Hemocue, a hemoglobinometer
employing the photometer principle, should be done.1
The American Association of Blood Banks or AABB
recommends 12.5 g/dl as the minimal hemoglobin requirement
for an allogenic donor.8 The FEU-NRMF Medical Center follows
http://philippinejournalofpathology.org | Vol. 2 No. 2 November 2017
Philippine Journal of Pathology | 8
the recommendation of AABB for the minimal hemoglobin
requirement for blood donation. In other countries, such as the
United Kingdom, there are separate criteria for male and female
donors, 12.5 g/dl for the former and 13.5 g/dl for the latter,3
a recommendation also made by the United States Agency for
International Development (USAID). AABB recommends the
use of at least 30 mL working solution that will allow a drop of
blood to fall approximately 3 inches after dropping (about 1 cm
above the surface of the solution).8 The USAID publication states
that 100 mL of working solution should be used with no mention
of the length that a drop should fall from the upper surface of the
solution to the inner surface of the bottom of the container, with
no recommended height of the fall of the drop of blood from
the capillet to the surface of the solution.1 At the FEU-NRMF
Medical Center, a 100 mL working solution in a 100 mL beaker
is used for testing, giving the solution an approximate depth of
3 inches from the upper surface of the solution to the bottom of
the container. The blood is dropped 1 cm above the surface of
the copper sulphate solution.
The difference between the practice in FEU-NRMF Medical
Center and the recommended standard operating procedures
of the USAID (with the exception of the separate hemoglobin
cut-off for non-pregnant females, the height of the fall of the
drop of blood from the capillet to surface area of solution, and
the depth that a drop of blood must sink from the surface of the
solution to the bottom), is the number of drops of blood that
can be tested in a 100 ml copper sulphate solution with specific
gravity of 1.053. The standard operating procedure of FEU-
NRMF Medical Center is to change the solution after 25 drops
have been introduced which conforms with the Model Standard
Operating Procedures for Blood Transfusion Service published
by the World Health Organization and the Technical Manual of
American Association of Blood Banks.3,4,8 The USAID, however,
has a different recommendation of using a 100 ml copper
sulphate solution for 50 tests, which if proven to still maintain its
specific gravity and therefore its sensitivity with the addition of
another 25 tests in the same solution, will be of great benefit to
blood banks that still use the method.6
Apart from the hemoglobin level of the blood, the working
temperature and other proteins may interfere with the testing.
Although it is said that correction for temperature is not needed
because the coefficient of expansion of copper sulphate solution
approximate closely those of blood and plasma.5 Reports
have been received by the California Blood Bank Society
in its e-Network Forum about the change in specific gravity
with temperature.2 Other proteins may also interfere and the
outcome may be deleterious if an anemic donor will be bled.
Such is the case of a patient who was bled with only 8 g/dl of
hemoglobin, the patient passed the copper sulphate method due
to hyperproteinemia secondary to multiple myeloma.9 These
other proteins in serum or whole blood may be tested using the
same principle with copper sulphate method which means that
they can influence the result of hemoglobin screening.10 This is
one of the limitations of Copper Sulphate method in hemoglobin
screening. However, such a case has not yet been reported in
FEU-NRMF Medical Center.
Two confounding variables were identified. One was the effect
of the use of venous blood with liquid anticoagulant and not
capillary blood. Since no study was found stating the difference
between the weight of anticoagulated blood and blood without
Dematera et al, Specific Gravity of 100 ml Copper Sulphate Solution in Hemoglobin Screening Philippine Journal of Pathology | 9

anticoagulant, it was assumed that the anticoagulant present in REFERENCES

the blood collection tubes could affect the result of the experiment
by diluting the blood. To minimize the possible error associated
with the use of liquid anticoagulant, spray dried ethylene di-
amine tetraacetic acid-anticoagulated (EDTA) lavender top tubes
were used. During the conduct of the study, another confounding
variable that was identified was the adherence of blood to the
stem of the buoy of hydrometer, adding to the weight of the buoy,
which caused a false decrease of the specific gravity. The plane of
the surface of copper sulphate solution will intersect with a lower
specific gravity number as the buoy becomes heavier. To resolve
the problem, the other method of measuring specific gravity
using refractometer was entertained, but was not employed as the
method requires removal of drops of copper sulphate solution
for the tests, decreasing the volume of the solution.
One limitation of the study is the conduct of experiments in
only two working temperatures, room temperature, which is
the recommended working temperature in blood banks and
laboratories, and at a higher temperature of at least 29°C.
Therefore, the study cannot make a recommendation for working
temperature lower than that of room temperature.
CONCLUSION
This paper has shown that there is no change in the specific
gravity of a 100 ml copper sulphate solution used for fifty tests
with sample of various hemoglobin levels conducted at different
working temperatures. Thus, a 100-mL copper sulphate solution
can be used for fifty tests using samples of various hemoglobin
levels at room temperature and at a higher temperature.
STATEMENT OF AUTHORSHIP
All authors certified fulfillment of ICMJE authorship criteria.
Author Disclosure
The authors declared no conflict of interest.
Funding Source
None.
1. Tondon R, Verma A, Pandey P, and Chaudhary R. Quality
evaluation of four hemoglobin screening methods in a blood
donor setting along with their comparative cost analysis in
an Indian scenario. Asian J Transfus Sci. 2009;3(2):66-9.
https://doi.org/10.4103/0973-6247.53874.
2. Problems with QC of Copper Sulfate? E-Network Forum-
California Blood Bank Society.
3. Guidelines for blood transfusion services in the United
Kingdom, 7th ed., UK blood transfusion and tissue
transplantation services, 2005. Available online: https://www.
gov.uk/government/uploads/system/uploads/attachment_
data/file/228828/0117033715.pdf.
4. Model standard operating procedures for blood transfusion
service. World Health Organization, New Delhi, 2002.
Available online: http://apps.searo.who.int/PDS_DOCS/
B0235.pdf ?ua=1.
5. Philips RA, Van Slyke DD, Hamilton PB, Dole VP, Emerson
K, Archibald RM. Measurement of specific gravities of
whole blood and plasma by standard copper sulfate solution. J
Biol Chem. 1950;183:305-30. Available online: http://www.
jbc.org/content/183/1/305.full.pdf+html.
6. Anemia detection methods in low-resource settings: a
manual for health workers. Seattle, Washington, USA: PATH
Publications, 1997. Available online: http://www.path.org/
publications/files/TS_anemia_guide_health_workers.pdf.
7. Sawant RB, Bharucha ZS, Rajadhyaksha SB.Evaluation
of hemoglobin of blood donors deferred by copper
sulfate method for hemoglobin screening. Transfus Apher
Sci. 2007;36(2):143-8. PMID: 17382593. https://doi.
org/10.1016/j.transci.2006.11.001.
8. Brecher ME, American Association of Blood Banks. Technical
Manual, 15th ed. Bethesda, Md.: American Association of
Blood banks, 2005. Available online: http://www.eqas.ir/
pdf/lib/AABB%20Technical%20Manual%2015TH.pdf.
9. Mannarino AD, Macpherson CR. Copper sulfate screening of
blood donors: report of a donor passing the test with less than
eight grams of hemoglobin. Transfusion:1963;3:398-400.
PMID: 14077075.
10. McPherson RA, Pincus MR, Henry JB. Henry's clinical
diagnosis and management by laboratory methods, 21st ed.,
Philadelphia: Saunders Elsevier, 2007. NLIM ID: 101289889
[Book].

Disclaimer: This journal is OPEN ACCESS, providing immediate access to its content on the principle that making research freely available to the
public supports a greater global exchange of knowledge. As a requirement for submission to the PJP, all authors have accomplished an AUTHOR
FORM, which declares that the ICMJE criteria for authorship have been met by each author listed, that the article represents original material,
has not been published, accepted for publication in other journals, or concurrently submitted to other journals, and that all funding and conflicts
of interest have been declared. Consent forms have been secured for the publication of information about patients or cases; otherwise, authors
have declared that all means have been exhausted for securing consent.

http://philippinejournalofpathology.org | Vol. 2 No. 2 November 2017

OPEN ACCESS – ORIGINAL ARTICLE

Proficiency Testing of Clinical Laboratories

for Bacteriology in the Philippines, 2009–2015
Melisa Mondoy,1 Julius Matt Rapanut,1 Mark Philip Bugayong,1 Razaele Aguinaldo,1 Rafael Navarro,1
Kristine Jeanne Yap,1 Ma. Theresa Kapawan,1 Daryl Joy Almonia,1 Grace Esparar,1 Alexander Sadiasa,1
Noel Macalalad,2 Lydia Sombrero,1 Maria Rosario Capeding,1 Socorro Lupisan3
1
Department of Microbiology, Research Institute for Tropical Medicine – Department of Health, Philippines
2
National Tuberculosis Reference Laboratory, Research Institute for Tropical Medicine – Department of Health, Philippines
3
Office of the Director, Research Institute for Tropical Medicine – Department of Health, Philippines

ABSTRACT

Introduction. The National External Quality Assessment Scheme (NEQAS) has been established by the
Department of Health–Philippines (DOH) to provide DOH-approved external quality assessment programs,
including the Proficiency Test (PT) for Bacteriology to clinical laboratories. The PT for Bacteriology aims to
monitor and evaluate laboratory capabilities in the identification of clinically important pathogens through
proficiency testing. Since then, participation in the NEQAS has been a requirement for clinical laboratories to
obtain a license to operate from the DOH–Health Facilities and Services Regulatory Bureau (HFSRB).

Objective. The objective of this report is to summarize and examine the results of the PT for Bacteriology from
2009 to 2015 and the performances of participating clinical laboratories throughout the Philippines.

Methodology. The Research Institute for Tropical Medicine National Reference Laboratory (RITM-NRL)
conducted orientation seminars between 2008 and 2009 to introduce clinical laboratories to the NEQAS.
Laboratories submitted their accomplished enrolment forms to RITM–NRL and paid the fees to enroll in the
PT. Participating laboratories were required to identify three analytes and perform antimicrobial susceptibility
test (AST) on one assigned analyte.

Results. A total of 468 laboratories participated over the seven-year period. The number of participating
laboratories obtaining a passing score of 80% and above had significantly increased from 2009 to 2015. Out
of the 144 laboratories consistently enrolled over the seven-year period, the proportion of participants with
scores of 80% and above had increased. Of the 468 participating laboratories throughout 2009 to 2015, 33.3%
were good performers; 6.6% were fair performers; and 60.0% were poor performers.

Conclusion. The increasing number of participating laboratories obtaining passing scores over the years
suggests overall improvement of the performance of clinical laboratories in bacteriology. Corrective actions
are still needed to address the situation regarding the poor performing laboratories. The assessments
done in 2008 and 2013 found that poorly performing laboratories lack trained personnel, resources, and
implementation of quality assurance procedures for bacteriological testing.

Key words: laboratory proficiency testing, bacterial identification, antibiotic susceptibility testing

INTRODUCTION
ISSN 2507-8364 (Online)
Printed in the Philippines. Clinical bacteriology laboratories carry out the detection and
Copyright© 2017 by the PJP.
isolation of bacterial pathogens for management and surveillance
Received: 29 September 2017.
Accepted: 2 November 2017. of infectious diseases. They are responsible for detecting antibiotic
Published online first: 3 November 2017. resistance, identifying outbreak pathogens, and communicating
https://doi.org/10.21141/PJP.2017.012 incidences and information concerning infectious diseases to
   public health authorities. These important tasks are the reason
Corresponding author: Melisa U. Mondoy, RMT, MPH that high quality testing, and accurate and precise results must
E-mail: mum_2468@yahoo.com
always be ensured.1

The Proficiency Test (PT) for Bacteriology assesses the ability of

clinical microbiology laboratories to identify and characterize
clinically important bacteria and conduct antimicrobial
susceptibility tests. It aims to improve the performances of
laboratories and ensure high quality and reliable testing in the
field of clinical bacteriology.2,3 In other countries, external quality
assessment schemes (EQAS) and PTs for clinical microbiology,

http://philippinejournalofpathology.org | Vol. 2 No. 2 November 2017

Mondoy et al, PT Bacteriology Philippines 2009–2015 Philippine Journal of Pathology | 11

had been influencing the improvement of the quality of testing throughout the seven-year period and to the data acquired from
and performance of participating laboratories in different time the assessments of selected participating laboratories.
periods.4–7 Improvement of laboratory performance can be
attained when sources of errors that result to poor performance METHODOLOGY
are identified and addressed.4,8,9
Baseline assessment of laboratories
In order to establish an effective public health laboratory A baseline on-site assessment of tertiary clinical laboratories
network in the Philippines and streamline its functions, the throughout the country was conducted by RITM-NRL in
Department of Health (DOH) of the Republic of the Philippines 2008. The assessment aimed to (1) monitor their compliance
issued the Department Order No. 393–E s. 2000. It designated with the minimum and essential requirements as set by
the Department of Microbiology of the Research Institute RITM–NRL (Table 1); (2) evaluate their capacity to isolate,
for Tropical Medicine (RITM) as the National Reference identify, and characterize medically important bacterial
Laboratory (NRL) for bacterial enteric diseases, emerging and pathogens; (3) identify their deficiencies, which may result
re-emerging bacterial diseases, and mycology. It also mandates to poor performance in bacteriological testing; (4) educate
RITM–NRL to maintain a quality assurance program for laboratorians on current microbiological advancements; (5)
clinical bacteriology laboratory tests.10 The Department and promote good laboratory practices. The list of tertiary
Administrative Order No. 2007–0027 and Memorandum No. laboratories provided by HFSRB served as the basis for the
2009–0086, were then issued by the DOH, which required number of laboratories to be assessed. The assessment covered
every clinical laboratory throughout the country to participate laboratory practices on specimen processing: (1) isolation and
in the National External Quality Assessment Schemes (NEQAS) identification of medically important bacteria; (2) methods for
in order to obtain a license to operate (LTO) from the DOH antimicrobial susceptibility testing; (3) internal and external
Health Facilities and Services Regulatory Bureau (HFSRB, quality assessment practices; (4) use of functional equipment,
formerly Bureau of Health Facilities and Services).11,12 NEQAS instruments, culture media, reagents, kits, glassware, and
issues DOH-approved external quality assessment programs disposables; and (5) waste management.
for bacteriology, parasitology, and mycobacteriology to clinical
laboratories by providing a proficiency test that aims to monitor Table 1. Number of times participants passed vs number of PT
and evaluate the laboratory’s capabilities to identify clinically participation, 2009-2015
important pathogens. Thus, the RITM–NRL has been providing No. of Annual Number of Times Passed
Total
annual PTs for bacteriology under the NEQAS for Bacteriology, Participation 0 1 2 3 4 5 6 7
Parasitology, and Mycobacteriology to clinical laboratories 1 33 16 49
2 21 4 3 28
since 2009.
3 19 22 8 1 50
4 8 10 14 8 1 41
This report summarizes and examines the results of the PT 5 13 13 11 13 6 3 59
for Bacteriology from 2009 to 2015 and the performances of 6 16 14 18 13 16 5 3 85
participating clinical laboratories. The information and analysis 7 8 21 29 25 30 20 14 9 156
Total 468
were only limited to the scores, regional location, ownership
Legend:  Poor  Fair  Good
type and accreditation category of 468 participants in the PT

Table 2. Biological standards used to perform quality control on the analytes and frequency of incorrect ID 2009-2015
Incorrect ID
Analyte (Binomial Name and Authority) ATCC® Standard No. of ID
(Percentage)
Acinetobacter lwoffii (Audureau) Brisou 17925 27 14 (51.9%)
Moraxella catarrhalis (Frosch and Kolle) Bovre 25238 544 278 (51.1%)
Candida tropicalis (Castellani) Berkhout 10610 10 5 (50.0%)
Enterobacter aerogenes Hormaeche & Edwards 13048 95 43 (45.3%)
Haemophilus influenzae (Lehmann & Neumann) Winslow et al. 49247 944 418 (44.3%)
Streptococcus pneumoniae (Klein) Chester 49619 766 317 (41.4%)
Enterococcus faecalis (Andrewes & Horder) Schleifer & Kilpper-Balz 19433 444 170 (38.3%)
Morganella morganii (Winslow et al.) Fulton 25830 352 131 (37.2%)
Streptococcus pyogenes Rosenbach 12344 89 32 (36.0%)
Streptococcus agalactiae Lehmann & Neumann 13813 378 134 (35.5%)
Shigella flexneri Castellani & Chalmers 12661 389 128 (32.9%)
Klebsiella oxytoca (Flugge) Lautrop 13182 748 233 (31.1%)
Klebsiella pneumoniae subsp. pneumoniae (Schroeter) Trevisan 13883 36 11 (30.6%)
Salmonella enterica subsp. enterica sv. Enteritidis1 (ex Kauffmann & Edwards) Le Minor & Popoff 49223 117 34 (29.1%)
Vibrio cholerae Pacini 14035 74 21 (28.4%)
Enterobacter cloacae subsp. cloacae (Jordan) Hormaeche & Edwards 35929 58 14 (24.1%)
Staphylococcus epidermidis (Winslow & Winslow) Evans 12228 148 34 (23.0%)
Serratia marcescens Bizio 43862 70 16 (22.9%)
Staphylococcus saprophyticus (Fairbrother) Shaw et al. 49453 505 113 (22.4%)
Proteus mirabilis Hauser 29906 101 20 (19.9%)
Pseudomonas aeruginosa (Schroeter) Migula 27853 114 16 (14.0%)
Salmonella enterica subsp. enterica sv. Typhi2 (ex Kauffmann & Edwards) Le Minor & Popoff 19430 333 40 (12.0%)
Candida albicans (Robin) Berkhout 90028 506 60 (11.9%)
Staphylococcus aureus subsp. aureus Rosenbach, methicillin-resistant3 BAA-1720 451 50 (11.1%)
Staphylococcus aureus subsp. aureus Rosenbach 25923 112 10 (8.9%)
Escherichia coli (Migula) Castellani & Chalmers 25922 55 3 (5.5%)
Total 7,466 2,345 (31.4%)
1
Classified as non-typhoidal Salmonella (NTS) along with other serovars such as Typhimurium
2
Also referred to as Salmonella Typhi
3
Also known as MRSA

http://philippinejournalofpathology.org | Vol. 2 No. 2 November 2017

Mondoy et al, PT Bacteriology Philippines 2009–2015 Philippine Journal of Pathology | 12

Enrolment in the proficiency tests unwanted organisms and tested for viability through routine
Since the DOH required clinical laboratories registered under culture examination. For the remaining treatments, three sets
tertiary category in the Center for Health Development (CHD) were incubated at 36±1ºC, 4±2 ºC, and ambient temperature,
to participate in the PT event for the first time in 2009, RITM– respectively. Growth was observed after three, five, and
NRL conducted orientation seminars between 2008 and 2009 seven days. After seven days of incubation, the analytes were
to introduce the participants to the NEQAS. Participating subcultured and re-identified through conventional methods
laboratories submitted their accomplished enrolment forms and commercial identification systems such as API® and
through courier, fax, e-mail, or personal delivery and paid the VITEK® 2.
fees before the scheduled testing event to be eligible for the PT.
In 2015, DOH required all clinical laboratories under primary, The Bacteriology PT program
secondary, and tertiary category performing bacteriological Participating laboratories were asked to identify each of the three
testing to participate in the PT.13 analytes by means of their routine methods or standard operating
procedures. They were also required to perform antimicrobial
Materials and analyte preparation susceptibility testing on one pre-assigned analyte using the panel
before use in the PT. Four sets of cultures of each of all the organisms used as analytes in the
of antibiotics
PT were prepared andrecommended by CLSI.
each set was subjected After
to each receiving
of the thetreatments.
four different analytes,For
Analyte culture, inoculation, and verification the first treatment, separate
participants packages
were given containing
fifteen workingone days
set of different analytesthe
to complete
random locations of participating laboratories throughout the country. The selected
were sent to
PT.
Clinically-significant bacteria were subcultured from stock laboratories were asked to return the sealed package to RITM. Upon return, the analytes
were examined for contamination by unwanted organisms and tested for viability through
cultures in skim milk-tryptone-glucose-glycerol (STGG) media14 The Overall Score, with a perfect rating of 100%, comprised of
routine culture examination. For the remaining treatments, three sets were incubated at
incubated at 36±1°C for 18 to 24 hours. Cultures were examined 75% for organism identification and 25% for AST. RITM–NRL
36±1ºC, 4±2 ºC, and ambient temperature, respectively. Growth was observed after three,
five, and seven days. After seven days of incubation, the analytes were subcultured and re-
for purity; assayed through conventional identification methods15 set the passing score to be 80%. A correct identification—with
identified through conventional methods and commercial identification systems such as
API® and VITEK® 2.
correct binomial name—amounts to 25 points; an acceptable
and commercial identification testing systems: API® (bioMérieux,
Marcy-l'Étoile, France) and VITEK® 2 (bioMérieux, Marcy- identification—with
The Bacteriology PT program correct genus but incorrect or unspecified
Participating laboratories were asked to identify each of the three analytes by means of their
l'Étoile, France); and compared to ATCC® biological standards species—amounts to 10 points; an incorrect one amounts to no
routine methods or standard operating procedures. They were also required to perform
(ATCC, Manassas, Virginia, USA) to verify their identities point. A
antimicrobial correct testing
susceptibility report of pre-assigned
on one antibiotic analyte
susceptibility amounts
using the panel to
of antibiotics
recommended by CLSI. After receiving the analytes, participants were given fifteen working
(Table 2). The analytes were inoculated in semi-solid sheep blooddaysone point the
to complete while
PT. an incorrect report amounts to no point. The
agar (SBA)16 contained in 2 mL-cryogenic vials (Corning Inc., identification of an additional organism would result into an
The Overall Score, with a perfect rating of 100%, comprised of 75% for organism identification
Corning, New York, USA) and incubated at 36±1°C for 18 to 24 andaddition
25% for AST. toRITM–NRL
the number of principal
set the passing organisms
score to be in the
80%. A correct equation
identification—with
correct binomial name—amounts to 25 points; an acceptable identification—with correct
hours prior to transport. but no addition to the points corresponding to the correct and
genus but incorrect or unspecified species—amounts to 10 points; an incorrect one amounts
to noacceptable identification.
point. A correct Thissusceptibility
report of antibiotic would eventually
amounts to one leadpointto while
the an
incorrect report amounts to no point. The identification of an additional organism would
Verification of analyte antimicrobial susceptibility reduction
result of the
into an addition overall
to the numberscore. Theorganisms
of principal following equation
in the equation represents
but no addition
Antimicrobial susceptibility of analytes was verified using BBL™ to thepoints
the computation
correspondingfor the overall
to the correctscore:
and acceptable identification. This would
eventually lead to the reduction of the overall score. The following equation represents the
Sensi-Disc™ Susceptibility Test Discs (Becton, Dickinson, and computation for the overall score:
Co., Sparks, Maryland, USA). The panel of antibiotics used
was based on the Performance Standards for Antimicrobial ( ) ( )
( )
Susceptibility Testing of the Clinical and Laboratory Standards
( )
Institute (CLSI, Wayne, Pennsylvania, USA).17

Packaging Each of the participating laboratories who had accomplished the

Analytes sent to participating laboratories were packaged
in accordance to the international standard of transporting
biohazard materials.18,19 Each vial was sealed with Parafilm
M® (Bemis Co. Inc., Oshkosh, Wisconsin, USA), individually
wrapped in a paper towel, and placed inside a 100 mm × 150 mm
resealable polypropylene resin bags along with other analytes.
The wrapped vials were then encased in 600 mL polypropylene
canister (Philtop Industries Inc., Valenzuela City, Metro Manila,
Philippines) and placed inside a 120 mm × 115 mm × 190 mm
Each of the participating laboratories who had accomplished the PT and submitted their
PT and submitted their answers to NEQAS received a certificate
answers to NEQAS received a certificate of participation, a summary of results of its PT
performance, and a learning monograph, which recommends standard methods of
of participation, a summary of results of its PT performance, and
identifying the analytes and performing AST.
a learning monograph, which recommends standard methods of
identifying
Evaluation the analytes
of the overall and
performance performing AST.
of laboratories
Participating laboratories were grouped according to the number of times they enrolled in
the annual PTs from 2009 to 2015 and the number of times they got a passing score of 80%.
Evaluation of the overall performance of laboratories
The performances of participating laboratories were classified as ―good’, ―fair‖, and ―poor‖
based on the number of times they passed the annual PT. ―Poor performers‖ refers to
Participating laboratories were grouped according to the number
participating laboratories who had not met the 80% passing rate for more than 50% of their
annual PT participation. ―Fair performers‖ refers to participating laboratories who had met
of times they enrolled in the annual PTs from 2009 to 2015
the passing rate in 50% of their annual PT participation. Finally, ―good performers‖ refers to
and the number of times they got a passing score of 80%. The
participating laboratories who had passed more than 50% of their annual PT participation.

corrugated box (Thousand Oaks Packaging Corp., Parañaque performances

Assessment
City, Metro Manila, Philippines) with the necessary attachments
and labels. The package also includes standard proficiency
testing guidelines that contain basic information and instructions
needed for the handling of the analytes and an answer sheet.
Quality Control of Transport Media and Packaged Analytes
The semi-solid sheep blood agar (SSBA) to be used as transport
media was assured for sterility and tested for culture response
before use in the PT. Four sets of cultures of each of all the
organisms used as analytes in the PT were prepared and each
set was subjected to each of the four different treatments. For
the first treatment, separate packages containing one set of
different analytes were sent to random locations of participating
laboratories throughout the country. The selected laboratories
were asked to return the sealed package to RITM. Upon
return, the analytes were examined for contamination by
of participating
of poor performing laboratories laboratories were classified as
“good’, “fair”, and “poor” based on the number of times they
passed the annual PT. “Poor performers” refers to participating
laboratories who had not met the 80% passing rate for more than
50% of their annual PT participation. “Fair performers” refers to
participating laboratories who had met the passing rate in 50% of
their annual PT participation. Finally, “good performers” refers to
participating laboratories who had passed more than 50% of their
annual PT participation.
Assessment of poor performing laboratories
Participating government laboratories that had been consistently
obtaining scores below 80% in the 2009–2012 PTs were selected
for an on-site reassessment in 2013. Details on the updated training
of laboratory personnel; availability of laboratory equipment,
reagents, culture media, antibiotics, and glassware; reliance on
automated and/or semi-automated systems for identification

http://philippinejournalofpathology.org | Vol. 2 No. 2 November 2017

Mondoy et al, PT Bacteriology Philippines 2009–2015
and AST; use of CLSI Performance Standards for Antimicrobial
Susceptibility Testing as guide for AST; availability of ATCC®
biological standards; and implementation of quality assurance
and control programs were identified.
Statistical analysis
Graphs were generated using Matplotlib version 2.0.0 pyplot
module20 in Python and all statistical analyses were done using
SciPy version 0.19.0 scipy.stats module.21 Friedman ranking test
was used to detect differences in the annual scores of consistently
enrolled participants in 2009–2015 and Nemenyi test was used
as the post hoc test to detect differences between the rankings of
annual scores obtained from Friedman test. Multiple comparisons
were employed using STAC Web Platform version 1.0.22
RESULTS AND DISCUSSION
2008 baseline assessment of laboratories
The HFSRB list included 400 tertiary laboratories throughout the
Philippines. Three hundred forty-seven (86.8% of 400) tertiary
clinical laboratories capable of doing bacteriological testing were
assessed: 25.1% (87/347) of which were located in the National
Capital Region; 21.6% (75/347) in Mindanao; 21.0% (73/347)
in North Luzon; 16.4% (57/347) in South Luzon; and 15.9%
(55/347) in the Visayas. Two hundred seventy-five (79.2% of 347)
were private; 70 (20.2% of 347) were government-owned; and
two (0.6% of 347) were semi-private. The remaining 53 (13.2%
of 400) in the list had already undergone closure or downgrade
during the assessment.
In the assessment, only 43.8% (152/347) of the laboratories could
perform Gram stain, acid-fast stain, negative stain, and wet mount;
17.3% (60/347) implemented internal quality control procedures
for media, reagents, stains, and antibiotic disks; and only 3.2%
(11/347) used ATCC biological standards for quality control
(Table 1). Only 35.7% (124/347) completed the required essential
major equipment and instruments; 5.8% (20/347) as to culture
media and supplements for primary isolation; 19.3% (67/347) as
to media for biochemical tests; 3.3% (11/347) as to supplements
for growth and identification. Notably, 67.7% (235/347) of the
laboratories were using human blood in the preparation of blood
agar plates, instead of the recommended sheep blood23, which
Figure 1. Number of participants from different regions in the Philippines, 2009–2015.
http://philippinejournalofpathology.org | Vol. 2 No. 2 November 2017
Philippine Journal of Pathology | 13
was used by 23.6% (82/347) of the laboratories, or horse blood,
which was used by the remaining 6.6% (23/347). Only 17.9%
(62/347) had complete sugars for carbohydrate utilization tests
and 2.9% (10/347) had complete antibiotics for AST. All in
all, only 2.6% (9/347) had complete required essential media
and reagents.
Of the 97.4% (338/347) remaining laboratories, 57.9% (201/347)
used commercially prepared kits while 24.8% (86/347) used
automated systems for identification of bacterial pathogens. For
AST, 2.9% (10/347) had complete required essential antibiotics
while 15.9% (55/347) of the remaining uses automated systems.
Only 82.9% (288/347) of laboratories were capable of
performing AST. Moreover, 76.9% (267/347) of laboratories
were performing disk diffusion and 16.7% (58/347) were using
automated systems for AST. Only 47.2% (164/347) were using
the latest edition of the Performance Standards for Antimicrobial
Susceptibility Testing17 by the Clinical and Laboratory Standards
Institute (CLSI), the recommended standard for AST methods
and interpretation.
Laboratory participation and performance in 2009–2015
Four hundred sixty-eight participants, comprised of 381
(81.4%) private laboratories and 87 (18.6%) government-owned
laboratories, enrolled in the NEQAS for Bacteriology between
2009 and 2015. Of the 450 (96.2% of 468) tertiary category
clinical laboratories, 80.7% (363/450) were privately owned, and
19.3% (87/450) were government owned. Eighteen (3.8% of 468)
private secondary category laboratories also enrolled in the PTs.
The number of participants was highest in the National Capital
Region (Figure 1) with 78 (27.3% of 286) participants in 2009,
which grew to 112 (29.5% of 403) in 2015.
The annual number of participants were the following: 286
(2009), 285 (2010), 264 (2011), 355 (2012), 364 (2013), 360 (2014),
and 403 (2015). Scores ranged from 0 to 100 in all years from
2009 to 2015. The mean scores and sample standard deviation
per year were: 63.9±28.2 (2009), 70.6±25.0 (2010), 63.1±24.6
(2011), 57.9±28.6 (2012), 60.0±34.3 (2013), 71.1±24.0 (2014),
and 75.2±27.3 (2015). The annual median scores were: 71.4
(2009), 75.1 (2010), 68.8 (2011), 60.0 (2012), 72.0 (2013), 72.0
Mondoy et al, PT Bacteriology Philippines 2009–2015 Philippine Journal of Pathology | 14

Figure 2. Number of participating laboratories and proportion of passers, 2009–2015; spearman’s ρ=0.821, for both annual number of
participants and number of passers; p̂ 2015 − p̂ 2009 = 23.9% and χ2 = 38.13

Figure 3. Classification of good, fair, and poor performers, 2009–2015, n=468.

(2014), and 80.0 (2015). The number of participants who obtained
scores of 80 and higher increased from 2009 (33.2%, 95/286)
to 2015 (57.1%, 230/403). Proportion of passing scores among
laboratories participated in PT in bacteriology in 2009–2015 are
represented by a line plot (Figure 2).
Out of the 156 (33.3% of 468) good performers, 23.1% (36/156)
participants passed all of the annual PTs they enrolled in the span
of seven years (Table 1). One hundred eighteen (25.2% of 468)
laboratories, on the contrary, never got a passing score in all the
PTs, in which they enrolled. Overall, poor performers comprise
the most number (60.0%, 281/468) of participating laboratories
(Figure 3). A proportion of 40.2% (35/87) government laboratories
and 70.4% (247/381) of privately owned laboratories performed
poorly in the PT over the seven-year period. While the overall
number of participating laboratories and the number of passers
were increasing, majority of participating laboratories performed
poorly in the PT over the seven years.

http://philippinejournalofpathology.org | Vol. 2 No. 2 November 2017

Mondoy et al, PT Bacteriology Philippines 2009–2015
Figure 4. Number and proportion of passers out of laboratories consistently enrolled, 2009–2015; spearman’s ρ=0.821 for the annual
proportion of passers of consistently enrolled laboratories.
One hundred forty-four laboratories (30.7% of 468) consistently
enrolled in the 2009–2015 PTs. The number of laboratories with
scores of 80% and above increased from 2009 (37.2%, 50/144) to
2015 (69.4%, 100/144) (Figure 4). Furthermore, the distributions
of scores over seven years are negatively skewed, which means the
mass of the distribution of scores each year is concentrated in the
region of high scores (Figure 5). The majority of distributions of
scores in 2010, 2011, 2013, 2014, and 2015 are clustered, resulting
to sharper peaks (leptokurtic profiles). The distribution of scores
in 2015 holds the highest kurtosis (excess kurtosis = 2.06), which
is the measure of the sharpness of the peaks, because of a surge
of participants obtaining scores between 90% and 100% (50.7%,
73/144). The highest mean score is found in 2015 (x̅ = 81.7) while
the lowest mean score is in 2012 (x̅ = 67.1), followed by the mean
score in 2009 (x̅ = 67.6) (Fig. 5). Comparison of annual scores
using Friedman test (F = 10.34; P < 0.001) and Nemenyi test as
post hoc analysis shows a significant difference between scores in
2009 and in 2015 (Z = 5.55; P < 0.001) with 2015 ranking as the
highest (r̅ = 4.95), 2009 as the third from the lowest (r̅ = 3.54),
and 2011 as the lowest (r̅ = 3.39) in seven years. The increasing
proportion of passers in the 144 consistently enrolled laboratories
and the significant difference between scores in 2009 and in
2015 suggest that the performance of the consistently enrolled
laboratories had generally improved over the seven-year period.
Participation in EQA programs has been proven to improve a
laboratory in many ways. It allows the participants to have an
idea of their capability and monitor continual improvement,
since it generates information that can be used to assess the
overall competence and needs of participants.24 It also brings
benefits and challenges to the participants, aside from meeting
regulatory requirements.1 The improvement in the performance
of bacteriology laboratories in the Philippines in the Proficiency
http://philippinejournalofpathology.org | Vol. 2 No. 2 November 2017
Philippine Journal of Pathology | 15
Test provided by NEQAS is comparable to the improvement of
laboratories that participated in different EQAS/PT in other
countries. In the 1982–1999 Tokyo Metropolitan Government
External Quality Assessment Program, an improvement in
the performance of independent laboratories in Tokyo, Japan
regarding the identification of H. influenzae, MRSA, and some
pathogenic enteric bacteria was observed.6 In the 1992–1996
Swiss External Quality Assessment Scheme in Bacteriology and
Mycology, the increasing mean scores of all participants and the
number of participating laboratories with high average scores
over the four year period reflected the improving performances
of participating laboratories.7 In the United States, the Clinical
Laboratory Improvement Amendments of 1988 (CLIA'88)
mandate universal requirements for all clinical laboratory-testing
sites. This mandate includes the provision of PT that defines
laboratory performance. Through PT as one of its tool, CLIA
has ensured the adherence of participating laboratories to good
clinical practices and improvement in the quality of laboratory
tests since 1994.25 External quality assessment programs are
recognized as an effective tool in improving the quality of medical
laboratories in Europe.26 Further improvements are being
considered to their existing EQA programs such as accreditation
of schemes and further integration to information technology27
that can also be applied in the Philippines.
Quality control of packaged analytes and the analyte
material
PTs and EQAS in other countries use either simulated clinical
samples or lyophilized cells as analytes. Simulated clinical
samples (e.g. nose swabs, artificial feces, simulated spinal fluid,
etc.) provide clinically relevant and realistic challenges yet they
require appropriate facilities and technology, and arduous
effort.28 Lyophilization of cells for transport is straightforward
Mondoy et al, PT Bacteriology Philippines 2009–2015 Philippine Journal of Pathology | 16

Figure 5. Histogram and box plot of scores plus annual mean scores of 144 laboratories consistently enrolled in the 2009–2015
proficiency tests.

and it protects cells from degradation; however, the subsequent biochemical tests. S. aureus is identified as Gram-positive coccus,
processes of reconstitution and multiple passages do not which is positive for catalase and coagulase tests. Salmonella enterica
demonstrate clinical relevance and realism. It completely lacks sv. Typhi can be distinguished from nontyphoidal Salmonella with
resemblance to clinical specimens.4 Furthermore, artificial its distinct biochemical characteristics: it is citrate-negative,
handling and significant matrix effects can affect the growth, ornithine-negative, and mucate-negative; it yields alkaline
colony morphology, and nutrient metabolism of organisms, thus products on aerobic environment, acidic products on anaerobic
affecting proper identification and characterization of analytes.28 environment; and it weakly produces hydrogen sulfide gas in
In this PT, the use of semi-solid SBA as matrix was proven to be triple sugar iron (TSI) agar. Moreover, S. enterica sv. Typhi can
effective in ensuring the viability of organisms during transport, be differentiated from other Salmonella serotypes through
through quality control. All of the isolates sent for quality control serological tests based on the antigenic properties of the somatic
throughout 2009 to 2015 were observed to be contaminant-free (O:9), flagellar (H-d), and capsular (Vi) antigens. The identity of
and viable.
Table 3. Frequency of incorrect results per analyte tested for
Identification and AST antibiotic susceptibility, 2009-2015
Bacteriology laboratories in the Philippines used conventional
Frequency of Incorrect
methods, manual commercial kits, and automated systems for Analyte Number of AST
Results (Percentage)
the characterization and identification of clinically significant
S. pneumoniae 717 337 (47.0%)
pathogens. The organisms identified with least difficulty were E. cloacae 203 87 (42.9%)
E. coli, S. aureus, MRSA, C. albicans, S. enterica sv. Typhi, and P. H. influenzae 1,422 566 (39.8%)
aeruginosa. In contrast, the six organisms identified with highest P. mirabilis 425 149 (35.1%)
difficulty were A. lwoffii, C. tropicalis, M. catarrhalis, E. aerogenes, H. S. epidermidis 66 22 (33.3%)
S. enterica (non-typhoidal) 217 61 (28.1%)
influenzae, and S. pneumoniae (Table 2). Additionally, the antibiotic P. aeruginosa 424 99 (23.3%)
susceptibilities of S. pneumoniae, E. cloacae, and H. influenzae were S. aureus 582 128 (22.0%)
the most difficult to determine (Table 3). MRSA 2,068 353 (17.1%)
S. flexneri 1,247 190 (15.2%)
S. enterica sv. Typhi 1,585 190 (12.0%)
The organisms identified with least difficulty are usually Total 8,956 2,182 (24.4%)
distinguished with colony examination and few straightforward

http://philippinejournalofpathology.org | Vol. 2 No. 2 November 2017

Mondoy et al, PT Bacteriology Philippines 2009–2015
the yeast, C. albicans, can be confirmed when it produces germ
tube during germination in horse serum at 37°C, and terminal
chlamydospores on hyphae or pseudohyphae during growth in
corn meal agar at 25°C. E. coli and P. aeruginosa can be identified
through examination of colony morphology in MacConkey agar
and a few basic biochemical tests.15
Some of the organisms identified with highest difficulty, A.
lwoffii and M. catarrhalis, are nonfermentative Gram-negative
bacteria that belong to the Moraxellaceae family. Acinetobacter
species are oxidase-negative, catalase-positive, indole-negative
coccobacillary bacteria. A. lwoffii can be differentiated from other
Acinetobacter species through carbon assimilation tests.15 Moraxella
species, on the other hand, are oxidase-positive, catalase-positive,
indole-negative coccoid or coccobacillary bacteria. They can be
differentiated from the similarly oxidase-positive and catalase-
positive Neisseria species through examination of the colonies in
agar: Moraxella colonies may be pushed intact across the plate with
a loop like a hockey puck; or through DNase and tributyrin tests.
M. catarrhalis can be distinguished from other Moraxella species
through its ability to reduce nitrate and nitrite and its inability
to alkalinize acetate and acidify ethylene glycol. Enterobacter
species belong to the Enterobacteriaceae family. E. aerogenes can
be differentiated from other Enterobacter species through lysine
decarboxylase, arginine dihydrolase, ornithine decarboxylase,
and carbohydrate fermentation tests.15 C. tropicalis, a non-albicans
Candida (NAC) yeast species,29 is germ tube-negative. It can be
distinguished from other Candida species through microscopic
examination of morphological features of the yeast on cornmeal
agar; through carbohydrate assimilation tests; and through
carbohydrate fermentation tests.15
In the 2008 assessment, majority (66.7%, 231/347) of the
laboratories assessed used human blood agar in the isolation,
detection, and characterization of clinically important
bacterial pathogens. These pathogens, especially fastidious
organisms such as S. pneumoniae and H. influenzae, are less likely
to be detected when using human blood agar for culture since
antibodies and residual antibiotics in human blood may inhibit
the growth of bacterial isolates. It will also result to pathogens
producing incorrect or varying hemolysis on the blood plate
agar which is one of the characteristics critical when identifying
a microorganism. Instead, trypticase soy agar plate with 5%
defibrinated sheep, goat, rabbit, or horse blood is recommended
for the preparation of blood agar plate and as primary culture
plate media for bacterial pathogens.23 Streptococcus pneumoniae and
H. influenzae are fastidious organisms, which grow best at 36±1°C
with around 5%–10% carbon dioxide or in a candle jar. S.
pneumoniae can be differentiated from other streptococci through
characterization of colonies on blood agar plates; optochin test;
and bile solubility test using sodium deoxycholate. H. influenzae,
on the other hand, requires hemin (X factor) and nicotinamide
adenine dinucleotide (V factor) for growth; thus, the chocolate
agar plate, which contains both factors, is used as the standard
growth medium.15,23 In addition, S. pneumoniae and H. influenzae
must be grown in Mueller-Hinton agar (MHA) supplemented
with additional growth factors for AST. MHA with 5% sheep
blood is the medium required for AST of S. pneumoniae by disk
diffusion. Plates must be incubated at 35±2°C with 5% CO2
for 20–24 hours. Haemophilus test medium (HTM; comprised
of MHA plus hematin, nicotinamide adenine dinucleotide, and
yeast extract) is required for the AST of H. influenzae by disk
diffusion, and plates must be incubated at 36±1°C with 5%–10%
CO2 for 16–18 hours.17
http://philippinejournalofpathology.org | Vol. 2 No. 2 November 2017
Philippine Journal of Pathology | 17
Organisms that are difficult to identify require additional tests,
equipment, media, supplements, and reagents. Failure to identify
organisms that require more complex bacteriological testing
can be attributed to the large proportion of laboratories lacking
minimum and required essential media and reagents, such as
sugars for carbohydrate utilization tests and amino acids for
amino acid metabolism tests, based on the result of the 2008
assessment. Also, failure to determine the correct antibiotic
susceptibility of bacteria through disk diffusion can be attributed
to the large proportion of laboratories that were not using the
latest edition of the Performance Standards for Antimicrobial
Susceptibility Testing by the CLSI in 2008. Laboratories are
expected to correctly interpret the zone diameter breakpoints
in disk diffusion according to the updated CLSI standards.
Moreover, accurate AST results cannot be achieved with the lack
of antibiotics, media (e.g. MHA, etc.), supplements (e.g. non-
human mammalian blood, hematin, etc.), and equipment (e.g.
CO2 incubators or candle jars, etc.).
2013 Assessment of poor performing government
laboratories for bacteriology
Only 31 government-owned laboratories that performed poorly in
the 2009–2012 PTs were assessed. Two (6.5% of 31) were found
to be non-functional due to a lack of budget. Only 12.9% (4/31)
of the laboratories had personnel with updated training; 45.2%
(14/31) used ATCC biological standards for quality control;
and only 29.0% (9/31) implemented SOPs and quality control
of culture media, antibiotics, and equipment. Only 9.7% (3/31)
had complete essential equipment; 9.7% (3/31) had complete
essential culture media and antibiotics for AST; and none (0/31)
of the laboratories had complete essential reagents. On the
other hand, 83.9% (26/31) had complete essential glassware.
Overall, majority of the assessed laboratories did not meet the
minimum and essential requirements, except for having complete
essential glassware.
Thirteen (41.9% of 31) laboratories use automated and semi-
automated equipment. Six laboratories (19.4% of 31) were using
VITEK® 2; four (12.9% of 31) were using API® identification
testing kits; and three (9.7% of 31) were using BBL™ Crystal™
Identification Systems (Becton, Dickinson and Co. Diagnostic
Systems, Sparks, Maryland, USA). Automated and semi-
automated systems require freshly grown isolates within 24
hours as its test template; hence, laboratorians still need the basic
materials, equipment, and skills to culture and isolate medically
important bacteria and fungi. Laboratorians also need to check the
viability and density measurement of the organisms to be tested
for AST since automated systems which conducts its AST based
on broth microdilution testing method, generally require more
than 105 viable cells.30 Moreover, failure to assign an identification
to an organism as a result of low discrimination and discordant
identifications by automated and semi-automated systems, still
warrants supplemental and confirmatory testing by conventional
methods,31 which require the necessary materials included in the
minimum and essential requirements for bacteriological testing.
The baseline assessment of the 347 tertiary laboratories conducted
in 2008 and the assessment of 31 poorly performing government
laboratories conducted in 2013 found almost similar findings: poor
performance was due to poor compliance to the recommended
minimum and essential requirements set by RITM–NRL. Both
assessments had recommended poor performing laboratories re-
training of laboratory personnel; acquisition of the unavailable
media, supplements, reagents, and instruments; management on
Mondoy et al, PT Bacteriology Philippines 2009–2015
quality control procedures for media, reagents, antibiotics, and
stains; use of the current CLSI standards for AST; and review of
skills for bacteria culture, isolation and detection.
More actions are still needed to have a better idea of the current
state of clinical bacteriological testing in the country and how it
affects the results that are being produced. A wider reassessment,
that will aim to include all of the participating laboratories, needs
to be carried out urgently and regularly in order to identify factors
that lead to poor performance and, likewise, ensure high quality
testing and accurate reporting of results. Other information can
also be acquired during the reassessment such as compliance or
deficiencies in skills, training, resources, and implementation of
quality assurance procedures. Further data on the methods used
(conventional, commercial or semi-/fully automated system)
and how it affects the performance of the laboratory can be
investigated. The NEQAS program was established to improve
the capacity of participating laboratories in producing quality
results. This will lead to the elevation of the state of clinical
bacteriology in the country and produce quality service for the
Filipino people. In aid of this vision, the RITM together with the
DOH offers trainings and assistance that can help the participating
laboratories in reaching this goal. Other ideas can be explored to
attain this goal such as creating a network among the laboratories
that may enable them to share knowledge and resources to
improve each other’s performance and capabilities. The data that
will be gathered in the following years and succeeding plans will
be included in future reports and studies.
CONCLUSION
An increasing number of participating laboratories had
participated in the PT for Bacteriology and the performances of
those consistently enrolled had generally improved over 2009–
2015. Moreover, a comparison between distributions of scores
over the seven-year period has shown an increase in the number
of participating laboratories obtaining high to perfect scores. This
progress demonstrates that the NEQAS for Bacteriology had
improved the quality and reliability of their methods in identifying
bacterial pathogens and detecting antibiotic resistance.
In contrast, the large portion of poorly performing laboratories
needs to be addressed. The baseline assessment in 2008 and
assessment of poor performers in 2013 identified the deficiencies
of clinical microbiology laboratories in skills, training, resources,
and implementation of quality assurance procedures. A
nationwide reassessment of participating laboratories needs to
be carried out urgently and regularly in order to identify factors
that lead to poor performance and, likewise, ensure high quality
testing and accurate reporting of results.
ACKNOWLEDGMENTS
The authors thank the medical laboratory scientists of the
National Reference Laboratories (NRL) under the RITM
Department of Microbiology: Josefina Geronimo and Rosa Mate
of NRL–Bacterial Enteric Diseases (BED); Rizalina Navarro
and Pearl Joy Nazareno of NRL–Mycology; Salvacion Rosario
Galit of NRL–Emerging and Re-emerging Bacterial Diseases
(ERB); and Gloria Reclusado of NRL–Invasive Bacterial Vaccine
Preventable Diseases (IBVPD). The authors likewise thank the
following administrative staff: Armando Martinez and Sheila Joy
Gonzaga of the RITM–NEQAS for Bacteriology, Parasitology,
and Mycobacteriology; and Natalie Del Mundo of the RITM
Department of Microbiology.
http://philippinejournalofpathology.org | Vol. 2 No. 2 November 2017
Philippine Journal of Pathology | 18
STATEMENT OF AUTHORSHIP
All authors certified fulfillment of ICMJE authorship criteria.
AUTHOR DISCLOSURE
The authors declared no conflict of interest.
FUNDING SOURCE
The 2009–2012 Proficiency Tests for Bacteriology were funded
by the Health Facilities and Services Regulatory Bureau and
the Health Facilities Development Bureau—both under the
Department of Health of the Republic of the Philippines.
References
1. Stang HL, Anderson NL. Use of proficiency testing as
a tool to improve quality in microbiology laboratories.
Clin Microbiol Newsl. 2013;35(18):145-52. PMCID:
PMC4696484. NIHMSID: NIHMS742893. https://doi.
org/10.1016/j.clinmicnews.2013.08.007.
2. WHO Southeast Asian Regional Office. Quality assurance
in bacteriology and immunology. New Delhi: World Health
Organization, 2012. http://apps.searo.who.int/PDS_
DOCS/B4871.pdf ?ua=1.
3. Jones RN, Glick T, Sader HS, et al. Educational antimicrobial
susceptibility testing as a critical component of microbiology
laboratory proficiency programs: American Proficiency
Institute results for 2007–2011. Diagn Microbiol Infect Dis.
2013;75(4):357-60. PMID: 23481025. https://doi.org/
10.1016/j.diagmicrobio.2013.01.027.
4. Snell JJ, De Mello JV, Gardner PS. The United Kingdom
national microbiological quality assessment scheme. J
Clin Pathol. 1982;35(1):82-93. PMID: 7061722. PMCID:
PMC497453.
5. Whitby JL, Black WA, Richardson H, Wood DE. System for
laboratory proficiency testing in bacteriology: organisation
and impact on microbiology laboratories in health care
facilities funded by the Ontario Government. J Clin Pathol.
1982;35(1):94-100. PMID: 7061723. PMCID: PMC497454.
6. Kumasaka K, Kawano K, Yamaguchi K, et al. A study of
quality assessment in clinical microbiology performance of
independent laboratories in Tokyo: 18-year participation in the
Tokyo Metropolitan Government External Quality Assessment
Program. J Infect Chemother. 2001(2);7:102-9. PMID:
11455500. https://doi.org/10.1007/s1015610070102.
7. Siegrist HH, Pünter-Streit V, von Graevenitz A. The Swiss
External Quality Assessment Scheme in Bacteriology
and Mycology 1992-1996. Accreditation Qual Assur.
1998;3(5):203-07.
8. Frean J, Perovic O, Fensham V, et al. External quality
assessment of national public health laboratories in Africa,
2002–2009. Bull World Health Organ. 2012(3);90:191-
9A. PMCID: PMC3314205. https://doi.org/ 10.2471/
BLT.11.091876.
9. Snell JJS. Problems in susceptibility testings—findings
of UK NEQAS for microbiology. J Antimicrob
Chemother. 1994;33:1-4. https://academic.oup.com/jac/
article/33/1/1/717194.
10. Romualdez A. Department Order No. 393-E s. 2000:
Designation of National Reference Laboratories and
transfer of corresponding equipment, instruments,
supplies, specimens, records from the Bureau of Research
Mondoy et al, PT Bacteriology Philippines 2009–2015 Philippine Journal of Pathology | 19

and Laboratories to the designated National Reference
Laboratories. November 2000. http://lcp.gov.ph/images/
Dept_Order_393E_s2000.pdf.
11. Duque F. Administrative Order No. 2007-0027: Revised
rules and regulations governing the licensure and regulation
of clinical laboratories in the Philippines. August 2007.
12. Duque F. Department Memorandum No. 2009-0086:
Implementation of External Quality Assessment Program as
a regulatory requirement for licensing of clinical laboratories.
February 2009.
13. Lutero N. Department Memorandum No. 2009-0086-B:
Amendment to Department Memorandum No. 2009-0086-
A entitled, “Implementation of External Quality Assessment
Program as regulatory requirement for licensing of clinical
laboratories.” September 2014. http://lcp.gov.ph/images/
Dept_Memo_2009_0086B.pdf.
14. O’Brien KL, Bronsdon MA, Dagan R, et al. Evaluation
of a medium (STGG) for transport and optimal recovery
of streptococcus pneumoniae from nasopharyngeal
secretions collected during field studies. J Clin Microbiol.
2001;39(3):1021-4. PMID: 11230421. PMCID: PMC87867.
https://doi.org/10.1128/JCM.39.3.1021-1024.2001.
15. Pfaller MA, Richter SS, Funke G, et al., eds. Manual of
Clinical Microbiology, 11th Edition. American Society of
Microbiology, 2015.
16. Atlas RM, Snyder JW. Handbook of media for clinical and
public health microbiology. Boca Raton: CRC Press, Taylor
and Francis Group, 2014.
17. Patel JB, Weinstein MP, Eliopoulos GM, et al. Performance
standards for antimicrobial susceptibility testing. 27th ed.
Clinical and Laboratory Standards Institute, 2017.
18. Dangerous goods regulations (iata--resolution 618
attachment “a”): effective 1 January-31 December 2015.
Montreal: Intl Air Transport Assn, 2014.
19. Chosewood LC, Wilson DE, eds. Biosafety in microbiological
and biomedical laboratories. 5th ed. Washington: U.S.
Department of Health and Human Services Public Health
Service Centers for Disease Control and Prevention National
Institutes of Health, 2010.
20. Droettboom M, Caswell TA, Hunter J, et al. Matplotlib/
Matplotlib: V2.0.0. January 2017.
21. Jones E, Oliphant T, Peterson P, et al. SciPy: Open Source
Scientific Tools for Python. 2001.
22. Rodriguez-Fdez I, Canosa A, Mucientes M, Bugarin A.
STAC: A web platform for the comparison of algorithms
using statistical tests. In: IEEE; 2015:1-8.
23. Castillo D, Harcourt B, Hatcher C, et al. Laboratory
Methods for the Diagnosis of Meningitis Caused by Neisseria
meningitidis, Streptococcus pneumoniae, and Haemophilus
influenza, 2nd ed. Geneva, Switzerland: World Health
Organisation Press, 2011.
24. Barbé B, Yansouni CP, Affolabi D, Jacobs J. Implementation of
quality management for clinical bacteriology in low-resource
settings. Clin Microbiol Infect. 2017;23:426-33. PMID:
28506781. https://doi.org/10.1016/j.cmi.2017.05.007.
25. Ehrmeyer SS, Laessig RH. Has compliance with CLIA
requirements really improved quality in US clinical
laboratories? Clin Chim Acta. 2004;346(1):37-43. PMID:
15234634. https://doi.org/10.1016/j.cccn.2003.12.033.
26. Crucitti T. National External Quality Assessment Schemes
for microbiology, parasitology, and virology in Europe.
Accreditation Qual Assur. 2001;6(8):379-81.
27. Libeer JC. Role of external quality assurance schemes in
assessing and improving quality in medical laboratories. Clin
Chim Acta. 2001;309(2):173-7. PMID: 11438297.
28. Noble MA. Advances in microbiology EQA. Accreditation
Qual Assur. 2002;7(8-9):341-4.
29. Krcmery V, Barnes AJ. Non-albicans Candida spp. causing
fungaemia: pathogenicity and antifungal resistance. J Hosp
Infect. 2002;50(4):243-60. PMID: 12014897. https://doi.
org/10.1053/jhin.2001.1151.
30. van Belkum A, Dunne WM. Next-Generation Antimicrobial
Susceptibility Testing. J Clin Microbiol. 2013;51(7):2018-
24. PMID: 23486706. PMCID: PMC3697721. https://doi.
org/10.1128/JCM.00313-13.
31. Kiska DL, Kerr A, Jones MC, et al. Accuracy of four
commercial systems for identification of Burkholderia
cepacia and other gram-negative nonfermenting bacilli
recovered from patients with cystic fibrosis. J Clin Microbiol.
1996;34(4):886-91. PMID: 8815102. PMCID: PMC228911.

Disclaimer: This journal is OPEN ACCESS, providing immediate access to its content on the principle that making research freely available to the
public supports a greater global exchange of knowledge. As a requirement for submission to the PJP, all authors have accomplished an AUTHOR
FORM, which declares that the ICMJE criteria for authorship have been met by each author listed, that the article represents original material,
has not been published, accepted for publication in other journals, or concurrently submitted to other journals, and that all funding and conflicts
of interest have been declared. Consent forms have been secured for the publication of information about patients or cases; otherwise, authors
have declared that all means have been exhausted for securing consent.

http://philippinejournalofpathology.org | Vol. 2 No. 2 November 2017

OPEN ACCESS – REVIEW ARTICLE

An Insight into the Histopathology of Oral Neoplasms with

Basaloid Morphology and a Working Classification
Manas Bajpai and Nilesh Pardhe

Department of Oral and Maxillofacial Pathology, NIMS Dental College, Jaipur, India

ABSTRACT

Basal cell tumors (BCT) are tumors usually derived from pluripotential stem cell compartments of the basal
layer of epidermis and/or oral epithelium. BCTs are infrequent entities in the oral cavity and are not discussed
separately in general and oral pathology. A literature review did not reveal any classification of tumors with
basaloid morphology. This paper is an attempt to categorize the oral neoplasms with basaloid morphology
and discuss their differential diagnoses in detail. A review of the literature was carried out to rule out the
frequency of different oral BCTs reported in the literature. Additionally, a simple working classification of oral
BCTS has been proposed. We hope that this classification will be helpful for oral and general pathologists
and students.

Key words: basal cell tumors, basaloid morphology, oral cavity

INTRODUCTION
ISSN 2507-8364 (Online)
Printed in the Philippines. Basal cell tumors in the oral cavity are rare. Due to their
Copyright© 2017 by the PJP.
overlapping histopathological features and admixture of basal cell
Received: 21 June 2017.
Accepted: 10 August 2017. and squamous cells on histopathological examination, these tumors
Published online first: 8 September 2017. often produce a diagnostic difficulty for pathologists and oral
https://doi.org/10.21141/PJP.2017.019 pathologists.1,2,3 At times, an immunohistochemical examination is
   required to arrive at a final diagnosis.4 Some authors also believe
Corresponding author: Manas Bajpai, MDS that “basaloid” patterns occurring anywhere in the body represent
E-mail: dr.manasbajpai@gmail.com
attempts at glandular differentiation.5,6 An exhaustive literature
review did not reveal any working classification of oral BCTs.
A simple working classification of Oral BCTs is proposed here
(Table 1). In this proposed working classification, oral BCTs can be
classified into tumors of the oral epithelium, minor salivary gland
tumors and odontogenic tumors.

Table 1. A Simple working classification proposed for oral BCTs

S. NO Origin Tumors
Tumors of 1. Basal cell carcinoma.
A
Oral epithelium 2. Basaloid squamous cell carcinoma
Tumors of odontogenic
B 1. Basal cell ameloblastoma
epithelium
Minor salivary gland 1. Basal cell adenoma.
C tumors with basaloid 2. Basal cell adenocarcinoma.
morphology 3. Adenoid cystic carcinoma (solid type)

A. Tumors derived from oral epithelium

1. Intra-oral basal cell carcinoma (IOBCC)

Basal cell carcinoma is the most common adnexal tumor; however
its occurrence in the oral cavity is rare and controversial.7-10
Clinically, they present as non-healing ulcers. Histopathologically,
they exhibit numerous tumor islands composed of basaloid
cells in the lamina propria (Figure 1). Tumor islands exhibit a
prominent palisading of peripheral basal cells (Figure 2). The
diagnosis of IOBCC solely on histopathological grounds, however,
is not easy, due to their histological resemblance with peripheral
ameloblastoma (PA).11,12 The differentiation between IOBCC and
PA is of utmost importance since the former is malignant.

Although IOBCC and PA may be distinguished by the presence of

reverse polarity in PA,13 immunohistochemistry is considered as the

http://philippinejournalofpathology.org | Vol. 2 No. 2 November 2017

Bajpai et al, Histopathology of Oral Neoplasms with Basaloid Morphology and a Working Classification
Figure 1. Tumor islands of basal cells in lamina propria (Hematoxylin
and eosin stain x20).
Figure 2. Tumor islands exhibit peripheral palisading (Hematoxylin
and eosin stain x40).
most reliable means of differentiation. Only 21 cases of IOBCC
have been reported in the literature to date.12 Some authors believe
that earlier reported cases of IOBCC were actually PA. In 2001,
Del Rosario, et al.14 reported the first well documented case of
IOBCC using Ber–EP4, a tumor marker that shows a positive
expression for basal cells, supporting its origin from the basal layer
of the oral epithelium. Calretinin, a 29 KDa protein, has been
found to show positive expression in neoplastic proliferation of
ameloblastic epithelium, specifically staining the stellate reticulum-
like cells of ameloblastoma.15-17 Calretinin is considered as an
additional important marker to differentiate PA from IOBCC.
http://philippinejournalofpathology.org | Vol. 2 No. 2 November 2017
Philippine Journal of Pathology | 21
2. Oral Basaloid Squamous cell carcinoma (OBSCC)
Basaloid squamous cell carcinoma (BSCC), as defined by the
World Health Organization, is an aggressive, high-grade variant
of squamous cell carcinoma (SCC), composed of both basaloid
and squamous components.18,19 BSCCs are common in the
oropharynx but rare in the oral cavity.20,21 Clinically, they present as
indurated masses with central ulceration.21,22 Histopathologically,
they may resemble the solid variant of adenoid cystic carcinoma
(ACC), adenosquamous carcinoma, and small cell neuroendocrine
carcinoma (SCNC).21-25 BSCC can be differentiated from ACC
on the basis of myoepithelial cells and basement membrane-like
material (both of which are found in ACC but absent in BSCC).
Moreover, the atypia in ACC is less pronounced in comparison to
BSCC (Figure 3).23-25
Figure 3. Infiltrating islands of basaloid cells with hyperchromatic
nuclei (Hematoxylin and eosin stain x40).
Immunohistochemically, the basement membrane-like material in
ACC shows positive expression for laminin and type IV collagen.
P63 shows a diffuse positive expression for the tumor cells of BSCC,
but is weakly expressed in ACC.24 Adenosquamous carcinoma
shows true ductal acinar differentiation and mucicarmine
positivity.23,25-27 BSCC does not show these features and can thus
be differentiated from adenosquamous carcinoma.24,26-27 On
the other hand, SCNC shows nuclear molding, hyalinization
and crushing artifacts on H&E, and immunohistochemically,
shows positive expressions for chromogranin and synaptophysin.
BSCC is devoid of all of these features.23-24,26 Wain’s criteria27 is
an essential parameter to diagnose BSCC. This criteria include
both histologic (peripheral palisading associated with SCC, high
nuclear-cytoplasmic ratio, high mitotic index, solid growth pattern)
and immunohistochemical features (positive expression for anti-
34BE1 and cytokeratin 5/6; negative expression for synaptophysin
and chromogranin, and Ber-EP4). Occurrence of BSCC in the
oral cavity is infrequent and very few case reports were found in
the literature.22-23,26
A proper diagnosis of Oral BSCC is important in order to plan
an appropriate treatment modality, considering its association with
poor prognosis.
B. Tumors derived from odontogenic epithelium
1. Basal cell ameloblastoma (BCA)
Ameloblastomas are benign tumors whose importance lies in
its potential to grow into enormous size with resulting bone
deformity.28 Basal cell ameloblastoma is a rare variant of solid
Bajpai et al, Histopathology of Oral Neoplasms with Basaloid Morphology and a Working Classification Philippine Journal of Pathology | 22

multicystic ameloblastoma (SMA) with only 11 cases reported

in the literature so far.29 Clinically they are similar to other
histopathological variants of SMA.29-31 Histopathologically,
they exhibit nests of basaloid cells that show intense basophilic
staining.29 The stellate reticulum-like cells are absent and central
cells may be polyhedral.28,29 The nuclear orientation of peripheral
cells is different from the other histopathological patterns of
ameloblastomas: they are usually cuboidal or columnar and do not
show reverse polarity (Figure 4). BCAs show a close resemblance
to BCC on histopathology; however a demarcation can be made
on immunohistochemical grounds by using Ber-EP4.29,30 The
prognosis and biological behavior of BCA is not clear, due to its
rarity and very few reported cases.

Figure 5. Isomorphic cells similar to basaloid cells with palisading

arrangement and distinctive basement membrane like material
(Hematoxylin and eosin stain x40).

Figure 4. Sheets of basaloid cells with few cells showing highly

intense basoliphic staining and peripheral cells with reversal of
polarity, the sheets are separated by sparse connective tissue
septa. The tissue is lacking stellate reticulum like cells which is the
hallmark of ameloblastoma (Hematoxylin and eosin stain x40).

C. Tumors derived from salivary gland epithelium

1. Basal cell adenoma

Basal cell adenomas (BCA) are rare benign salivary gland tumors,
most often originating from the parotid gland.32 BCAs originating
from the minor salivary glands are comparatively rare and only
13 cases have been reported in the literature. Histopathologically,
they are comprised of isomorphic cells similar to basaloid cells
with palisading arrangement and distinctive basement membrane-
like material (Figure 5). BCAs share a close resemblance with
canalicular adenoma and Basal cell adenocarcinomas (BCAC).
The trabecular–tubular variant of BCA may be misdiagnosed as
canalicular adenoma on low power view, and a proper inspection
on high power exhibits the presence of both basal and luminal
cells with more collagenized stroma compared to canalicular
adenoma.33,34 BCACs, on the other hand, are not encapsulated
and tend to invade the underlying connective tissue stroma.34,35
2. Basal cell adenocarcinoma
Basal cell adenocarcinomas (BCAC) represent the malignant
counterpart of basal cell adenoma, believed to arise from
pluripotent ductal reserve cells.36-38 Histopathologically, they are
characterized by sheets of basaloid cells with hyperchromatic
nuclei (Figure 6). Some sheets show peripheral palisading. Some
tumors show nests invading the connective tissue stroma.   It
is necessary to differentiate BCAC from other basaloid cell
Figure 6. Isomorphic cells similar to basaloid cells with palisading
arrangement and distinctive basement membrane like material
(Hematoxylin and eosin stain x40).
tumors because of the differences in prognosis and potential
differences in treatment.
3. Adenoid cystic carcinoma
Adenoid cystic carcinoma (ACC) was originally described by
Lorain and Laboulbene in 1853. In 1859, Billroth suggested the
name cylindroma.39 ACC is a rare tumor, accounting for less than
1% of all head and neck neoplasms and about 4 – 10 % of all
salivary gland neoplasms. Histopathologically, ACC shows three
different patterns, tubular, cribriform and solid.40 The solid pattern
of ACC is believed to be the most aggressive form with poor
prognosis.39 Solid ACC is characterized histopathologically by
tumor nests or islands completely filled with basaloid cells without
cystic spaces.

http://philippinejournalofpathology.org | Vol. 2 No. 2 November 2017

Bajpai et al, Histopathology of Oral Neoplasms with Basaloid Morphology and a Working Classification
CONCLUSION
It can be concluded that oral BCTs are unusual and may represent
diagnostic difficulties on microscopic examination because of
their overlapping features. This paper is an attempt to discuss the
histopathology and differential diagnosis of various oral neoplasms
with basaloid morphology. A simple working classification of oral
BCTs has been proposed with the aim of helping pathologists
distinguish between various oral entities with basaloid features.
STATEMENT OF AUTHORSHIP
All authors certified fulfillment of ICMJE authorship criteria.
Author Disclosure
The authors declared no conflict of interest.
Funding Source
None.
REFERENCES
1. Tellechea O, Reis JP, Domingues JC, Baptista AP. Monoclonal
antibody Ber-EP4 distinguishes basal-cell carcinoma from
squamous- cell carcinoma of the skin. Am J Dermatopathol.
1993;15(15):452–5. PMID: 8238781.
2. Nemade SV, Rokade VV. Basaloid carcinoma: an unusual
presentation. Indian J Clin Pract. 2013; 23(11):728-30.
http://imsear.hellis.org/handle/123456789/182519.
3. Nagao T, Sugano I, Ishida Y, Hasegawa M, Matsuzaki O,
Konno A, et al. Basal cell adenocarcinoma of the salivary
glands: comparison with basal cell adenoma through
assessment of cell proliferation, apoptosis, and expression of
p53 and bcl-2.Cancer. 1998; 82:439-47. PMID: 9452259.
4. Carr RA, Taijbee SM, Sanders DSA. Basaloid skin tumours:
basal cell carcinoma. Curr Diagn Pathol. 2007; 13(4):252–72.
https://doi.org/10.1016/j.cdip.2007.05.005.  and neck: a clinicopathological and follow-up study of 40
5. Basarab T, Orchard G, Russell-Jones R. The use of
immunostaining for bcl-2 and CD34 and the lectin peanut
agglutinin in differentiating between basal cell carcinomas
and trichoepitheliomas. Am J Dermatopathol 1998;
20(5):448–52. PMID: 9790103.
6. Thariat J, Badoual C, Faure C, Butori C, Marcy PY, Righini
CA. Basaloid squamous cell carcinoma of the head and neck:
role of HPV and implication in treatment and prognosis.  J
Clin Pathol. 2010; 63(10):857–66. PMID: 20876315. https://
doi.org/10.1136/jcp.2010.078154.
7. Bajpai M, Pardhe N, Arora M. Intra–oral basal cell
carcinomaan immunohistochemical interpretation using Ber-
Ep4. J Ayub Med Coll Abbottabad. 2016; 28(2):438. PMID:
28718582.
8. Mori M, Morimoto Y, Yoshimura Y, Kawamura H. Enzymatic
histochemical demonstration of basal-cell carcinoma in
the oral cavity. Oral Surg Oral Med Oral Pathol. 1968;
25(5):746–55. PMID: 5239097.
9. Bath-Hextall F, Leonardi-Bee J, Smith C, Meal A, Hubbard R.
Trends in incidence of skin basal cell carcinoma. Additional
evidence from a UK primary care database study. Int J
Cancer. 2007; 121(9):2105–8. PMID: 17640064. https://doi.
org/10.1002/ijc.22952.
10. Liroff KP, Zeff S. Basal cell carcinoma of the palatal mucosa.
J Oral Surg. 1972; 30(10):730-3. PMID: 4506539.
http://philippinejournalofpathology.org | Vol. 2 No. 2 November 2017
Philippine Journal of Pathology | 23
11. Bajpai M, Pardhe N. Peripheral ameloblastoma with mixed
histological patterns. Cukurova Med J. 2015; 40(Suppl
1):151–5. https//doi.org/10.17826/cutf.32647.
12. Woods TR, Cohen DM, Islam MN, Kratochvil FJ, Stewart
JC, Reeder SL, et al.. Intraoral basal cell carcinoma, a rare
neoplasm: report of three new cases with literature review.
Head Neck Pathol. 2014; 8(3):339-48. PMID: 24202723.
PMCID: PMC4126916. https://doi.org/10.1007/s12105-
013-0505-5.
13. Philipsen HP, Reichart PA, Nikai H, Takata T, Kudo Y.
Peripheral ameloblastoma: biological profile based on 160
cases from the literature. Oral Oncol. 2001; 37(1):17-27.
PMID: 11120479.
14. Del Rosario RN, Barr RJ, Jensen JL, Cantos KA. Basal cell
carcinoma of the buccal mucosa. Am J Dermatopathol.
2001; 23(3):203–5. PMID: 11391100.
15. DeVilliers P, Liu H, Suggs C, Simmons D, Daly B, Zhang
S, et al. Calretinin expression in the differential diagnosis of
human ameloblastoma and keratocystic odontogenic tumor.
Am J Surg Pathol. 2008; 32(2):256-60. PMID: 18223328.
https://doi.org/10.1097/PAS.0b013e3181452176.
16. Alaeddini M, Etemad-Moghadam S, Baghaii F. Comparative
expression of calretinin in selected odontogenic tumours:
a possible relationship to histogenesis.  Histopathology.
2008; 52(3):299-304. PMID: 18269580. https://doi.org/
10.1111/j.1365-2559.2007.02948.x.
17. Anandani C, Metgud R, Singh K. Calretinin as a
diagnostic adjunct for ameloblastoma. Pathol Res Int. 2014;
2014:308240. PMID: 24839578. PMCID: PMC4009281.
https://doi.org/ 10.1155/2014/308240.
18. Ide F, Shimoyama T, Horie N. Basaloid squamous cell
carcinoma versus basal cell ameloblastoma. Oral Oncol.
1998; 34(2):154-5. PMID: 9682780.
19. Greene FL, Page DL, Fleming ID, eds. AJCC/UICC cancer
staging handbook: TNM classification of malignant tumors.
7th ed. New York: Springer-Verlag, 2009.
20. Ereño C, Gaafar A, Garmendia M, Etxezarraga C, Bilbao
FJ, López JI. Basaloid squamous cell carcinoma of the head
cases and review of the literature. Head Neck Pathol. 2008;
2(2):83–91. PMID: 20614328. PMCID: PMC2807543.
https://doi/org/10.1007/s12105-008-0045-6.
21. Patil AV, Tupsakhare SD, Shah K, Gabhane M, Ali FM.
Basaloid squamous cell carcinoma of gingiva: a new case and
review of literature. Am J Cancer Case Rep. 2014; 2:99-107.
22. Sundharam BS, Krishnan PA. Basaloid squamous cell
carcinoma report of a case and review of literature. Indian J
Dent Res. 2003;14(3):184‑6. PMID: 15164662.
23. Ide F, Shimoyama T, Horie N. Kusama K. Basaloid squamous
cell carcinoma of the oral mucosa: a new case and review
of 45 cases in the literature. Oral Oncol. 2002; 38(1):120‑4.
PMID: 11755833.
24. Emanuel P, Wang B, Wu M, Burstein DE.
Immunohistochemistry in the distinction of adenoid cystic
carcinoma from basaloid squamous cell carcinoma. Mod
Pathol. 2005; 18(5):645-50. PMID: 15529180. https://doi.
org/10.1038/modpathol.3800329.
25. Begum S, Westra WH. Basaloid squamous cell carcinoma
of the head and neck is a mixed variant that can be
further resolved by HPV status. Am J Surg Pathol. 2008;
32(7):1044–50. PMID: 18496144. https://doi.org/10.1097/
PAS.0b013e31816380ec.
26. Vasudev P, Boutross-Tadross O, Radhi J. Basaloid squamous
cell carcinoma: two case reports. Cases J. 2009; 2:9351.
Bajpai et al, Histopathology of Oral Neoplasms with Basaloid Morphology and a Working Classification Philippine Journal of Pathology | 24

PMID: 20062602. PMCID: PMC2804002. https://doi.
org/10.1186/1757-1626-2-9351.
27. Wain SL, Kier R, Vollmer RT, Bossen EH. Basaloid-squamous
carcinoma of the tongue, hypopharynx, and larynx: report
of 10 cases. Hum Pathol. 1986; 17(11):1158–66. PMID:
3770734.
28. Bajpai M, Agarwal D, Bhalla A, Kumar M, Garg R, Kumar
M. Multilocular unicystic ameloblastoma of mandible. Case
Rep Dent 2013; 2013:835892.  PMID: 24106618. PMCID:
PMC3782764. https://doi.org/ 10.1155/2013/835892.
29. Kramer IR, Pindborg JJ, Shear M. histological typing of
odontogenic tumors, 2nd ed. Berlin: Springer-Verlag, 1992.
30. Saify F, Sharma N. Basal cell ameloblastoma: a rare
case report and review of literature. Oral Maxillofac
Pathol J 2010; 1:1-7. http://www.ompj.org/files/
b9724b4e67cc8a4760a2004b52b6550a-fatima.pdf.
31. Shakya H, Khare V, Pardhe N, Mathur E, Chouhan
M. Basal cell ameloblastoma of mandible: a rare case
report with review. Case Rep Dent. 2013; 2013:187820.
PMID: 23653864. PMCID: PMC3638548. https://doi.
org/10.1155/2013/187820.
32. Chiu NC, Wu HM, Chou YH, Li WY, Chiou YY, Guo WY,
et al. Basal cell adenoma versus pleomorphic adenoma of the
parotid gland. AJR Am J Roentgenol. 2007; 189(5): W254-1.
PMID: 17954621. https://doi.org/10.2214/AJR.07.2292.
33. Batsakis JG, Luna MA, el-Naggar AK. Basaloid
monomorphic adenomas. Ann Otol Rhinol Laryngol.
1991; 100(8):687–90. PMID: 1872522. https://doi.
org/10.1177/000348949110000818.
34. Bajpai M. Canalicular adenoma arising in buccal mucosa. J
Coll Physician Surg Pak. 2016; 26(11):46. PMID: 27981939.
35. Fonseca I, Soares J. Basal cell adenocarcinoma of minor
salivary and seromucous glands of the head and neck region.
Semin Diagn Pathol. 1996; 13(2):128-37. PMID: 8734419.
36. Hirsch DL, Miles C, Dierks E. Basal cell adenocarcinoma of
the parotid gland: report of a case and review of the literature.
J Oral Maxillofac Surg. 2007; 65(11):2385-8. PMID:
17954345. https://doi.org/10.1016/j.joms.2006.07.021.
37. Parashar P, Baron E, Papadimitriou JC, Ord RA, Nikitakis
NG: Basal cell adenocarcinoma of the oral minor salivary
glands: review of the literature and presentation of two cases.
Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2007,
103(1):77-84. PMID: 17178498. https://doi.org/10.1016/j.
tripleo.2005.12.021.
38. Jung MJ, Roh JL, Choi SH, Nam SY, Kim SY, Lee SW,
et al. Basal cell adenocarcinoma of the salivary gland: a
morphological and immunohistochemical comparison with
basal cell adenoma with and without capsular invasion.
Diagn Pathol. 2013; 8:171. PMID: 24143938. PMCID:
PMC4016524. https://doi.org/10.1186/1746-1596-8-171.
39. Martínez-Rodríguez N, Leco-Berrocal I, Rubio-Alonso L,
Arias-Irimia O, Martínez-González JM. Epidemiology and
treatment of adenoid cystic carcinoma of the minor salivary
glands: a meta-analytic study.  Med Oral Patol Oral Cir
Bucal. 2011; 16(7):e884-9. PMID: 21743416.
40. Eneroth CM, Hjertman L, Moberger G. Adenoid cystic
carcinoma of the palate. Acta Otolaryngol.1968; 66(3):248–
60. PMID: 4303189.

Disclaimer: This journal is OPEN ACCESS, providing immediate access to its content on the principle that making research freely available to the
public supports a greater global exchange of knowledge. As a requirement for submission to the PJP, all authors have accomplished an AUTHOR
FORM, which declares that the ICMJE criteria for authorship have been met by each author listed, that the article represents original material,
has not been published, accepted for publication in other journals, or concurrently submitted to other journals, and that all funding and conflicts
of interest have been declared. Consent forms have been secured for the publication of information about patients or cases; otherwise, authors
have declared that all means have been exhausted for securing consent.

http://philippinejournalofpathology.org | Vol. 2 No. 2 November 2017

* This advertisement is a complimentary service of the PJP for member societies/organizations.
OPEN ACCESS – CASE REPORT

The Morphologic Profile of Inflammatory Bowel Disease and the

Diagnostic Problem of Crohn’s Disease versus TB Colitis – A Case Series
Maria Lourdes Tilbe, Francia Victoria De Los Reyes, Ricka Cu, Kathleen Perez

University of the East Ramon Magsaysay Memorial Medical Center, Quezon City, Philippines

ABSTRACT

The aim of this study is to describe the morphologic profile of the biopsy and resection specimen that were
diagnosed with Crohn’s disease and ulcerative colitis in the University of the East Ramon Magsaysay Memorial
Medical Center (UERMMMC) from 2008-2016. Features that classify the specimen as Inflammatory Bowel
Disease – Indeterminate Type are also presented. Considerations for the definitive IBD classification after an
initial indeterminate diagnosis by morphology are also briefly discussed. Biopsy and resection specimen that
were diagnosed with Crohn’s disease, cannot exclude TB Colitis, are also presented; and the subsequent steps
for a definitive classification are also discussed. All the patients included underwent an endoscopic biopsy,
and are categorized by histopathologic diagnoses, age, sex, and GIT segment involved in the endoscopic
procedure. Patients that underwent subsequent resection due to the disease condition are also identified.

Comparison of the histologic findings observed in the patients, with the microscopic basis for the diagnosis
recommended by the European consensus on the histopathology of inflammatory bowel disease (2013), and
with the histologic features described by Patil et al., (2015) for the inflammatory disorders of the large intestine,
is done. The histologic features described by Lamps (2015) for the gastrointestinal TB is used in the evaluation
of the findings in the patients diagnosed with Crohn’s disease, cannot exclude TB Colitis.

There are 5 Crohn’s disease patients, accounting for 0.8% of all patients with lower GIT inflammatory conditions,
and 10 ulcerative colitis patients, accounting for 1.6% of all patients with lower GIT inflammatory conditions.
Seven patients, which comprise 1.1% of all patients with lower GIT inflammatory conditions, have the
diagnosis of indeterminate colitis. The histologic features of 6 out of 7 patients that had the initial diagnosis of
indeterminate colitis presented with morphologic features that favored an ulcerative colitis, but with Crohn’s
disease features. In comparison, one patient who had an initial diagnosis of indeterminate colitis presented
with morphologic features that favored Crohn’s disease but with ulcerative colitis features. In these patients,
correlation with chronology of symptoms and associated ancillary procedures that can classify the patients
as CD or UC are recommended to the gastroenterologist attending such patients so that a more definitive
classification can be done.

Four patients, accounting for 0.6% of all lower GIT inflammatory conditions, were initially diagnosed as Crohn’s
disease, cannot exclude TB Colitis. This is in contrast with 34 patients who were diagnosed with Chronic
Granulomatous Inflammation, Tuberculosis which accounted for 5.7% of all patients that were diagnosed with
inflammatory conditions of the lower GIT. The remaining 536 patients were composed of acute self-limited/
infectious colitis, ischemic colitis, eosinophilic colitis, inflammatory polyp, and nonspecific inflammation.

With the trend of increasing incidence of Inflammatory Bowel Disease in Asia, comparison of the more commonly
seen causes of chronic inflammation of the gastrointestinal tract with a condition that appears to have a
growing incidence in the region is necessary for optimal diagnostic protocol, management, and quality of care.

Key words: inflammatory bowel disease, Crohn’s disease, ulcerative colitis, indeterminate colitis, intestinal
tuberculosis, colitis, morphology, histopathology

INTRODUCTION
ISSN 2507-8364 (Online)
Printed in the Philippines. Inflammatory bowel disease (IBD), comprising of the two
Copyright© 2017 by the PJP.
disorders ulcerative colitis (UC) and Crohn’s disease (CD), is
Received: 1 April 2017.
Accepted: 3 June 2017. a disease condition that results from a chronic, inappropriate
Published online first: 7 August 2017. immune activation in the mucosa with subsequent involvement
https://doi.org/10.21141/PJP.2017.013 of the submucosa for ulcerative colitis, and full-thickness wall
involvement for Crohn’s disease. Although known to be more
Corresponding author: Francia Victoria A. De Los Reyes, MD
frequent in North America, northern Europe, and Australia,
E-mail: kaidelosreyes@gmail.com
there is a trend of increasing incidence documented in Asia,
Africa, and South America.

Hypothesis regarding the role of the luminal gut microbiota and

the changes in gut microbiome composition due to improved

http://philippinejournalofpathology.org | Vol. 2 No. 2 November 2017

Tilbe et al, Inflammatory Bowel Disease and the Diagnostic Problem of Crohn’s Disease versus TB Colitis Philippine Journal of Pathology | 27

food storage condition, and decreased food contamination

of previously documented commonly occurring food-borne
infectious organisms have been described. The role of changes
in the gut microbial flora triggers a cascade of persistent
inflammation in susceptible hosts that manifest as chronic
gastrointestinal symptoms. Although, much is yet to be discovered
regarding the mechanisms of this.1

Intestinal tuberculosis (TB), on the other hand, is a disease

condition that has a high disease burden in developing countries.
To apply this, in the Philippines, TB is the sixth leading cause of
morbidity and mortality, and is the ninth out of the 22 highest
TB-burden countries in the world. The country likewise has one
of the highest burdens of multidrug-resistant TB.2 Intestinal TB
belongs under the broader category of abdominal TB, which has
been documented to constitute about 12% of extra-pulmonary
TB and 1%–3% of the total TB cases.3 However, no multicenter
study in the country documenting the trend of incidence has been
documented to specify the incidence or prevalence of intestinal
TB alone versus all other abdominal TB.

Both of the two disease conditions, IBD and intestinal TB have

features constituting chronic inflammation, segmental or diffuse
involvement, prolonged treatment requirement, and significant
interplay of host immune-response with gut microbiome-
related injury. Comparatively, it has been documented that
there is an overlap in the genes responsible for the immune-
mediated mechanism of IBD and the immune response to
mycobacteria infection, including Mycobacterium tuberculosis and
Mycobacterium leprae.1,4 As such, comparison of the morphologic
features of IBD and intestinal TB may be necessary in countries
where there is an increasing incidence of one and a consistently
high incidence of the other.
To address such concern in our local setting, this paper describes
the morphologic features of the biopsy and/or resection specimen
of the patients diagnosed with CD, UC, and IBD-Indeterminate
(IBD-IC), and CD vs TB colitis in the University of the East
Ramon Magsaysay Memorial Medical Center from 2008-2016.
The aim of comparing the morphologic features of IBD and
indicating instances when TB cannot be completely excluded
is so that there is an initial groundwork for establishing an
algorithm that can be used in diagnosing IBD and excluding
TB, or concluding a concurrent TB infection given a particular
morphologic pattern.
CASE
To determine the prevalence of IBD in our institution, we
reviewed all the surgical pathology reports in the UERMMMC
Pathology Laboratory database from 2008-2016 and determined
the occurrence of the various morphologic diagnosis of the
inflammatory conditions of the lower gastrointestinal tract.
The census was generated using the morphologic diagnosis that
was reported in our institution for the past 8 years, and were
compared with the morphologic findings used by Odze et al., in
Figure 1. Inflammatory diseases of the ileum, colon, and anorectal
region in the UERMMMC Pathology Laboratory from 2008 to
2016 (n=596).
2015 discussing the disorders of the GIT to ensure the timeliness
of reporting such morphologic features. The census included
inflammatory polyp, chronic nonspecific inflammation, active
colitis, chronic active colitis, ischemic colitis, eosinophilic colitis,
diagnosis of colitis with an adenoma seen in another segment
of the GIT but with no malignancy, TB colitis, CD, UC, IBD-
indeterminate, and CD but TB colitis cannot be completely
excluded. All reports with the surgical pathology diagnosis
of acute appendicitis, ruptured viscus that was not secondary
to a known chronic inflammatory condition, post-operative
complications, diverticular disease, and malignancy-associated
lesions without a previously documented association with IBD,
were excluded. The patients with the diagnosis of CD, UC, IBD-
indeterminate, CD but cannot exclude TB were described in
terms of the male-to-female ratio, age, and GIT segment involved
in the endoscopic or surgical resection procedures (Table 1).
Comparison of the morphologic findings of the included reports,
with the microscopic basis for the diagnosis recommended by
the European consensus on the histopathology of inflammatory
bowel disease of 2013,5 and with the histologic features described
by Patil et al., in 2015 for the inflammatory disorders of the large
intestine, and the histologic features described by Lamps in 2015
for the gastrointestinal TB, were done.
Using these parameters, a total of 596 patients that were diagnosed
with inflammatory conditions of the lower gastrointestinal tract
were included in the census.

Table 1. Characteristics of IBD patients and intestinal TB vs. CD patients

Diagnosis Number of Cases Age Mean (Range) M/F Site of Involvement by Frequency
Crohn’s Disease 5 35.4 (17-74) 5/0 ileum > stomach, cecum, ascending colon, descending colon, rectum
Ulcerative Colitis 10 49 (25-77) 5/5 sigmoid colon > rectum > descending colon > ascending colon,
transverse colon > cecum, anastomotic site (s/p right hemicolectomy)
Indeterminate Colitis 7 48.8 (17-72) 5/2 cecum > rectum > ileum,transverse colon, sigmoid colon > anal canal
Intestinal TB vs. 4 39.5 (26-66) 4/0 Ileum > cecum, ascending colon, transverse colon, descending colon,
Crohn’s Disease rectum

http://philippinejournalofpathology.org | Vol. 2 No. 2 November 2017

Tilbe et al, Inflammatory Bowel Disease and the Diagnostic Problem of Crohn’s Disease versus TB Colitis Philippine Journal of Pathology | 28

Figure 2. Frequency of specific morphologic features in Crohn’s disease (n= 5).

+ minor morphologic criteria Patil et al., 2015.
* morphologic criteria European Consensus on the histopathology of Crohn’s disease, 2013

Figure 3. Frequency of specific morphologic features in ulcerative colitis (n=10).

± histologic features of chronicity of UC lesion Patil et al., 2015,
+ histologic features of activity of UC Patil et al., 2015,
* morphologic criteria for active European Consensus on the histopathology of ulcerative colitis, 2013

Among all of these, only 5 patients were diagnosed with Crohn’s
disease, accounting for 0.8% of all included patients. The patients
diagnosed with Crohn’s disease were all male, with the age range
of 17-74 years old, and the sites involves are the following in
descending order of frequency: ileum in 4 patients, and stomach,
cecum, ascending colon, descending colon, and rectum with
involvement found in 1 patient each. The most common major
pathologic findings include transmural lymphoid aggregates,
segmental disease, granulomas, fistulas, and fissuring ulcers.
Only focal crypt irregularity among the secondary pathologic
features is consistently observed. All the major pathologic
features indicated by Patil et al., and all the features enumerated
under the 2013 consensus are observed in the patients (Figure 2).
In contrast to CD, ulcerative colitis was observed in 10 patients,
and this comprised 1.6% of the population included. In this
group, there is a 1:1 male-to-female ratio, and the age range
is similarly wide like in CD, with the patients’ ages ranging
from 25 to 77 years old. The sites involved are the following, in
descending order of frequency: sigmoid colon with 6 patients
noting involvement, rectal involvement in 5 patients, descending
colon involvement in 3 patients, ascending colon and transverse
colon involvement in 2 patients, cecal involvement in 1 patient,
and an anastomotic site in a status post right hemicolectomy
patient in 1 patient. For all patients diagnosed with ulcerative
colitis, the most commonly observed features include diffuse
mixed lymphocytic and plasmacytic infiltrate within the lamina
propria, crypt abscess, and crypt architectural distortion. All of
the patients presented with a chronic active type of disease with
no fibrosis observed (Figure 3).
Seven patients, comprising 1.1% of the included population, were
given the diagnosis of indeterminate colitis. Among the patients
diagnosed with Inflammatory Bowel Disease-indeterminate
colitis, the age range is 17-72 years old, and a 2.5:1 male-to-
female ratio was noted. The sites involved in descending order
of frequency included cecum in 4 patients, rectum in 3 patients,
ileum in 2 patients, transverse colon in 2 patients, sigmoid colon

http://philippinejournalofpathology.org | Vol. 2 No. 2 November 2017

Tilbe et al, Inflammatory Bowel Disease and the Diagnostic Problem of Crohn’s Disease versus TB Colitis
in 2 patients, and anal canal in 1 patient. The histologic features
of 6 out of 7 indeterminate colitis favored ulcerative colitis,
and only one patient had a morphologic diagnosis that favored
Crohn’s disease more than ulcerative colitis.
Although it is important to note that indeterminate colitis is an
interim diagnosis that requires further work-up for a definitive
classification, it is equally important for us to determine what
kind of pitfalls were present during the histopathologic evaluation
of such specimen and identify the morphologic features that
precludes the definitive classification of CD or UC. Morphologic
Diagnosis of IBD-Indeterminate type in the UERMMMC is
an interim diagnosis and made only after exclusion of all other
causes of colitis and the biopsy clearly has morphologic features
pertaining to an IBD morphology, and when only one or two
features of chronicity and one or two features of activity for
ulcerative colitis were observed.
The most commonly observed features that caused the diagnosis
of indeterminate colitis were divided into ulcerative colitis with
Crohn’s-like features, and Crohn’s disease with ulcerative colitis–
like features. Crohn’s disease with UC-like features were noted
as persistently superficial fissuring ulcers in a discontinuous
disease with anal fistula formation, but with no features
indicating granuloma formation, transmural lymphoplasmacytic
inflammation, or lymphoid hyperplasia. In contrast, UC with
CD–like features were noted in those with superficial mucosal
involvement which manifests as mucosal ulceration with absent
granuloma formation but is discontinuous and has lymphoid
hyperplasia with no cryptitis. In these patients, correlation with
the clinical course and ancillary laboratory tests that can provide
information whether the associated features of the patient’s
gastrointestinal lesion were more likely associated with CD or UC
were done in coordination with the attending gastroenterologist
so that a more definitive classification can be made. In patients
with more morphologic features consistent with CD, treatment
for CD was initiated by the attending gastroenterologist,
and treatment for UC was initiated in patients with more
morphologic features consistent with UC. In indeterminate
colitis, patients with CD-like lesions but lack granuloma or
transmural inflammation may have undergone biopsy prior to
the transmural involvement or development of granuloma of the
segment sampled. In comparison, patients with UC-like features
but have patchy disease may belong to the small population of
UC with an initially segmental disease because there is limited
involvement of particular colon segments, for example a diffuse
involvement of the left side of the colon with a patchy involvement
of the right side of the colon, which will become confluent towards
the progression of UC into a diffuse involvement.
Also documented were 4 patients, accounting for 0.6% of all the
patients included, have the diagnostic problem of CD, cannot
totally rule out TB colitis. This is interpreted in the setting of
a greater prevalence of clear cut TB colitis patients with 34
patients, comprising of 5.7% of all included patients, diagnosed
with intestinal TB. The work-up of all patients with the
morphologic diagnosis of CD cannot exclude TB were reviewed
for the history of active or latent TB, status of ancillary testing for
Mycobacterium TB such as PCR of endoscopic biopsy specimen
and AFP special stain, taken at the same time as the specimen with
the problematic diagnosis. In these patients, the age range is 26-
66 years old, all patients are males, and the sites involves are the
following in descending order of frequency: ileum in 3 patients,
and 1 patient each for cecum, ascending colon, transverse colon,
http://philippinejournalofpathology.org | Vol. 2 No. 2 November 2017
Philippine Journal of Pathology | 29
descending colon, and rectum. All four patients with chronic
granulomatous inflammation, consider TB colitis versus Crohn’s
disease show focal and discontinuous chronic inflammation.
No discontinuous crypt distortion and no irregular villous
architecture were seen. One patient also showed a lesion in the
ileum with granulomas with multinucleated giant cells. In such
situation, the consideration of intestinal TB was entertained due
to the high incidence of the disease in the country. All the biopsy
specimen also showed no Mycobacterium tuberculosis bacilli on
AFB stain. Clinical evaluation also showed no evidence of an
acute or latent TB infection in all four patients, and as such were
managed for CD.
However, one patient that had been undergoing treatment for
CD for three months presented with an exacerbation of CD
and underwent right hemicolectomy. The resection specimen
showed positive Mycobacterium tuberculosis bacilli in the
areas exhibiting caseation necrosis, whereas the biopsy showed
negative findings on MTB PCR and AFB special stain in the
specimen from the cecum and the rectum which was done three
month prior to the exacerbation. In this patient, there was non-
caseation necrosis in the biopsy specimen of the cecum, and in
the subsequent sampling of the cecum after right hemicolectomy
was done, but caseation necrosis was noted in the transverse
colon segment of the resection specimen. The conversion from a
previously negative to a positive TB involvement may indicate a
latent TB infection that was activated upon immunosuppression
during the course of treatment for Crohn’s disease.6
DISCUSSION
The diagnosis of IBD requires the correlation of endoscopic
findings that provides information on the gross features of the
intestinal architecture, such as luminal caliber, distensibility,
and macroscopic mucosal lesions, with the morphologic features
noted in the histopathologic evaluation because even grossly
unremarkable looking mucosa may harbor critical features
that clinch the diagnosis of CD or UC. It is equally important
to emphasize that multiple slide sections from the sampled
segments are required and although there is no consensus as of
the publication of Langer et al., in 2014 regarding the number of
sections required for an adequate diagnosis, the recommendation
of step-sections of two to three tissue levels, having five or more
sections is useful to exhaust the features which may otherwise not
be visualized if there is a limited sampling.7 This is particularly
useful in our institution when faced with vague features such
as poorly formed granulomas, or noncaseating granulomas in
a resection specimen with another lesion that has a caseating
granuloma.
Extraintestinal manifestations of IBD are also important but
more so because having a particular IBD increases the chance
of a patient developing a disease associated with one type versus
another, for example Primary Sclerosing Cholangitis is more
likely if the patient has ulcerative colitis than if the patient has
Crohn’s disease. Although if a patient presents with symptoms
of rectal bleeding, mucoid discharge from the rectum, frequent
stools, and associated liver disease manifesting as cholestasis,
the diagnosis of ulcerative colitis is highly likely and quite
warranted. However, the cornerstone of diagnosing IBD is still
clinical constellation of symptoms, endoscopic findings, and
morphologic features. As such, documenting the morphologic
features that allows institutions to create an algorithm that can
streamline the evaluation of chronic inflammatory lesions that
Tilbe et al, Inflammatory Bowel Disease and the Diagnostic Problem of Crohn’s Disease versus TB Colitis Philippine Journal of Pathology | 30

may have mimics is necessary so that a standardized system to the section of anatomic pathology with full, informed consent
based on morphologic parameters established in published of specimen evaluation and non-profit academic discussion
literature can be used. Also, documenting problematic situations or report.
unique to regions with infectious processes that mimics IBD or
complicates IBD may help in addressing future concerns related STATEMENT OF AUTHORSHIP
to such mimics. The standardized system based on morphologic
parameters should incorporate ruling out TB when the classic All authors certified fulfillment of ICMJE authorship criteria.
morphology of TB is not seen.
Author Disclosure
Although this study is limited by the lack of information on the
gross findings seen on endoscopic evaluation, the inclination The authors have declared no conflict of interest.
of this study is to establish the morphologic features based on
histopathology and to discuss the features that influence favoring Funding Source
the diagnosis of one specific lesion versus another when a case is
under a larger general category. None.

Future studies to determine the incidence of CD and UC, and its
association with TB is recommended to determine whether there
is an increasing trend of IBD and whether IBD treatment will
lead to a higher occurrence of TB reactivation.
CONCLUSION
Given that there is an increasing trend of IBD in Asia, there
should be a working system to classify such patients based on
standardized morphologic parameters based on published
literature that also reflect the current practices in areas with a
higher incidence of IBD. Likewise, the algorithm for diagnosis
should incorporate ruling out TB when the classic morphology of
TB is not seen, and should address the development of active TB
in those with latent TB infection that had undergone treatment
for IBD. With the trend of increasing incidence of Inflammatory
Bowel Disease in Asia, comparison of the more commonly seen
causes of chronic inflammation of the gastrointestinal tract,
particularly TB, with a condition that appears to have a growing
incidence in the region, such as IBD, is necessary for optimal
management and improved quality of care.
ACKNOWLEDGMENTS
The authors would like to acknowledge the support of the faculty
and staff of the Department of Pathology, College of Medicine,
University of the East Ramon Magsaysay Memorial Medical
Center, and the Section of Histopathology, Pathology Laboratory
of the University of the East Ramon Magsaysay Memorial
Medical Center.
ETHICAL CONSIDERATION
This case report has no studies performed to animal or human
participants. This case report includes only the specimen
submitted by the patient for surgical histopathology evaluation
REFERENCES
1. Turner JR. The Gastrointestinal Tract. In: Kumar V,
Abbas AK, Aster JC ed. Robbins and Cotran Pathologic
Basis of Disease, 9th ed. Philadelphia: Elsevier-Saunders;
2015: 796-800.
2. Vianzon R, Garfin AMC, Lagos A, Belen R. The
tuberculosis profile of the Philippines, 2003–2011: advancing
DOTS and beyond.  Western Pacific Surveillance and
Response Journal. 2013;4(2):11-6. https://doi.org/10.5365/
wpsar.2012.3.4.022.
3. Sheer TA, Coyle WJ. Gastrointestinal tuberculosis. Curr
Gastroenterol Rep. 2003;5(4):273-8. PMID: 12864956.
4. McNees A, Markesich D, Zayyani N, Graham D.
Mycobacterium paratuberculosis as a cause of Crohn’s
disease. Expert Rev Gastroenterol Hepatol. 2015;9(12):1523-
34. PMCID: PMC4894645. NIHMSID: NIHMS787513.
https://doi.org/10.1586/17474124.2015.1093931.
5. Magro F, Langner C, Driessen A, et al. European consensus
on the histopathology of inflammatory bowel disease.  J
Crohns Colitis. 2013;7(10):827-51. https://doi.org/10.1016/j.
crohns.2013.06.001.
6. Ye L, Liu J, Lin Z, Cao Q. Does infliximab therapy increase
incidence of tuberculosis in patients with inflammatory
bowel disease in an endemic area: a nationwide study
from China. Poster Presentation to the 12th Congress of
European Crohn’s and Colitis Organization, Barcelona
2017. https://www.ecco-ibd.eu/index.php/publications/
congress-abstract-s/abstracts-2017/item/p568 -does-
inf liximab-therapy-increase-incidence-of-tuberculosis-in-
patients-with-inflammatory-bowel-disease-in-an-endemic-
area-a-nationwide-study-from-china-2.html.
7. Langer C, Magro F, Driessen A, Ensari A, et al. The
histopathological approach to inflammatory bowel disease:
a practice guide. Virchows Arch. 2014;464(5):511-27. PMID:
24487791. https://doi.org/10.1007/s00428-014-1543-4.

Disclaimer: This journal is OPEN ACCESS, providing immediate access to its content on the principle that making research freely available to the
public supports a greater global exchange of knowledge. As a requirement for submission to the PJP, all authors have accomplished an AUTHOR
FORM, which declares that the ICMJE criteria for authorship have been met by each author listed, that the article represents original material,
has not been published, accepted for publication in other journals, or concurrently submitted to other journals, and that all funding and conflicts
of interest have been declared. Consent forms have been secured for the publication of information about patients or cases; otherwise, authors
have declared that all means have been exhausted for securing consent.

http://philippinejournalofpathology.org | Vol. 2 No. 2 November 2017

OPEN ACCESS – AUTOPSY VAULT

Intravascular Large B-Cell Lymphoma:

A Continuing Clinical Enigma
Raymundo Lo1 and Ivy Carol Lique2

Department of Laboratories, Cardinal Santos Medical Center

1

Division of Pathology, Philippine Children’s Medical Center

2

ABSTRACT

Intravascular large B-cell lymphoma (IVLBCL) is a rare form of extranodal diffuse large B-cell lymphoma
characterized by the proliferation of lymphoma cells in the lumen of small blood vessels. Clinical presentation
varies among reported cases and diagnosis can be challenging for both clinicians and pathologists. We
report a case of a 64-year-old female with a history of prolonged fever. Diagnosis was suspected clinically
due to thrombocytopenia and elevated serum lactate dehydrogenase after exhausting work-up for an
infectious etiology. IVLBCL was established on post-mortem examination upon finding infiltration of CD20-
positive neoplastic cells in several organs in the absence of lymph node involvement.

Key words: lymphoma, large B cell, intravascular, fever of unknown origin

INTRODUCTION
ISSN 2507-8364 (Online)
Printed in the Philippines. Intravascular large B-cell lymphoma (IVLBCL) is a rare type
Copyright© 2017 by the PJP.
of non-Hodgkin’s lymphoma found in adults. Since its discovery
Received: 27 July 2017.
Accepted: 22 August 2017. in the 1960’s, most of the available information regarding this
Published online first: 24 August 2017. disease entity has been collected through individual case reports,
https://doi.org/10.21141/PJP.2017.014 with an estimated incidence of less than one person per million.
Few reports cover large series of cases. A study of 38 Western
Corresponding author: Ivy Carol A. Lique, MD
patients diagnosed with intravascular lymphoma was made in
E-mail: aibi.lique@gmail.com
2004 in relation to clinical presentation and natural history.1 The
largest study to date reported a series of 96 patients diagnosed
with IVLBCL in Japan, addressing clinical profiles, outcomes
and prognostic factors.2

IVLBCL is characterized by the selective growth of neoplastic

cells within the blood vessel lumina.3 It has been dubbed “the
oncologist’s great imitator” due to its protean manifestation. The
disease manifests as fever of unknown origin and is frequently
diagnosed post-mortem due to its aggressive clinical course.4
Neoplastic cells are not usually seen in the peripheral blood
smear, but laboratory findings of anemia, elevated serum lactate
dehydrogenase, thrombocytopenia and leukopenia should raise
a suspicion for IVLBCL.5 Increased awareness of this disease
entity, for both clinicians and pathologists, may clinch the
diagnosis in the future.

CASE

This is a case of a 64-year-old female who was admitted due to

a three-week history of intermittent fever. She had no associated
symptoms such as cough or colds. The past medical, personal and
social history were unremarkable. Physical examination revealed
palpable cervical lymph nodes and lower gastrointestinal
bleeding secondary to hemorrhoids; the rest were unremarkable.
Several diagnostic work-ups were done to determine the etiology
of the fever. Complete blood counts show anemia (8.8 g/dL)
and thrombocytopenia (71-137 x 109/L). She had normal levels
of white blood cells with predominance of segmenters. Blood
culture was negative. CT scan of the chest reveal non-specific
pulmonary nodules in the right lung and cardiomegaly. To rule
out a malignant etiology of gastrointestinal bleeding, abdominal

http://philippinejournalofpathology.org | Vol. 2 No. 2 November 2017

Lo et al, Intravascular Large B-Cell Lymphoma: A Continuing Clinical Enigma
CT scan was also done which showed dilated and tortuous blood
vessels on both liver lobes and esophageal varices, suggestive of
portal hypertension. These findings, however, could not explain
the cause of fever. Gastroscopy and colonoscopy findings were
non-contributory. During the hospital stay, she developed
cough associated with difficulty of breathing. Chest radiograph
showed streaky hazy infiltrates in both bases for which she was
managed as a case of hospital-acquired pneumonia and started
on antibiotics. Work-up for autoimmune disorders (ANA, C3 and
RF) were negative. At this time, a hematolymphoid malignancy
was being considered. Bone marrow biopsy findings showed a
variably cellular marrow (70-90%) with mild panhyperplasia
and slight lymphocytosis. No definite lymphoid aggregates or
granulomatous infiltrates are seen. A correlation with clinical
findings was recommended. Serum lactate dehydrogenase
was requested and was found to be elevated at 3349 U/l. On
her 3rd hospital week, the patient had episodes of waxing and
waning of sensorium associated with a rigid neck. Cranial
MRI and CSF studies were done to rule out meningitis which
all turned out to be unremarkable. With the patient’s history of
prolonged fever without an infectious focus and a significantly
elevated LDH (6000 U/l), consideration at that time was leaning
towards intravascular lymphoma. Further work-up was done at
the interim, but bone marrow biopsy results were still negative.
The condition of the patient gradually deteriorated and she
succumbed on the 24th hospital day.
Autopsy was performed 17 hours after the patient’s demise.
On external examination, she had multiple flat, irregular,
erythematous lesions distributed on her left shoulder, right
forearm, abdomen and lower extremities (Figure 1). There were
no palpable masses or lymphadenopathies. Cardiomegaly (430
grams; normal 179-385 grams) and splenomegaly (265 grams;
normal 55-195 grams) was noted after weighing all the organs.
The right and left ventricular walls were hypertrophic. Both lungs
had boggy, subcrepitant parenchyma. The liver was not enlarged.
Although smooth upon palpation, the parenchyma appeared
to have small nodules which led us to assume the patient has
micronodular cirrhosis which would explain her signs of portal
hypertension. Macroscopic examination of the gastrointestinal
tract showed esophageal varices and gastric ulcers and a colonic
polyp. Infarcts were noted the base of the pons, left cerebellar
peduncle and left internal capsule (Figure 2). The endocrine and
genitourinary organs were unremarkable. Representative sections
were taken and submitted for histopathological examination.
A B
Figure 1. Skin lesions. (A) Flat, irregular, red to violaceous, rash-like lesion on the right upper arm; (B) Flat skin lesion on the left shoulder.
http://philippinejournalofpathology.org | Vol. 2 No. 2 November 2017
Philippine Journal of Pathology | 32
Microscopic examination reveal aggregates of atypical lymphoid
cells in the small to medium-sized blood vessels and sinusoids of
the following organs: lungs, liver, spleen, kidneys, uterus, cervix,
brain, heart and thyroid. These cells have increased nuclear-
to-cytoplasmic ratio, irregular nuclei, some with prominent
nucleoli. Immunohistochemical staining revealed positivity for
B-cell marker CD20, and negative for CD3, CD10 and CD30.
Post-mortem bone marrow sample was noted to be hypercellular
(70-80%) with trilineage maturation. Immunohistochemical
staining with CD20, however, was negative. The findings of
intravascular neoplastic proliferation of atypical lymphocytes
in several organs, absence of lymph node involvement, and
positivity for CD20 led us to the diagnosis of intravascular
diffuse large B-cell lymphoma (Figure 3).
DISCUSSION
Intravascular large B-cell lymphoma (IVLBCL) is a rare form
of extranodal diffuse LBCL characterized by proliferation
of lymphoma cells within the lumina of vessels, particularly
capillaries, with exception of large arteries or veins.3 It was
previously called angiotropic large cell lymphoma. This entity
is typically found in adults, with a median age of 67 years, and
is found to have equal distribution among both sexes. It has
an aggressive clinical course, usually widely disseminated and
may present virtually on any organ. Lymph nodes are usually
spared. Intravascular growth pattern has been hypothesized to
be secondary to a defect in homing receptors on the neoplastic
cells such as lack of CD29 and CD54 (ICAM-1) adhesion
β -molecules.4 Fever of unknown origin is a prominent sign and
is seen in approximately 45% of cases. 5 Laboratory findings
are not specific but should raise IVLBCL suspicion, and these
include anemia, elevated serum lactate dehydrogenase, elevated
erythrocyte sedimentation rate, thrombocytopenia, leukopenia
and hypoalbuminemia. Majority of the studies have shown
neoplastic cells to be absent in peripheral blood examination.6
Western and Asian variants have been identified based on
clinical presentation. Patients from Western countries display a
high frequency of CNS and skin involvement, while those from
Asian countries show hemophagocytic syndrome, bone marrow
involvement, fever, hepatosplenomegaly and thrombocytopenia.7
In a clinicopathological study of diagnosed IVLBCL cases in
China, 8 out of 13 patients displayed bone marrow involvement,
supported by immunohistochemistry. They concluded that a
morphological “sinusoidal pattern” is essential to the diagnosis
Lo et al, Intravascular Large B-Cell Lymphoma: A Continuing Clinical Enigma Philippine Journal of Pathology | 33

A B

C D

Figure 2. Gross appearance of the organs. Cut sections of the liver (A) and spleen (B). The right and left lungs (C) have red to brown, soft,
boggy, sub-crepitant parenchyma; air spaces are not enlarged. Focal, dark brown, infarct-like lesions are noted on the brain parenchyma.
The arrow points to the lesion seen in the internal capsule (D).

of IVLBCL in a bone marrow biopsy.8 In our case, however,
bone marrow biopsy results were negative.
Hepatic injury was clinically evident in this case. In the wards,
she was noted to have elevated serum ammonia, SGPT, alkaline
phosphatase and bilirubin levels. Esophageal varices and
hemorrhoids support the diagnosis of portal hypertension on
Doppler ultrasound. Consequently, the increased portal blood
flow led to enlargement of the spleen. Another IVLBCL case
with the same manifestation was reported in a 62-year-old
male,9 but no thorough discussion was made regarding the
portal hypertension. Microscopically, the liver of our patient was
not cirrhotic. Histologic examination showed diffuse sinusoidal
infiltration of the liver parenchyma. Lymphoma has been cited
as a cause neoplastic occlusion of the portal vein.10 Though
IVLBCL is said to be restricted to the smallest of blood vessels,
one case report mentioned the embolization of lymphoma cells
in the hepatic portal vein, splenic vein and mesenteric vein.11
Cutaneous involvement varies in appearance and may present as
painful indurated erythematous eruptions, poorly circumscribed
violaceous plaques, to palpable purpura or small red palpable
spots. Unfortunately for our case, a skin biopsy was not carried
out on post-mortem examination. One study recommends
performing skin biopsy irrespective of the presence or absence
of skin lesions in patients who are suspected to have IVLBCL
after they have concluded its high sensitivity compared to bone
marrow biopsy.12 Symptoms secondary to CNS involvement are
common and varied and may range from sensory and motor
deficits, altered conscious state, paresthesias to seizures.13
Quite unusual in this case is the presence of the neoplastic cells
confined in the small blood vessels of the uterus and cervix.
Although it has been frequently mentioned in different studies
that IVLBCL can virtually involve any organ, the infiltration
of the blood vessels in the gynecologic tract is rarely noted. At
least 3 case reports describe the diagnosis of IVLBCL in the
uterus, cervix and ovaries14-16 —all of which noted the absence of
a defined mass macroscopically, and confirming the diagnosis
on histopathological examination.
Patients with IVLBCL have a poor prognosis, partly due
to its protean manifestation and diagnostic delays. With its
high overall mortality rate, more than half of the patients are
diagnosed post-mortem.17 It responds poorly to chemotherapy
and neither clinical types nor clinical parameters can predict
survival, apart from better prognosis for cases with disease
limited to the skin.

http://philippinejournalofpathology.org | Vol. 2 No. 2 November 2017

Lo et al, Intravascular Large B-Cell Lymphoma: A Continuing Clinical Enigma Philippine Journal of Pathology | 34

A B

C D

E F

Figure 3. Intravascular large cell B-lymphoma. Proliferation of neoplastic lymphoid cells within the lumen of small to medium-
sized blood vessels are noted in the following organs: (A) Lungs, H&E, 10x (B) Liver, H&E, 40x (C) Spleen, H&E, 40x (D) Uterus,
H&E, 40x. (E) Hypercellular bone marrow with trilineage maturation. Immunohistochemistry with CD3, CD20 and CD30 were all
negative. (F) Neoplastic cells found in the blood vessels of the lungs show strong, cytoplasmic reactivity to CD20, 40x. The same
immunohistochemistry pattern was noted in the liver, spleen, kidneys, uterus, cervix, brain, heart and thyroid.

CONCLUSION thyroid function tests, a differential diagnosis of IVLBCL should

Despite numerous efforts, a definitive diagnosis of B-cell
lymphoma was not established before the patient’s demise. In
an adult patient who presents with fever of unknown origin
associated with anemia, elevated serum lactate dehydrogenase,
thrombocytopenia and leukopenia, altered hepatic, renal or
be considered. A bone marrow or skin biopsy may be helpful.
However, should the case present as a clinical dilemma such
that diagnosis cannot be rendered prior to the patient’s demise,
postmortem examination is recommended to further increase
the awareness for this disease entity and to better understand
its pathogenesis.

http://philippinejournalofpathology.org | Vol. 2 No. 2 November 2017

Lo et al, Intravascular Large B-Cell Lymphoma: A Continuing Clinical Enigma Philippine Journal of Pathology | 35

STATEMENT OF AUTHORSHIP 8. Wang J, Ding W, Gao L, et al. High frequency of bone

All authors certified fulfillment of ICMJE authorship criteria.
Author Disclosure
The authors declared no conflict of interest.
Funding Source
None.
REFERENCES
1. Ferreri A, Campo E, Seymour JF, et al. Intravascular
lymphoma: clinical presentation, natural history,
management and prognostic factors in a series of 38 cases,
with special emphasis on the ‘cutaneous variant’. Br J
Haematol. 2004;127(2):173-83. PMID: 15461623. https://
doi.org/10.1111/j.1365-2141.2004.05177.x.
2. Murase T, Yamaguchi M, Suzuki R, et al. Intravascular large
B-cell lymphoma (IVLBCL): a clinicopathological study of
96 cases with special reference to the immunophenotypic
heterogeneity of CD5. Blood. 2007;109(2):478-85. PMID:
16985183. https://doi.org/10.1182/blood-2006-01-021253.
3. Nakamura S, Ponzoni M, Campo E. Intravascular large
B-cell lymphoma. In S. Swerdlow, E. Campo, Harris NL,
editors. WHO classification of tumours of haematopoeitic
and lymphoid tissues, 4th ed. Lyon: IARC. 2008, pp.252-3.
4. Ponzoni M, Arrigoni G, Gould VE, et al. Lack of CD29
(beta1 integrin) and CD 54 (ICAM-1) adhesion molecules in
intravascular lymphomatosis. Hum Pathol. 2000;31(2):220-
6. PMID: 10685637.
5. Holmes NE, Gordon CL, Lightfoot N, et al. Intravascular
large B cell lymphoma: an elusive cause of pyrexia of unknown
origin diagnosed postmortem. Clin Infect Dis. 2010; 51(9):
e61-4. PMID: 20868278. https://doi.org/10.1086/656684.
6. Zuckerman D, Seliem R, Hochberg E. Intravascular
lymphoma: the oncologist's "great imitator". Oncologist.
2006;11(5):496-502. PMID: 16720850. https://doi.org/
10.1634/theoncologist.11-5-496.
7. Ponzoni M, Ferreri AJ, Campo E, et al. Definition, diagnosis,
and management of intravascular large B-cell lymphoma:
proposals and perspectives from an international consensus
meeting. J Clin Oncol. 2007;25(21):3168-73. PMID:
17577023. https://doi.org/10.1200/JCO.2006.08.2313.
marrow involvement in intravascular large B-cell
lymphoma: a clinicopathological study of 13 cases in China.
Int J Surg Pathol. 2016;25(2):118-26. PMID: 27553679.
https://doi.org/10.1177/1066896916665203.
9. Fiegl M, Greil R, Pechlaner C, Krugmann J, Dirnhofer
S. Intravascular large B cell lymphoma with a fulminant
clinical course: a case report with definite diagnosis post
mortem. Ann Oncol. 2002;13(9):1503-6. PMID: 12196378.
10. Khanna R, Sarin S. Non-cirrhotic portal hypertension-
-diagnosis and management. J Hepatol. 2014;60(2):
421-41. PMID: 23978714. https://doi.org/10.1016/j.jhep.
2013.08.013.
11. Yasuda, H, Ando J, Matsumoto T, et al. Intravascular large
B cell lymphoma with hepatic portal vein, splenic vein
and mesenteric vein tumour embolism. Histopathology.
2010;57(4):648-50. PMID: 20955393. https://doi.
org/10.1111/j.1365-2559.2010.03660.x.
12. Matsue K, Asada N, Odawara J, et al. Random skin biopsy
and bone marrow biopsy for diagnosis of intravascular large
B cell lymphoma. Ann Hematol. 2011;90(4):417-21. PMID:
20957365. https://doi.org/10.1007/s00277-010-1101-3.
13. Orwat DE, Batalis NI. Intravascular large B-cell lymphoma.
Arch Pathol Lab Med. 2012;136(3):333-8. PMID: 22372911.
https://doi.org/10.5858/arpa.2010-0747-RS.
14. Sur M, Ross C, Moens F. Intravascular large B-cell
lymphoma of the uterus: a diagnostic challenge. Int J
Gynecol Pathol. 2005;24(2):201-3. PMID: 15782078.
15. Shigematsu Y, Matsuura M, Tsuyama N, et al. Intravascular
large B-cell lymphoma of the bilateral ovaries and uterus
in an asymptomatic patient with a t(11;22)(q23;q11)
constitutional translocation. Intern Med. 2016;55(21):3169-
74. PMID: 27803414. PMCID: PMC5140869. https://doi.
org/ 10.2169/internalmedicine.55.6578.
16. Fournier M, Hourseau M, Chis C, Luton D, Koskas M.
Uterine presentation of an intravascular large B-cell
lymphoma diagnosed by PET/CT and histology. Case Rep
Clin Pathol. 2014;1(2):105-8. https://doi.org/10.5430/crcp.
v1n2p105.
17. Wahie S, Dayala S, Husain A, Summerfield G, Hervey
V, Langtry JA. Cutaneous features of intravascular
lymphoma.  Clin Exp Dermatol.  2011;36(3):288–91.
PMID: 21418271. https://doi.org/10.1111/j.1365-2230.
2010.03934.x.

Disclaimer: This journal is OPEN ACCESS, providing immediate access to its content on the principle that making research freely available to the
public supports a greater global exchange of knowledge. As a requirement for submission to the PJP, all authors have accomplished an AUTHOR
FORM, which declares that the ICMJE criteria for authorship have been met by each author listed, that the article represents original material,
has not been published, accepted for publication in other journals, or concurrently submitted to other journals, and that all funding and conflicts
of interest have been declared. Consent forms have been secured for the publication of information about patients or cases; otherwise, authors
have declared that all means have been exhausted for securing consent.

http://philippinejournalofpathology.org | Vol. 2 No. 2 November 2017

OPEN ACCESS – BRIEF COMMUNICATIONS

External Quality Assessment Scheme for Transfusion Transmissible

Infections among Blood Service Facilities in the Philippines, 2016
Kenneth Aristotle Punzalan, Rhoda Yu, Iza Mae Chamen

Research Institute for Tropical Medicine – Department of Health, Philippines

ABSTRACT

The External Quality Assessment Scheme for Transfusion Transmissible Infections in the Philippines aims to
raise the standards of quality testing for infectious diseases in blood units.

The National Blood Program lists more than 200 Blood Service Facilities (BSF) in the country in which
162 participated in the 2016 EQAS test event. These participants were given an EQAS panel composed
the HVHT4320 serology program and MLRA415 malaria program. The panels should be treated by the
participants as routine donor samples to simulate the actual laboratory process which allows the NRL and
the participant to check and validate the entire blood unit screening process.

The results were submitted via an online informatics system and were analyzed by One World Accuracy
Canada using the ISO 13528:2008 Robust Statistics method (Huber’s Method) to identify outliers. Qualitative
results were evaluated and compared with the reference results of the NRL to which non-concordance
would mark their results aberrant. The results of the test event showed a number of participants having
aberrant results due to either random or systematic errors.

Data gathered from this EQAS test event are used to improve the processes of the blood service facility to
ensure quality testing.

Key words: quality assurance, blood donor serology, transfusion transmissible infections, proficiency testing

INTRODUCTION
ISSN 2507-8364 (Online)
Printed in the Philippines. External Quality Assessment is a crucial aspect of quality assurance
Copyright© 2017 by the PJP.
in medical laboratories. The results generated from each test event
Received: 30 June 2017.
Accepted: 10 August 2017. continuously reflect the analytical quality of the measurements
Published online first: 15 August 2017. performed by the participating laboratory and the performance
https://doi.org/10.21141/PJP.2017.015 can also be compared with other laboratories using the same
instrument or method.1
Corresponding author: Kenneth Aristotle P. Punzalan, RMT
E-mail: kenn.punzalan@gmail.com, tti.nrl@gmail.com
The External Quality Assessment Scheme (EQAS) for Transfusion
Transmissible Infections (TTI) in the Philippines is a mandatory
requirement for licensing of Blood Service Facilities whose
category are Blood Centers and/or Blood Bank with Additional
Functions2 that aims to raise the standards on quality testing of
blood units and assess each phase of testing to determine inter-
laboratory comparison.

This activity intends to assess the quality of blood unit testing

of blood service facilities in the Philippines for the EQAS 2016
test event.

Methodology

Panel Composition

The TTI EQAS test event consists of two panels, the HVHT4320
for blood donor serology, and the MLRA415 for malaria slide
microscopy. The HVHT4320 consists of twenty (20) pooled
plasma samples obtained from blood donors from different regions
of the country. Each pooled sample was prepared by mixing
similar volumes of at least two samples that had similar antibody
and antigen profiles. All samples were subjected to filtration prior

http://philippinejournalofpathology.org | Vol. 2 No. 2 November 2017

Punzalan et al, External Quality Assessment Scheme for Transfusion Transmissible Infections Philippine Journal of Pathology | 37

60 56

50

40

30
21
20 14
11
10 7 6 5 6 6 5 6 5
3 4 4 3
0
I II III IV-A IV-B V VI VII VIII IX X XI XII XIII CAR NCR

Figure
Figure 1. 1.distribution
Regional Regionalofdistribution
participants. of participants.

DataThe
to aliquoting. Analysis
samples were aliquoted and their homogeneity Results AND Discussion
confirmed.
ISOThe serology profile
13528:2005 Robustfor Statistics
HIV, HBV, method
HCV, Syphilis
(Huber’s Method) was used to identify outlying results
of each sample were identified using a chemiluminescence assay
(numerical test results found to be statisticallyMajority
(ChLIA), enzyme immunoassay (EIA), Rapid Plasma Reagin
of the participants used the ChLIA platform (48.77%)
different from other test results reported by
in testing the panels followed by EIA (29.63%). 6.79% used a
participants that tested the same sample
(RPR), Particle Agglutination (PA) and Western Blot (WB). in the same assay)
combination of ChLIA for the
and created
EIA, 1.85%peer
used groups.
rapid testAkits
peer group is defined as a set of laboratories that alone,utilize the same
and 12.96% used a test formatofand
combination eitherassay
ChLIA,test
EIA,
Program code MLRA415 consists of five (5) blood smears. The
kit for screening TTI. The said method uses the Rapid meanTest asKits
an(RDT), Rapid Plasma
estimator Reagin (RPR),
and outlying testand Particle
results
samples were obtained from Malaria patients in Palawan and Agglutination (PA).
preparedwere removed
by the from statistical
NRL for Malaria and other calculation.
Parasites of the Qualitative results of the BSF were compared with
Researchthe qualitative
Institute reference
for Tropical Medicine. results of the NRL Discrepancy
4.94% of thebetween the two
total participants results
had data entrywould mark
errors or clerical
a result aberrant. errors (e.g. reactive test results were interpreted as negative or
Participants vice versa).

RESULTS AND
The Multimarker Blood DISCUSSION
Serology EQAS panel ID HVHT4320 Of the 162 participants, 29.01% reported aberrant results for
Majority of the EQAS
and Malaria Microscopy participants
Panel IDused the ChLIA
MLRA415 were platform (48.77%)
the HVHT4320 in testing
serology panel. Athe
totalpanels
of 13,374followed
results were
distributed to 162
by EIA participants
(29.63%). nationwide.
6.79% used aThese participants of ChLIA
combination reportedandby the participants
EIA, 1.85% usedand 91
rapid(0.68%)
testwere marked as
kits alone,
enrolled for the EQAS 2016 test event with a corresponding aberrant. From the aberrant results, 47 (51.65%) were reported as
andfee12.96%
registration used a
to cover expenses forcombination
the test event. of either ChLIA, EIA, Rapid Test Kits (RDT), Rapid Plasma
false positive, 27 (29.67%) were reported as false negative, and 17
Reagin (RPR), and Particle Agglutination (PA). (18.68%) were reported as inconclusive. From the 27 false negative
Majority of the participants were private institutions (43%) results, 11 (40.74%) were due to clerical errors.
followed closely by government institutions (41%) and the
4.94% of the total participants had data entry errors or clerical errors (e.g. reactive test results
remainder are from the Philippine Red Cross (16%). Figure 1 Distribution of aberrant results by platform and analyte for the
were
shows the interpreted
distribution as negative
of participants by region. or vice versa). initial panel is shown in Table 1. These aberrant results were either
due to data entry errors, sample mix-up or sample carry-over
Data Analysis
Of the 162 participants, 29.01% reported aberrant (particularly
resultswhere
for an
theinstrument
HVHT4320 was used in assay panel.
serology set-up). A
total of Robust
ISO 13528:2005 13,374Statistics
results method
were reported
(Huber’s Method)by the participants and 91 (0.68%) were marked as
The following criteria must be met for a participant to be classified
was usedaberrant. From the
to identify outlying aberrant
results (numericalresults, 47found
test results (51.65%) were
as an reported
unsatisfactory as false
performer positive,
in the HVHT4320 27 (29.67%)
initial panel:
to be statistically
were reporteddifferent as
from othernegative,
false test results and
reported by
17 (18.68%)
(a) atwere reported
least one as inconclusive.
false negative From
result; (b) at least thepercent
twenty 27
participants that tested the same sample in the same assay) for (20%) false positive results. In accordance with these criteria,
false negative results, 11 (40.74%) were due to clerical errors.
the created peer groups. A peer group is defined as a set of corresponding participants were given an investigation checklist
laboratories that utilize the same test format and assay test kit for to assist them in identifying errors and make the necessary
Distribution
screening TTI. The said of method
aberrant uses results
the meanby as platform
an estimatorand corrective
analyteactions
for the initial
and/or panel is shown
troubleshooting in Table
methods. A 2nd set1. of
and outlying test results were removed from statistical calculation. the HVHT4320 panel
These aberrant results were either due to data entry errors, sample mix-up or sample carry- were given to the participants for retesting
Qualitative results of the BSF were compared with the qualitative if the identified unsatisfactory performance was due to a testing
over (particularly
reference results where an
of the NRL Discrepancy instrument
between was used in assay set-up).
the two results error. Participants with aberrant results due to transcription errors
would mark a result aberrant. were only given an investigation/troubleshooting checklist and a

Table 1. Number of aberrant results per transfusion transmissible infections testing platform (HVHT4320 1st panel), EQAS 2017
HIV HBV HCV SYP TOTAL
Platform
FN INC FP FN INC FP FN INC FP FN INC FP ABERRANT
ChLIA 1 (1.10%) 0 (0.00%) 4 (4.40%) 7 (7.69%) 0 (0.00%) 17 (18.68%) 5 (5.49%) 3 (3.30%) 4 (4.40%) 1 (1.10%) 2 (2.20%) 0 (0.00%) 44 (48.35%)
EIA 1 (1.10%) 3 (3.30%) 11 (12.09%) 1 (1.10%) 1 (1.10%) 4 (4.40%) 3 (3.30%) 0 (0.00%) 3 (3.30%) 0 (0.00%) 0 (0.00%) 4 (4.40%) 31 (34.07%)
RDT 0 (0.00%) 4 (4.40%) 0 (0.00%) 6 (6.59%) 0 (0.00%) 0 (0.00%) 1 (1.10%) 0 (0.00%) 0 (0.00%) 0 (0.00%) 0 (0.00%) 0 (0.00%) 11 (12.09%)
RPR N/A N/A N/A N/A N/A N/A N/A N/A N/A 1 (1.10%) 4 (4.40%) 0 (0.00%) 5 (5.49%)
TOTAL 2 (2.20%) 7 (7.69%) 15 (16.48%) 14 (15.38%) 1 (1.10%) 21 (23.08%) 9 (9.89%) 3 (3.30%) 7 (7.69%) 2 (2.20%) 6 (6.59%) 4 (4.40%) 91 (100.00%)
Legend: FN – False Negative, FP – False Positive, INC – Inconclusive, HIV – Human Immunodeficiency Virus, HBV – Hepatitis B Virus, HCV – Hepatitis C Virus, SYP – Syphilis

http://philippinejournalofpathology.org | Vol. 2 No. 2 November 2017

 Punzalan et al, External Quality Assessment Scheme for Transfusion Transmissible Infections Philippine Journal of Pathology | 38

written recommendation. Eight (8) participants were identified RECOMMENDATION

with transcription errors which they have recognized in the given
investigation checklist. Ten (10) participants were given a second
set of samples wherein one had reported a false negative result.
For the MLRA415 panel, 33% of the participants reported
aberrant results with 8.64% reporting false positive results and
30.25% reporting false negative results.
Figure 2 shows the distribution of grades of the participants. They
have been evaluated and graded as follows:
• Excellent – 100% acceptable results on the initial panel (all
final results were correctly identified in comparison with the
reference results);
• Very Satisfactory – Less than 100% acceptable results on the
initial panel without being given a second panel for retesting.
• Satisfactory – 100% acceptable results on retesting of the
second panel; or had an aberrant result in the initial panel
due to a clerical error, given that the participant was able to
identify this error through the EQAS investigation checklist.
• Poor – Participant did not follow minimum requirements
of testing as per DOH Circular No. 2013-0132 or less than
100% acceptable results on retesting of the second panel; or
had an aberrant result in the initial panel due to a clerical
error which the participant had failed to identify in the EQAS
investigation checklist.
8%
8%
The participating laboratory should be responsible in reviewing
their EQAS report and in discussing it to the people involved in
the process since this is an opportunity for improvement by way
of a corrective action. The analyzed data can improve the quality
of results from the participants as this can be used to as evidence
to introduce or improve the quality assurance of the laboratory.3
An increase in the number of EQAS test events within a year
would be of value in the improvement of the BSF processes.
AcknowledgmentS
The authors thank the TTI-NRL staff, Dr. Catherine Masangkay
and Dr. Socorro Lupisan of the Research Institute for Tropical
Medicine (RITM), the Health Facility Development Bureau, the
Health Facility Services and Regulatory Bureau, and the National
Voluntary Blood Services Program of the Department of Health,
the National Council for Blood Services–Technical Working
Group, the Department of Parasitology (RITM), the Philippine
Red Cross – National Blood Center (Port Area), the Asian Hospital
and Medical Center, and OneWorld Accuracy – Canada.
We also extend our thanks to all the participating Blood Service
Facilities for their support.
STATEMENT OF AUTHORSHIP
All authors certified fulfillment of ICMJE authorship criteria.
Author Disclosure

Excellent The authors declared no conflict of interest.

Very Satisfactory
15% 8% Funding Source
8% Satisfactory
None.
Poor

69% Excellent REFERENCES

15% Very Satisfactory
1.
Kristensen GB. Flowchart for Handling Deviating Results
Satisfactory from External Quality Assessment. Int J Health Care Qual
Poor Assur. 2010; 20(1):37.
2. Department of Health. DOH Department Memorandum No.
Figure 2. Distribution of grades for69%the EQAS 2016 test event. 2009-0086B: Amendment to Department Memorandum No.
ure 2. Distribution of grades for the EQAS 2016 test event. 2009-0086-A entitled, “Implementation of external quality
Conclusion assessment program as regulatory requirement for licensing
of clinical laboratories.” 8 September 2014. Retrieved
The TTI EQAS is a valuable management tool aimed to improve from  http://ttinrl. com/wp-content/uploads/2014/11/
ONCLUSION the efficiency and service of a laboratory. While this event has DM-2009-0086-B.pdf.
ure
e TTI2.EQAS
Distribution of grades
is ashown
valuable for the
a number of EQAS
management 2016 test
participants
tool event.
failing,
aimed the
to results
improve should
thebe
efficiency and Health
3. World serviceOrganization.
of WHO manual for organizing a
aboratory. While used as
thisanevent
opportunity to compare
has shown their activities
a number and remodelfailing, the
of participants national
resultsexternal
shouldquality assessment programme for health
their current practices based on what they would learn. A strong laboratories and other testing sites. Geneva, Switzerland,
used as an opportunity to compare their activities and remodel their current practices
NCLUSION commitment from top-level managers of these participants is 2016. Available from: http://www.who.int/hiv/pub/
sed on whatessentialthey would learn.
theseAtool
strong commitment from top-level managers of these
TTI EQAS is a valuable to improve
management processes.
aimed to improve the efficiency and service of
toolkits/manual-external-quality-assessment-testing/en/.
rticipants is essential to improve these processes.
aboratory. While this event has shown a number of participants failing, the results should
used as an opportunity to compare their activities and remodel their current practices
COMMENDATION
ed on what theyDisclaimer:
would learn.This journal
A strongis OPEN ACCESS, providing
commitment from immediate
top-level access to its content
managers on the principle that making research freely available to the
of these
eticipants
participating laboratory
public
is essential supportsshould
to improve athese
greater be responsible
global
processes. in reviewing
exchange of knowledge. their EQAS
As a requirement reporttoand
for submission inall authors have accomplished an AUTHOR
the PJP,
cussing it to the FORM, which declares
people that thein
involved ICMJE criteria
the for authorship
process sincehave thisbeen
is met
anby opportunity
each author listed, that the article represents original material,
for
COMMENDATION has not been published, accepted for publication in other journals, or concurrently submitted to other journals, and that all funding and conflicts
provement by way of a corrective action. The analyzed data can improve the quality of
of interest should
participating laboratory have beenbe declared. Consent forms
responsible have been secured for the publication of information about patients or cases; otherwise, authors
ults from the participants as this can be usedinto reviewing
as evidence their EQAS report
to introduce and in
or improve the
cussing it to thehave declared
people that all means
involved in have process
the been exhausted
since forthis
securing
is anconsent.
opportunity for
ality assurance of the laboratory.3 An increase in the number of EQAS test events within a
rovement by way of a corrective action. The analyzed data can improve the quality of
ar would be of value in the improvement of the BSF processes.
ults from the participants as this can be used to as evidence to introduce or improve the
ality assurance of the laboratory.3 An increase in the number of EQAS test events within a
r would be of value in the improvement of the BSFhttp://philippinejournalofpathology.org
processes. | Vol. 2 No. 2 November 2017
KNOWLEDGEMENTS
e authors thank the TTI-NRL staff, Dr. Catherine Masangkay and Dr. Socorro Lupisan of the
OPEN ACCESS – IMAGES IN PATHOLOGY

Osteolipoma: A Rare Variant of the Common Lipoma

Emilio Villanueva III1 and Ariel Vergel de Dios2

Department of Laboratories, University of the Philippines-Philippine General Hospital

1

Department of Pathology, University of the Philippines-College of Medicine

2

A 78-year-old female consulted for a ten-year gradually enlarging,

Key words: osteolipoma, lipoma, variant
right medial thigh mass, measuring 40 x 40 x 30 cm at time of
consult. Physical examination shows right lower extremity
external rotation, left lower extremity genu varum, and difficulty
in walking due to mass effect. No imaging procedures was done;
the patient was immediately scheduled for surgery after pre-
operative clearance. Excision of the thigh mass was performed
to relieve the patient of the mass effect. Intraoperative finding
was a fibro-fatty mass located in the medial compartment of the
thigh. There was no attachment to the femur nor the major blood
vessels. The mass was submitted for histopathologic examination.

Gross examination shows yellow to cream/yellow, ovoid,

fibrofatty to firm tissue with cream/white to cream/yellow
smooth, glistening cut sections, with patchy areas of calcifications
and fibrosis. Histopathologic examination shows mature adipose
tissue with admixed mature lamellar bone (Figure 1) and areas
with hyaline cartilage undergoing ossification (Figure 2). The
adipocytes are monotonous and monomorphic. There is no
nuclear atypia, lipoblasts, mitotic activity, nor necrosis seen. The
case was signed out as osteolipoma.

Figure 1. Mature adipose tissue with admixed mature lamellar

bone (Hematoxylin and Eosin at 40x).

ISSN 2507-8364 (Online)

Printed in the Philippines.
Copyright© 2017 by the PJP.
Received: 12 July 2017.
Accepted: 29 July 2017.
Published online first:
https://doi.org/10.21141/PJP.2017.016
  
Corresponding author: Emilio Q. Villanueva III, MD, RMT,
MT(ASCPi)
E-mail: drevilthird@gmail.com

Figure 2. Mature adipose tissue with hyaline cartilage undergoing

ossification (Hematoxylin and Eosin at 40x).

http://philippinejournalofpathology.org | Vol. 2 No. 2 November 2017

Villanueva et al, Osteolipoma: A Rare Variant of the Common Lipoma Philippine Journal of Pathology | 40

Lipomas are the most common benign soft tissue tumor occurring
in subcutaneous tissues. Most patients are adults in 30’s to 40’s.
It is comprised of ma­ture adipocytes without atypia.1,2 Variants
of lipomas exist, having other mesenchymal components such as
fibrous, smooth muscle, myeloid, chondral, vascular, or osseous
tissue present admixed with the adipocytes. The nomenclature of
the different variants depends on the type of tissue admixed with
the adipocyte such as fibrolipoma, leiomyolipoma, myelolipoma,
chondrolipoma, angiolipoma, and osteolipoma, respectively.2
The rare variant osteolipoma is composed of mature lamellar
bone interspersed within the adipose tissue.3 Microscopically, they
appear as predominantly mature adipose tissues with irregularly
distributed mature lamellar bone with areas of ossification. This
is the main morphologic criteria of the diagnosis.4
The principal pathologic differential diagnosis of a deep-seated
lipoma is a well-differentiated liposarcoma. It is a deep-seated
tumor common in adults above 50 years old. Morphologically,
it is also composed of mature adipocytes. It is differentiated by
the presence of scattered hyperchromatic nuclei, mostly situated
within the fibrous septa.5
There are two main theories regarding the pathogenesis of
osteolipoma: first, they may be directly derived from multipotent
mesenchymal cells;2 another, they may arise after repetitive
trauma, ischemia, or metabolic changes initiating osseous
metaplasia. The adipose tissue component strengthens this
osteoblastic activity.4,6
References
1. Cheng S, Lu SC, Zhang B, Xue Z, Wang HW. Rare
massive osteolipoma in the upper part of the knee in a young
adult. Orthopedics. 2012;35(9):e1434-7. PMID: 22955415.
https://doi.org/10.3928/01477447-20120822-35.
2. Demiralp B, Alderete JF, Kose O, Ozcan A, Cicek I,
Basbozkurt M. Osteolipoma independent of bone tissue:
a case report. Cases J. 2009;2:8711. PMID: 19918398.
PMCID: PMC2769468. https://doi.org/10.4076/1757-
1626-2-8711.
3. Fritchie KJ, Renner JB, Rao KW, Esther RJ. Osteolipoma:
radiological, pathological, and cytogenetic analysis of three
cases. Skeletal Radiol. 2012;41(2):237-44. PMID: 21822651.
https://doi.org/10.1007/s00256-011-1241-0.
4. Electricwala AJ, Panchwagh Y, Electricwala JT. Giant
osteolipoma fixed to the greater trochanter of the femur in
a seventy-year-old elderly woman. Cureus. 2017;9(2):e1036.
PMID: 28357168. PMCID: PMC5356992. https://doi.
org/10.7759/cureus.1036.
5. Fisher C, Montgomery EA, Thway K. Biopsy interpretation
of soft tissue tumors. Philadelphia: Lippincott Williams &
Wilkins, 2011.
6. Heffernan EJ, Lefaivre K, Munk PL, Nielsen TO,
Masri BA. Ossifying lipoma of the thigh. Br J Radiol.
2008;81(1968):e207-10. PMID: 18628326. https://doi.
org/10.1259/bjr/38805072.

Osteolipomas have good prognosis similar with simple lipoma.

Surgical excision is the recommended treatment.1,4

Disclaimer: This journal is OPEN ACCESS, providing immediate access to its content on the principle that making research freely available to the
public supports a greater global exchange of knowledge. As a requirement for submission to the PJP, all authors have accomplished an AUTHOR
FORM, which declares that the ICMJE criteria for authorship have been met by each author listed, that the article represents original material,
has not been published, accepted for publication in other journals, or concurrently submitted to other journals, and that all funding and conflicts
of interest have been declared. Consent forms have been secured for the publication of information about patients or cases; otherwise, authors
have declared that all means have been exhausted for securing consent.

http://philippinejournalofpathology.org | Vol. 2 No. 2 November 2017

OPEN ACCESS – DIAGNOSTIC PERSPECTIVES

Contrast-Enhanced Spectral Mammography:

A Radiologic-Pathologic Perspective of a
Novel Functional Imaging Modality for Breast Cancer
Ma. Theresa Buenaflor1 and Francis Moria2

Health Cube Advanced Medical Imaging Unit-San Juan City, Philippines

1

College of Medicine, St. Luke’s Medical Center-Quezon City, Philippines

2

ABSTRACT

Contrast-enhanced Spectral Mammography (CESM) is an emerging and promising functional imaging

modality that tries to address the paucity of physiologic-based tumor imaging for the detection of
breast cancer.

This article describes two cases of women with non-dense and dense breasts presenting with clinically palpable
breast masses and the depiction of breast cancer utilizing Contrast-enhanced Spectral Mammography.

Key words: Contrast-Enhanced Spectral Mammography (CESM), Digital Breast Tomosynthesis, Magnetic
Resonance Imaging, Low energy, Subtracted Image, Full-Field Digital Mammography (FFDM)

INTRODUCTION
ISSN 2507-8364 (Online)
Printed in the Philippines. Mammography is the only breast imaging modality with a
Copyright© 2017 by the PJP.
demonstrated ability to reduce mortality.1 A review by Myers
Received: 29 September 2017.
Accepted: 2 November 2017. et al., confirmed the findings of several published studies that
Published online first: 15 November 2017. screening mammography in women aged 40-79 reduces breast
https://doi.org/10.21141/PJP.2017.017 cancer mortality rates by 20%-50%, with extent of benefit
varying by age, as well as study design (RCT vs. observational).2
Corresponding author: Ma. Theresa S. Buenaflor, MD, FPCR However, mammography has a population-based sensitivity of
E-mail: buenates2@gmail.com
only approximately 80%1 which is further corroborated by the
findings of Carney et al., that showed that with increasing breast
density, the sensitivity of mammography decreases to 62% in
women with dense breasts.3

Breast density refers to the proportion of glandular and fibrous

breast tissue to the amount of fatty tissues in a woman’s breast.
It has been shown that women who have high density breasts are
4-5x more likely to get breast cancer than women with low breast
density.4,5 It is also statistically significantly greater among Asian
women than among African American and white women.6

Contrast-Enhanced Spectral Mammography (CESM)

Contrast-enhanced Spectral Mammography (CESM) is a novel
imaging modality that demonstrates the physiologic uptake of
contrast by breast cancer. The depiction of breast cancers using
contrast media is based on the biologic principle of the rapid
formation of tumoral microvessels that render malignancy-
associated vessels more permeable to contrast agent than normal
tissue, resulting in tumor enhancement.7

It has been proposed by Chang et al., that the use of a standard

iodinated CT contrast agent and x-ray imaging might also give
functional information with a preferential uptake in breast
cancers.8 An early study done among 26 subjects in 2003 by Lewin
et al., of the University of Colorado utilizing dual-energy contrast-
enhanced mammography showed tumor enhancement in 13 of
the subjects that had subsequent biopsy-proven invasive cancers.9

Contrast-enhanced Spectral Mammography was introduced in

Europe in June 2010 and received FDA approval in the United

http://philippinejournalofpathology.org | Vol. 2 No. 2 November 2017

Buenaflor et al, Contrast-Enhanced Spectral Mammography Philippine Journal of Pathology | 42

A B C D

E F

Figure 1. A 63-year-old post-menopausal female with a newly palpable right breast mass with no family history of breast cancer. (A,
B) Low-energy (LE) Mediolateral Oblique (MLO) and Craniocaudal (CC) views of the right breast, which has a fatty breast composition,
showing an irregular mass of high density at the lower inner quadrant. (C, D) Subtracted images (SI) in MLO and CC projections
show avid enhancement of the right lower inner quadrant breast mass. No other abnormal enhancing lesions are demonstrated.
The background parenchyma also shows no enhancement. (E) Ultrasound correlate of the said mass shows an irregular markedly
hypoechoic solid mass. (F) Elastography (which is a measure of tissue stiffness) shows the mass to be significantly hard compared to
the adjacent fat and glandular tissues.

States on October 2011. The first center in the UK to acquire the
technology was Nottingham Breast Unit and in the United States,
early adopters include Memorial Sloan-Kettering Cancer Center
in 2010. In Southeast Asia, the early proponents of CESM are
Taiwan and Thailand in 2012.
The advantages of using CESM are that it is similar in diagnostic
performance with Magnetic Resonance Imaging. Two studies
have shown the similarity of Contrast-enhanced Spectral
Mammography to MRI. Jochelson et al., found that CESM and
MRI have equal sensitivity (96%) while Fallenberg et al., found
CESM to have 100% sensitivity compared with 97% sensitivity
for MRI.10,11 This was further corroborated by Lee-Felker et al.,
who also had similar sensitivity of CESM to MRI (94% vs. 99%)
as well as having a significantly higher PPV (Positive Predictive
Value) of 93% compared to 60% of MRI.12
It can be used in patients with contraindications to doing MRI
such as claustrophobia and/or averse to gadolinium contrast.
Furthermore, a recent study by Patel et al., showed that CESM
had a reduced exam time of 7-10 minutes compared to MRI
with 30-60 minutes as well as reduced staff time of 25 minutes
compared to 60 minutes.13
The disadvantages include its contraindication for use in patients
with abnormal renal function or if they have a known reaction
to iodine contrast. Furthermore, it is not advised for pregnant or
lactating women or those who are diagnosed with hyperthyroidism.
How is it performed?
Before a CESM exam is initiated, a thorough history is elicited
from the patient with emphasis on allergy history and previous

http://philippinejournalofpathology.org | Vol. 2 No. 2 November 2017

Buenaflor et al, Contrast-Enhanced Spectral Mammography Philippine Journal of Pathology | 43

A B

Figure 2. Histopathologic features of the high-density mass seen in the right breast of the patient discloses invasive ductal carcinoma.
(A) Seen are neoplastic ductal structures infiltrating the surrounding structures including the adjacent adipose tissue (H&E, 40x).
(B) Other areas prominently show the formation of new blood vessels amidst clusters of tumor cells with associated extensive
desmoplasia (H&E, 100x).

or known allergy to iodine contrast media. The creatinine level
is obtained at least a week before the scheduled exam. Ideally,
for premenopausal women, the timing of the exam should
coincide with Days 7-14 of her menses, to reduce background
parenchymal enhancement.
An IV is inserted into the forearm or antecubital vein and a power
injector at a rate of 3 ml/s infuses iodinated contrast agent. The
volume is typically calculated at 1.5-ml/kg bodyweight. The
iodine concentration ranges from 300 mg/ml to 370 mg/ml.
After infusion of the contrast media, let 2 minutes pass before
positioning the patient for the standard mammographic views
(Mediolateral Oblique and Craniocaudal views) of each breast.
For each projection, two energy pairs – low energy and high
energy are generated in a single compression. Severe acute
reactions to contrast media occur in 4/10,000 (0.04%) patients.14
According to a study of Lalji et al., the low-energy CESM images
are non-inferior to Full-Field Digital Mammography (FFDM)
images with no significant differences in image quality, average
glandular dose, and contrast detail.15 The LE images therefore
are equivalent to a standard mammogram. The additional
radiation dose from the HE images in CESM was approximately
20% that of routine Full-Field Digital Mammography or the
equivalent of 1 additional view.10
function, kinetics of distribution of blood into the capillary bed,
leakage across the capillary walls, and volume of the interstitial
space.16
In our current setting, the detection of breast cancer mainly utilizes
analog film mammography, conventional digital mammography,
digital breast Tomosynthesis (DBT/2D+3D Mammography) and
breast ultrasound, which are based on morphologic (anatomic)
information, as opposed to MRI (Magnetic Resonance Imaging)
which gives functional information. MRI, however, is limited in
its use in our local setting because of its limited availability and
the cost is prohibitive.
The sensitivity of CESM was found to be high (98%),
underscoring its potential to rival the diagnostic performance
of MRI, but with added advantages of improved accessibility
and lower cost.18 In women with dense breasts, Cheung et
al., demonstrated that CESM is superior to mammography in
both sensitivity and specificity with improvement from 71.5% to
92.7% and 51.8% to 67.9%, respectively.19
Akin to the improvements and technological advances made
in the field of Pathology, namely, with the development of
novel molecular characterization of breast cancer with cellular
markers, functional-based imaging of breast cancer is poised to
change the paradigm of current diagnostic practice.

DISCUSSION Dual-energy Contrast-enhanced Spectral Mammography may

The core principle in functional imaging is based on tumor
enhancement secondary to tumor neoangiogenesis. The process
of tumor neoangiogenesis plays a central role in the growth and
spread of tumors.16 Tumor cells secrete vascular endothelial
growth factor (VEGF), a potent angiogenesis activator that
stimulates the formation and proliferation of endothelial cells.17
The newly grown vessels are immature and differ from normal
capillaries. They are tortuous and irregular, resulting in poorly
efficient perfusion, they are leaky (especially to macromolecules),
and they are independent of the normal mechanisms of regulation
of the capillary blood flow. Hemodynamic characteristics of
immature neovessels can be conservatively assessed by dynamic
contrast-enhanced magnetic resonance imaging or computed
tomography. Tissue enhancement depends on arterial input
provide added value in determining the microcalcifications that
show enhancement with a diagnosis favorable to cancer or a lack
thereof as virtually diagnostic for non-malignant or noninvasive
subgroup of cancers.20 Likewise, its ability to identify multifocal or
multicentric disease enables it to adequately and simultaneously
stage both breasts21 for better pre-biopsy planning.
Local Experience
The first institute to acquire Contrast-enhanced Spectral
Mammography is Health Cube Advanced Medical Imaging
Unit in March 2016. It was initially utilized as part of the
surveillance monitoring of patients with either mastectomy or
post-breast conservation surgery and is currently integrated into
the diagnostic workflow in the work-up of patients with clinically
suspicious findings, particularly those who have dense breasts.

http://philippinejournalofpathology.org | Vol. 2 No. 2 November 2017

Buenaflor et al, Contrast-Enhanced Spectral Mammography Philippine Journal of Pathology | 44

A B C D

E F

Figure 3. A 56-year-old premenopausal female presenting with a palpable left breast mass, Family history revealed she had two (2) sisters
who had breast cancer in their 50’s. (A, B) LE MLO and CC views of the left breast showing heterogeneously dense breast composition.
There is an irregular mass of increased density at the mid upper quadrant and a second equal density mass with partly obscured margins at
the upper outer quadrant (C, D) Subtracted images (SI) in MLO and CC projections show an enhancing irregular mass at the mid upper left
breast and shows the second enhancing mass with lobulations at the upper outer quadrant on a background of moderate parenchymal
enhancement. (E, F) SI Image of the left CC view and the correlate ultrasound image showing multifocal breast lesions at the 12 o’clock
(orange arrow) and 2 o’clock (orange arrowhead) positions.

The two cases included in this case series showcase the ability of
CESM to image cancer whether in dense or non-dense breasts.
The first case illustrates cancer without background parenchymal
enhancement in a non-dense breast while the second case shows
two (2) foci of cancer in a patient with dense breasts with additional
background parenchymal enhancement.
Contrast-enhanced spectral mammography stands to be a viable
and practical diagnostic imaging modality that can contribute to
increased cancer detection rate and improve breast cancer care in
our country.
AcknowledgmentS

CONCLUSION The authors thank the following esteemed colleagues: Sherry L.

The trend towards molecular and functional-based diagnosis of
breast pathology will continue and potentially become the standard
of care in the near future, making it possible for a tailored and
targeted approach in the improved management of breast cancer.
Lee, MD, FPCS, FPSGS of Cardinal Santos Medical Center, and
Timothy James Lam, MD of the University of the East Ramon
Magsaysay Memorial Medical Center for the patient referrals
and Paulo Giovanni L. Mendoza, MD, FPSP of Cardinal Santos
Medical Center for his invaluable input on the histologic findings.

http://philippinejournalofpathology.org | Vol. 2 No. 2 November 2017

Buenaflor et al, Contrast-Enhanced Spectral Mammography Philippine Journal of Pathology | 45

A B

Figure 4. Microscopic appearances of the core biopsy taken from the enhancing left breast mass identified in the patient showing
invasive ductal carcinoma. The tumor is very cellular and is composed of neoplastic cells disposed in tongues, cords and groups with
attempts to form ducts (A) Note the pronounced desmoplastic reaction, which adds to the density seen radiographically. Some areas of
the lesion reveal an abundance of well- and newly-formed blood vessels (B) (H&E, 100x).

Ethical Consideration
Patient consent was obtained before submission of the manuscript.
Statement of Authorship
All authors certified fulfillment of ICMJE authorship criteria.
AUTHOR DISCLOSURE
The authors declared no conflicts of interest.
FUNDING SOURCE
None.
References
1. Jochelson M. Advanced imaging techniques for the detection
of breast cancer. Am Soc Clin Oncol Educ Book. 2012:65-
9. PMID: 24451711. https://doi.org/10.14694/EdBook_
AM.2012.32.65.
2. Myers ER, Moorman P, Gierisch JM, et al. Benefits and
harms of breast cancer screening: a systematic review.
JAMA. 2015;314(15):1615-34. PMID: 26501537. https://
doi.org/10. 1001/jama.2015.13183.
3. Carney PA, Miglioretti DL, Yankaskas BC, et al.  Individual
and combined effects of age, breast density, and hormone
replacement therapy use on the accuracy of screening
mammography. Ann Intern Med. 2003:138(3):168-75.
PMID: 12558355.
4. Boyd NF, Guo H, Martin LJ, et al. Mammographic density
and the risk and detection of breast cancer. N Engl J Med.
2007;356(3):227-36. PMID: 17229950. https://doi.org/
10.1056/NEJMoa062790.
5. Yaghjyan L, Colditz GA, Collins LC, et al. Mammographic
breast density and subsequent risk of breast cancer
in postmenopausal women according to tumor
characteristics. J Natl Cancer Inst. 2011;103(15):1179-89.
PMID: 21795664. PMCID: PMC3149043. https://doi.
org/10.1093/jnci/djr225.
6. del Carmen MG, Halpern EF, Kopans DB, et al.
Mammographic breast density and race. AJR Am J
Roentgenol. 2007;188(4):1147-50. PMID: 17377060.
https://doi.org/10.2214/AJR.06.0619.
7. Lobbes MB, Lalji U, Houwers J, et al. Contrast-enhanced
spectral mammography in patients referred from the breast
cancer screening programme. Eur Radiol. 2014;24(7):1668-
76. PMID: 24696228. https://doi.org/10.1007/s00330-
014-3154-5.
8. Chang CH, Nesbit DE, Fisher DR, et al. Computed
tomographic mammography using a conventional body
scanner. AJR Am J Roentgeol. 1982;138(3):553-8. PMID:
6978009. https://doi.org/10.2214/ajr.138.3.553.
9. Lewin JM, Isaacs PK, Vance V, Larke FJ. Dual-energy
contrast-enhanced digital subtraction mammography:
feasibility. Radiology. 2003;229(1):261-8. PMID: 12888621.
https://doi.org/10.1148/radiol.2291021276.
10. Jochelson MS, Dershaw DD, Sung JS, et al. Bilateral contrast-
enhanced dual-energy digital mammography: feasibility
and comparison with conventional digital mammography
and MR imaging in women with known breast carcinoma.
Radiology: 2013;266(3):743-51. PMID: 23220903. https://
doi.org/10.1148/radiol.12121084.
11. Fallenberg EM, Dromain C, Diekmann F, et al. Constrast-
enhanced spectral mammography vs. MRI: initial results in
the detection of breast cancer and assessment of tumor size.
Eur Radiol. 2014;24(1):256-64. PMID: 24048724. https://
doi.org/10.1007/s00330-013-3007-7.
12. Lee-Felker SA, Tekchandani L, Thomas M, et al. Newly
diagnosed breast cancer: comparison of contrast-
enhanced spectral mammography and breast MR imaging
in the Evaluation of Extent of Disease. Radiology.
2017;285(2):389-400. PMID: 28654337. doi.org/10.1148/
radiol.2017161592.
13. Patel BK, Gray RJ, Pockaj BA, Potential cost-savings
of contrast enhanced digital mammography. AJR Am
J Roentgenol. 2017;208(6):W231-7. PMID: 28379734.
https://doi.org/10.2214/AJR.16.17239.
14. Katayama H, Yamaguchi K, Kozuka T, Takashima T, Seez
P, Matsuura K. Adverse reactions to ionic and nonionic
contrast media. A report from the Japanese Committee on

http://philippinejournalofpathology.org | Vol. 2 No. 2 November 2017

Buenaflor et al, Contrast-Enhanced Spectral Mammography Philippine Journal of Pathology | 46

the Safety of Contrast Media. Radiology. 1990;175(3):621-
8. PMID: 2343107. https://doi.org/10.1148/radiology.175.
3.2343107.
15. Lalji UC, Jeukens CRLPN, Houben I, et al. Evaluation
of low-energy contrast-enhanced spectral mammography
images by comparing them to full-field digital mammography
using EUREF image quality criteria. Eur Radiol.
2015:25(10):2813–20. PMCID: PMC4562003. https://doi.
org/10.1007/s00330-015-3695-2.
16. Cuenod CA, Fournier L, Balvay D, Guinebretière JM.
Tumor angiogenesis: pathophysiology and implications
for contrast-enhanced MRI and CT assessment. Abdom
Imaging. 2006;31(2):188-93. PMID: 16447089. https://doi.
org/10.1007/s00261-005-0386-5.
17. Weis SM, Cheresh DA. Tumor angiogenesis:
molecular pathways and therapeutic targets. Nat Med.
2011;17(11):1359-70. PMID: 22064426. https://doi.org/
10.1038/nm.2537.
18. Tagliafico AS, Bignotti B, Rossi F, et al. Diagnostic performance
of contrast-enhanced spectral mammography: systematic
review and meta-analysis. Breast. 2016;28:13-9. PMID:
27161411. https://doi.org/10.1016/j.breast.2016.04.008.
19. Cheung YC, Lin YC, Wan YL, et al. Diagnostic
performance of dual-energy contrast-enhanced subtracted
mammography in dense breasts compared to mammography
alone: interobserver blind- reading analysis. Eur Radiol.
2014;24(10):2394-403. PMID: 24928280. https://doi.
org/10.1007/s00330-014-3271-1.
20. Cheung YC, Yuan YH, Lin YC, Lo YF, Tsai HP, Ueng
SH, et al. Dual-energy contrast-enhanced spectral
mammography: enhancement analysis on BI-RADS 4 non-
mass microcalcifications in screened women. PLOS ONE.
2016;11(9):e0162740. https://doi.org/10.1371/journal.
pone.0162740.
21. Bhimani C, Malta D, Roth RG, Liao L, Timney E, Brill K,
Germaine P. Contrast-ehanced spectral mammography:
technique, indications, and clinical applications. Acad
Radiol 2017;24(1):84-8. PMID: 27773458. https://doi.
org/10.1016/j.acra.2016.08.019.

Disclaimer: This journal is OPEN ACCESS, providing immediate access to its content on the principle that making research freely available to the
public supports a greater global exchange of knowledge. As a requirement for submission to the PJP, all authors have accomplished an AUTHOR
FORM, which declares that the ICMJE criteria for authorship have been met by each author listed, that the article represents original material,
has not been published, accepted for publication in other journals, or concurrently submitted to other journals, and that all funding and conflicts
of interest have been declared. Consent forms have been secured for the publication of information about patients or cases; otherwise, authors
have declared that all means have been exhausted for securing consent.

http://philippinejournalofpathology.org | Vol. 2 No. 2 November 2017

OPEN ACCESS – DIAGNOSTIC PERSPECTIVES

Alocilja Magnetic Nanoparticles capture

Escherichia coli O157:H7 isolates
Dodge Lim,1,6,7 Rovi Gem Villame,2 Gloria June Quiñones,3 Dave de Vera,3 Rebecca Notorio,3 Lilia Fernando,4,7
Evangelyn Alocilja5,7
1
National Tuberculosis Reference Laboratory, Research Institute for Tropical Medicine-Department of Health, Philippines
2
Department of Food Science and Chemistry, College of Science and Mathematics, University of the Philippines Mindanao
3
Electron Microscopy Laboratory, Research Institute for Tropical Medicine-Department of Health, Philippines
4
Nano-Biotechnology Laboratory, National Institute of Molecular Biology and Biotechnology (BIOTECH), University of the Philippines Los Baños
5
Alocilja Nano-Biosensors Lab, Biosystems and Agricultural Engineering, Michigan State University
6
RITM TB Study Group
7
Global Alliance for Rapid Diagnostics (GARD)

INTRODUCTION
Key words: Alocilja magnetic nanoparticles, E. coli
O157:H7, TEM images, cell capture Escherichia coli O157:H7 (EcO157) is a notorious foodborne
pathogen known to cause bloody diarrhea and can even lead to
death. Current detection methods, though highly sensitive, are
lengthy and labor-intensive thus an alternative that is simple,
ISSN 2507-8364 (Online) rapid, low-cost and equally sensitive is necessary. Hence, an
Printed in the Philippines. enabling method is the use of functionalized Alocilja magnetic
Copyright© 2017 by the PJP.
Received: 29 September 2017. nanoparticles (AMN), known to have high surface reactivity
Accepted: 17 November 2017. and can easily capture target biomolecules without the use of
Published online first: 18 November 2017. antibodies, such as microbial cells, in crude samples by means
https://doi.org/10.21141/PJP.2017.018 of a magnet. AMN, patented after its inventor Dr. Evangelyn
   Alocilja, is composed of iron oxide/glycan core/shell structure
Corresponding author: Dodge R. Lim, RN
E-mail: dodge.lim@gmail.com
with an average size of 180-450 nm and with superparamagnetic
properties. AMN has been reported to capture Salmonella enterica,
Bacillus cereus and Mycobacterium smegmatis without the use of
antibodies or peptides.1-4

In this preliminary work, our group tested the ability of AMN to

capture a model organism, E. coli O157:H7 isolates provided by
the National Institute of Molecular Biology and Biotechnology
(BIOTECH), University of the Philippines Los Baños (UPLB)
Accession No. 10308 from dairy cattle (Bos taurus L.) feces.5 O157
latex agglutination test (Oxoid Ltd., Thermo-Fischer Scientific,
UK) was used to confirm the identity of the isolates. This strain
was characterized through polymerase chain reaction (PCR)
to carry shiga toxin-producing genes such as stx1 which causes
severe and fatal disease.

To demonstrate this, 100 µL of AMN solution (5 mg/mL) was

added to a tube containing 1 mL of a 5-hr old pure EcO157
broth culture (with an initial population of ~108 CFU/mL).
The mixed solution was then serially diluted and spot plated on
Tryptic Soy Agar (TSA) (18-24 hours, 37°C) to determine the
cell population prior to AMN capture. A serially diluted tube
was sealed and gently mixed by inversion followed by a 5-min
incubation at ambient conditions to allow conjugation of AMN
to the cells. Magnetic separation for 1 min was performed
to immobilize the resultant AMN-EcO157 complex. The
supernatant was aspirated and discarded, and the AMN-EcO157
complex was resuspended in phosphate buffered solution (pH =
7.4). Spot plating on TSA was done to determine the population
of bound cells. The percent cell capture efficiency (%CCE) was
calculated by dividing the log10 of CFU/mL of captured cells
over the log10 of CFU/mL before capture. The average %CCE
of AMN towards pure EcO157 is 88.1±1.5 at pH = 7.4.

In order to visualize the capture of EcO157 by AMNs, the residual

samples were further analyzed through transmission electron
microscopy (TEM). Samples (50 to 100 µL) were dropped onto

http://philippinejournalofpathology.org | Vol. 2 No. 2 November 2017

Lim et al, Alocilja Magnetic Nanoparticles capture E. coli O157:H7 isolates
Figure 1. An AMN-EcO157 complex (TEM, mag: 2000x).
Figure 2. AMNs capturing aggregates of Ec0157 (TEM, 2500x).
Figure 3. EcO157 captured by few AMNs (TEM, 3000x).
a 200 mesh formvar coated EM grids for 3 minutes at 25°C and
drained. Grids were placed in a pre-labeled polystyrene petri dish
lined with Whatmann filter paper and dried in electric desiccator
cabinet overnight and examined using the JEOL JEM-1220
TEM under direct magnification of 2000x-3000x at 100 kV.
http://philippinejournalofpathology.org | Vol. 2 No. 2 November 2017
Philippine Journal of Pathology | 48
TEM micrographs confirmed conjugation between the AMPs
and EcO157. Figure 1 shows that AMPs were effective in
capturing the model pathogen by surrounding the entire cell.
Aggregates of EcO157 were seen to interface with the AMNs
in Figure 2. Also, it can be noted here that AMNs tend to heap
up when far from biotic cells. In Figure 3, bacterial capture is
evident despite the presence of a few AMNs.
Such capture of AMNs to EcO157 can be exploited to develop
a potential for simple, centrifuge-free, preconcentration step
for further downstream processing such as gDNA extraction,
and sensitive DNA-based biosensor detection. Further studies
are recommended to optimize test and apply AMN to capture
cells from crude samples. The capture of AMNs to pathogens
are governed by a number of biological phenomena, such as
microbial adhesion, cell surface hydrophobicity, aggregation
, biofilm formation, and surface to surface mediation such as
hydrodynamic, Lifshitz-Van der Walls, electrostatic, acid-base
and hydrophobic interaction forces.6-8 AMN in solution increases
particle density and surface area which promotes higher Brownian
movement of the bacteria and AMNs.6-8 Moreover, ionic and
electrostatic interaction between the positively charged AMNs
and negatively charged bacterial cell surface adds to the cohesive
dynamics of the interaction.9-10 Carbohydrate-binding proteins
on bacterial cell wall also promotes aggregation and conjugation
to nanoparticles.11 Compounding all these interactive forces
contributes to the synergy of cell capture by AMNs.
Acknowledgments
We thank Dr. Socorro P. Lupisan, Dr. Amado O. Tandoc III, Dr.
Ma. Cecilia G. Ama, Dr. Alpha Grace Cabic, Ms. Rocelle Marie
Agero (Research Institute for Tropical Medicine); Dr. Rosario G.
Monsalud, Dr. Francisco Elegado, David Joram Mendoza, Ma.
Theresa Jonna A. Atienza, Ma. Theresa Perez (BIOTECH, UP
Los Baños).
Statement of Authorship
All authors certified fulfillment of ICMJE authorship criteria.
AUTHOR DISCLOSURE
The authors declared no conflicts of interest.
FUNDING SOURCE
This study was funded by the Research Institute for Tropical
Medicine and is a recipient of the UP System Emerging
Interdisciplinary Research (EIDR) Grant.
References
1. Alocilja EC. Laboratory Research Division Brown Bag
Presentation: nanotechnology for rapid diagnosis of
infectious diseases. Metro Manila, Philippines: Research
Institute for Tropical Medicine; 2017.
2. Zhang D, Carr DJ, Alocilja EC. Fluorescent bio-barcode
DNA assay for the detection of Salmonella enterica serovar
Enteritidis. Biosens Bioelectron 2009;24(5):1377–81. PMID:
18835708. https://doi.org/10.1016/j.bios.2008.07.081.
3. Vetrone SA, Huarng MC, Alocilja EC. Detection of Non-
PCR Amplified S. enteritidis genomic DNA from food
Lim et al, Alocilja Magnetic Nanoparticles capture E. coli O157:H7 isolates Philippine Journal of Pathology | 49

matrices using a gold-nanoparticle DNA biosensor: a proof-
of-concept study. sensors 2012;12(12):10487–99. PMCID:
PMC3472839.
4. Pal S, Ying W, Alocilja EC, Downes FP. Sensitivity and
specificity performance of a direct-charge transfer biosensor
for detecting Bacillus cereus in selected food matrices.
Biosyst Eng. 2008;99(4):461–8. https://doi.org/10.1016/j.
biosystemseng.2007.11.015.
5. Rundina MCN. Isolation and characterization of Shiga
(Vero) Toxin-Producing Escherichia coli O157:H7 in
dairy cattle (Bos Taurus) from selected farms in Luzon,
Philippines. College, Laguna, Philippines: University of the
Philippines, Los Baños; 2004 [master’s thesis].
6. Krasowska A, Sigler K. How microorganisms use
hydrophobicity and what does this mean for human
needs? Front Cell Infect Microbiol 2014;4:112. PMCID:
PMC4137226. https://doi.org/10.3389/fcimb.2014.00112.
7. Xuan Y, Li Q , Hu W. Aggregation structure and thermal
conductivity of nanofluids. AIChE J 2003;49(4):1038–43.
https://doi.org/10.1002/aic.690490420.
8. Boks NP, Norde W, van der Mei HC, Busscher HJ. Forces
involved in bacterial adhesion to hydrophilic and hydrophobic
surfaces. Microbiology. 2008;154(10):3122–33. PMID:
18832318. https://doi.org/10.1099/mic.0.2008/018622-0.
9. van Loosdrecht MC, Lyklema J, Norde W, Zehnder AJB.
Bacterial adhesion: a physicochemical approach. Microb
Ecol. 1989;17(1):1–15. PMID: 24197119. https://doi.
org/10.1007/BF02025589.
10. van Loosdrecht MC, Lyklema J, Norde W, Schraa G,
Zehnder AJ. Electrophoretic mobility and hydrophobicity as
a measured to predict the initial steps of bacterial adhesion.
Appl Environ Microbiol. 1987;53(8):1898–901. PMCID:
PMC204021.
11. dela Fuente JM, Penadés S. Glyconanoparticles: types,
synthesis and applications in glycoscience, biomedicine and
material science. Biochim Biophys Acta. 2006;1760(4):636–
51. PMID: 16529864. https://doi.org/10.1016/j.bbagen.
2005.12.001.

Disclaimer: This journal is OPEN ACCESS, providing immediate access to its content on the principle that making research freely available to the
public supports a greater global exchange of knowledge. As a requirement for submission to the PJP, all authors have accomplished an AUTHOR
FORM, which declares that the ICMJE criteria for authorship have been met by each author listed, that the article represents original material,
has not been published, accepted for publication in other journals, or concurrently submitted to other journals, and that all funding and conflicts
of interest have been declared. Consent forms have been secured for the publication of information about patients or cases; otherwise, authors
have declared that all means have been exhausted for securing consent.

http://philippinejournalofpathology.org | Vol. 2 No. 2 November 2017

* This advertisement is a complimentary service of the PJP for member societies/organizations.
 Instructions to Authors
The Philippine Journal of Pathology (PJP) is an open-access, peer-reviewed, English language, medical and health
science journal that is published continuously online and semi-annually in print by the Philippine Society of Pathologists,
Inc. (PSP, Inc). All manuscripts must be submitted through the PJP Official Website (Open Journal Systems)
(http://philippinejournalofpathology.org). All other correspondences and other editorial matters should be sent via
electronic mail to philippinepathologyjournal@gmail.com.
Articles and any other material published in the PJP represent the work of the author(s) and do not reflect the opinions of
the Editors or the Publisher. Articles that do not subscribe to the Instructions to Authors shall be promptly returned.
ARTICLE SECTIONS
The PJP welcomes manuscripts on all aspects of
pathology and laboratory medicine, to include
cytology, histopathology, autopsy, forensic pathology,
clinical chemistry, clinical microscopy, medical
microbiology, parasitology, immunology, hematology,
blood banking, medical technology, laboratory
diagnostics, laboratory biosafety and biosecurity,
laboratory management, and quality assurance.
The PJP accepts original articles, review articles, case
reports, feature articles, brief communications, autopsy
cases, editorials, or letters to the Editor.
Original articles
The research must have received institutional review board
approval that is explicitly stated in the methodology. The
abstract should contain no more than 200 words with a
structured format consisting of the objective/s, methodology,
results and conclusion. A manuscript for original articles should
not exceed 25 typewritten pages (including tables, figures,
illustrations and maximum of 30 references) or 6000 words.
Reviews
Review articles, both solicited and unsolicited, provide
information on the “state of the art.” PJP reviews not only
summarize current understanding of a particular topic but
also critically appraise relevant literature and data sources,
describe significant gaps in the research, and future
directions. The abstract should be from 50 to 75 words and
should not be structured. A manuscript for reviews should not
exceed 15 typewritten pages (including tables, figures,
illustrations and maximum of 50 references) or 4000 words.
Case Reports
This type of article pertains to single or multiple reports of well-
characterized cases that are highly unusual, novel, or rare; or
with a unique or variant presentation, evolution or course; or
that represent an unexpected or uncommon association of
two or more diseases or disorders that may represent a
previously unsuspected causal relationship; or that are
underreported in the literature. The abstract should be from
50 to 75 words and should not be structured. A manuscript for
case reports should not exceed 10 typewritten pages
(including tables, figures, illustrations and maximum of 15
references) or 3000 words.
Feature articles
The PJP may feature articles, either as part of an issue theme
or a special topic on pathology by a local or international
expert or authority. The abstract should be from 50 to 75 words
and should not be structured. A manuscript for feature articles
should not exceed 25 typewritten pages (including tables,
figures, illustrations and maximum of 30 references) or 6000
words.
Autopsy Vault
The PJP highly welcomes articles on autopsy protocols of
cases. The article must include a summary presentation of the
history, evaluation and work-up, clinical course of a case,
followed by the autopsy procedure performed, gross and
http://philippinejournalofpathology.org | Vol. 2 No. 2 November 2017
microscopic findings, discussion, learning points and
conclusion. The PJP recognizes the instructional and
educational value of articles under this section. The abstract
should be from 50 to 75 words and should not be structured.
A manuscript for the Autopsy Vault should not exceed 25
typewritten pages (including tables, figures, illustrations and
maximum of 30 references) or 6000 words.
Images in Pathology
Images of unique, interesting, or highly educational cases
encountered in hematology, cytology, histopathology, or
medical microbiology, may be submitted under this section,
and may include photomicrographs, gross pictures, machine
read-outs, among others. A brief history, the photograph(s)
and short discussion of the case. No abstract is required. A
manuscript for Images in Pathology should not exceed 500
words, with maximum of 10 references. This is distinct from the
Case Report which is a full write up.
Brief Communications
Brief Communications are short reports intended to either
extend or expound on previously published research or
present new and significant findings which may have a major
impact in current practice. If the former, authors must
acknowledge and cite the research which they are building
upon. The abstract should be from 50 to 75 words and should
not be structured. A manuscript for brief communications
should not exceed 5 typewritten pages (including tables,
figures, illustrations and maximum of 10 references) or 1500
words.
Editorials
Recognized leaders in the field of pathology and laboratory
medicine may be invited by the Editor-in-Chief/Editorial Board
to present their scientific opinion and views of a particular
topic within the context of an issue theme or issues on
scholarly publication. No abstract or keywords necessary.
Letters to the Editor
PJP welcomes feedback and comments on previously
published articles in the form of Letters to the Editor.
No abstract or keywords are necessary. A Letter to the Editor
must not exceed 2 typewritten pages or 500 words.
Special Announcements
Special announcements may include upcoming conventions,
seminars or conferences relevant to pathology. The Editors
shall deliberate and decide on acceptance and publication
of special announcements. Please coordinate with the
Editorial Coordinator for any request for special
announcements.
COVER LETTER
A cover letter must accompany each manuscript citing
the complete title of the manuscript, the list of authors
(complete names, position/designation and institutional
affiliations), with one (1) author clearly designated as
corresponding author, providing his/her complete
institutional mailing address, institutional telephone/fax
number, and work e-mail address. The PJP Cover Letter
Template must be used.
Instruction to Authors
PJP AUTHOR FORM
For submissions to the PJP to be accepted, all authors
must read and sign the PJP Author Form consisting of:
(1) the Authorship Certification, (2) the Author Declaration,
(3) the Statement of Copyright Transfer, and (4) the
Statement of Disclosure of Conflicts of Interest. The
completely accomplished PJP Author Form shall be
scanned and submitted along with the manuscript.
No manuscript shall be received without the PJP Author
Form.
GENERAL FORMATTING GUIDELINES
 Authors must use the standard PJP templates for
each type of manuscript. These templates are
aligned with the most current versions of the
EQuaToR Network guidelines and checklists
(http://equatornetwork.org).
 The manuscript should be encoded on the template
using Microsoft Word (2007 version or later version),
single-spaced, 2.54 cm margins throughout, on A4
size paper. Preferred fonts may include Century
Gothic (template default), Times New Roman, or
Arial.
 The manuscript should be arranged in sequence as
follows: (1) Title Page, (2) Abstract, (3) Text, (4)
References, (5) Tables, and (6) Figures & Illustrations.
 All the sheets of the manuscript should be labelled
with the page number (in Hindu-Arabic Numerals)
printed on the upper right corner.
 References should pertain directly to the work being
reported. Within the text, references should be
indicated using Hindu-Arabic numerals in
superscripts.
SPECIFIC FORMATTING GUIDELINES
Title and Authors
 The title should be as concise as possible.
 A running title (less than 50 characters) shall also be
required. The running title is the abbreviated version
of the title that will be placed in the header. The
running title should capture the essence of the
manuscript title.
 The full name of the author(s) directly affiliated with
the work should be included (First name, Middle initial
and Last name). The order of authorship shall be the
prerogative of the author(s).
 There are 4 criteria for authorship (ICMJE
recommendations). These are captured in the PJP
Author Form.
o Substantial contributions to the conception or design of
the work; or the acquisition, analysis, or interpretation of
data for the work; AND
o Drafting the work or revising it critically for important
intellectual content; AND
o Final approval of the version to be published; AND
o Agreement to be accountable for all aspects of the work
in ensuring that questions related to the accuracy or
integrity of any part of the work are appropriately
investigated and resolved.
 The highest educational attainment or title of the
authors should be included as an attachment
whenever appropriate (MD, PhD, et cetera).
 Name and location of no more than one (1)
institutional affiliation per author may be included.
 If the paper has been presented in a scientific forum
or convention, a note should be provided indicating
the name of the forum or convention, location
(country), and date of its presentation.
http://philippinejournalofpathology.org | Vol. 2 No. 2 November 2017
Philippine Journal of Pathology | 52
Abstract
 For manuscripts under the “Original Article” section:
the abstract should contain no more than 300 words
with a structured format consisting of the following
standard headings: objective/s, methodology, results
and conclusion.
 For manuscripts under the “Feature Article,” “Review
Article,” “Case Report,” “Brief Communications,” and
“Autopsy Vault” sections: the abstract should be no
more than 200 words and need not be structured.
 Letters to the Editor and editorials do not require an
abstract.
Keywords
At least three (3) keywords but no more than six (6),
preferably using terms from the Medical Subject
Headings (MeSH) list of Index Medicus, should be listed
horizontally under the abstract for cross-indexing of the
article.
Text
 The text should be organized consecutively as
follows: Introduction, Methodology, Results
and Discussion, Conclusion (IMRaD format), followed
by Disclosures, Acknowledgments and References.
 All references, tables, figures and illustrations should
be cited in the text, in numerical order.
 All abbreviations should be spelled out once (the first
time they are mentioned in the text) followed by the
abbreviation enclosed in parentheses. The same
abbreviation may then be used subsequently instead
of the full names.
 All measurements and weights should be in System
International (SI) units.
 Under Methodology, information should be provided
on institutional review board/ethics committee
approval or informed consent taking (if appropriate).
 Acknowledgements to individuals/groups of persons,
or institution/s who have contributed to the
manuscript but did not qualify as authors based on
the ICMJE criteria, should be included at the end of
the text just before the references. Grants and
subsidies from government or private institutions
should also be acknowledged.
References
 References in the text should be identified by Hindu-
Arabic Numerals in superscript on the same line as the
preceding sentence.
 References should be numbered consecutively in the
order by which they are mentioned in the text. They
should not be alphabetized.
 All references should provide inclusive page
numbers.
 Journal abbreviations should conform to those used
in PubMed.
 A maximum of six authors per article can be
cited; beyond that, name the first three and add “et
al.”
 The style/punctuation approved by PJP conforms to
that recommended by the International Committee
of Medical Journal Editors (ICMJE) available
at http://www.icmje.org. Examples are shown below:
One to Six Authors
Krause RM. The origin of plagues: old and new. Science.
1992;257:1073-1078.
Instruction to Authors Philippine Journal of Pathology | 53

Mokdad AH, Bowman BA, Ford ES, Vinicor F, Marks JS,
Koplan JP. The continuing epidemics of obesity and
diabetes in the US. JAMA. 2001;286(10):1195-1200.
More than Six Authors
Rhynes VK, McDonald JC, Gelder FB, et al. Soluble HLA
class I in the serum of transplant recipients. Ann Surg.
1993; 217 (5): 485–9.
Authors Representing a Group
Moher D, Schulz KF, Altman D; for the CONSORT Group.
The CONSORT statement: revised recommendations for
improving the quality of reports of parallel-group
randomized trials. JAMA. 2001;285(15):1987-1991.
Book
Byrne, DW. Publishing your medical research paper:
What they don't teach in medical school. Baltimore:
Williams & Wilkins, 1998.
World Wide Web
Barry JM. The site of origin of the 1918 influenza
pandemic and its public health implications.
[Commentary]. JTranslational Med. January 20,
2004;2(3):1-4. http://www.translational-
medicine.com/content/2/1/3. Accessed November
18, 2005.
Tables
 Cite all tables consecutively in the text and number
them accordingly.
 Create tables preferably using Microsoft Excel with
one table per worksheet.
 Tables should not be saved as image files.
 The content of tables should include a table number
(Hindu-Arabic) and title in capital letters above the
table.
 Place explanatory notes and legends, as well as
definitions of abbreviations used below the table. For
legends, use small letters (i.e., a, b, c, d).
 Each table must be self-explanatory, being a
supplement rather than a duplicate of information in
the text.
 Up to a maximum of five (5) tables are allowed.
Figures and Graphs
 Figures or graphs should be identified by Hindu-
Arabic Numeral/s with titles and explanations
underneath.
 The numbers should correspond to the order in which
the figures/graphs occur in the text.
 Figures & graphs should not be saved as image files.
For illustrations and photographs, see next section.
 Provide a title and brief caption for each figure or
graph. Caption should not be longer than 15-20
words.
 All identifying data of the subject/s or patient/s under
study such as name or case numbers, should be
removed.
 Up to a maximum of five (5) figures and graphs are
allowed.
Illustrations and Photographs
 Where appropriate, all illustrations/photographic
images should be at least 800 x 600 dpi and
submitted as image files (preferably as .png, .jpeg or
.gif files).
 For photomicrographs, the stain used (e.g. H & E) and
magnification (e.g. X400) should be included in the
description.
 Computer-generated illustrations which are not
suited for reproduction should be professionally
redrawn or printed on good quality laser
printers. Photocopies are not acceptable.
 All letterings for illustration should be of adequate size
to be readable even after size reduction.
 Place explanatory notes and legends, as well as
definitions of abbreviations used below the
illustration/photograph.
 Up to a maximum of five (5) illustrations/ photographs
are allowed.
N.B.: For tables, figures, graphs, illustrations and photographs
that have been previously published in another journal or book,
a note must be placed under the specific item stating that such
has been adapted or lifted from the original publication.
This should also be referenced in the References portion.

EDITORIAL PROCESS (Figure 1)

 The Editorial Coordinator shall review each submission to check if it has met aforementioned criteria and provide
feedback to the author within 24 hours.
 Once complete submission is acknowledged, the manuscript undergoes Editorial Board Deliberation to decide
whether it shall be considered or not for publication in the journal. Within five (5) working days, authors shall be notified
through e-mail that their manuscript either (a) has been sent to referees for peer-review or (b) has been declined
without review.
 The PJP implements a strict double blind peer review policy. For manuscripts that are reviewed, authors can expect
a decision within ten (10) working days from editorial deliberation. There may be instances when decisions can take
longer: in such cases, the Editorial Coordinator shall inform the authors.
 The editorial decision for manuscripts shall be one of the following: (a) acceptance without further revision, (b)
acceptance with minor revisions, (c) major manuscript revision and resubmission, or (d) non-acceptance.
 Accepted manuscripts are subject to editorial modifications to bring them in conformity with the style of the journal.
Copyediting and layout shall take five (5) working days, after which the manuscript is published online.
 All online articles from the last six (6) months shall be collated and published in print as a full issue.

EDITORIAL OFFICE CONTACT INFORMATION:

The Philippine Journal of Pathology
2nd Floor, Laboratory Research Division
Research Institute for Tropical Medicine
Filinvest Corporate City
Alabang, Muntinlupa City 1781
Editor-in-Chief: Amado O. Tandoc III, MD, FPSP
Telefax number: (+632)8097120
E-mail: philippinepathologyjournal@gmail.com
Website: http://philippinejournalofpathology.org

http://philippinejournalofpathology.org | Vol. 2 No. 2 November 2017

Instruction to Authors Philippine Journal of Pathology | 54

24 hours upon submission

5 working days
10 working days
5-10 working days
5 working days upon
re-submission

Figure 1. Editorial Process Flow.

http://philippinejournalofpathology.org | Vol. 2 No. 2 November 2017

 PJP AUTHOR FORM

For submissions to the PJP to be accepted, all authors must read and sign this PJP Author Form consisting of: (1) the
Authorship Certification, (2) the Author Declaration, (3) the Statement of Copyright Transfer, and (4) the Statement of
Disclosure of Conflicts of Interest. The completely accomplished PJP Author Form shall be scanned and submitted along
with the manuscript. No manuscript shall be received without the PJP Author Form.

COMPLETE TITLE OF MANUSCRIPT

________________________________________________________________________________________________________________________
________________________________________________________________________________________________________________________
________________________________________________________________________________________________________________________
AUTHORSHIP CERTIFICATION
In consideration of our submission to the Philippine Journal of Pathology (PJP), the undersigned author(s) of the
manuscript hereby certify, that all of us have actively and sufficiently participated in (1) the conception or design of
the work, the acquisition, analysis and interpretation of data for the work; AND (2)drafting the work, revising it critically
for important intellectual content; AND (3) that we are all responsible for the final approval of the version to be
published; AND (4) we all agree to be accountable for all aspects of the work in ensuring that questions related to
the accuracy or integrity of any part of the work are appropriately investigated and resolved.
AUTHOR DECLARATIONS
The undersigned author(s) of the manuscript hereby certify, that the submitted manuscript represents original,
exclusive and unpublished material. It is not under simultaneous consideration for publication elsewhere.
Furthermore, it will not be submitted for publication in another journal, until a decision is conveyed regarding its
acceptability for publication in the PJP.
The undersigned hereby certify, that the study on which the manuscript is based had conformed to ethical standards
and/or had been reviewed by the appropriate ethics committee.
The undersigned likewise hereby certify that the article had written/informed consent for publication from involved
subjects (for case report/series only) and that in case the involved subject/s can no longer be contacted (i.e.,
retrospective studies, no contact information, et cetera), all means have been undertaken by the author(s) to obtain
the consent.
AUTHOR STATEMENT OF COPYRIGHT TRANSFER
Furthermore, the undersigned author(s) recognize that the PJP is an OPEN-ACCESS publication which licenses all
published manuscripts to be used for building on and expanding knowledge, for non-commercial purposes, so long
as the manuscripts are properly cited and recognized (Attribution-NonCommercial-ShareAlike 4.0 International
Creative Commons License [CC BY-NC-SA 4.0]. The undersigned author(s) hereby, transfer/assign or otherwise convey
all copyright ownership of the manuscript to the PJP.
AUTHOR DISCLOSURE OF CONFLICTS OF INTEREST
In order to ensure scientific objectivity and independence, the PJP requires all authors to make a full disclosure of areas of
potential conflict of interest. Such disclosure will indicate whether the person and/or his/her immediate family has any
financial relationship with pharmaceutical companies, medical equipment manufacturers, biomedical device
manufacturers, or any companies with significant involvement in the field of health care. Place all disclosures in the table
below. An extra form may be used if needed.
Examples of disclosures include but not limited to: ownership, employment, research support (including provision of equipment or
materials), involvement as speaker, consultant, or any other financial relationship or arrangement with manufacturers, companies or
suppliers. With respect to any relationships identified, author(s) must provide sufficiently detailed information to permit assessment of the
significance of the potential conflict of interest (for example, the amount of money involved and/or the identification of any value of
goods and services).
AUTHOR NAME RELATIONSHIP MANUFACTURER/ SUPPLIER/ COMPANY

All disclosures shall remain confidential during the review process and the nature of any final printed disclosure will be
determined by the PJP. If there are no conflicts of interest to disclose, the author(s) should check the box below.

I/We do not have any conflicts of interest to disclose.

Author Name Signature Date

(MM/DD/YYYY)

______________________________________________________ ________________________ ___________________________

______________________________________________________ ________________________ ___________________________

______________________________________________________ ________________________ ___________________________

______________________________________________________ ________________________ ___________________________

______________________________________________________ ________________________ ___________________________

http://philippinejournalofpathology.org | Vol. 2 No. 2 November 2017

 PATIENT CONSENT FORM
For case report and image submissions to the PJP to be accepted, the author/s must ensure that patients or
patients’ legal guardian/relative have provided informed consent to publish information about them in the journal.
The completely accomplished PJP Patient Consent Form shall be scanned and submitted along with the manuscript.
No case report and image shall be received without the PJP Consent Form.

Name of person described in article or shown in photograph:_______________________

__________________________________________________________________________________
Subject matter of photograph or article (brief description):
__________________________________________________________________________________
__________________________________________________________________________________
__________________________________________________________________________________
(The Subject matter of the photograph or article is hereafter termed as the “INFORMATION.”)
Title of article:
__________________________________________________________________________________
__________________________________________________________________________________

I, _________________________________________ , give my consent for this information

[please insert your full name]
about MYSELF/MY CHILD OR WARD/MY RELATIVE relating to the subject matter
[please underline correct description]
above to appear in the Philippine Journal of Pathology (PJP) subject to its

publication policies and ethical standards.

I have seen and read the material to be submitted to the PJP and thoroughly understand the
following:
• The Information will be published in the PJP without my name. It is the obligation of the PJP to make
all attempts, within its reasonable jurisdiction and authority, to ensure my anonymity.
• The Information may also be placed on the PJP website.
• The PJP shall not allow the Information to be used for advertising or packaging or to be used out of
context (i.e., used to accompany an entirely different article or topic).
• I can withdraw my consent at any time before publication, but once the Information has already
been sent to press, it is my understanding that it will not be possible to revoke the consent.

Signed:__________________________________ Date:______________________
[signature over complete name]

Witness:
Signed:__________________________________ Date:______________________
[signature over complete name]

http://philippinejournalofpathology.org | Vol. 2 No. 2 November 2017

 PEER REVIEWERS

Bernadette G. Reyna Asuncion, MD

National University of Singapore

Jose M. Carnate Jr., MD

University of the Philippines-College of Medicine

Ann Margaret V. Chang, MD

St. Luke’s Medical Center-Quezon City

Jundelle Romulo K. Jalique, RN, MSPH,

Biostatistics(c)
Philippine Heart Center

Raymundo W. Lo, MD
St. Luke’s Medical Center-Quezon City

Frederick R. Llanera, MD
Philippine Heart Center

Paulo Giovanni L. Mendoza, MD

Makati Medical Center

Prof. Emeritus Florinia E. Merca, PhD

University of the Philippines-Los Baños

Minnie Jane A. Pineda, MD

Philippine Heart Center

Glenda Lyn Y. Pua, MD

St. Luke’s Medical Center-Quezon City

Ivy A. Rosales, MD
Massachusetts General Hospital, USA

Amado O. Tandoc III, MD

Research Institute for Tropical Medicine

Enrico D. Tangco, MD
Asian Hospital and Medical Center

Merva Soluk Tekkeşin, DDS, PhD

Institute of Oncology, Istanbul University, Turkey

Felipe S. Templo Jr., MD

Philippine Heart Center

http://philippinejournalofpathology.org | Vol. 2 No. 2 November 2017

  Online and Printed
 100% Open Access
 Peer Reviewed
 Continuous
Publication model
 No Author
Processing Fees
 Streamlined process
from submission
to publication
 24/7 web-based
technical support

GET PUBLISHED IN THE NEW

PHILIPPINE JOURNAL OF PATHOLOGY!
The Philippine Journal of Pathology (PJP) is an open-access, peer-reviewed, English
language, medical science journal published by the Philippine Society of Pathologists,
Inc. It shall serve as the official platform for publication of high quality original articles,
case reports or series, feature articles, and editorials covering topics on clinical and
anatomic pathology, laboratory medicine and medical technology, diagnostics,
laboratory biosafety and biosecurity, as well as laboratory quality assurance.

The journal's primary target audience are laboratorians, diagnosticians, laboratory

managers, pathologists, medical technologists, and all other medical and scientific
disciplines interfacing with the laboratory. For instructions and more information, visit
our Official Website at:

http://philippinejournalofpathology.org
 Philippine Journal of Pathology
Committee on Publications | Philippine Society of Pathologists, Inc.
E-mail: philippinejournalofpathology@gmail.com
Website: http://philippinejournalofpathology.org
 Volume 25 Number 1 October 2017 Issue

PRESIDENT’S CORNER
Honoring the Past
Roberto C. Tanchanco, MD

EDITORIAL
Philippine Journal of Nephrology Online
Pelagio L. Esmaquel Jr., MD

ORIGINAL ARTICLES
Peritoneal Equilibration Test (PET) Analysis among Filipino Children on Chronic Peritoneal Dialysis at National
Kidney & Transplant Institute: A Cross-Sectional Study
Elmer Kent A. Lopez, MD, Malou Saga-Valdez, MD, Zenaida L. Antonio, MD, Ofelia R. De Leon, MD, Ma.
Angeles G. Marbella, MD, Violeta M. Valderrama, MD, Ma. Lorna Lourdes L. Simangan, MD

A Comparison of Three Prediction Models for Acute Kidney Injury Requiring Renal Replacement Therapy after
Coronary Artery Bypass Graft Surgery
Ailene R. Buelva-Martin, MD and Oscar D. Naidas, MD

CASE REPORT
Cerebral Salt Wasting Syndrome in a Patient with Subarachnoid Hemorrhage: A Case Report
Renz Michael F. Pasilan, MD and Pelagio L. Esmaquel Jr., MD

PERSPECTIVES IN NEPHROLOGY
An Opinion on Using and Doing Local Health Research in the Philippines
Melvin R. Marcial, MD

Official Publication of the Philippine Society of Nephrology, Inc.

 EDITORIAL TEAM

Editor-in-Chief Pelagio L. Esmaquel Jr., MD

Associate Editor Ma. Norma V. Zamora, MD
Section Editor Margarette Ruth L. Bernardo, MD
Technical Reviewer Jundelle Romulo K. Jalique, RN, MSPH
Biostatistics (c)
Copyeditor Amado O. Tandoc III, MD
Editorial Coordinator Melissa O. Tandoc, RN

PUBLISHER

Philippine Society of Nephrology Officers & Board of Trustees 2017

President Roberto C. Tanchanco, MD

Vice-President Helen T. Ocdol, MD
Secretary Elizabeth Angelica L. Roasa, MD
Treasurer Elizabeth S. Montemayor, MD
Board Members Noel M. Castillo, MD
Ronald S Perez, MD
Maalidin B. Biruar, MD
Gingerlita Alla-Samonte, MD
Ma. Daylinda Aniceto-Chung, MD
Immediate Past President Victor S. Doctor, MD
 Volume 25 No. 1 October 2017

TABLE OF CONTENTS

PRESIDENT’S CORNER
Honoring the Past 2
Roberto C. Tanchanco, MD

EDITORIAL
Philippine Journal of Nephrology Online 4
Pelagio L. Esmaquel Jr., MD

ORIGINAL ARTICLES
Peritoneal Equilibration Test (PET) Analysis among Filipino Children on Chronic Peritoneal 6
Dialysis at National Kidney & Transplant Institute: A Cross-Sectional Study
Elmer Kent A. Lopez, MD, Malou Saga-Valdez, MD, Zenaida L. Antonio, MD, Ofelia R. De
Leon, MD, Ma. Angeles G. Marbella, MD, Violeta M. Valderrama, MD, Ma. Lorna Lourdes
L. Simangan, MD

A Comparison of Three Prediction Models for Acute Kidney Injury Requiring Renal 13
Replacement Therapy after Coronary Artery Bypass Graft Surgery
Ailene R. Buelva-Martin, MD and Oscar D. Naidas, MD

CASE REPORT
Cerebral Salt Wasting Syndrome in a Patient with Subarachnoid Hemorrhage: A Case
20
Report
Renz Michael F. Pasilan, MD and Pelagio L. Esmaquel Jr., MD

PERSPECTIVES IN NEPHROLOGY
An Opinion on Using and Doing Local Health Research in the Philippines 26
Melvin R. Marcial, MD

Author Certification Form 31

Information for Authors 33
 President’s Corner

Roberto C. Tanchanco, MD, Honoring the Past

FPCP, FPSN, MBA

President, Philippine Society Why publish? Why revive the Philippine Journal of
of Nephrology
Nephrology (PJN)? This must be one of the most
Associate Professor, Ateneo
School of Medicine & Public overwhelming question that comes to mind given the
Health already existing and steadily increasing number of
Head, Section of Nephrology, publications which, according to the International
Department of Medicine, The Association of Scientific Technical and Medical Publishers is
Medical City estimated at 28,100 active scholarly peer-reviewed journals
Consultant Director, Kidney
in the late 2014 (plus 6450 non-English language journals),
Transplantation Program, The
collectively publishing about 2.5 million articles a year. And
Medical City
this has been steadily increasing at a rate of about 3 – 3.5%
per year.1 Locally, HERDIN (Health Research and
This graphic representation of theInformation
Development “Glomerulus”Network)
(artist: unknown) graced
the national the
health
cover of the print issue of the Philippine Journal of Nephrology only once,
research repository of the Philippines lists a total of 71 the
maiden issue Volume 1 No. 1 1986.
indexed journals, of which 22 are peer-reviewed.2

To the great majority of the scientific publishing world, the

The first issue of persuasive reason
the Philippine to publish
Journal probably liescame
of Nephrology in theout estimated
in the
1
$10 billion-dollar annual worth of revenue. But to the
first quarter of 1986, during the presidency of Dr. Adriano G. de la Paz,
Philippine Society of Nephrology Inc. (PSN) the answer lies
and with Dr. Filoteo A. Alano as the founding editor in chief. Both men
in the very core of its existence. The very first line of the PSN
wrote of the needvision
for astates
scientific publication made by the society itself
its “… adherence to the highest standard of
in order to pursueexcellence
the mission in of the Philippine
training Societyinof the
and research Nephrology
field of
Inc. (PSN) to advance the science
nephrology.” The of nephrology,
same principle isand
echoedto fulfill
in the thevery
dream
first
_________ of its members toline“have a vehicle to share their works and
of its stated mission “…promotes and disseminates ideas with
Correspondence: others.” current knowledge and information in nephrology.” This is
Roberto C. Tanchanco, MD, very true and current now as it was then when the same
FPCP, FPSN, MBA There were eight articles in that
opinion was maidenbyissue,
expressed and itA.isAlano
Dr. Filoteo rather interesting
in the very first
Medical Arts Tower 1004, The that the topics written then
editorial arePhilippine
of the still veryJournal
relevant today: Twenty-one
of Nephrology in 1986.3
Medical City, Ortigas Avenue, years before the recent tragic hazing death of a University of Sto. Tomas
Pasig City Publication is an integral part of research activity; writing
Tel. No.: (632)6356789 local (UST) Law freshman, Dr. Melchor M. Chan, Dr. Oscar D. Naidas, Dr.
and disseminating the knowledge gained from the
5120 Libertad Nazareno-Rosales, Dr. Alberto Daysog and, Dr. Aurora
systematic process of answering a scientific question is part
Fax No.: (632)7063203 Padolina-Perez ofofthea Renal Unit of the Sto. Tomas University Hospital
E-mail: obettmd@gmail.com continuum that enriches the body of knowledge.
reported on the high incidence
However, of acuteofrenal
the explosion failurewith
information in healthy college
the introduction
students who underwent
of new andfraternity hazing;
ever changing Dr. Ma. Linda
technologies Tantoco
and media and
demand
Dr. Filoteo A. Alano
thatwrote a review
publication muston Adult
also keepPolycystic Kidney
up with these Disease
changes and
Creative Commons License
(ADPKD); and Dr. trends.
PH Feng oneisofnow
There theainternational
compelling needcontributing editors
for publishers and
Attribution-Noncommercial-Share journals
wrote about the Asian to provide
connection accessnephritis.
of lupus to the recent and relevant
Alike 4.0 [CC BY-NC-SA 4.0]. researches that adheres to the standard of ethics in research
and publication. These are the same
Tanchanco RC

2 | www.pjnonline.con | Vol. 25 No. 1 October 2017

 Tanchanco RC
This, I believe, is the essence of PSN launching its own
journal of nephrology, the burning desire of our
founders: our desire to be relevant, to remain relevant,
and to leave a lasting legacy of relevance. What we
hope to impart, and what we hope to leave behind,
when we publish our own peer reviewed journal on a
regular basis, is a record of our contribution to the
science and the history of nephrology, our own
thoughts and experiences that enrich the global body
of knowledge by documenting our own hypotheses,
observations, and analyses.
It has been quite a struggle for the journal to maintain
its operation, given that over the past 21 years we
have only managed to publish 14 issues. We look at
this number squarely in the face, and we declare with
grit and determination that we shall push forward and
get this journal moving again. As we relaunch this
journal, we draw inspiration from the scholarly spirit of
the founders of our journal, and we entrust our new
editor in chief, Dr. Pelagio L. Esmaquel, Jr., and his
team, with the task of leading all of us on this journey
of realizing the global recognition of the Philippine
Journal of Nephrology.
Indeed, by pursuing the future of our journal, we truly
honor our past.
Vol. 25 No. 1 October 2017 | www.pjnonline.com | 3
 Editorial

Pelagio L. Esmaquel Jr., MD Philippine Journal of Nephrology Online

Editor-in-Chief
Philippine Journal of Why publish? Why Journal
revive oftheNephrology
Philippine (PJN)?
JournalThis
of
Why publish? Why revive the Philippine
Nephrology Online
Nephrology (PJN)? This must be one
must be one of the most overwhelming question that comes to mind given of the most
the already existing overwhelming question that
and steadily increasing comes
number to mind given
of publications the
which,
already existing and steadily increasing number of
according to the International Association of Scientific Technical and
publications which, according to the International
Medical Publishers is estimated at 28,100 active scholarly peer-reviewed
Association of Scientific Technical and Medical Publishers is
journals in the late 2014 (plus 6450 non-English language journals),
estimated at 28,100 active scholarly peer-reviewed journals
collectively publishing about
in the late 2.5
2014million articles
(plus 6450 a year. And
non-English this has
language been
journals),
1
steadily increasing at a rate of about 3 – 3.5% per year. Locally, HERDIN
collectively publishing about 2.5 million articles a year. And
(Health Research and this Development Information
has been steadily increasing atNetwork) the national
a rate of about 3 – 3.5%
1
health research repository
per year. of the Philippines
Locally, lists (Health
HERDIN a total of 71 indexed
Research and
journals, of which 22Development Information Network) the national health
are peer-reviewed. 2

research repository of the Philippines lists a total of 71

To the great majority of the
indexed scientific
journals, publishing
of which world, the persuasive
22 are peer-reviewed. 2

reason to publish probably lies in the estimated $10 billion-dollar annual

To the great majority of the scientific publishing world, the
worth of revenue.1 But to the Philippine Society of Nephrology Inc. (PSN)
persuasive reason to publish probably lies in the estimated
the answer lies in the very core of its existence. The very first1 line of the
$10 billion-dollar annual worth of revenue. But to the
PSN vision states itsPhilippine
“… adherence to the highest standard of excellence in
Society of Nephrology Inc. (PSN) the answer lies
training and research in very
in the the core
fieldofofitsnephrology.”
existence. TheThe
verysame principle
first line is
of the PSN
echoed in the very firststates
vision line its
of “…
its adherence
stated mission “…promotes
to the highest standardand of
disseminates current knowledge and information in nephrology.”
excellence in training and research in the field of This is
_________ very true and current now as itThe
nephrology.” was samethen when isthe
principle sameinopinion
echoed the verywas
first
Correspondence:
line of
expressed by Dr. Filoteo its stated
A. Alano in themission “…promotes
very first and
editorial of thedisseminates
Philippine
Pelagio L. Esmaquel Jr., MD
2406 One San Miguel Avenue current
Journal of Nephrology in 1986. knowledge
3 and information in nephrology.” This is
Condominium, San Miguel very true and current now as it was then when the same
Ave. cor. Shaw Blvd., Ortigas Publication is an opinion
integral
waspart of by
expressed research
Dr. Filoteo activity; writing
A. Alano in the veryand
first
Center, Pasig City, Philippines disseminating the editorial
knowledgeof the Philippine
gained fromJournal
the of in 1986.3of
Nephrologyprocess
systematic
Tel. Nos. :(632) 6871-1198,
answering a scientific question is part of a continuum that enriches the
(632) 687-1187 Publication is an integral part of research activity; writing
E-mail: pheljrmd@gmail.com body of knowledge. However, the explosion of information with the
and disseminating the knowledge gained from the
ORCiD ID: introduction of newsystematic
and everprocess
changing technologies
of answering and media
a scientific demand
question is part
http://orcid.org/0000-0002- that publication mustof also keep up with
a continuum that these
enricheschanges and trends.
the body There
of knowledge.
6520-2514
is now a compellingHowever,
need forthepublishers
explosionand journals towith
of information provide access to
the introduction
the recent and relevant researches
of new that adheres
and ever changing to the standard
technologies and mediaofdemand
ethics
that publication
in research and publication. Thesemust alsosame
are the keep up with these
necessary changes and
requirements
Creative Commons License
for PJN to stay relevant with the trends defining the medical landscapeand
trends. There is now a compelling need for publishers of
Attribution-Noncommercial-Share journals to provide access to the
research today: research management, big data analytics, solutionrecent and relevant
Alike 4.0 [CC BY-NC-SA 4.0]. researches that adheres to the standard of ethics in research
contents and reuse of contents.1,4
and publication. These are the PL
Esmaquel same

4 | www.pjnonline.con | Vol. 25 No. 1 October 2017

 Esmaquel PL
Online publication has increased tremendously the
production and reach of scholarly works. This has been
the trend that served the need of the research
landscape for the past 2 decades and will continue to
serve in the years to come. Different models of online
publication exist, of these about 10,046 are published
online using fully open access model as listed in the
Directory of Open Access Journals.5 Fully open access
model is considered the “Gold” model wherein the
final published citable article is available immediately
and readily at the journal’s website without
restrictions to its access and; its use and reuse is
likewise free of restriction subject to proper citation
and attribution.1
Quality and trust in published data has always been
anchored on peer-review process and despite its
perceived shortcomings and limitations is still
considered fundamental to research communication.
Different models of peer-review process are also
available. The broad category of models includes:
blinded (either single-blind where the reviewer is
aware of who is the author or double-blind wherein
both the author and the reviewers are not aware of
each other’s identity) and; open peer-review, where
both the author and the reviewers are aware of each
other’s identity. There is also a trend in peer-review
and selection process to consider the “soundness
rather than the significance” of the articles to be
published; articles are selected on the basis that the
research was conducted soundly rather on the
subjective relevance, significance or impact of the
research.1 PJN would like to strike a balance and have
adopted a single-blind peer review process and in
selecting papers based not just on the soundness of the
research but also on its significance and relevance to
our local setting. This will also in a way support the
various advocacy that PSN would like to embrace and
embark on.
PSN is herein reviving the Philippine Journal of
Nephrology, as the official tagline states: PJN is an
open access, peer-reviewed, English-language, medical
science journal now on its new online platform.
This new online publication catalogued as Volume 25
Issue number 1 comes after a 7-year hiatus; the last
print issue was published in 2009 under the editorship
of Dr. Luis V. Limchiu. PJN endeavors as well to make
available online all the previous print issues, the
digitized copies are uploaded and can be retrieved at
the archive section of our website
http://www.pjnonline.com And to correct the
catalogue numbering, the last Volume issued in 2009
should hence be referred as number 24 instead of 23 it
has been mistakenly tagged.
REFERENCES
1. Ware M, Mabe M. The STM report: an overview of
scientific and scholarly journal publishing 4th
edition. London: STM Association, 2015. Available
from:
http://www.stmassoc.org/2015_02_20_STM_Rep
ort_2015.pdf.
2. HERDIN. Retrieved from: http://www.herdin.ph/
index.php/journals.
3. Alano FD. Editorial. Philippine Journal of
Nephrology. Jan-Mar 1986;1(1).
4. Youngshuk C. Global trends in medical journal
publishing. J Korean Med Sci. 2013 Aug;28(8): 1120-
1. Published online 2013 31.
DOI:10.3346/jkms.2013.28.8.1120.
5. DOAJ. Retrieved from: https://doaj.org.
Vol. 25 No. 1 October 2017 | www.pjnonline.com | 5
 Original Article

Peritoneal Equilibration Test (PET) Analysis among Filipino Children

on Chronic Peritoneal Dialysis at the National Kidney and Transplant Institute:
A Cross-Sectional Study
Elmer Kent A. Lopez, MD, Malou Saga-Valdez, MD, Zenaida L. Antonio, MD, Ofelia R. De Leon, MD, Ma. Angeles
G. Marbella, MD, Violeta M. Valderrama, MD, Ma. Lorna Lourdes L. Simangan, MD

ABSTRACT
Background: Peritoneal Equilibration Test (PET) is a simple means of characterizing solute transport rates across
the peritoneum. It may supply useful information on peritoneal solute transfer characteristics in children on
peritoneal dialysis (PD) and facilitate individualized PD prescription.
Objective: To determine the peritoneal membrane characteristics of Filipino children by performing PET to
children on chronic peritoneal dialysis, thereby classifying them into low, low- average, high-average and high
transport types.
Methods: The study was conducted at the National Kidney and Transplant Institute, Department of Pediatric
Nephrology Out-patient Clinic using purposive convenient sampling. A PET was done to each patient. Data
analysis was carried out using frequency, percentage distribution, mean and standard deviation in analyzing the
demographic characteristics. One-Way Analysis of Variance and Pearson Chi-Square Test/Fisher-Exact Test were
used in determining association between PET and possible factors affecting its result at 0.05 level of significance.
Results: A total of 30 pediatric patients on chronic peritoneal dialysis were enrolled. Majority of subjects were
predominantly adolescents, with a mean age of 14.3+ 3.196 years old. There were 60% males and 40% females.
Chronic glomerulonephritis was the leading cause of ESRD in 83.3%. Seventy seven percent of the population
had normal BMI for age and sex percentile, followed by 20% underweight subjects and a case of overweight
(3%). PET results revealed 53.3% as low average transporters, 30% as low transporters while 16.7% as high
average transporters.
Conclusion: Filipino children on chronic peritoneal dialysis in a specialty center were predominantly classified as
low average transporters, followed by low transport type category. There was no significant association
between PET type and factors: age, sex, cause of ESRD, weight, height, body surface area (BSA), body mass index
(BMI) and duration of dialysis.

Key words: dialysis adequacy, pediatric, peritoneal dialysis, peritoneal equilibration test (PET), peritoneal
function test

__________________________________________________________________________________________________________________________________________

Received: 7 August 2017. Accepted: 29 September 2017. Copyright © 2017

Corresponding author: Elmer Kent A. Lopez, MD
Department of Pediatric Nephrology, National Kidney Institute
East Avenue, Diliman, Quezon City 1100, Philippines
Tel. No.: (63) 981-0300, 981-0400 local 2172
Fax No.: (63) 922-5608/ 928-0355
E-mail: doktorkent@yahoo.com; nktipedianephro@gmail.com
PJN is an OPEN-ACCESS publication, wherein all published
articles/materials are open to be used to expand the body of
knowledge in the field of Medicine - Nephrology, for non-commercial
purposes, provided the article/s used are properly cited and
recognized according to International Creative Commons License
Attribution-Noncommercial-Share Alike 4.0 [CC BY-NC-SA 4.0].

6 | www.pjnonline.com| Vol. 25 No. 1 October 2017

INTRODUCTION
The high and increasing incidence of end-stage renal
disease (ESRD) is consuming a major portion of health
care resources for both pediatric and adult
populations. While the incidence rates for pediatric
ESRD have remained relatively constant at 14 million
children under the age of 19 years, many adults with
ESRD suffer from a kidney disease that began as
chronic kidney disease (CKD) during childhood.1 In the
Philippines, there were 97 new cases of CKD recorded
in 2014 which constitutes 6.4% of the renal
admissions and admission referrals according to
unpublished Pediatric Renal Census of the Pediatric
Nephrology Society of the Philippines (PNSP) in which
52% of them were initiated on peritoneal dialysis
(Valderrama V, 2014, unpublished data).
Peritoneal dialysis (PD) represents a well-established
dialysis modality for pediatric patients. It is currently
the dialysis treatment modality most commonly
prescribed for children and adolescents that offers
several advantages over hemodialysis (HD).1
However, a significant number of patients drop out of
peritoneal dialysis due to inadequate dialysis.
Experience shows that an appropriate regimen on one
patient may not be sufficient for another.2 A
Peritoneal Equilibration Test (PET) evaluation
conducted soon after the initiation of dialysis to
determine the transport capacity of a patient’s
peritoneal membrane is an important factor in
determining the optimal dialysis prescription. The
National Kidney Foundation Kidney Disease Outcomes
Quality Initiative (NKF-K/DOQI) clinical practice
guideline for peritoneal dialysis adequacy
recommends peritoneal membrane transport testing
when clinically indicated.3
The PET is a semi-quantitative assessment of
peritoneal membrane transport function in patients
on peritoneal dialysis.4 The standardized PET
developed by Zbylut Twardowski defines the
peritoneal membrane’s clearance and ultrafiltration
rates by measuring dialysate to plasma ratios of
creatinine and glucose under special conditions. Once
membrane permeability is identified, clinicians can
more accurately select a PD regimen to optimize
dialysis based upon other parameters such as patient
weight, food consumption and urea generation rates.3
Presently, PET in children is not being widely utilized
in our country. Its determination among pediatric
patients is of great importance in optimizing
peritoneal treatment prescription to achieve
significant adequacy in dialysis treatment. A
preliminary study on the evaluation of PET among
Filipino children on chronic peritoneal dialysis using
Baxter system in our institute was done in 2011 but
the study population then was small. Hence, this
study was conducted as a follow up study on the
evaluation of PET using the Fresenius system.
OBJECTIVES
The main objective of the study was to determine the
peritoneal membrane characteristics of Filipino
children on chronic peritoneal dialysis (CPD) at NKTI
by performing PET. Specifically, it aimed to determine
the demographic profile and baseline characteristics
of children on CPD and classify patients as to
peritoneal membrane transport type. Lastly, to
determine the association of PET type as to age, sex,
cause of ESRD, weight, height, body surface area
(BSA), body mass index (BMI) and duration of dialysis.
METHODS
This was a follow up baseline study on peritoneal
equilibration test on pediatric patients on chronic
peritoneal dialysis in tertiary subspecialty center. The
sample size was determined based on the previous
preliminary study of 7 subjects of the same study
design. A purposive convenient sampling wherein 30
available children aged 18 years old and below,
maintained on chronic peritoneal dialysis for at least 1
month at NKTI were enrolled in this cross-sectional
prospective study. Excluded were patients who had
history of peritonitis within a month prior to study,
dehydrated or fluid overloaded and those with PD
Vol. 25 No. October 2017 | ww.pjnonline.com | 7
catheter malfunctioning. It was performed at the diagnosed pediatric ESRD patients from January 2013
Department of Pediatric Nephrology Out-patient to December 2014 maintained on CAPD at 4
Department (NKTI-OPD). exchanges per day regimen. The summary of the
demographic characteristics of the study participants
All subjects were recruited in both pay and service is shown in Tables 1 and 2.
clinics. Personal Information Sheet (PIS), as well as
Table 1. Characteristics of study participants (n=30)
informed consent or assent was obtained before Demographic Minimum Maximum Mean Std
participation as approved by the Institutional Review characteristics Deviation
Board (IRB). Anonymity of the subjects was Age (years) 6 18 14.30 3.196
maintained by giving unique numbers for Duration of 2 23 10.88 6.79
PD (months)
identification. Confidentiality of the results and 2)
BMI (kg/m 12.60 26.00 18.40 3.06
information gathered from the study was also PET (D/P crea) 0.41 0.790 0.57 0.11
observed.
Table 2. Demographic characteristics of study participants (n=30)
A Peritoneal Equilibration Test of Fresenius system
Demographic characteristic Frequency %
protocol was done in each patient after clinical Sex
consultation. Patients were required to have a Male 18 60.0
complete drainage after 8- to 12-hour overnight drain Female 12 40.0
Total 30 100
prior to the study. A fresh 2.3% glucose peritoneal
Native renal disease
dialysis solution was infused with the volume of Chronic glomerulonephritis 25 83.3
1100ml/m2BSA. A 10ml-dialysate sample was sent to IgM nephropathy 1 3.3
laboratory for creatinine and glucose determination Membranoproliferative GN 1 3.3
at 0-hour (PET 1), 2-hour (PET 2) and 4-hour (PET 3) Focal segmental GN 1 3.3
IgA nephropathy 1 3.3
dwell time. At 2-hour dwell time, blood sample was
Dysplastic kidneys 1 3.3
also extracted for serum creatinine and glucose. The Total 30 100
remaining volume was drained, weighed and Nutritional status
recorded. For the correction factor, creatinine and Normal 23 77.0
Underweight 6 20.0
glucose were determined from a new 2.3% dialysate.
Overweight 1 3.0
PET was computed using ratio of dialysate creatinine Total 30 100
and plasma creatinine (D/P crea) and was interpreted Type of transporter
accordingly. Low 9 30.0
Average 16 53.3
High 5 16.7
For data analysis, descriptive analysis was carried out Total 30 100
by using mean and standard deviation for continuous
variables while frequency and percentage distribution Majority of subjects were predominantly adolescents,
for categorical variables. One-Way Analysis of with a mean age of 14.3+ 3.196 years old. Average
Variance (ANOVA) was utilized for inferential analysis duration of peritoneal dialysis was 10.88+ 6.792
of continuous variables while Pearson Chi-Square Test months. There were 60% males and 40% females.
or Fischer Exact Test for categorical variables at 0.05 Chronic glomerulonephritis was the leading cause of
level of significance. ESRD in 83.3%. Seventy seven percent of the
population had normal BMI for age and sex
RESULTS percentile, followed by 20% underweight subjects and
The study population included 30 pediatric patients a case of overweight (3%).
on chronic peritoneal dialysis. All of them were newly

8 | www.pjnonline.com | Vol. 25 No. 1 October 2017

As shown in Figure 1, PET (D/P crea) results revealed
53.3% as low average transporters, 30% as low
transporters while 16.7% as high average
transporters. No subjects were classified as high
transporters.
ultrafiltration volume. Low average transporters have
a D/P crea at 4 hours between 0.50 and 0.64. They
would be expected to have high average D/D0 glucose
and high average net ultrafiltration values. High

Table 3. Association of categorical variables to type of

transporter
Type of transporter
Low Average High
Low Demographic
16.7% 30% Count Col% Count Col% Count Col% p-value+
characteristic
Sex 0.41
Low Average Male 4 44.4 10 62.5 4 80
Female 5 77.8 6 37.5 1 20
53.3% 0.97
Native renal disease
High Average Chronic 7 0 15 93.8 3 60
glomerulonephritis
IgM nephropathy 0 0 1 6.3 0 0
Membrano- 0 0 0 0 1 20
proliferative GN
Focal segmental 0 0 0 0 1 20
Figure 1. Distribution of subjects as to type of transporter. GN
IgA nephropathy 1 11.1 0 0 0 0
Pearson Chi-Square Test or Fischer Exact Test Dysplastic kidneys 1 11.1 0 0 0 0
Nutritional status 0.416
revealed that sex, native renal disease and nutritional
Normal 7 77.8 13 81.3 3 60
status showed no proven association with the type of 1 11.1 3 18.8 2 40
Underweight
transporters (Table 3). Overweight 1 11.1 0 0 0 0
One-way ANOVA revealed that there was no Total 9 100 16 100 5 100
statistical significant correlation between PET (D/P + p- value < 0.05 statistically significant association

crea) and age, duration of peritoneal dialysis and

body mass index (Table 4).
Table 4. Association of continuous variables to type of
transporter
DISCUSSION Demographic Mean Std Min Max p–
characteristic n deviation value+
(profile)
Peritoneal equilibration test (PET) is an easy,
Low 9 14.22 3.77 8 18 0.915
inexpensive and reliable test to assess peritoneal Age Average 16 14.50 3.39 6 18
transport type and provide information about (years) High 5 13.60 1.48 12 16
peritoneal clearance of solutes and ultrafiltration. Total 30 14.30 3.20 6 18
Low 9 8.78 6.18 3 19
Peritoneal transport type classification is recognized Duration
Average 16 10.59 6.78 2 22 0.915
not only as an aid for prescription, but also as a of PD
High 5 15.60 6.88 5 23
prognostic index.5 (months)
Total 30 10.88 6.80 2 23
Low 9 19.40 3.97 14.10 26.00 0.509
Results from the PET classify patients into 4 basic BMI Average 16 18.05 2.70 12 23.10
2
groups, namely low, low average, high average and (kg/m ) High 5 17.72 2.42 60 21.50
Total
high transporters.6 Low transporters have 4-hour D/P 30 18.40 3.06 15 26.00
+ p- value < 0.05 statistically significant association10
crea <0.49 and high D/D0 glucose and a high net

Vol. 25 No. 1 October 2017 | www.pjnonline.com | 9

average transporters have a 4-hour D/P crea
between 0.65 and 0.81 and would also be expected to
have low average values for average net filtration.
High transporters have a D/P creatinine at 4 hours
>0.82 and would be expected to have low D/D0
glucose and low net filtration.
In this study, great majority of pediatric patients on
chronic peritoneal dialysis were classified as low
average transporters (53.3%). They have good net
ultrafiltration and adequate solute clearance which
best require standard CAPD dose. Low transport type
ranked second (30%). This transport type has
inadequate solute clearance but with excellent net
ultrafitration which requires high dose, longer dwell
CAPD or hemodialysis. The remaining 16.7% were
high average transporters which have both adequate
solute clearance and net ultrafiltration which best
prefer any regimen. No patients fit under high
transport type category which have excellent solute
clearance and but with poor net ultrafiltration that
require automated peritoneal dialysis (APD) regimen.
These findings are consistent with the unpublished
preliminary results of similar study done at NKTI
which revealed four out of seven Filipino children
were classified as low average transporters (Saga-
Valdez, 2011,unpublished data). However, in the
study of Liu et al., among children between 2-14 years
old, PET showed 70% of CAPD Chinese children fit into
high and high average transport categories.7 The
same trending was also reported in the study of Aksu
et al., in 21 Turkish children on CAPD.8 Extreme
difference of age groups between both studies
showed contrasting results of PET. Although this is
speculative, age group could possibly affect the
transport type in children, favoring low and low
average transport type to older age groups. This may
mean the older and the bigger were the subjects, the
lower would be the PET value. This may be the reason
why Filipino children in this study tend to be low and
low average transporters since our study subjects
were predominantly adolescents (84%) who were
10 | www.pjnonline.com | Vol. 25 No. 1 October 2017
bigger in size and weight. If ever we had greater
number of younger patients in our study, then
probably there were some subjects fit into high
transport type category.
In a study by Mendley et al., found out American
children age 2 years old and below transport glucose
and creatinine more rapidly than do children 3 to 14
years old and adults. Children 3 to 14 years old
transport glucose more rapidly than do adults.9 As
also cited in the study of Schaefer et al., the transfer
rates of most solutes were correlated with each other
but individual variation of peritoneal permeability for
different solutes was high. The permeability of all
solutes tended to be inversely correlated with body
size.10 Exact correlation was not exhibited in our study
since study subjects were mostly adolescents and no
patients below 6 years old were included.
Similar with adults, Filipino children in our PET study
had the same transport type category comparable to
the study by Uncanin et al., in which 63.3% of Bosnian
adults who were low average transporters.5 Adults
and adolescents probably have nearly similar
physiologic and anatomic peritoneal functions. More
than 50% of our patients in this study were young
adults who may be already attained the same
transport type capacity and function with that of
adult peritoneal system.
However, factors possibly affecting PET such as age,
sex, cause of ESRD, weight, height, BSA, BMI and
duration of peritoneal dialysis revealed no significant
correlation to PET in this study (P-value > 0.05).
Nonetheless, this finding cannot be generalized due
to the sample size factor and that the study
population was not normally distributed.
In the study of Avellan-Boza et al., there were also no
significant differences between age, gender, diabetes
mellitus, serum albumin, C reactive protein and the
type of peritoneal transport, even when previous
studies have revealed a higher proportion of men,
diabetic patients and low serum albumin
concentration in the high transporter group in adult
Costa Rican cohorts.11
However, in a PET study in Australia and New Zealand
with 3,188 adult patients, high transporter PET was
associated with increased age and ethnicity but not
associated with gender, diabetes and other co-morbid
conditions, smoking, previous hemodialysis therapy or
transplantation, or residual renal function.12 A similar
association between increasing age and high
transporter status at dialysis initiation was noted in a
second smaller study from Spain.13
There were limited published literatures about PET
used in the evaluation of PD adequacy especially
among Asian children. Hence, the results of this study
may be used as pioneer baseline data for PET among
Filipino children on chronic peritoneal dialysis.
However, further studies are encouraged to address
the limitations to yield more valid and meaningful
conclusion.
CONCLUSION
The author concludes that Filipino children on CPD in
a specialty center were predominantly classified as
low average transporters, followed by low transport
type category. They best require standard CAPD
regimen and high dose, long dwell time CAPD,
respectively.
Furthermore, no significant association was confirmed
between PET (D/P crea) and possible factors affecting
its result such as age, sex, native renal disease,
weight, height, BSA, BMI and duration of peritoneal
dialysis.
Recommendations
Larger sample population is recommended to assess
correlation of PET across possible factors affecting its
result such as age, sex, cause of ESRD, weight, height,
BSA, BMI and duration of dialysis. Random sampling
method of selecting subjects is also highly
recommended. Multicenter studies should also be
conducted to achieve a valid conclusive finding of PET
among Filipino children on chronic peritoneal dialysis.
Funding/Disclosure
The Department of Pediatric Nephrology of NKTI
solely funded this research project. There were no
outside sources of funding like pharmaceutical
company taken in the completion of this study.
About the Paper
This research paper placed 2nd (Oral Presentation) in
the Annual Completed Research Contest during 36th
PSN Annual Convention, last April 21, 2016 at EDSA
Shangri-La Hotel, Mandaluyong City, Manila.
It placed 2nd (Oral Presentation) in the Research
Contest, Prospective Category, Annual Research
Forum 2015, Dec 9, 2015, Dr. Enrique T. Ona
Auditorium, NKTI, East Ave, Quezon City.
It was presented orally during the Research Forum of
the 21st PNSP Annual Convention, Nov 20, 2015,
Crown Plaza Hotel, Ortigas Ave, Pasay City.
Author Details
National Kidney and Transplant Institute
REFERENCES
1. Avner ED, Harmon WE, Niaudet P, Yoshikawa N (eds).
th
Pediatric Nephrology, 6 edition. Berlin: Springer-
Verlag, 2009.
2. Peritoneal dialysis policies, procedure and guidelines, Da
Vita Inc. Policy:5-10-06. https://med.uth.edu/
internalmedicine/files/2013/10/07-Adequacy-
Peritoneal-Dialysis.pdf.
3. Peritoneal Dialysis Adequacy Work Group. Clinical
practice guidelines for peritoneal dialysis adequacy. Am
J Kidney Dis. 2006;48 Supp 1:S98-129. PMID: 16813998
DOI: 10.1053/j.ajkd.2006.04.006.
4. Misra M, Khanna R. The clinical interpretation of
peritoneal equilibration test. Semin Dial.
2014;27(6):598-602. PMID: 25139767 DOI:
10.1111/sdi.12285.
5. Uncanin S, Rasić S, Rebić B, et al. The importance of
using peritoneal equilibration test for the peritoneal
transport type characterization in ambulatory periotenal
Vol. 25 No. 1 October 2017 | www.pjnonline.com | 11
 dialysis patients. Bosn J Basic Med Sci. 2010;10 Suppl
1:S40-3.PMID: 20433430.
6. Twardowski ZJ, Nolph KD, Khanna R, et al. Peritoneal
equilibration test. Pert Dial Bull 1987;7:138-47.
7. Yao Y, Chen Y, Yang JY, Huang JP, Xiao HJ, Liu JC.
Peritoneal equilibration test and results analysis in
children undergoing chronic peritoneal dialysis.
Zhonghua Er Ke Za Zhi. 2007;45(3):189-93. PMID:
17504622.
8. Aksu N, Yavaşcan Ö, Kara OD, Anil M. Peritoneal
equilibration test in children. Ege Journal of Medicine.
2008;47(3):183-6.
9. Mendley SR, Majkowski NL. Peritoneal equilibration test
results are different in infants, children and adults. J Am
Soc Nephrol. 1995;6(4):1309-12. PMID: 8589303.
10. Schaefer S, Langenbeck D, Heckert KH, Schärer K, Mehls
O. Evaluation of peritoneal solute transfer by the
12 | www.pjnonline.com | Vol. 25 No. 1 October 2017
peritoneal equilibration test in children. Adv Perit Dial.
1992;8:410-5. PMID: 1361835.
11. Avellan-Boza M, Hernández F, Ramos-Esquivel A.
Peritoneal equilibration test in Costa Rica: discrepancies
from other populations. Int J Nephrol. Hindawi
Publishing Corp. 2014(2014), Article ID 326163.
DOI:10.1155/2014/326163.
12. Rumpsfeld M, McDonald SP, Purdie DM, Collins J,
Johnson DW. Predictors of baseline peritoneal transport
status in Australian and New Zealand peritoneal dialysis
patients. Am J Kidney Dis. 2004;43(3):492-501. PMID:
14981608.
13. Selgas R, Bajo MA, Cirugeda A, et al. Ultrafiltration and
small transport initiation of PD: questioning the
paradigm of peritoneal function. Perit Dial Int
2005;25(1):68-76. PMID: 15770928.
 Original Article

A Comparison of Three Prediction Models for Acute Kidney Injury Requiring Renal
Replacement Therapy after Coronary Artery Bypass Graft Surgery
Ailene R. Buelva-Martin, MD* and Oscar D. Naidas, MD*

ABSTRACT
Background. Acute kidney injury (AKI) following cardiac surgery is associated with increased post-operative
morbidity and mortality. Scoring systems to predict acute kidney injury requiring renal replacement therapy
(RRT) among patients undergoing cardiac surgery have been developed to assess risk pre-operatively and
assist clinicians in the management post-operatively. These predictive models have good discriminative value.
The significance of this study is to determine the most predictive model by comparing the 3 models that can
be utilized and applied in our setting.
Objective. To compare the Cleveland Score by Thakar, Simplified Renal Index (SRI) by Wijeysundera, and
Simplified Bedside Risk tool by Mehta in predicting acute kidney injury requiring renal replacement therapy
among patients who underwent cardiac surgery.
Methods. Cross sectional analytic study of 427 patients who underwent coronary artery bypass graft surgery
at the St. Luke's Medical Center, Quezon City from January 2009-October 2014.
Results. Acute kidney injury was documented in 25.5% (n=109) of subjects, 13.3% (n=57) underwent post-
operative renal replacement therapy (RRT), either intermittent hemodialysis or continuous renal replacement
therapy. Discrimination for the prediction of RRT was good for the three scoring models using areas under the
receiver operating characteristic curve (AUROCs): 0.94 (95% CI, 0.916 to 0.963) using Mehta; 0.92 (95% CI,
0.890 to 0.944) using Thakar, and 0.90 (95% CI, 0.867 to 0.926) using SRI. Mehta showed the highest
predictive value, with significant difference with SRI (p = 0.0053).
Conclusion. The Bedside Tool for Predicting Risk of Postoperative Dialysis by Mehta, et al., has the highest
predictive value among the three models. However, compared to Cleveland score by Thakar, Mehta does
better by only 2% and is not statistically significant. Mehta compared to SRI, does better by 4% and is
statistically significant. Hence, among the three models, Mehta and Thakar have the greatest predictive value
in assessing the risk for acute kidney injury requiring renal replacement therapy after coronary bypass.

Key words: acute kidney injury, coronary surgery, predictive models, risk for renal replacement therapy

__________________________________________________________________________________________________________________________________________

Received: 7 August 2017. Accepted: 17 September 2017. Copyright © 2017

Corresponding author: Ailene R. Buelva-Martin, MD
St. Luke’s Medical Center, Quezon City
279 E. Rodriguez Sr. Ave, Quezon City, 1112 Metro Manila
Tel. No.: (632) 723-0101 local 4736
E-mail: arbuelva@gmail.com
PJN is an OPEN-ACCESS publication, wherein all published
articles/materials are open to be used to expand the body of
knowledge in the field of Medicine - Nephrology, for non-commercial
purposes, provided the article/s used are properly cited and
recognized according to International Creative Commons License
Attribution-Noncommercial-Share Alike 4.0 [CC BY-NC-SA 4.0].

Vol. 25 No. 1 October 2017 | www.pjnonline.com | 13

INTRODUCTION
Acute Kidney Injury (AKI) after cardiac surgery results
in increased morbidity and mortality. One of the most
common cardiac surgery is the Coronary Artery
Bypass Grafting (CABG). About 33% develop AKI
among patients who undergo cardiac surgery and
even a minimal elevation of serum creatinine
postoperatively is associated with long term
mortality.1 Mortality in patients who develop severe
AKI requiring dialysis is high about 50-80%.2,3
There have been risk factors that have been identified
preoperatively from previous studies that may cause
acute kidney injury requiring renal replacement
therapy and from these factors, predictive scorings
have been established.4-7
In 1997, a cohort study be Chertow et al., identified
10 variables related to baseline cardiovascular disease
and renal function that were found to be independent
predictors of acute renal insufficiency requiring
dialysis after cardiac surgery. Stratification of patients
included low-risk (0.4%), medium-risk (0.9% to 2.8%),
and high-risk (≥5.0%) for acute kidney injury requiring
renal replacement therapy based on these factors.8
In 2004, retrospective cohort study was done by
Wijeysundera et al., known as the Simplified Renal
Index (SRI), 7 variables with 8 definitions were
identified eGFR of 31-60mL/min, eGFR <30ml/min,
DM, LVEF < 40%, Previous cardiac surgery, Procedures
other than isolated coronary artery bypass graft or
isolated atrial septal defect repair, non-elective
procedure, and preoperative intra-aortic balloon
pump.9
In 2005, a cohort included 450, 000 patients from the
US Society of Thoracic Surgeons National Cardiac
Surgery database was done by Mehta et al. The
simplified bedside risk tool identified 10 factors
independently associated with increased
14 | www.pjnonline.com | Vol. 25 No. 1 October 2017
postoperative dialysis (age, race, chronic lung disease,
DM, CHF, recent MI, preoperative creatinine, prior
cardiac surgery, type of surgery, cardiogenic shock).10
A study between 1993 and 2002 was done by Thakar
et al., a large cohort consisting of 33,217 patients who
underwent open-heart surgery at the Cleveland Clinic
Foundation. This prediction model was known as
Cleveland Score. It identified 10 variables which
includes: sex, COPD, DM, CHF, IABP, LVEF 35%,
preoperative creatinine, emergency surgery, type of
surgery, prior cardiac surgery.11,12
There have been studies which compared different
prediction models to assess the best predictive model
for acute kidney injury requiring dialysis post cardiac
surgery. In 2010, a study by Engelberger et al,
compared the Cleveland score, the Mehta score, and
the SRI score. The Cleveland and Mehta score
consistently showed significantly better
discrimination compared with the SRI score (p
<0.001).13
Two local unpublished studies validated SRI and
Cleveland score compared to SRI. Study by Karim et
al.14 showed discrimination test for SRI using area
under the receiving operating characteristics (ROC)
curve with an area under the curve (AUC) of 0.975.
The study by Bautista-Duque et al.,15 Cleveland
scoring has an AUROC of 0.957 and predicts better by
6% compared with SRI.
This study aims to compare the 3 models namely:
Cleveland Score, Simplified Renal Index, and
Simplified Bedside Risk tool by Mehta to assess which
model can better predict risk for acute kidney injury
after coronary artery bypass graft in our institution.
METHODS
Study Design
A cross-sectional analytic study
Subject Inclusion Criteria
All adult patients (age >18 y/o) who underwent
Coronary Artery Bypass Grafting from January 2009 to
October 2014 at St. Luke’s Medical Center, Quezon
City
Subject Exclusion Criteria
Patients with End stage renal disease maintained on
hemodialysis
Patient who already underwent hemodialysis pre-
operatively
Patients with eGFR <15ml/min
Patients with missing data.
General Objective
To compare Cleveland Score, Simplified Risk Scoring,
and Bedside Risk tool in predicting acute kidney injury
requiring renal replacement therapy among patients
who underwent cardiac surgery.
Specific Objective
To compare the prognostic ability of the Cleveland
Score, Simplified Risk Scoring, and Bedside Risk tool in
predicting acute kidney injury requiring RRT among
patients who underwent cardiac surgery from January
2009 to October 2014.
Outcomes
Primary outcome
Postoperative Acute Kidney Injury requiring renal
replacement therapy in the hospital
Secondary outcome
Postoperative Acute Kidney Injury not requiring
hemodialysis
Data Collection
All patients who met the inclusion criteria from
January 1, 2009 to October 30, 2014 were included in
the study. The predictor variables and demographic
characteristics (age, race, sex), other medical
conditions (Diabetes Mellitus, COPD, recent MI of <21
days, CHF, NYHA class, cardiogenic shock, ejection
fraction, operative characteristics (presence of
previous cardiac surgery, previous surgery,
preoperative IABP), urgency of the procedure were
collected from the Cardiovascular Disease Information
System. Laboratory data were gathered from the
Health Care System. Pre-operative creatinine
clearance was assessed by computing the eGFR using
the CKD-EPI equation. All patients were evaluated
and calculated using the three prediction models:
Cleveland scoring system by Thakar, et al., Simplified
Renal Index by Wijeysundera et al., and the Bedside
Tool for Predicting Risk of Postoperative Dialysis by
Mehta, et al.
The Clinical Protocol and all relevant documents were
reviewed and approved by the Institutional Ethics
Review Committee.
Data Analysis
The baseline clinical and biochemical features of the
population were presented as means + SD for
continuous data and percentages were used for
categorical data. The t test was used to compare
continuous variables between groups, and Fisher
exact test was used to compare categorical variables.
Acute kidney injury as defined by an absolute increase
by 0.3 mg/dl from the baseline creatinine were
16
determined. Acute kidney injury requiring renal
replacement therapy were determined and the area
under the curve was determined on each prediction
model. Statistical analysis was performed using the
IBM SPSS program and evaluated at p value of <0.05
level of significance. Sample size estimation: A sample
size of 448 is required assuming a prevalence of 5% of
patients requiring RRT among patients undergoing
cardiopulmonary bypass, with 80% reliability and
maximum allowable error of 0.05.12 With a sample
size of only 427, power is 78%.
RESULTS
A total of 481 patients underwent cardiac surgery
Vo. 25 No. October 2017 | www.pjnonline.com | 15
within the 6-year period. After exclusion (ESRD is increasing risk for RRT for each increasing class as
patients n=9, incomplete data n=31, missing charts follows 1.29%, 2.33%, 50%, 88.8% respectively.
n=14), 427 patients were included in our study. Mean
age of the study subjects is 60 years, predominantly Table 2. Cleveland risk categories in association with the
development of AKI requiring RRT
male (Table 1). Total RRT
Cleveland Score % Cl
(n) YES NO
Table 1. Baseline characteristics <0.0001
Class 1 Low risk 77 1 76 1.29 to
On-Pump CABG
0.0768
n=427 0.0095
Age, mean (SD) 59.9 (8.8) Intermediate
Class 2 257 6 251 2.33 to
Risk
Sex Male --no. (%) 351 (82.2) 0.0512
Female 76 0.3954
Clinical history- no. (%) Class 3 High Risk 84 42 42 50 to
0.6046
Congestive heart failure 120 (28)
0.5433
COPD 54 (12.6) Class 4 Very high Risk 9 8 1 88.8 to
Diabetes mellitus 252 (59) >0.9999
Hypertension 386 (90) Total 427 57 370
Dyslipidemia 372 (87)
Previous cardiac surgery 2 (0.5)
The Simplified Renal Index (SRI) by Wijeysundera et
Previous PCI 11 (2.5)
Acute or recent MI 46 (10.7) al., includes 7 variables and 8 definitions categorized
Left ventricular ejection fraction into 3 (low, intermediate, high risk). This study also
<= 35% 29 (6.8) showed increased risk of renal replacement therapy
>35% 398 (93)
with increasing category as follows 0%, 20%, 75%,
Preoperative use of
20 (4.6) respectively (Table 3).
intraaortic balloon pump
Number of vessels involved
Multivessel 400 (93) Table 3. SRI risk categories in association with development of
Single vessel 27 (6.3) AKI requiring RRT
Surgery Total RRT
407 (95) SRI % Cl
(n) YES NO
CABG only
0.0000 to
CABG + valve surgery 20 (4.6) 0-1 Low risk 197 0 197 0
0.023
Emergency surgery 19 (4.4) Intermediate 0.1512 to
Pre-operative creatinine >=1.2 266 (62.3) 2-3 210 42 168 20
Risk 0.2595
0.5275 to
4 High Risk 20 15 5 75
0.8919
Acute kidney injury was documented in 25.5% Total 427
(n=109) of subjects, 13.3% (n=57) underwent post-
operative renal replacement therapy (RRT), either The Bedside Tool for Predicting Risk of Postoperative
intermittent hemodialysis or continuous renal Dialysis by Mehta, et al., has 10 variables and 15
replacement therapy. definitions. There is no stratification from low risk to
The Cleveland Score by Thakar et al., includes 10 high risk in this model. The simplified model
variables and 13 definitions. It is categorized into 4: coefficients were converted into an additive risk
class I (scores of 0-2), class 2 (scores of 3-5), class 3 score, corresponding to a percentage risk for RRT. In
(scores of 6-8) and class 4 (scores of 9-17), with risk of this study, there was no RRT from score of 0 to 21 out
RRT increasing for each class. Table 2 shows the of 238 patients; scores 22-40, there was 54 out of 185
number of patients at each score level and the (29%); and scores >40, 3 underwent RRT out of 4
corresponding frequency of AKI requiring RRT. There patients (75%). The highest score was 67% was with 1

16 | www.pjnonline.com | Vol. 25 No. 1 October 2017

patient who underwent RRT. not statistically significant. Previous study done
support this wherein Cleveland Score by Thakar had
Predictive accuracy using the AUROC showed an area the highest predictive value compared with Mehta.
under the curve of 0.94 (cut-off value of 0.5)
demonstrating very good discriminative power of the
Bedside Tool for Predicting Risk of Postoperative
Dialysis by Mehta, et al., comparable with Thakar with
AUROC of 0.92 and SRI of 0.90 (Table 4). Predictive
accuracy of the three prediction models as seen in
Figure 1.

Table 4. AUROC of the three prediction models

a b
Models AUC SE 95% CI P-value
Bedside Tool for
Predicting Risk of
0.916 to
Postoperative 0.0123 0.000
0.94 0.963
Dialysis by
Mehta, et al.
Cleveland Scoring 0.890 to
0.0237 0.000
by Thakar et al 0.92 0.944
Simplified Renal
Index (SRI) by 0.867 to
0.0169 0.000
Wijeysundera et 0.90 0.926
al Figure 1. Comparison of Area Under the Receiver
Operating Characteristic curves (AUROCs) of the three
The three prediction models have good discriminative prediction model.
power. However, comparing the 3 models, Mehta has
the highest predictive value and has significant Table 5. Pairwise comparison of ROC curves
difference with SRI (p=0.0053), while Mehta vs. MEHTA~THAKAR
Thakar has no significant difference (p=0.23) (Table 5). Different between areas 0.023
95% Confidence Interval -0.0146 to 0.0607
Significance level p=0.2299
DISCUSSION MEHTA~SRI
Different between areas 0.0435
In this study, three prediction models of acute kidney 95% Confidence Interval 0.0129 to 0.0741
injury from cardiac surgery were compared. All three Significance level p=0.0053
models show good discriminative value. The Bedside
Tool for Predicting Risk of Postoperative Dialysis by
Cleveland scoring by Thakar showed AUROC of 0.92.
Mehta, et al., showed the highest predictive value
This scoring also has 10 variables but with 13
with AUROC of 0.94. Cleveland score by Thakar also
definitions and has a simpler schema on scoring
showed good discriminative value with AUROC of
compared with Mehta. The variables included sex and
0.92, followed by SRI at 0.90. Mehta scoring has 10
presence of CHF without categorizing the NYHA class
variables and 15 definitions. These variable included
compared with Mehta which specifically included
age, race, NYHA Class IV, recent myocardial infarction
NYHA Class IV. Although Thakar is lower only by 2% in
and cardiogenic shock which were absent in the other
its predictive value compared to Mehta, it is not
two models. Although Mehta has the highest
statistically significant.
predictive value compared to Thakar, the values are

Vol. 25 No. 1 Ocotber 2017 | www.pjnonline.com | 17

Simplified risk index has the lowest number of
variables of 7 with 8 definitions. SRI also has a good
discriminatory value at 0.90 but the lowest among the
three models. This may be because the predicting
variables were also present in the other two models.
LIMITATIONS
The study has small sample size. Computed sample
size was 448 to get a power of 80%. This study only
has 427 patients with a computed power of 78%.
CONCLUSION
The Bedside Tool for Predicting Risk of Postoperative
Dialysis by Mehta, et al., has the highest predictive
value among the three models. However, compared
to Cleveland score by Thakar, Mehta does better by
only 2% and is not statistically significant. Because of
this, Thakar may be preferred over Mehta because of
the less number of variables and the simplicity of the
model. Mehta compared to SRI, does better by 4%
and is statistically significant.
Among the three models, Bedside Tool for Predicting
Risk of Postoperative Dialysis by Mehta et al. and
Cleveland Score by Thakar et al. have the greatest
predictive value in assessing acute kidney injury
requiring renal replacement therapy after coronary
bypass.
Acknowledgment
The authors thank Drs. Marizel Karim and Aina
Bautista-Duque for sharing their manuscripts and to
the Cardiovascular Disease Information System for
the data.
Funding
None.
Disclosure
None.
About the Paper
This research paper was selected as Oral Presentation
Finalist at the Philippine Society of Nephrology last
18 | www.pjnonline.com | Vol. 25 No. 1 | October 2017
April 15, 2015 in Shangri-La Hotel, Philippines.
This research paper was selected as Poster
Presentation at the American Society of Nephrology
last November 15, 2015 in San Diego, USA
Author Details
*Ailene R. Buelva-Martin, MD; Member, Research
Committee of the Philippine Society of Nephrology
**Oscar D. Naidas, MD; Past Chairman and Associate
Professor, Department of Medicine, St. Luke’s
Medical Center, Quezon City and St. Luke’s College of
Medicine.
REFERENCES
1. Loef BG, Epema AH, Smilde TD, et al. Immediate
postoperative renal function deterioration in
cardiac surgical patients predicts in-hospital
mortality and long-term survival. J Am Soc
Nephrol. 2005;16(1):195-200. PMID: 15563558
DOI: 10.1681/ASN.2003100875.
2. Mangano C, Diamondstone LS, Ramsay JG,
Aggarwal A, Herskowitz A, Mangano DT. Renal
dysfunction after myocardial revascularization:
risk factors, adverse outcomes and hospital
resource utilization. Ann Intern Med.
2008;128(3):194–203. PMID: 9454527.
3. Rosner MH, Okusa MD. Acute kidney injury
associated with cardiac surgery. Clin J Am Soc
Nephro. 2006;1(1):19–32. PMID: 17699187 DOI:
10.2215/CJN.00240605.
4. Candela-Toha A, Elías-Martin E, Abraira V, et al.
Predicting acute renal failure after cardiac surgery:
external validation of two new clinical scores. Clin
J Am Soc Nephrol. 2008;3(5):1260-5. PMCID:
PMC2518781 DOI:10.2215/CJN.00560208.
5. Knapik P, Rozentryt P, Nadziakiewicz P, Polon'ski L,
Zembala M. Retrospective cross-validation of
simplified predictive index for renal replacement
therapy after cardiac surgery. Interact Cardio Vasc
Thorac Surg. 2008;7(6):1101-6. PMID: 18669528
DOI: 10.1510/icvts.2008.181438.
6. Mirmohammad-Sadeghi M, Naghiloo A,
Najarzadegan MR. Evaluating the relative
frequency and predicting factors of acute renal
 failure following coronary artery bypass grafting.
ARYA Atheroscler. 2013;9(5):287–92. PMCID:
PMC3845695.
7. Vives M, Monedero P, Perez-Valdivieso JR, et al.
External validation and comparison of three scores
to predict renal replacement therapy after cardiac
surgery: a multi-center cohort. Int J Artif Organs.
2011;34(4),327-91. DOI:10.5301/IJAO.2011.7728.
8. Chertow G, Lazarus J, Christiansen C, et al.
Preoperative renal risk stratification. Circulation.
1997;95(4):878–84. PMID: 9054745.
9. Wijeysundera DN, Karkouti K, Dupuis JY, et al.
Derivation and Validation of a simplified predictive
index for renal replacement therapy after cardiac
surgery. JAMA. 2007;297(16):1801-9. PMID:
17456822 DOI: 10.1001/jama.297.16.1801.
10. Mehta RH, Grab JD, O'Brien SM, et al. Bedside tool
for predicting the risk of postoperative dialysis in
patients undergoing cardiac surgery. Circulation.
2006;114(21):2208-16. PMID: 17088458 DOI:
10.1161/CIRCULATIONAHA.106.635573.
10. Thakar CV, Liangos O, Yared JP, et al. ARF after
open heart surgery: influence of gender and race.
Am J Kidney Dis. 2003;41(4):742-51. PMID:
12666060.
11. Thakar CV, Liangos O, Yared JP, et al. ARF after
open heart surgery: influence of gender and race.
Am J Kidney Dis. 2003;41(4):742-51. PMID:
12666060.
Vol. 25 No. 1 October 2017 | www.pjnonline.com | 19
12. Thakar CV, Arrigain S, Worley S, Yared JP, Paganini
EP. A clinical score to predict acute renal failure
after cardiac surgery. J Am Soc Nephrol
2005;16(1):162-8. PMID: 15563569 DOI:
10.1681/ASN.2004040331.
13. Englberger L, Suri RM, Li Z, et al. Validation of
clinical scores predicting severe acute kidney
injury after cardiac surgery. Am J Kidney Dis.
2010;56(4):623-31. PMID: 20630639 DOI:
10.1053/j.ajkd.2010.04.017.
14. Karim M, Naidas O. Validation of Simplified Renal
Index Scoring to predict acute kidney injury after
cardiac surgery among patients with stable kidney
function. 2009. Unpublished manuscript.
15. Bautista-Duque A, Manlutac B. A Validation of the
Cleveland score and comparison with the
simplified renal index in predicting acute kidney
injury requiring renal replacement therapy after
cardiac surgery among patients in St. Luke’s
Medical Center, Quezon City. Unpublished
manuscript.
16. KDIGO Clinical Practice Guideline for Acute Kidney
Injury. Kidney International Supplements.
2012;2(1):8-12. Available at:
http://www.kdigo.org/clinical_practice_guideline
s/pdf/KDIGO%20AKI%20Guideline.pdf
 Case Report

Cerebral Salt Wasting Syndrome in a Patient with Subarachnoid Hemorrhage:

A Case Report
Renz Michael F. Pasilan, MD* and Pelagio L. Esmaquel Jr., MD**

ABSTRACT

Hyponatremia is a common condition following acute brain injury, the two main causes of which are the
Syndrome of Inappropriate Antidiuretic Hormone (SIADH) and the Cerebral Salt Wasting Syndrome (CSWS).
Differentiating the two conditions is important due to the divergent management approach. We present a
case of hyponatremia in a 36-year-old female attributed to CSWS after subarachnoid hemorrhage and
endovascular coiling of cerebral aneurysm. There are no established guidelines for the diagnosis of CSWS thus,
a high degree of suspicion and accurate assessment of the volume status with clinical and objective
parameters is essential in differentiating it from SIADH to avoid catastrophic complications. Aggressive salt
and fluid management, together with fludrocortisone administration, was successfully used to achieve
hemodynamic stability and prevent further neurologic deterioration in this case.
.
Key words: hyponatremia, cerebral salt wasting, syndrome of inappropriate anti-diuretic hormone,
fludrocortisone

INTRODUCTION Differentiating these two conditions is important for

Hyponatremia is a common condition following
acute brain disorders. It occurs in more than 50% of
patients with subarachnoid hemorrhage (SAH), with
differing onset during hospitalization. It is associated
with an increased length of hospital stay and seizure
occurrence.1,2
Previous reports point to Cerebral Salt Wasting
Syndrome (CSWS) as the most common cause of the
electrolyte imbalance after SAH, however current
retrospective studies have identified Syndrome of
Inappropriate Antidiuretic Hormone release (SIADH)
as the more common etiology of hyponatremia.1,2
the contrasting management; CSWS requires
vigorous salt replacement to compensate for the
renal salt wasting whereas SIADH needs fluid
restriction as excessive antidiuretic hormone is the
primary cause of the relative water excess.3
Unfortunately, both conditions can present similarly
in terms of clinical presentation, and laboratory
features such as a low serum osmolality, high urine
osmolality, and a high urine sodium level.4,5 The main
difference is the extracellular fluid volume state;
SIADH presents with either euvolemic or
hypervolemic state, in contrast to the volume
depleted state in CSWS.

__________________________________________________________________________________________________________________________________________

Received: 7 August 2017. Accepted: 23 September 2017. Copyright © 2017

Corresponding author: Renz Michael F. Pasilan, MD
Asian Hospital and Medical Center, 2205 Civic Drive, Filinvest
City, Alabang, Muntinlupa City 1780, Philippines
Tel. No.: (632) 771-9000
Fax No.: (632) 876-5710
E-mail: rmpasilan@gmail.com
PJN is an OPEN-ACCESS publication, wherein all published
articles/materials are open to be used to expand the body of
knowledge in the field of Medicine - Nephrology, for non-commercial
purposes, provided the article/s used are properly cited and
recognized according to International Creative Commons License
Attribution-Noncommercial-Share Alike 4.0 [CC BY-NC-SA 4.0].

20 | www.pjnonline.com | Vol. 25 No. 1 October 2017

We present a case of Cerebral Salt Wasting
Syndrome in a 36-year-old female that occurred after
coiling of cerebral aneurysm post subarachnoid
hemorrhage event, highlighting the importance of
differentiating it with SIADH.
CASE PRESENTATION
This is a case of a 36-year-old Filipino woman who
presented at the Emergency room due to a transient,
fifteen second loss of consciousness following a
sudden onset of severe generalized headache with
associated vomiting episodes. Initial examination
showed: stable vital signs with unremarkable
regional physical examination findings; neurologic
examination - Glasgow coma score of 15, supple neck
with no nuchal rigidity, and no sensory or motor
deficits; laboratory examination revealed normal
hemogram, blood electrolytes and other chemistries.
Cranial computerized tomography angiogram (CTA)
was done after findings of subarachnoid
hemorrhage on plain scan. CTA showed a saccular
aneurysm in the left supraclinoid inernal carotid
artery near its bifurcation with the MI segment of the
left middle cerebral artery. The patient was started
on medical decompression therapy while preparing
for immediate cerebral endovascular intervention.
Intraoperative findings noted a 1.8 mm x 1.2 mm left
anterior choroidal artery aneurysm near the
branching of the anterior choroidal artery from the
left internal carotid artery. Coil embolization was
performed, achieving occlusion of 95% of the
aneurysm. The immediate postoperative period was
generally uneventful; the patient was stable with no
appreciated sensory or motor deficits but with a
persistent generalized headache.
Succeeding days of hospitalization showed the
patient having persistent polyuria, averaging more
than five liters in a 24-hour period during the 6th
hospital day, despite discontinuation of mannitol
(Figures 1 and 2).

144 3000

142
2500
140

24 Hour Sodium intake

138 2000
Serum Sodium

136
1500
134

132 1000

130
500
128

126 0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Hospital Day
24 hour Sodium intake Serum Sodium

Figure 1. Graph of serum sodium vs 24-hour sodium intake during hospitalization.

Vol. 25 No. 1 October 2017 | www.pjnonline.com | 21

 15000
24 hour Fluid Intake and Output

10000

5000

-5000

-10000

-15000
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Fluid Output -4203 -4140 -6722 -5400 -5330 -5300 -5450 -3850 -5565 -7315 -8995 -9440 -1021 -9530 -6440 -4950 -1850 -2000
Fluid Intake 4905 4443 5100 5500 4915 4400 4195 2730 4620 6430 7800 8690 8950 9240 7950 2120 1480 2100
Hospital Day

Fluid Intake Fluid Output

Figure 2. Graph of the 24-hour fluid intake and output.

Diabetes insipidus (DI) was initially considered as the ducing the hemodynamic instability due to volume
possible cause of polyuria, however the presence of
an inappropriately concentrated urine in the
background of hypoosmolar, hyponatremic state is
not consistent with a diagnosis of DI and is more
compatible with both SIADH and CSWS. However,
due to the apparent clinical euvolemic state of the
patient, SIADH was initially entertained as the more
appropriate diagnosis, thus fluid restriction was
started.
th th
During the 7 and 8 hospital days, the serum
sodium started to increase in response to the
reduced fluid load given to the patient. However,
th
during the 9 hospital day, the patient developed
increasing dysphasia and agnosia; she became
hemodynamically unstable, with hypotensive
episodes at 80/60 responsive to intravenous fluid
resuscitation. Cranial non-contrast magnetic
resonance imaging was done which showed an acute
infarct in the left parietal lobe. A central venous line discontinuing it after two weeks.
was also inserted revealing initial venous pressure
readings of 3-4 cm. The diagnosis was reconsidered
to a possible Cerebral Salt Wasting Syndrome due to
the persistent polyuria and computed negative salt
and fluid balance, the latter of which possibly pro-
contraction.
The patient was then managed with aggressive
intravenous saline infusion, targeted towards
restoring salt and fluid balance; these measures
stabilized the patient’s hemodynamics thereby
preventing further progression of her neurologic
condition. Thereafter, the salt and fluid balance was
maintained by corresponding modification in oral
sodium intake (diet and sodium chloride tablet
supplementation) to match the estimated daily
sodium loss. Due to persistent polyuria and
increasing saline requirement, fludrocortisone was
started on the 11th hospital day at an initial dose of
100 mcg/day and subsequently increased to 200
mcg/day on 13th hospital day. Succeeding days
showed progressive decrease in urine output and
sodium requirement, thus the dosage was tapered
down and maintained at 100 mcg/day before
On her follow up, after a month of discontinuing
fludrocortisone and sodium supplementation, the
patient remained hemodynamically stable with no
neurologic deficits; her salt and fluid balance was

22 | www.pjnonline.com | Vol. 25 No. 1 October 2017

also maintained with a regular diet. euvolemic, leading to an initial diagnosis of SIADH.
However, as noted during the succeeding hospital
DISCUSSION days, the persistent polyuria, negative fluid balance,
In literature, the two most common causes of and episodes of hypotension together with low CVP
hyponatremia occurring after subarachnoid values (<4), led us to reconsider the diagnosis which
hemorrhage are SIADH and CSWS. Previously, studies is more consistent with CSWS. Other proposed
done on hyponatremic patients post SAH identify distinguishing characteristics are shown in Table 1.
CSWS as the more common etiology; however, two
large recent prevalence studies made by Kao and Table 1. Characteristics of the Syndrome of
Sherlock et al., demonstrate that SIADH is the most Inappropriate Antidiuretic Hormone (SIADH) and
common cause of hyponatremia in SAH patients.1,6 Cerebral Salt Wasting Syndrome (CSWS)
CSW SIADH
Distinguishing between these two conditions is Signs of
therapeutically important due to the contrasting dehydration on Variably
Absent
approach to management; fluid restriction is physical present
employed for SIADH while vigorous sodium and fluid examination
replacement corrects the volume contraction and Central venous
↓ ↑ or normal
hyponatremia in CSWS.4 As demonstrated in our pressure
case, catastrophic complications such as cerebral Plasma volume ↓ ↓ or normal
vasospasm leading to cerebral infarction may occur Sodium balance Negative Variable
after coiling; this condition can be triggered and or Fractional sodium
↑↑ ↑ or normal
aggravated by hemodynamic instability produced by excretion
volume depletion. Correct identification and Hematocrita ↑ Unchanged
appropriate management of co-morbid conditions Plasma urea/
↑ Normal
associated with brain injury problems like creatinine ratio
hyponatremia is therefore of paramount importance Plasma potassium
↑ or normal ↓ or normal
to prevent possible catastrophic events. Identifying concentration
one over the other may prove to be difficult due to Serum uric acid
↓ or normal ↓
the many similarities in the presentation of both concentration
SIADH and CSWS. Adapted from Betjes MG. Hyponatremia in acute
brain disease: the cerebral salt wasting syndrome,
Eur J Intern Med. 2002;13(1):9-14. PMID
Currently, there are no consensus criteria for the
11836078.
diagnosis of CSWS.1 The only key difference between ↑ Increase, ↓ Decrease
CSWS and SIADH is the presence of volume a
Hematocrit does not differentiate
depletion, which is characteristically found in CSWS.5 postoperatively
Clinically, extracellular fluid volume loss can be
manifested by symptoms such as weakness, light- Delayed neurological deterioration is a common
headedness, and syncope; and physical findings sequela after SAH; this includes cerebral vasospasm,
which include orthostatic hypotension, dry mucous hydrocephalus and seizures.10 Cerebral vasospasm
membranes, and tachycardia.7 However, these complicates approximately two-thirds of patients
findings have both low sensitivity and specificity.8 who survive their initial episode or who were
Another option to determine volume status is via successfully treated surgically or endovascularly.11
invasive hemodynamic monitoring, demonstrated as Vasospasm can be asymptomatic; symptoms usually
low pulmonary capillary wedge pressure or central develop when cerebral blood flow falls below a
venous pressure.2,3,9 During the first few days of certain ischemic threshold. This can be the net result
hospitalization, our patient appeared clinically of vasoconstriction, impaired autoregulation, and

Vol. 25 No. 1 October 2017 | www.pjnonline.com | 23

inadequate intravascular volume.12 The condition
usually develops four to nine days following SAH,
often heralded by worsening headache and
increasing blood pressure, eventually progressing
into confusion and a decreased level of
consciousness with focal neurologic deficits.10,13 In
CSWS, the renal salt wasting often disturbs the
delicate balance during the management of SAH; the
decrease in plasma volume could potentially worsen
cerebral blood flow. This was demonstrated in our
patient while undergoing fluid restriction during the
7th to the 9th day of hospitalization; the ischemic
event could have been precipitated by induced
volume contraction. Subsequent repletion of the
sodium load, and in effect the expansion of the
extracellular fluid volume status, gradually improved
the neurologic function of the patient.
The management in CSWS is characterized by
aggressive sodium replacement to compensate for
the salt wasting by using either an isotonic or
hypertonic saline infusion.3 Frequent monitoring of
sodium and fluid balances, as well as daily weight
measurements are essential to estimate body fluid
changes. Fluid restriction, the cornerstone of
management in SIADH, is deleterious in CSWS as
demonstrated in a study done by Widjicks et al.
Almost half of the study patients treated with fluid
restriction developed cerebral infarction, most of
which were clinically diagnosed with SIADH.
Although volume status was not clearly defined in
the study, the authors implied that if the study
population were indeed hypovolemic, fluid
restriction may have aggravated the decreased
cerebral perfusion pressure and causing
14
vasospasm. Other treatment strategies that can be
employed involves administration of corticosteroids
such as fludrocortisone, a potent mineralocorticoid
that acts on the distal tubules, stimulating
reabsorption of sodium and water, leading to
extracellular fluid expansion.15 This decreases the
daily sodium requirement needed to maintain
balance and also acts to stop the natriuresis-induced
polyuria. This strategy was highly effective in our
case as fludrocortisone decreased the urine output
and sodium requirement (Figures 1 and 2).
24 | www.pjnonline.com | Vol. 25 No. 1 October 2017
CONCLUSION
The differentiation of CSWS versus SIADH occurring
after an acute brain disorder can be challenging due
to significant overlap between them. An accurate
assessment of the volume status with clinical and
objective parameters is critical to make the correct
diagnosis and thus avoid untoward clinical
consequences.
Acknowledgment
None.
Funding
None.
Disclosure
None.
Author Details
*Renz Michael F. Pasilan, MD; Internal Medicine
Resident in Training Year Level-I, Asian Hospital and
Medical Center
**Pelagio L. Esmaquel, Jr. MD; Training Officer
Internal Medicine Residency Training Program, Asian
Hospital and Medical Center
REFERENCES
1. Kao, L, Al-Lawati Z, Vavao J, Steinberg GK, Katznelson
L. Prevalence and clinical demographics of cerebral salt
wasting in patient with aneurysmal subarachnoid
hemorrhage. Pituitary 2009;12(4):347-51. PMID:
19462244 DOI: 10.1007/s11102-009-0188-9.
2. Palmer BF. Hyponatremia in a neurosurgical patient:
syndrome of inappropriate antidiuretic secretion
versus cerebral salt wasting. Nephrol Dial Transplant.
2000;15(2):262-8. PMID: 10648680 DOI:
10.1093/ndt/15.2.262.
3. Cerdà-Esteve M, Cuadrado-Godia, E, Chillaron JJ, et al.
Cerebral salt wasting syndrome: review. Eur J Intern
Med. 2008;19(4):249-54. PMID: 18471672 DOI:
10.1016/j.ejim.2007.06.019.
4. Nakajima H, Okada H, Hirose K, et al. Cerebral salt
wasting syndrome and inappropriate antidiuretic
hormone syndrome after subarachnoid hemorrhaging.
Intern Med. 2017;56 (6):677-80. PMCID: PMC5410479
DOI: 10.2169/internalmedicine.56.6843.
5. Tanaka T, Uno H, Miyashita K, Nagatsuka K. Cerebral
salt wasting syndrome due to hemorrhagic brain
infarction: a case report. J Med Case Rep. 2014;8:259.
PMCID: PMC4124770 DOI: 10.1186/1752-1947-8-259.
6. Sherlock M, O’Sullivan E, Agha A, et al. The incidence
and pathophysiology of hyponatremia after
subarachnoid hemorrhage. Clin Endocrinol (Oxf).
2006;64(3):250-4. PMID: 16487432 DOI:
10.1111/j.1365-2265.2006.02432.x.
7. Harrigan MR. Cerebral salt wasting syndrome. Crit Care
Clin. 2001;17(1):125-38. PMID: 11219225.
8. Spasovski G, Vanholder R, Allolio B, Annane D, Ball S,
Bichet D, et al. Clinical practice guideline on diagnosis
and treatment of hyponatremia. Eur J Endocrinol.
2014;170(3):G1-47. PMID: 24569125 DOI:
10.1530/EJE-13-1020.
9. Betjes MG. Hyponatremia in acute brain disease: the
cerebral salt wasting syndrome. Eur J Intern Med.
2002;13(1):9-14. PMID: 11836078.
10. Kassel NF, Sasaki T, Colohan ART, Nazar G. Cerebral
vasospasm following aneurysmal subarachnoid
hemorrhage. Stroke. 1985;16(4):562-72. PMID:
3895589.
11. Sterns RH, Silver SM. Cerebral salt wasting versus
SIADH: What difference? J Am Soc Nephrol.
2008;19(2):194-6. PMID: 18216309 DOI:
10.1681/ASN.2007101118.
12. Keyrouz, D; Clinical review: prevention and therapy of
vasospasm in subarachnoid hemorrhage. Crit Care
Vol. 25 No. 1 October 2017 | www.pjnonline.com|25
2007;11(4):220. PMCID: PMC2206512 DOI:
10.1186/cc5958.
13. Suhardja A. Mechanisms of Disease: roles of nitric
oxide and endothelin-1 in delayed cerebral vasospasm
produced by aneurysmal subarachnoid
hemorrhage. Nat Clin Pract Cardiovasc Med.
2004;1(2):110-6; quiz 2 p following 116. PMID:
16265315 DOI: 10.1038/ncpcardio0046.
14. Widjicks EF, Vermeulen M, Hijdra A, Van Gijn J.
Hyponatremia and cerebral infarction in patients with
ruptured aneurysms: is fluid restriction harmful? Ann
Neurol. 1985;17(2):137-40. PMID: 3977297 DOI:
10.1002/ana.410170206.
15. Mori T, Katayama Y, Kawamata T, Hirayama T.
Improved efficiency of hypervolemic therapy with
inhibition of natriuresis by fludrocortisone in patients
with aneurysmal subarachnoid hemorrhage. J
Neurosurg. 1999 Dec;91(6):947-52. PMID: 10584839
DOI:10.3171/jns.1999.91.6.0947.
 Perspectives in Nephrology

Melvin R. Marcial, MD An Opinion on Using and Doing Local Health Research in

Associate Professor 1, the Philippines
Why publish? Why revive the Philippine Journal of
University of Santo Tomas
Nephrology (PJN)? This must be one of the most
Faculty of Medicine and The importance of overwhelming
research in medical
Surgery questioneducation
that comes andto clinical practice
mind given the
is conspicuous. According to The CHED Memorandum Order
already existing and steadily increasing number of (CHED MO)
No. 40 series 2015publications
for medical which,
curriculum, graduates
according to ofthebasic medical
International
education should beAssociation
able to assume any ofTechnical
of Scientific the following roles:Publishers
and Medical 1. Generalis
estimated
Medical Practitioner, at 28,100
2. Health active scholarly
Professions peer-reviewed journals
Teacher/Academician, 3.
Researcher/Medicalin Scientist/Innovator,
the late 2014 (plus 6450 4.non-English language journals),
Health Administrator, 5.
collectively publishing about 2.5 million articles
Health Information Manager, 6. Health Economist and 7. Health Policy a year. And
this has been steadily increasing at a rate of about 3 – 3.5%
Maker. These roles project the1 requisite character of a 5-star physician.1
per year. Locally, HERDIN (Health Research and
Development Information Network) the national health
Multitasking as we are, majority would not have any qualms in assuming
research repository of the Philippines lists a total of 71
all the other roles indexed
except journals,
that of being a researcher. Need I ask what
of which 22 are peer-reviewed.2
reasons we may have that makes us not to be quite confident in
To being
assuming such role of the great majority of the scientific publishing world, the
a researcher?
persuasive reason to publish probably lies in the estimated
1
Furthermore, CHED$10 MO billion-dollar
No. 40 stated annual
that, worth
using aofholistic
revenue. But toand
approach the
Philippine Society of Nephrology Inc.
critical thinking, the basic physician must be able to formulate, (PSN) the answer lies
in the very core of its existence. The very first line of the
implement research proposal, and disseminate research results. In
PSN vision states its “… adherence to the highest standard
difficult to diagnose or treat cases, research capability likewise is
of excellence in training and research in the field of
employed by conducting literature search, critically appraise selected
nephrology.” The same principle is echoed in the very first
1
_________ journal or article, and
linemake
of itsclinical
stateddecision
mission based on appraisal.
“…promotes and disseminates
Correspondence: current knowledge and information in nephrology.” This is
Melvin R. Marcial, MD Thus, as a physician,verywe areandexpected
true to create
current now new
as it was knowledge
then thru
when the same
University of Santo Tomas
research (a constructivist)
opinion was thatexpressed
would be by relevant
Dr. FiloteotoA. the health
Alano in thecare
very
Faculty of Medicine and
Surgery needs of our country first (a reconstructivist)
editorial and toJournal
of the Philippine make ofuse of current
Nephrology in
3
2nd floor St. Martin de Porres 1986.
researches to help us in our clinical practice (a pragmatist). We should
Building, UST España therefore be both a producer and a consumer of knowledge using
Boulevard, Sampaloc, Manila, Publication is an integral part of research activity; writing
research that is evidence-based. These are the qualities of a 21st century
Philippines, 1008 and disseminating the knowledge gained from the
E-mail: lifelong learner. systematic process of answering a scientific question is part
mp_marcial@yahoo.com
of a continuum that enriches the body of knowledge.
We have no problem using research
However, as a consumer
the explosion of knowledge,
of information with but
the
producing new knowledge thru research? Need I ask what reasons
introduction of new and ever changing technologies and we
may have (though mediaI am sure
demandwe that
always yearn for
publication it), also
must for the
keepseeming
up with
Creative Commons License
Attribution-Noncommercial-Share
theseaptly
disinterest or as I may changes
say, and trends. There is
disappointment in now a compelling
conducting need
research
Alike 4.0 [CC BY-NC-SA 4.0]. for publishers
to generate new knowledge? and journals to provide access to the recent
and relevant researches that adheres to the standard of
ethics in research and publication. These are the same

26 | www.pjnonline.com | Vol. 25 No. 1 October 2017

 Marcial MR
Completed research paper is a definite requirement
for graduation from premedical courses to post
graduate trainings. Need I ask what happened to such
research graduation requirements? How many of
such were published, or even presented as poster at
local or international forum? How about the quality
and scope of the paper? Do we really need to make it
a requirement for graduation, whether in medicine
proper, internship, residency or fellowship? (I
suppose I anticipate some violent reactions with
regards to this). Are we really producing quality paper
worthy of publication or international presentation?
Would apprenticeship or formal research fellowship
be more appropriate requirement of competence?
Isn’t exposure to an ideal research environment an
inherent requirement before requiring it to be a
prerequisite for graduation? Is research really for
everybody?
Majority of health research are usually institutional
experiences that cannot be translated to represent
the true clinical picture of the country. Multicenter
studies, more importantly, research papers that are
national in scope are like needle in a haystack. This
personal observation has been confirmed when I
accessed HERDIN (Health Research and Development
Information Network), a database that serves as the
national health repository of the Philippines.2 It
provides a quick and easy access to more than 50,000
citations and bibliographic information from
published and unpublished health research in the
country. How many of us include this commendable
repository of local research in our literature search
whether for our own research or for clinical decision
making? Though some institutions have their own
research databases, HERDIN includes all private and
government institutions. Why is it that multicenter
studies or research that is national in scope are rare, if
I may offer my view? The challenges perhaps lie in the
following: the idiosyncrasies of some institutions and
medical societies in sharing their database for
research purposes (simply put…unwillingness to share
database and collaborate with other institutions, in
case of medical societies, the very tedious process of
seeking approval for full access); the difficulty of
creating, organizing a network and getting the ethical
considerations/approval (which can be a major cause
of delay due to bulk of workload and limited time
allotted per month by majority of members who are
all multitasking) and; the financial constraint inherent
with a large scale work.
How frequent in our conferences and literature
search do we make use of HERDIN? Majority for sure
prefers to access only international databases
overlooking the fact that we have our very own
HERDIN. Local studies have its own merits, and would
it be more relevant clinically in using our local data
first than anything else? Are we still trapped in the
idea of local research being less credible than
international studies? Are we not yet through with
our colonial mentality? This oversight of HERDIN also
results to duplication of research with limited scope
as shown by many local institutional experience
studies. Will such research stand on its own to stand
for the Philippines’ current health status?
Likewise, we should be aware that there is Philippine
Health Research Registry (PHRR), a publicly accessible
database on newly approved health research.3 It
includes clinical trials and non-clinical studies
conducted in the Philippines. The registry is compliant
with the World Health Organization (WHO) standard
for clinical trials registry. The PHRR monitors the kinds
of on-going and newly-approved research to know
who funds what kind of project, compel researchers
to submit final reports for research they conducted,
avoid duplication of research, and ensure equal
access opportunity for prospective clinical trial
participants.
Vol. 25 No. October 2017 | www.pjnonline.com | 27
 Opinion on doing and using local health research
How many times have you experienced attending a
conference whether here or abroad when a data on
Asia is projected on the screen, Philippines is nowhere
to be found? Are we not part of Asia? In a rare case
Philippines was included in the data, our contribution
is too small or unimportant to be worth
consideration.
According to Dr. Jaime Montoya, Executive Director of
the Philippine Council for Health Research and
Development (PCHRD), research in the Philippines
should be dynamic, realistic, responsive, and
relevant.4 If we are given a chance to evaluate the
bulk of research done in our country based on the
parameters stated, what could be the answer?
Subjectively, with confidence though, I can say it is far
from these factors mentioned above. He stated that
the majority of health research produced in the
Philippines remains unpublished, which hampers our
ability to share the knowledge created by our national
health research system.
The number of well-planned research (published or
not) pale in comparison to the opposite. Is doing a
quality research reserved for a chosen few...when I
say a chosen few, those who are doing research as an
advocacy...a vocation if I may say? Need we all must
have masteral degree in clinical epidemiology or other
related courses to “speak the language" to be familiar
with the intricacies of having our research proposal
approved by the institutional or national programs
with health initiatives agenda? We know very well
that the number of highly-skilled researchers in our
country or per institution is wanting. Up to when can
we count on these handful of breed of true scientists?
Every mission and vision of all medical schools and all
medical societies/training institutions include
research as one of their institutional thrust. This put
research always in the forefront ... supposedly a
28 | www.pjnonline.com | Vol. 25 No. 1 October 2017
priority. Or Is it just a case of a lip service? Let me
define what lip service means, avowal of advocacy,
adherence, or allegiance expressed in words but not
backed by deeds.5 Many may not agree with me. An
endowment fund for research and/or allocation of a
certain budget for the purpose of research is not
enough. Ideally, it must be paired with the needed
structure, networking and opportunity to present
and/or published both locally and/or internationally
with the ultimate goal of being translated into
practice and policy. The PCHRD recognized the lack of
training and laboratory facilities needed to produce
leading research work, particularly in the different
teaching hospitals and medical centers.
Majority of our medical graduates would not consider
doing research as a career in itself. The mindset is
that it is difficult, not financially rewarding (not true in
it strictest sense) and all the other challenges
mentioned above. Compared to European countries,
USA as well as our neighboring Asian countries like
Japan, Singapore, Taiwan and China, who have a
sound research infrastructure and networking, highly-
skilled researchers, stable financial resources, good
and reliable platform to present, publish, translate
and use research results, doing research as a career is
very rewarding both financially and professionally.
What is the use of having research priorities and
database for each specialty societies if these cannot
be realized and translated into policy and practice?
Seeing how these countries present their research
during conventions and recognizing the effort of their
team members as they flash the slide showing their
research laboratories is really a source of envy. What
is the status of our country in terms of international
representation research wise?
There are still many issues to consider in using and
doing local research in our country. However, my
prayers would be the following:
 Marcial MR
An extensive use of local research using HERDIN and
local medical publications (regardless of institutional
source of the research paper) in all case conferences/
discussions alongside updated international research.
The PCHRD’s information strategy includes expanding
medical informatics services, and using information
technology to offer broader access to health research
done by Filipino researchers. This will establish
awareness of the availability/non- availability of local
research on certain topic, which will be a basis of
possible new research. Likewise, it would avoid
duplication of research.
All institutions/medical societies must aim for a global
recognition in the field of research by doing
collaborative high impact papers that is national in
scope and following the established research
priorities. Sharing of database among institutions can
be formalized and protected by creating
Memorandum of Agreement which is imperative so
that our health care research can be presented
internationally.
The PCHRD has a lot of funding available as well as
from other private and government sectors. Effective
information dissemination is a tall order. Most
importantly, simplify the procedure in applying for
research grant.
Ideally, research laboratories where basic research
can be conducted, must be set up in strategic location
throughout our country subsidized both by the
private and government sectors. An alternative for
this would be upgrading the existing laboratories in all
medical schools that would be able to accommodate
and produce basic research. This kind of set up would
encourage medical students/postgraduate trainees to
engage in basic research.
One of the ways to increase the pool of researchers, is
to encourage the medical societies to establish
Fellowship Program on Research in their respective
specialization after the usual clinical fellowship
program. The newly graduate subspecialist would
have an ample clinical experience and would be able
to focus on research alone. The program can generate
well planned research as an output. Those who would
apply to this research fellowship program must be
given an enticing monthly stipend or a research grant
that can afford them a comfortable life, and must
have access to the database of all the training
institutions under the said specialty.
The medical curriculum in general must likewise be
responsive to the real healthcare needs of the country
by giving equal importance to research. Medical
students must have an access or exposure to
institutions with well-established research
infrastructures by collaboration and exchange
programs. This will heighten the interest of medical
students to make research as their main career track.
As a final point, the best way to be known globally is
to make use of our own data, creation of accessible
national databases for all diseases and align these to
our research priorities, establish genuine institutional
collaboration, judicious use of resources, mediocre
free attitude, encourage out of the box thinking,
reduce bureaucracy in all institutions especially when
accessing data and seeking approval, circumvent lip
service, have a growth mindset instead of a fixed one,
and the most important of all, be patriotic.
REFERENCES
1. CHED Memorandum Order No. 40 Series Of
2015, Subject: policies, standards and
guidelines. For the Doctor of Medicine (M.D.)
Program, Retrieved September 28, 2017, from
Republic of the Philippines Office of the
Vol. 25 No. October 2017 | www.pjnonline.com | 29
 Opinion on doing and using local health research
President Commission on Higher Education
Web site: http://www.ched.gov.ph/wp-
content/ uploads/2014 /12/Public-
Consultation-on-the-PSG-for-Doctor-of-
Medicine-Program-Aligned-to-Outcomes-
Based-Education-December-19-2014.pdf.
2. HERDIN (Health Research and Development
Information Network) Website: Retrieved
September 28, 2017 http://www.herdin.ph/.
3. Information Services, The Philippine Health
Research Registry (PHRR). Retrieved
September 28, 2017. The Philippine Council
for Health Research and Development
30 | www.pjnonline.com | Vol. 25 No. 1October 2017
(PCHRD) Website: http://www.pchrd.
dost.gov.ph/ index.php/programs-and-
services/ information-services.
4. Priorities for Health Research in the
Philippines, Retrieved September 28, 2017.
COHRED, the Council on Health Research for
Development Website:
http://www.cohred.org/perspectives/
priorities-for-health-research-in-the-
philippines/.
5. Meriam Webster Website: Retrieved
September 28, 2017. https://www.merriam-
webster.com/dictionary/lip% 20service.
 AUTHOR CERTIFICATION
Submissions of manuscript for consideration and possible publication in the Philippine Journal
of Nephrology must be accompanied by the following attestation:

(1) Authorship Certification

(2) Author Declaration
(3) Statement of License to Publish, and
(4) Statement of Disclosure of Conflicts of Interest

*please check accompanying box to signify agreement

COMPLETE TITLE OF MANUSCRIPT

______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________

AUTHORSHIP CERTIFICATION

In consideration of our submission to the Philippine Journal of Nephrology (PJN), I/We hereby
certify, that all the undersigned author/s have actively contributed and participated sufficiently
in the content of the submitted manuscript; fulfilling the following criteria of contribution: (1)
conceived and/or design the work that led to the submitted manuscript, the acquisition,
analysis and/or played an important role in the interpretation of the results; (2)drafted and/or
revised the manuscript and; (3) approved the final version herein submitted.

AUTHOR DECLARATIONS

I/We hereby certify, that the submitted manuscript is an original intellectual creative work that
has not been published and/or is currently submitted for consideration in any other
publication. I/We further affirm not to submit the same to another publication pending final
decision of PJN to this submission.

I/We hereby certify, that the study on which the manuscript is based, conformed to ethical
standards and/or had been reviewed by the appropriate ethics review board/committee.

Vol. 25 No. 1 October 2017 | www.pjnonline.com | 31

 AUTHOR STATEMENT OF LICENSE TO PUBLISH

I/We hereby certify that we recognize and accept that the Philippine Journal of Nephrology is
an OPEN-ACCESS publication, wherein all published articles/materials are open to be used to
expand the body of knowledge in the field of Medicine - Nephrology, for non-commercial
purposes, provided the article/s used are properly cited and recognized (Attribution-
Noncommercial-Share Alike 4.0 International Creative Commons License [CC BY-NC-SA 4.0]. The
undersigned author(s) hereby grants the Philippine Society of Nephrology, Philippine Journal of
Nephrology the exclusive license to publish. The author/s hereby retain the copyright
ownership of the published article unless otherwise explicitly agreed as state herein below. As
copyright owner of the published article, the undersigned author/s will only release for public
use such article six (6) months after the date of its publication. Furthermore, I/We hereby
affirm to cite the publication reference and DOI number of the published article, Furthermore;

I/We the undersigned author/s hereby also convey all the copyright
ownership of the manuscript to the Philippine Society of Nephrology and its
publication arm – PJN.

AUTHOR DISCLOSURE OF CONFLICTS OF INTEREST

The Philippine Journal of Nephrology requires all authors to make a full disclosure of areas of
potential conflict of interest; the absence of any interest to disclose must likewise be stated.
The undersigned author/s hereby attest that such declaration is contained in the body of the
submitted manuscript and/or as Annex attached and indicated in the body of manuscript.

I/We do not have any conflicts of interest to disclose.

Author/s Name (Print) Signature Date

_______________________________ _______________________ ____________

_______________________________ _______________________ ____________

_______________________________ _______________________ ____________

_______________________________ _______________________ ____________

_______________________________ _______________________ ____________

_______________________________ _______________________ ____________

32 | www.pjnonline.com | Vol. 25 No. 1 October 2017

 INSTRUCTIONS FOR SUBMISSIONS
Please note: Below are only guidelines that
author should follow to keep the manuscript at a
length that will sustain readership. Please
provide manuscript in Word document format,
along with the figures and tables.
Original articles describe investigations and
original research that represent new and
significant contributions and advances in
nephrology.
Instructions:
 Total word count (excluding abstract,
references and text for tables and
figures) should not exceed 4000 words
 Abstract should be no longer than 250
words
 Total number of tables and figures and
tables should not exceed 6
 Suggested limit of 30 references and
should be limited to recent works
Review articles examine major areas or sub-
specialty in the field of nephrology. The purpose
is to describe new developments, summarize
progress or analyze published evidence.
Instructions:
 Total word count (excluding abstract,
references and text for tables and
figures) should not exceed 4000 words
 Abstract should be no longer than 250
words
 Total number of tables and figures and
tables should not exceed six
 Suggested limit of 35 references
Vol. 25 No. 1 October 2017 | www.pjnonline.com | 33
Editorials are most often solicited by the
Editors, and are related to an article published in
the same issue. They express the opinions and
views of recognized experts on a specific topic.
Instructions:
 Total word count should not exceed
1500 words (excluding references and
text for tables and figures)
 No abstract
 Total number of tables and figures and
tables should not exceed two
 Limit of 8 references
 Limited or no subheadings within the
body of the manuscript
Commentaries are most often solicited by the
Editors, and are not related to a specific article.
They express the opinions and views of
recognized experts on a specific topic. The
commentary format may be used for ongoing
dialogues, discussions of controversial issues, or
subjective articles of interest in any field of
nephrology.
Instructions:
 Total word count should not exceed
2000 words (excluding references and
text for tables and figures)
 No abstract
 Total number of tables and figures and
tables should not exceed 2
 Limit of 8 references
 Limited or no subheadings within the
body of the manuscript
Practice guidelines and published statements,
intended to guide clinical and patient care (for
example, Guidelines, Recommendations,
Consensus Statements, and Position Papers).
Instructions:
 Total word count (excluding abstract,
references and text for tables and
figures) should not exceed 4000 words
 Abstract should be no longer than 250
words
 Total number of tables and figures and
tables should not exceed 6
 Suggested limit of 30 references
Letters to the Editor should comment on work
previously published in PJN. Publication is
based on the decision of the Editorial Board,
who occasionally may ask experts on the merit
of the contents. The Editors may invite a reply to
the letter by the original author. The Editor may
consider publication of a letter that comments on
other matters of interest to Nephrology.
However, this section is not considered to be an
appropriate venue for publishing new data
without peer review. Studies with scientific
merit should be considered for submission as an
Original Article or Short Communication.
Instructions:
 Total word count should not exceed 750
 No tables or figures are to be included
 Limit of 5 references
Perspectives in nephrology discuss significant
topics and issues relevant to nephrology. These
articles are typically from a more personal or
opinion-based standpoint than a Review Article.
Perspectives should state the topic and
background information concisely, discuss
opposing viewpoints, and make
recommendations for further investigations or
actions. Interested authors should correspond
34 | www.pjnonline.com | Vol. 25 No. 1 October 2017
with the editor prior to submission to discuss the
suitability of the proposed subject matter.
Instructions:
 Total word count (excluding abstract,
references and text for tables and
figures) should not exceed 2500 words
 Abstract should be no longer than 250
words
 Total number of tables and figures and
tables should not exceed 4
 Suggested limit of 30 references
Short communications are brief reports of
preliminary or limited results of original
research, observations, or case series on the
causes, mechanisms, diagnosis, course,
treatment, and prevention of kidney diseases.
Instructions:
 Total word count (excluding abstract,
references and text for tables and
figures) should not exceed 1500 words
 Abstract should be no longer than 250
words and must not contain headings
 Total number of tables and figures and
tables should not exceed 3
 Suggested limit of 20 references
Case reports on nephrology-specific cases.
Cases will typically be judged on clinical
interest and educational value to the nephrology
field and NOT novelty or rarity.
Instructions:
 Total word count should not exceed
1500 (excluding abstract, references and
text for tables and figures)
 Include an unstructured abstract of no
more than 250 words that summarizes
the report
 Include a concise overview describing
the case and brief literature review
 Limit of 4 tables or figures
  Limit of 25 references

Meeting reports should focus on key  Abstract should be no longer than 250
developments presented and discussed at words
Nephrology convention, symposia and related  Total number of tables and figures and
meeting. tables should not exceed four
 Suggested limit of 20 references
Instructions:
 Total word count should not exceed
3500 (excluding abstract, references and
text for tables and figures).

Vol. 25 No. 1 October 2017 | www.pjnonline.com | 35

 AUTHORS' PROFESSIONAL AND ETHICAL RESPONSIBILITIES

Philippine Journal of Nephrology adheres to the International Committee of Medical Journal Editors’
(ICMJE) recommendations for the Conduct, Reporting, Editing and Publication of Scholarly Work in
Medical Journals, which can be found at http://www.icmje.org/.

Authorship
The ICMJE definition of author requires the person to have contributed directly to the intellectual content
of the paper and should meet ALL the following criteria:
 Substantial contributions to the conception or design of the work; or the acquisition, analysis, or
interpretation of data for the work; AND
 Drafting the work or revising it critically for important intellectual content; AND
 Final approval of the version to be published; AND
 Agreement to be accountable for all aspects of the work in ensuring that questions related to the
accuracy or integrity of any part of the work are appropriately investigated and resolved.
Other persons who may have made direct or indirect contributions to the work but cannot be considered
authors based on the above criteria, should be listed in the Acknowledgments section. Because
acknowledgment may imply endorsement by acknowledged individuals of a study’s data and conclusions,
the corresponding author must obtain written permission to be acknowledged from all acknowledged
individuals.
When submitting a group author manuscript, the corresponding author should clearly indicate the
preferred citation and should clearly identify all individual authors as well as the group name. Other
members of the group should be listed in the acknowledgements.

Role of the Corresponding Author

The corresponding author is the individual who takes primary responsibility for communication with the
journal during the manuscript submission, peer review, and publication process. Only one author can be
the corresponding author and who shall be responsible for the following:
 Comply with all the submission requirements including all the required forms and consent;
 Ensure that all authors have reviewed and approved the final version of the manuscript prior to
submission;
 Inform the other authors on the decision, reviewer comments, and other messages from the
journal, and distribute proofs among coauthors for review;
 Return corrections and ensure that all authors approve each version of the article
 Correspond with the PJN regarding critiques of the work and cooperate with any requests from
the journal for data or additional information should questions about the paper arise after
publication.

36 | www.pjnonline.com | Vol. 25 No. 1 October 2017

Sources of support
Sources of support for research, including funding, grants, equipment, and drugs, must be disclosed in the
Acknowledgment section. There must also include a description of the role played by the funding source
in the collection of data, analysis, interpretation and preparation of the manuscript; if the funding source
has no such involvement, this should be stated as such.

Conflict of interest
All authors must disclose any conflict of interest, or declare if they have none.
Please download and accomplish the “Author Certification Form.”

Informed consent
Identifying information, including patients' names, initials, or hospital numbers, should not be published
in written descriptions, photographs, and pedigrees unless the information is essential for scientific
purposes and the patient (or legal guardian) gives written informed consent for publication.

Vol. 25 No. 1 October 2017 | www.pjnonline.com | 37

 MANUSCRIPT PREPARATION GUIDELINES
Authors may also refer to the International Committee of Medical Journal Editors (ICMJE)'s
"Manuscript Preparation" guidelines for additional advice on appropriate manuscript preparation.
Structure and Presentation
The manuscript should be written as concisely as
possible. Focus on the content rather than the
look of the manuscript. Please refer to the
prescribed word limit in the section
“INSTRUCTION FOR SUBMISSION” for
specific manuscript category.
Use at least single line spacing throughout,
including in the references and figure legends.
Use a common font such as Verdana, Arial,
Helvetica, or Times in size 11 or 12 points.
Avoid using manuscript formatting except for
italic, superscript and subscript.
For section and subsection headings, please use
the heading styles built into your word
processing template to a maximum of three
levels.
All papers must contain the following items,
when applicable:
Title Page
The title page should include the following:
 The title of the article (150 characters
maximum, using sentence case). It
should reflect the content of the article.
 Full names of the authors (last, given,
middle initial), with academic degree(s)
attained or registration; avoid including
affiliation title e.g. Member, Diplomate,
Fellow etc. Correct: Zamora, Ma.
Norma V. MD. Incorrect: J.A. Smith
MD FRCP.
38 | www.pjnonline.com | Vol. 25 No. 1 October 2017
 The affiliation for each author. For each
affiliation, include the name of the
department (if any), the institution, the
city, the province and country where the
work was done. Link the authors to their
designations using these characters in
the order shown: * (asterisk, never
superscripted) ** double asterisk and so
on.
 At least three potential reviewers (name,
affiliation and email address), who
could, in the author’s opinion, expertly
review the manuscript. The Editors,
however, reserve the right to choose all
reviewers. These reviewers should not
have published with any of the co-
authors during the past 2 years and
should not currently work or collaborate
with one of the institutes of the co-
authors of the submitted manuscript.
 A shortened version of the title for use
as a running header (no more than 60
characters, upper case).
 The full name of the corresponding
author, with postal address, e-mail
address, and fax and telephone numbers.
 Acknowledgments of grant support and
of individuals who were of direct help
in the preparation of the study or the
manuscript. State also if there is none.


  A word count for the text only
(excluding abstract, acknowledgments,
figure legends, and references).
 The number of figures and tables.
 List of meeting/s or scientific forum
where the materials have been
previously presented or is under
consideration for presentation. Indicate
the name, place, date of meeting and
any prize or awards
Abstract and key words
Include a structured abstract of no more than
250 words for original and review articles.
Use these subheadings:
 Background or Objective
 State the purpose of objective of
the study
 Methods
 Generally the following are
included:
 Study design
 Setting
 Subjects, participants,
patients or population
 Results
 Conclusions (or Summary)
After the abstract, list up to eight key words or
phrases for journal (not library database)
indexing. A list of key words is required for all
submissions except editorials and commentaries.
Present the key words in one paragraph,
separated by commas, with no terminal
punctuation.
Text
Organization
Organize the text using the applicable structure
from the list set out here.
 Introduction (or Background)
 Methods
 Results
Vol. 25 No. 1 October 201746 | www.pjnonline.com | 39
 Discussion
 Conclusions (or Summary)
 Acknowledgments
 Conflict of Interest Disclosures
 References
 Appendices (optional)
 Figure Legends
 Tables
Abbreviations
Multi-word phrases used frequently (four times
or more) in the text may be abbreviated if
necessary. Introduce the abbreviation in
parentheses after the first occurrence of the
phrase, [for example, “chronic kidney disease
(CKD)”. Note that sentences may never begin
with an abbreviation.
Abbreviations for units of measurement and
standard scientific symbols (for example, 3 mL,
Na, BUN) may be used without explanation.
Units of Measurement
Use the SI system, and its standard symbols,
throughout the manuscript. When units other
than SI units are widely used, they can be
indicated in parentheses after the SI unit.
Dates and Times
All dates are to be presented in the form Month
dd yyy: for example, September 25, 2017. Times
are to be presented using the 24-hour clock.,
using “h” as a separator between the hour and
the minutes: for example, 8h30, 17h00.
Proprietary and Generic Names
Use generic names for all drugs.
References
Provide direct references to original research
sources when possible and if available Digital
Object Identifiers (DOIs) or URL. Avoid using
abstract as references.
The manuscript’s reference list must be
numbered (using Arabic
numerals) consecutively in the order in which
the references are first cited in the text. Citations
appearing in tables and figures must fit into the
numbering sequence from the point at which the
table or figure is first mentioned in the text.
Reference style and format: please consult –
http://www.nlm.nih.gov/bsd/uniform_require
ments.html
Figures
Figures for reproduction should approximately
fit within the typeset area of the journal. The
following resolutions are optimal:
 Black-and-white line drawings, 600–
1200 dpi
 Line drawings with some grey or
coloured lines, 600 dpi
 Illustrations and photographs, 300 dpi
Authors should supply electronic versions of the
figure content in EPS, GIF, TIFF, or JPEG
format. Other formats, such PDFs, may be used,
but are not preferred. Drawings in made in
Microsoft Word and Powerpoint are
discouraged, because the display of such
drawings may not be reproduced as intended by
the author.
Tables
Authors are asked to keep each table to a
reasonable size; minimize the use of
abbreviations, and if abbreviations must be used,
use only well-known and accepted forms. The
same data should not be presented in both a table
and a figure.
Tables are to be numbered using uppercase
40 | www.pjnonline.com | Vol. 25 No. 1 October 2017
roman numerals (I, II, III, and so on) in the order
in which they are cited in the article text. Tables
should also have a title (above the table) that
summarizes the whole table; it should be no
longer than 15 words.
Reporting Guidelines
Philippine Journal of Nephrology adheres to the
recommendation of ICMJE to follow guidelines
in reporting research study. Please refer to
the EQUATOR Network for a more detailed
description and applicable guideline to be used
for specific study designs example, CONSORT
for randomized trials, STROBE for
observational studies, PRISMA for systematic
review and meta-analysis, and CARE for case
report, etc.
Copyright Notice
The author retains the Copyright for articles
published in the Philippine Journal of
Nephrology unless specifically attested in the
“Author Certification”. What is required of the
author is to submit a signed “Author
Certification” granting PJN and or PSN the
exclusive license to publish such work.
Indicated as well in the certification is the
recognition and acceptance that PJN is an
OPEN-ACCESS publication, wherein all
published articles/materials are open to be used
to expand the body of knowledge in the field of
Medicine - Nephrology, for non-commercial
purposes, provided the article/s used are
properly cited and recognized according
to International Creative Commons License
Attribution-Noncommercial-Share Alike
4.0 [CC BY-NC-SA 4.0].
 What We Publish
Original articles
Original articles describe investigations and original research that represent new and significant contributions and new
information in Nephrology.
Review articles
Review articles examine major areas or sub-areas in the field of Nephrology. The purpose is to describe new
developments, summarize progress or analyze published evidence. Solicited an unsolicited review articles are subject to
peer review process prior to acceptance for publication.
Editorials
Editorials are most often reserved for Editors of the PJN. Editorials can also be solicited upon approval by the Editorial
Board, and are related to an article published in the same issue. They express the opinions and views of recognized
experts on a specific topic.
Commentaries
Commentaries may be solicited by the Editorial Board, or by the Officers and/or Board of Trustees of the Philippine Society
of Nephrology Inc. and are not limited to a specific published article. They express the opinions and views of recognized
experts on a specific topic. The commentary format may be used for ongoing dialogues, discussions of controversial
issues, or subjective articles of interest in any field of Nephrology.
Practice guidelines
Clinical practice guidelines and published statements, intended to guide clinical and patient care (for example, Guidelines,
Recommendations, Consensus Statements, and Position Papers).
Letters to the Editor
Letters to the Editor should comment on work previously published in Philippine Journal of Nephrology.
Publication is based on the decision of the Editorial Board, who may ask experts on the merit of the contents. The Editors
may invite a reply to the letter by the original author. The Editor may consider publication of a letter that comments on
other matters of interest to the Philippine Society of Nephrology. This section is not considered to be an appropriate
venue for publishing new data without peer review. Studies with scientific merit should be considered for submission as an
Original Article or Short Communication.
Perspectives in Nephrology
These articles discuss significant topics and controversies relevant to Nephrology and current clinical practice. These
articles are typically from a more personal or opinion-based standpoint than a Review Article. Perspectives should state
the topic and background information concisely, discuss opposing viewpoints, and make recommendations for further
investigations or actions. Interested authors should correspond with the Editorial Board prior to submission to discuss the
suitability of the proposed subject matter.
Insights can be any of the following:
 An inspiring reflection on any aspect of clinical practice
 A patient or circumstance who changed or inspire change of practice
 A positive reflection on teaching experiences
 A paper that changed your practice or thinking
Short communications
These articles are brief reports of preliminary or limited results of original research, observations, or case series on the
causes, mechanisms, diagnosis, course, treatment, and preventive health care in Nephrology.
Case reports
Case report articles report on Nephrology cases. Cases will typically be judged on clinical interest and educational value to
the science and practice of nephrology field and NOT novelty or rarity.
Meeting reports
Reports should focus on key developments presented and discussed at Philippine Society of Nephrology related meeting.
 Editorial Office: Philippine Society of Nephrology, Inc.
2406 One San Miguel Avenue Condominium, San Miguel Ave. cor. Shaw Blvd., Ortigas
Center, Pasig City, Philippines
Telephone number :(632) 6871-1198, (632) 687-1187
E-mail: phil.journal.nephrology@gmail.com

www.pjnonline.com
 Volume 18 Number 3
July-September 2017

• PCCP Position Statement on E- Cigarettes

• Respiratory disease during pregnancy
• MDMA-induced pneumothorax
• Overlap syndrome with ILD
• ACOS in asthma and COPD cohorts
• HRCT and PFT in bronchiectasis
• Three clinical phenotypes of COPD
• Pneumonia in lung cancer
 PHILIPPINE JOURNAL OF CHEST DISEASES
AN OFFICIAL PUBLICATION OF THE
PHILIPPINE COLLEGE OF CHEST PHYSICIANS

Editor-in-Chief
Evelyn Victoria E. Reside, MD, FPCCP

Managing Editor
Camilo C. Roa, Jr., MD, FPCCP

Reviewers
Christine Chavez, MD, FPCCP Ma. Bella R. Siasoco, MD, FPCCP
Richmond. B. Ceniza, MD, FPCCP Tim S. Trinidad, MD, FPCCP
Rosalyn H. Sebastian, MD, FPCCP Jennifer Ann M. Wi, MD, FPCCP

Copy Editor
Blesilda O. Adlaon

Editorial Assistant
Ivan Noel G. Olegario, MD, MDC

PHILIPPINE COLLEGE OF CHEST PHYSICIANS OFFICERS 2017-2018

Charles Y. Yu, MD, FPCCP

President

Lenora C. Fernandez, MD, FPCCP

Vice President

Malbar G. Ferrer, MD, FPCCP

Secretary

Ivan N. Villespin, MD, FPCCP

Treasurer

Gregorio P. Ocampo, MD, FPCCP

Imelda M. Mateo, MD, FPCCP
Eileen G. Aniceto, MD, FPCCP
Ma. Janeth T. Samson, MD, FPCCP
Jubert P. Benedicto, MD, FPCCP
Board Members

Vincent M. Balanag Jr., MD, FPCCP

Immediate Past President

The opinions and data expressed in the Philippine Journal of Chest Diseases (PJCD) are those of the individual authors. They are not
attributable to the editors or editorial board of the PJCD and should not be regarded as the official stand of/or endorsement by the
Philippine College of Chest Physicians. References may be made in the articles regarding drug usage, which may not be included in the
current prescribing information. The reader is, thus, urged to check the full prescribing information of drugs. No part of the PJCD may be
reproduced without the written permission of the publisher.

Address all communication and manuscripts for publication to the following: The Editor, Philippine Journal of Chest Diseases, 84-A Malakas
St., Pinyahan, Quezon City. Email: secretariat@philchest.org. Phone: (+632) 924 9204.
 INSTRUCTIONS TO AUTHORS
The Philippine Journal of Chest Diseases
publishes scientific papers in the field of
pulmonary medicine. These papers may be in the
form of collective and current reviews (state of the
art, meta-analyses), original investigations, case
reports, editorials or letters to the editor. All
manuscripts must be submitted electronically to
secretariat@philchest.org. Manuscripts should be
single spaced and left-justified, including
references. Use 10-point type, approximately 1-
inch margins, and format for 8 ½ x 11 paper. The
editorial staff requires files that can be opened and
manipulated in Word 2004-2009, PowerPoint or
Excel.
Accepted manuscripts become the property of the
Philippine College of Chest Physicians and are
published with the understanding that they are not
for publication elsewhere without approval.
These manuscripts are subject to editorial
modification.
Generally, write using the first person, active
voice; for example, “We analyzed data,” not
“Data were analyzed.” The Abstract
and acknowledgments or disclaimers are the
exceptions to this guideline, and should be written
in the third person, active voice; “The authors
analyzed,” “The authors wish to thank.”
Supply a title page as the first page of the
manuscript with the following information:
1. The manuscript’s full title which should
provide sufficient information regarding the
contents of the manuscript.
2. All authors should provide their complete
names, professional titles, and institutional
affiliations. Include an author byline that lists
all authors’ full names and academic degrees
above a Masters; for example, “Juana Cruz,
MD, PhD, and Juan Ramos, MD”. Also
include sentence-style bios for each author
than list position(s) or title(s) and institutional
affiliation(s); for example, “Dr. Cruz is
assistant professor, Section of Pulmonary
Medicine, Department of Internal Medicine,
State University College of Medicine”.
3. Contact information (address and email
address, plus telephone and/or fax) for the
corresponding author.
4. Disclosure of funding received for this work
from any organization or company.
5. State if the paper has been presented in any
convention and whether any awards have
been conferred on the paper.
Abstract. The abstract should not be longer than
250 words. It should contain a summary of what
was done in the study, including objectives, study
design, important results and conclusions. Only
findings restricted to the study should be
mentioned in the abstract. For research reports
only, abstracts must be in the structured form of
four paragraphs, with headings Purpose,
Methods, Results, and Conclusions; and must
include the year of the study. The authors should
also provide three key words under which the
article can be indexed.
Headings
For all manuscripts. Use main headings and
short subheadings as needed. Do not create a
heading at the very top of the manuscript (e.g.,
“Introduction”), since layout constraints make
such headings unworkable. Text should be set in
Times New Roman font, 10 point in size, and
single-spaced. The main heading of the online-
only text should be in 12 point and boldface;
subheadings should be in 10-point and boldface.
If subheadings are used, two or more such
headings must be used, as in outline style.
For research reports. Structure the body of the
manuscript using the headings Introduction,
Methods, Results, and Conclusions. At least a full
paragraph of text must precede the Introduction
heading, for layout reasons.
For articles. Create headings that are substantive
and interesting and that will give readers a sense
of the article’s organization. Make headings as
short as is feasible. At least a full paragraph of
text must precede the initial heading, for layout
reasons.
Text. Formal scientific or technical style shall be
followed in writing the manuscripts. All
abbreviations should be spelled out when used
for the first time. For standard terminology,
such as chronic obstructive pulmonary disease
 INSTRUCTIONS TO AUTHORS
(COPD) or forced vital capacity (FVC), only
standard abbreviations should be used. Information
or data that is best described in tables should be
presented as such. Tables which duplicate
information provided in the text shall be removed.
Generic names of drugs shall be used except in
instances where trade names are vital, such as in
clinical trials.
Tables and Figures. Only tables cited in the text
should be included. All tables should be called out
in the text and shall be numbered in ascending
order depending on the sequence they were
referred to in the text. A different order for tables
and figures is to be used. Symbols are * † ‡ § ¶.
A single table or figure with the appropriate labels
should be printed on a single page. The text and
data in online tables should be Arial font, 10 point
in size, and single-spaced. The table title should be
set in Arial font 12 point, and bold. Headings
within tables should be set in 10 point bold.
Explanatory notes or legends should be written
at bottom of the table or figure. Table titles should
make the table sufficiently understandable
independent of the manuscript. Typically, include
type of data, number and type of respondents, place
of study, year of study. Titles should be placed
directly above the table, not in a data cell. Columns
should be clearly labeled, including unit of
measure.
Footnotes: If information is needed to make the
table understandable that won’t easily fit into the
table title or data cells, create one or more
footnotes. Table footnotes should be set in 8 point
and single-spaced. Place footnotes at the bottom of
the table, not in a data cell. All abbreviations
should also be explained.
Figures. Only figures (or pictures) cited in the text
should be included. All figures should be called out
in the text and shall be numbered in ascending
order depending on the sequence they were
referred to in the text. A different order for tables
and figures is to be used.
Figures are acceptable as Excel, PowerPoint
or Word 2004-2009 files. All files supplied must be
“live” figures that can be opened and formatted.
PDFs and JPGs are not accepted. Figures should
be two-dimensional; black-and-white or
grayscale; and without gridlines or background
shading. X and Y axes, if present, must be
labeled.
Figure legends should make the figure
sufficiently understandable independent of the
manuscript. Legends should be placed on the last
page in the manuscript. All figures should be
separated from the text file, yet bundled into a
common file, if possible, with individual figures
separated by page breaks.
The editorial staff reserves the right to determine
whether the graphical instruments are appropriate
for the information being imparted and modify or
request modification/s for inappropriate
illustrations. The editorial staff reserves the right
to generate illustrations compatible with the
professional standards of the journal.
References. Authors are responsible for the
accuracy and completeness of their references and
for correct text citations. All references should be
identified at the appropriate parts of the text using
Arabic numerals enclosed in parentheses. All
references should then be typed double-spaced at
the end of the manuscript and numbered
according to the order they were cited in the text.
Journal references should include the names of all
the authors and inclusive page numbers.
Abbreviations of names of journals should
conform to those used in the Index Medicus.
For world wide web citations, follow the
following format: <author’s name> <title of
document> <<URL>> <date of document>
(accessed <date accessed>). You may break
URLS across lines, but if possible, arrange for
breaks to occur only at punctuation separators
(but not on hyphens, and don’t ever add hyphens).
Samples of the style to be followed in the listing
references are enumerated below:
JOURNAL ARTICLE: Tanchuco JQ, Young J.
Normal standards for spirometric tests in Filipino
children. Chest Dis J 1989. 16:93-100.
 INSTRUCTIONS TO AUTHORS
BOOK: Kelley MA, Fishman AP. Exercise
Testing. In: Pulmonary Diseases. 2 edition.
Fishman AP, (ed.). McGraw-Hill Book Co.; 1989.
pp.2525-2532.
WORLD WIDE WEB: Horton M, Adams R.
Standard for interchange of USENET messages
Request for comment s 1036, Network Working
Group. <ftp://ftp.demon.co.uk/pub/doc/rfc/rfc1036.
txt> Dec.1987 (Accessed 19 June 1995)
Personal communications, unpublished data or
manuscripts in preparation should not be used as
numbered reference. Instead, these may be cited in
parentheses or as a footnote on the page where they
are mentioned. Authors assume responsibility for
verifying the accuracy of their cited reference.
Advertisements. All requests for rates should be
add-ressed to: The Business Manager, Philippine
Journal of Chest Diseases, PCCP Secretariat, 84-A
Malakas St., Brgy. Pinyahan, Diliman, Quezon
City (Telephone No. 924-9204 and Fax No. 924-
0144). The journal also accepts announcements
from institutions or professional
invitations to forthcoming symposia or convention
for publication at minimal cost depending on
available space.
Reprints. Requests for additional reprints of
individual articles should be addressed to: The
Editor-In-Chief, Philippine Journal of Chest
Diseases, PCCP Secretariat, 84-A Malakas St.,
Brgy. Pinyahan, Diliman, Quezon City (Telephone
No. 924-9204 and Fax No. 924-0144). Author/s of
each manuscript are entitled to 25 copies of the
article. These shall be sent to the major author.
Requests for reprints should be addressed to the
senior author. Reprints of entire issues may be
provided at cost, depending on availability of
copies.
Subscriptions. All requests for subscriptions should
be addressed to: The Business Manager, Philippine
Journal of Chest Diseases, PCCP Secretariat, 84-A
Malakas St., Brgy. Pinyahan, Diliman, Quezon City
(Telephone No. 9249204 and Fax No. 924-0144. E-
mail address secretariat@philchest.org. One issue
(P120.00). Back issues (depending on availability
P120.00).
 JULY-SEPTEMBER 2017 VOLUME 18 NUMBER 3

1 EDITORIAL

3 Case series: Pathologies of the respiratory system during pregnancy

Rianne dela Cruz, MD; Sherry Gail Jaloro, MD; Jewel Cordelle Nuñal, MD; Ma.
Kriselda Karlene Tan, MD; Ralph Elvi Villalobos, MD; Lenora Fernandez, MD, FPCCP;
Albert Albay, Jr., MD, FPCCP; Jubert Benedicto, MD, FPCCP

13 Overlapping Overlaps: A Case Report

Maria Cristina A. Maranion, MD; Shariff Amiloari S. Manibpel, MD; Sonde Cris A.
Punay, MD

20 Prevalence of Asthma-COPD Overlap Syndrome (ACOS) in Patients Presenting with

Asthma or COPD in the OPD of the UP-PGH Section of Pulmonary Medicine: A
Pilot Study
Mariella Macrina Araneta-Cuňada, MD; Ralph Elvi Villalobos, MD; Lenora C.
Fernandez, FPCP, FPCCP

26 Clinical Correlation of the Radiologic Findings and Pulmonary Function of Patients

with Bronchiectasis: a Lung Center of the Philippines Experience
Joice Bumanglag-Dela Cruz, MD; Guia Elena Imelda R. Ladrera, MD, FPCP, FCCP

38 Prevalence and Characteristics of the Three Clinical Phenotypes of Chronic

Obstructive Pulmonary Disease at Lung Center of the Philippines
May N. Sabando, MD; Luisito Idolor, MD, FPCCP

48 Clinical Profile and Outcome of Lung Cancer Patients with Pneumonia Admitted at
Lung Center of the Philippines: A 5-year Retrospective Study
Tuesday N. Girado, MD, FPCP, FPCCP; Daphne D. Bate, MD, FPCP, FPCCP
EDITORIAL
From the necessary
to the impossible
Evelyn Victoria E. Reside, MD, FPCCP
Editor-in-Chief
“Start by doing what’s necessary, then
what’s possible; and suddenly you are doing the
impossible.”
– Saint Francis of Assisi
This quote from St. Francis of Assisi
accurately sums up the journey of the Philippine
Journal of Chest Diseases (PJCD) from its
inception, its ups and downs, and hopefully to its
successful recognition and indexing in the
Western Pacific Region Index Medicus
(WPRIM). Looking back, the road to this
present issue was a long and winding one, with
several snags and hitches, but the color and the
challenges along the way are giving the journal
its history and character.
Our Issue Number 3 for the year
recognizes the scientific work of our members
and fellows-in-training, who continue to nurture
their passion for research and support the journal
in the process. Most of the articles in this issue
focus on pulmonary infections and obstructive
lung disease, and sensibly so, since year after
year for the last several years, Pneumonia and
COPD have remained significant respiratory
illnesses in the Philippines. According to the
2014 Philippine Health Statistics from the
Department of Health, Respiratory Tuberculosis
(TB), TB Other Forms, Bronchitis, and Acute
Lower Respiratory Tract Infections and
Pneumonia continue to figure prominently in our
1 Philipp J Chest Dis 2017
national morbidity and mortality data.1 Because of
this, it is no surprise that data abound on these
respiratory conditions. However, since these
illnesses continue to persist among the top leading
causes of morbidity and mortality, it is evident
that our clinical data and research outcomes have
yet to be translated into meaningful public health
steps to create significant change in our country’s
health profile.
It is easy to consider the hospital and the
clinic to be entirely separate from the public health
domain. But it is evident that, despite their
differences, they need to be synergistic—one
feeding off the other to create healthier
communities. The clinician-researcher will have
various resources available to him or her, and
these will be different from the tools of the public
health physician, but they should be working
towards the same goal: the data gathered and
analyzed by the clinician-researcher must be
useful for application in the field, and vice versa,
and if not, and questions abound, then that sets the
stage for further research.
For it is equally important to know what
happens to our patients after they are discharged
from our hospitals, or exit our clinics—when they
reach home and re-integrate into their
communities at home and at work. Sometimes
what happens to our patients outside of our
hospitals and clinics are even more significant
than we think, especially considering the factors
of infectious diseases, exposure to second- and
even third-hand smoke, climate change,
environmental air quality, not to mention
cultural dimensions of health behavior and the
effects of family structure.
Although cigarette consumption has
decreased from 10.6 sticks daily per smoker in
2009 to 7 sticks per day per smoker in 2015,2 it
is difficult to say that this was the direct effect
of either the Sin Tax Law or the Graphic
Health Warnings Act, or both, or neither one.
Indeed, research is still lacking on the actual
effects of these legislative milestones, although
admittedly this will take considerable time and
resources to fully investigate. Moreover, much
research has been done on antimicrobial effects
of the various bugs (old and new) causing
pneumonia and other respiratory infections, but
up-to-date local data are lacking for topics such
as physician prescribing habits and preferences
for antibiotics, and immunization profiles of
the elderly.
Admittedly though, much has been
gained by the Sin Tax Law in terms of pushing
forward the Department of Health’s agenda.
But this influx of money to support the medical
needs of indigent patients and the growth and
development of our country’s health facilities
should be accompanied by an equally robust
research environment, more so for the
evaluation and monitoring of the effectivity and
responsiveness of our public health programs.
I am fully aware that this type of public
health research may not be the most inviting, or
the most common, for the clinician-researcher,
but they can and should be done. There was also a
time in the past when the movers behind the
PJCD never talked about indexing, but it can and
should be done.
Let us stretch our creativity and think out
of the usual research box. The challenge is not
just to lose ourselves in mounds of patient charts
to review them for historical data, or to
expectantly wait for patients to report for
scheduled follow-up visits for a pharmaceutical
clinical trial; but rather, an equally great challenge
is to roll up our sleeves and look to communities
for answers to our questions. And perhaps then,
once we have the patient and community
together—the forest AND the trees—the
seemingly impossible dream of a healthy
Philippines will become more possible.
References:
1. Asuncion IL, Benegas-Segarra A. 2014
Philippine Health Statistics. Manila:
Department of Health; 2014.
2. Kalusugan Pangkalahatan 2010-2016: An
Assessment Report. Manila: Department of
Health; 2016.
Vol. 18Vol.
| Issue
18 | 03
Issue
| September
02 | June 2017 2
Respiratory conditions in pregnancy

CASE SERIES

Case series: Pathologies of the respiratory system during

pregnancy
Rianne dela Cruz, MD; Sherry Gail Jaloro, MD; Jewel Cordelle Nuñal, MD; Ma. Kriselda
Karlene Tan, MD; Ralph Elvi Villalobos, MD; Lenora Fernandez, MD, FPCCP; Albert Albay,
Jr., MD, FPCCP; Jubert Benedicto, MD, FPCCP

Section of Pulmonary Medicine, University of the Philippines – Philippine General Hospital

ABSTRACT
The pregnant female may experience a multitude of physiologic changes that are a unique occurrence
only in pregnancy and a significant proportion of these alterations may involve the respiratory system.
Pregnancy may also bring about differences not only in the normal functioning but also on the diseased
state leading to some diseases being worsened or exacerbated by pregnancy, while some being
improved. Because of the unique interplay of these factors in pregnancy, it is important for pulmonologists
to be acquainted with the different conditions that are common in pregnant patients, for the timely and
proper management is paramount to a successful pregnancy and healthy mother and infant. Here, we
present three unique cases, each highlighting different commonly encountered diseases in pregnancy,
together with the proper management plan for each case.

CASE 1: ASTHMA IN PREGNANCY On the day of admission, there was

M.M is a 37-year-old female, G3P2 (2002), 9
3/7 weeks age of gestation (AOG), who
complained of dyspnea. She had a past history of
childhood bronchial asthma and would take as-
needed salbutamol tablet for exacerbations. She
denies worsening of symptoms during her present
pregnancy. Her last exacerbation was 1 month prior
to admission, where she was prescribed
maintenance inhaled salmeterol/fluticasone with
poor compliance. She has no known triggers. Her
two previous pregnancies were both full term and
uneventful.
Both parents are asthmatics. No other
heredofamilial disorders noted. She was a previous
smoker with a 1-pack-year smoking history. She
does not drink alcoholic beverages. She is currently
unemployed.
One week prior, she complained of cough
associated with progressive shortness of breathing
occurring daily and nightly awakenings due to
dyspnea. She self-medicated with oral salbutamol
as needed with slight relief of symptoms.
worsening of dyspnea and she was rushed to the
emergency room, where she was noted to be
lethargic and in respiratory distress. Vital signs
were as follows: blood pressure (BP) of 160/90
mmHg, heart rate (HR) of 130 beats per minute
(bpm) and respiratory rate (RR) of 40 cycles per
minute (cpm). Her oxygen saturation was 69% at
room air. There was note of wheezes in all lung
fields. The patient was promptly intubated and
hooked to mechanical ventilation. She was
nebulized with salbutamol (3 doses) and given
intravenous (IV) hydrocortisone 100 mg and
magnesium sulfate 2 g IV bolus. She was then
transferred to the medical intensive care unit
(ICU).
In the ICU, piperacillin-tazobactam 4.5 g IV
8-hourly and azithromycin 500 mg once daily
were initiated after infiltrates on chest x-ray were
noted. She was then referred to the pulmonary
medicine service.
On the second hospital day, the patient had
no dyspnea and had stable vital signs. She was

3 Philipp J Chest Dis 2017


able to tolerate continuous positive airway
pressure (CPAP) mode, with an FiO2 of 30%, with
pressure support of 4 mmH20, positive end-
expiratory pressure of 5 mmH20 and rapid shallow
breathing index of 45. Her arterial blood gases were
unremarkable. She was then extubated and
transferred to the medical ward the next day.
The final diagnosis was acute respiratory
failure type I secondary to status asthmaticus;
community-acquired pneumonia (CAP), high risk;
uterine pregnancy, 9 3/7 weeks AOG.
Discussion
Respiratory physiology during pregnancy
During normal pregnancy there is a 20%
increase in oxygen consumption and a 15%
increase in the maternal metabolic rate. These
demands are met by several physiologic changes
during pregnancy.1 To compensate for the
increased oxygen demand of pregnancy, minute
volume is increased by 40%–50%. This
hyperventilation is due to an increasing tidal
volume which are due to the stimulatory effect of
progesterone on the respiratory center.2
With the progress of pregnancy, the
circumference of the lower chest wall increases by
5-7 cm with an increase in the anteroposterior and
transverse diameters, resulting in widening of costal
angle from 68° to 103°. This compensates for the
eventual elevation of the diaphragm because as the
uterus enlarges, it pushes the diaphragm upward
approximately 4-5 cm, resulting in a reduction in
the functional residual capacity (FRC) by about
18%. Because of this change, pregnant women
more rapidly desaturate during hypopneic periods
due to loss of reserve lung volume.3 Pregnancy
does not change forced vital capacity (FVC), forced
expiratory volume in one second (FEV1) or peak
expiratory flow rate (PEFR). As in the general
population, FEV1 and PEFR during pregnancy
correlate well with asthma symptoms and
exacerbations making them acceptable
measurements to help monitor asthma control.4
Dela Cruz, et al
Minute volume/ventilation and total volume both
increase by 30%-50%.
Effect of pregnancy on asthma
As a consequence of pregnancy-associated
immunological and clinical changes, asthma
improves in approximately one-third of pregnant
women, remains the same in one-third and worsen
in the rest.5 The underlying immunological
mechanisms are mostly unknown and biomarkers
predicting deterioration are lacking.
The prevalence of bronchial asthma varies
between 3%-9% of all pregnancies and
approximately 6% of patients get hospitalized due
to acute exacerbation. Worsening of asthma during
pregnancy is related to the baseline asthma
severity. Schatz et al6 enrolled 1,739 pregnant
asthmatics before 26 weeks of gestation and
classified them into mild, moderate and severe
disease groups. They noted that 51.9% of those in
the severe group have an asthma exacerbation,
25.7% of the moderate group and 12.6% of the
mild group.6
Despite the lack of studies directly
addressing possible mechanisms, several authors
have proposed that maternal hypoxia,
inflammation, asthma exacerbation, smoking and
altered placental function may contribute to poor
pregnancy outcomes in females with asthma.
These mechanisms lead to low birth weight,
preterm labor, preeclampsia and caesarean
delivery.7
In the local setting, a study done in our
institution showed that both maternal and neonatal
outcomes are compromised among pregnant
asthmatics as compared to pregnancies not
complicated by asthma. Pregnant asthmatics were
significantly more likely to have preeclampsia,
caesarean delivery and longer hospital stay. They
are significantly more likely to have preterm
infants, lower mean birth weight and longer
neonatal hospital stay.8 Table 1 summarizes the
results of this study.
Vol. 18 | Issue 03 | September 2017 4
 Respiratory conditions in pregnancy

Table 1. Pregnancy outcomes between pregnant and non-pregnant asthmatics in the Philippine General
Hospital (2000)
Outcome Asthmatics(%) Control RR (95% CI for RR) P Value Adjusted RR
N=184 N=205
Caesarean Section 56(30.47%) 3( 1.5%) 20.8 (6.62<RR<65.3) <0.0001 15.59 ( 4.65-
52.29) P<0.001

Preeclampsia 19 (10.3%) 3(1.5%) 2.12 (2.06<RR<23.5) 0.000157 9.78 (2.79-34.2)

p=0.004
Length of hospital 97(53%) 87(42%) 1.24 0.0426 2.10(1.29-3.41
stay >3 days (1.01<RR<1.53) p=0.0026
Gest. HTN 8 (4.3%) 3 (1.5%) 2.97 0.087 NS
(0.8<RR<11.03)
Forceps 15 17(8.3%) 0.98 0.96 NS
(8.2%) (0.51<RR<1.91)
PROM 4(2.2%) 2(1.0%) 2.23 0.43 NS
(0.41<RR<12.02)
Placenta Previa 1(0.5%) 0(0%) —- — NS
Intubation 1(0.5%) 0 —- — NS
Preterm 27 9(4.4%) 3.34 0.00048 3.46
(14.7%) (1.61<RR<6.92) (1.57-7.64)
p=0.0021
Length of Neonatal 91(49%) 93(45%) 1.09 0.4197 1.76
Stay >3D (0.88<RR<1.34) (1.12-2.77)
p=0.0143
Low birth weight 41(22%) 32(16%) 1.43 (0.94<RR<2.17) 0.0924 NS
<2.5 kg
SGA 21 34 (16.6%) 0.69 0.144 NS
(11.4%) (0.41<RR<1.14)
LGA 3 (2.5%) 3 (2.5%) 0.62 0.376 NS
(0.21<RR<1.81)
RR=relative risk; HTN=hypertension; PROM=premature rupture of membranes; SG=small for gestational age; LGA=large for
gestational age; NS=not significant.

Management of exacerbations during pregnancy ventilation is of particular concern.11 The clinical

Treatment is no different from the emergency
management of acute severe asthma outside
pregnancy that includes repetitive administration of
inhaled short acting B-agonists, with early
introduction of systemic corticosteroids and oxygen
support.9 These patients should be closely
monitored and their treatment titrated according to
their response to medications administered.10
For pregnant patients with status asthmaticus
requiring intensive care, approach to mechanical
criteria for intubating a pregnant patient are similar
to those in nonpregnant patients and include
increased work of breathing, mental status
deterioration, hemodynamic instability and
inability to protect the airway or manage
secretions. The physiologic changes of pregnancy
should be taken into account such as increase O2
demand, respiratory alkalosis, decrease in FRC and
decrease in respiratory compliance. The presence
of mucosal edema, capillary engorgement and

5 Philipp J Chest Dis 2017


increase in breast size, warrant a 0.5mm smaller
endotracheal tube compared to nonpregnant of
similar height and age.12 Although a PaO2 of
55mmHg and SpO2 of 88% would be tolerated
in the general population, adequate fetal
oxygenation requires a PaO2 of 70mmHg,
which responds to a maternal SpO2 of about
95%.13
In general, a slow respiratory rate, low
tidal volume, high peak inspiratory flow rate are
set to allow greater time for exhalation of the
tidal volume and therefore prevent air
trapping.14
Management of stable asthma in pregnancy
The management strategy is complex and
should be carried out for a long period. It
includes an objective evaluation of maternal and
fetal clinical conditions, avoidance or control of
triggering factors, pharmacological treatment
and educational and psychological support.15
Follow-up in the clinic once every 1–2 weeks
until asthma is controlled and then monthly
throughout pregnancy
All pregnant asthmatic women should be
up to date on influenza and pneumococcal
vaccines as respiratory infections are frequent
triggers for asthma exacerbation. They should
avoid nonimmunologic triggers and reduce
exposures to allergens.
Asthma in pregnancy needs to be treated
and drugs are necessary, since uncontrolled
asthma represents a risk factor to both the
mother and the fetus. Only 0.7% of drugs carry
a Pregnancy Risk Category A classification and
the vast majority are in B and C. In particular,
66% of all medications with a pregnancy
category are now in Pregnancy Risk Category
C. Table 2 summarizes the drug classes of
commonly used asthma drugs.
The management of asthma during
pregnancy should be based upon objective
assessment of symptom control, risk factors for
poor asthma outcomes. Treatment of asthma is
Dela Cruz, et al
Table 2. Summary of pregnancy category of
commonly used asthma drugs in pregnancy.
Drug Class Pregnancy Category
Beta-agonists Category C
Anticholinergics Category C
Inhaled Corticosteroids Category B
Leukotriene Receptor Category B
Antagonists
Cromolyn Category B
Methylxanthine Category C
Systemic Category C (Category D
Corticosteroids in first trimester)
Category B=Animal reproduction studies have failed to
demonstrate a risk to the fetus and there are no adequate and
well-controlled studies in pregnant women.
Category C=Animal reproduction studies have shown an
adverse effect on the fetus and there are no adequate and well-
controlled studies in humans, but potential benefits may warrant
use of the drug in pregnant women despite potential risks.
Category D=There is positive evidence of human fetal risk
based on adverse reaction data from investigational or
marketing experience or studies in humans, but potential
benefits may warrant use of the drug in pregnant women despite
potential risks.
the same as in non-pregnant asthmatics based on
the stepwise approach to asthma control.10 Inmost
w omen, asthma reverts back to the pre-pregnancy
level of severity within 3 months after delivery. All
asthma medications should be continued during
pregnancy and lactation.7
Patients’ education is mandatory to optimize
the outcomes of therapy in asthmatic patients.
However, in the case of pregnant women, strict
and repeated reassurance on the significance and
safety of a regular therapy for controlling airway
inflammation is definitely essential to ensure
adequate compliance.
CASE 2: TUBERCULOSIS (TB) IN
PREGNANCY
A.B. is a 25-year-old woman, G2P1 (1001),
on her 29th week of pregnancy, with regular
prenatal check-ups at a local health center. She
was treated for 6 months for smear-positive TB in
2008, after which there was documentation of
sputum smear conversion was documented.
Vol. 18 | Issue 03 | September 2017 6
Respiratory conditions in pregnancy
Two weeks prior, she complained of cough
with greenish sputum, anorexia, malaise and
undocumented fever. She also had watery, non-
mucoid, non-bloody diarrhea (2-3 bowel
movements per day). She was given cefuroxime
and metronidazole for 2 weeks, but the symptoms
persisted. While fetal movements were perceived
to be normal and no vaginal bleeding or spotting
was noted, the persistence of symptoms prompted
consult at the obstetric admitting section (OBAS).
She was received at the OBAS awake,
alert, ambulatory and not in cardiorespiratory
distress. She was cachectic and had dry oral
mucosa. No cervical lymphadenopathy was noted.
She had equal chest expansion and crackles on
bilateral lower lung fields. She was tachycardic
but has regular rhythm and has poor skin turgor
with delayed capillary refill time.
Abdominal examination done by the
perinatologists showed a fundic height of 22 cm
and fetal heart tones appreciated at the left lower
quadrant. No uterine contractions were noted.
Internal exam revealed a normal external
genitalia, parous vagina and a cervix that was 1-
cm dilated but uneffaced.
She was managed as a case of acute
gastroenteritis with signs of dehydration, CAP,
preterm labor, to rule out gastrointestinal and
pulmonary TB.
She was given cefixime and metronidazole
as antibiotics, nifedipine as tocolytic and
dexamethasone. Upon further workup, her
sputum, stool and urine AFB all yielded positive
results. She was managed as bacteriologically-
confirmed TB and given isoniazid, rifampicin,
pyrazinamide and ethambutol pending the results
of sputum TB culture. Streptomycin was
deliberately not given due to the feared risk of
ototoxicity in the developing fetus.
On her 34th week of gestation, she had
labor pains and fetal monitoring showed fetal
distress hence an emergency cesarean section was
performed. She gave birth to a live baby boy, 2.5
7 Philipp J Chest Dis 2017
kg, small for gestational age, APGAR 8,9. The
anti-TB regimen was continued and the baby was
also given isoniazid prophylaxis despite negative
gastric aspirate GeneXpert. The patient and her
son are soon discharged asymptomatic and on
regular follow-up at te outpatient department.
Discussion
Global and local burden of TB in pregnancy
Because of the complex issues surrounding
pregnant patients, the World Health Organization
has identified TB in pregnancy as a key target
area to keep focus on to reach the 2030 End TB
strategy.16 The Southeast Asian region has the
second highest burden of TB in pregnant women
with an estimated 2.4 cases per 1,000 pregnant
women and contributes to 31% of the global
prevalence of TB.17 In the region, the Philippines
has the second highest prevalence rate of TB in
pregnant women, after Cambodia.
In recent years, a significant proportion of
deaths due to TB occur in pregnant women and
because of improving obstetric care in the recent
years, deaths due to obstetric causes have been
declining, while deaths from infectious causes
(especially TB) in pregnant women are on the
rise.18,19
Pathophysiology of TB in pregnant women
The risk of TB in pregnant women is two-
fold. One is the detrimental effects of TB in a
pregnant woman and the other is the seemingly
adverse effects of pregnancy itself to the
progression of TB. It has also been shown that
pregnancy itself confers and increased risk for TB
compared to the general population. One study
done in the UK showed an almost 1.7 times
increased risk of contracting TB in pregnant
women compared to the non-pregnant female
population.20
In pregnant women, there is a blunted TH1
pro-inflammatory response by the body, which
leads to either masking or more severe symptoms,

increased susceptibility to new infections and
increased probability of reactivation.21Pregnant
patients are no different compared to the general
population in terms of symptoms, with the most
common presentation still chronic cough, fever
and anorexia.
However, diagnosis of TB can be difficult
in pregnant women for a variety of reasons.
Physiologic changes of pregnancy may mask
symptoms of TB. It may be difficult to recognize
anorexia and malaise because these two
symptoms are more often attributed to the
pregnancy itself. It is also difficult to assess
weight loss during pregnancy.22
TB in pregnant women has been shown to
increase the risk of intrauterine growth
retardation, premature birth and low birthweight.
It is important to emphasize that late treatment of
TB in pregnant women leads to worse outcomes,
including 10x increased risk of dying. Women
with active TB during the third trimester has a
15% risk of transmitting their infection to their
newborns.
Diagnosis of TB in pregnant women
Because of the non-specific presentation of
TB in pregnant women, timely diagnosis is
essential for the successful treatment of TB. The
diagnosis of TB in pregnant women is not
different compared to the non-pregnant
population. The standard diagnostic test is two
sputum AFB smears and if one is positive, then it
is considered bacteriologically confirmed TB.
However, in the era of rapid diagnostic
tests, the role of GeneXpert is becoming more
popular, although the Clinical Practice Guidelines
for the Diagnosis, Treatment, Prevention and
Control of Tuberculosis in Adult Filipinos – 2016
Update has not yet considered the GeneXpert as a
first-line test for diagnosis of TB in pregnant
women.23 Nonetheless, in a study done
specifically in pregnant women, GeneXpert was
found to be more sensitive than standard AFB
Dela Cruz, et al
smears (80.8% vs 50.0% for AFB smear) and is as
specific (97.1% vs 100%).24
With regards to radiologic examinations in
pregnancy, it has long been established that chest
x-ray with abdominal shield is considered low
risk for adverse events in both the mother and the
fetus during pregnancy,25 but the risk is not zero.
Therefore, in pregnant patients, chest-xray should
only be used to diagnose TB if all other non-
invasive tests are inconclusive.
Treatment of TB in pregnancy
Treatment of TB in pregnant women adhere
to these two basic tenets: (1) “A successful TB
treatment is essential for a successful pregnancy”
and; (2) “The dangers of untreated TB is much
worse than the dangers of anti-TB medications.”
All first line drugs except streptomycin are safe in
pregnancy. Only ethambutol is considered
category A but pyrazinamide, isoniazid and
rifampicin also have excellent safety profiles.26
However, streptomycin is associated with
ototoxicity in the developing fetus. The standard
regimen is the same as the general population and
an alternative regimen is 2 months of HRE
followed by 7 months of HR.
Unlike the first-line medications, the
second-line anti-TB medications are more toxic
both to the mother and fetus and more careful
planning is warranted. A referral to a specialty
center is warranted for cases of multidrug-
resistant TB in a pregnant patient.27 Pregnancy
warrants an increase in the frequency of
monitoring (monthly alanine transaminase
examinations) during TB treatment because
pregnancy confers increased risk for isoniazid-
induced hepatotoxicity.28
Breastfeeding and neonatal care of infants of
mothers with TB
Breastfeeding is an important aspect in the
care of the newborn. Numerous studies have
shown that all first-line and second-line drugs
Vol. 18 | Issue 03 | September 2017 8
Respiratory conditions in pregnancy
are safe to give in breastfeeding mothers because
their concentrations are too low to cause harm in
the infant. It is also important to note that, while
anti-TB medications are excreted in small
amounts in breastmilk, TB bacilli can be secreted
in significant amounts. Therefore, it is
recommended that a mother infected with TB
should undergo 2 weeks of anti-TB treatment
before she can commence breastfeeding.29
In terms of neonatal care, it is suggested
that if the infant has a positive GenXpert result
(from gastric aspirate), the baby should undergo a
full course of treatment for TB. Infants with no
evidence of active TB infection should still be
given isoniazid prophylaxis for 6 months,
especially if the mother has TB up to the third
trimester.
CASE 3: PULMONARY PROCEDURAL
CONSIDERATIONS DURING PREGNANCY
J.B. is a 27-year-old female who was
pregnant (32 weeks AOG), G1P0, who came in
for hemoptysis. Five years prior, she was
diagnosed with sputum-positive PTB and treated
for 6 weeks with Category I PTB treatment, with
subsequent sputum conversion. Two years later,
she complained of nonproductive cough, with no
associated fever or night sweats. She consulted at
a local hospital and was managed as a case of
sputum-negative TB with Category II treatment.
There was recurrence of nonproductive cough
after a year and Category II treatment was
repeated. She then became pregnant with the
present pregnancy. However, she complained of
cough with intermittent hemoptysis. A chest x-ray
showed an aspergilloma, thus prompting the
present consult.
On physical examination, she was awake,
comfortable and not in distress. Her vital signs
were as follows: BP of 110/70 mmHg, HR of 92
bpm, RR of 20 cpm and O2 saturation of 97%.
Breath sounds were decreased on the left lung
fields. Other physical examination findings were
9 Philipp J Chest Dis 2017
unremarkable. At this time, the patient was
diagnosed with a left upper lung mass,
aspergilloma for consideration; PTB with
bronchiectasis; uterine pregnancy at 32 weeks
AOG (G1P0).
A multidisciplinary conference was
conducted to discuss JB’s case. The consensus
was to bring the pregnancy to term and do
elective Caesarean section. A chest computerized
tomography (CT) scan and subsequent surgery for
the aspergilloma was planned after delivery. No
TB retreatment was initiated at this time due to
negative results of TB workup.
JB was able to carry her pregnancy to term
and delivered a live baby girl. She was
undergoing preparations for lung resection
surgery at the time of writing.
Respiratory diagnostic and procedural issues in
pregnancy
A pulmonary function test (PFT) was
requested in anticipation of a lung resection
surgery due to the diagnosis of aspergilloma.
Normal pregnancy is a physiological state that
does not require PFT.30 During the first and
second trimester, the lung function is relatively
normal. During the third trimester, the pulmonary
function becomes compromised with a decrease in
PEFR. The usual problem with doing a PFT in
pregnant patients is not in performing the test, but
in interpreting and reporting the results against
normal or nonpregnant reference ranges.
Furthermore, it is not advisable to do a pulmonary
function test in pregnant patients with pre-
eclampsia or a cervical cerclage. Finally, parity
has no effect on lung function until the woman
has delivered three times. Thereafter, a slight
compromise in lung function is seen.31,32
Bronchoscopy aids in the diagnosis and
management of patients, pregnant or non-
pregnant, presenting with hemoptysis. However, it
has its own specific risks, including those related
to the procedure and those from conscious sedati-

on.33 Risks related to conscious sedation
include medication-related teratogenesis,
induction of premature labor, maternal cardiac
arrhythmias, depressed mental status with
resultant hypoventilation, airway vulnerability,
possible pulmonary aspiration and respiratory
distress. Risks related to the performance of the
procedure itself include barotrauma,
pneumothorax, hypoxemia, airway hyper-
reactivity, pulmonary hemorrhage, systemic
hypotension and hypertension.
Medications commonly used in pregnant
women such as lidocaine, beta-2 agonist,
submucosal epinephrine, midazolam and
propofol must be used cautiously and in low
doses only. The maximum recommended dose
of 4% Lidocaine topical solution should be less
than 300mg and should not exceed 4.5 mg per
kg body weight.
Beta-2 agonists have an FDA Pregnancy
Risk category of C and must not be used
routinely. If needed, minimally required dose
should be given. Submucosal injection of
epinephrine should be used in pregnancy only if
the potential benefit justifies the potential risk
to the fetus. Midazolam (Category D) is the
preferred benzodiazepine for flexible
bronchoscopy, but should only used when
absolutely necessary, in low doses and with
caution.
Initial assessment of the patient prior to
bronchoscopy must include previous instances
of complicated conscious sedation and allergies.
During the general physical examination,
specific attention must be given to assess
airway patency. During the procedure,
continuous monitoring with intermittent
sphygmomanometry, cardiac rhythm, rate
monitoring and pulse oximetry (to maintain
97%-100% O2 saturation) are recommended.
Capnography is optional but the general goal is
to avoid hypoventilation during the procedure.
There are no formal recommendations
regarding fetal heart monitoring during flexible
Dela Cruz, et al
bronchoscopy.34
Emergent bronchoscopy in pregnancy
should be performed if lifesaving regardless of
the stage of pregnancy or status of the fetus.
However, it must be done in close coordination
with the obstetrician and the perinatologist.
Non-emergent bronchoscopy should be
postponed until the patient has given birth, if
possible, or if there is a good chance of
delivering a viable healthy newborn after 28
weeks of pregnancy. One may also consider
using new technology to substitute for
bronchoscopy such as 3D CT or virtual
bronchoscopy.
Treatment of aspergilloma during pregnancy
Treatment of aspergilloma during
pregnancy remains controversial and
problematic, with little consensus amongst
experts mainly because of the variability of the
underlying lung disease process. Aspergillomas
may resolve clinically without overt
pharmacologic or surgical intervention in up to
10% of patients. The major justification for
surgery and arterial embolization is the risk of
life-threatening hemoptysis, which has an
associated mortality of 5%-10% or greater.35
There has paucity of literature regarding
thoracic resectional surgery on pregnant
women. The problem confronting the surgeon is
whether pulmonary resection could be
performed during gestation with safety to the
mother and fetus. Available literature shows
that in the presence of standard indications,
pulmonary resection may be safely performed
on patients, even on the second trimester of
pregnancy, with only a 0%-8% fetal mortality
and at most 3% maternal mortality.36
In pregnant women who are poor surgical
candidates, medical treatment options are
limited due to toxicity and teratogenicity issues,
as well as lack of available data on safety in
pregnancy. Amphotericin B is the agent on
which the most information is available, and is
Vol. 18 | Issue 03 | September 2017 10
 Respiratory conditions in pregnancy
the agent of choice for all serious fungal
infections in pregnancy, including aspergilloma.
Fetal toxicity is rare, maternal toxicity is similar
to non-pregnant patients, and animal studies do
not show teratogenicity. Hemoptysis can
usually be controlled with oral tranexamic acid.
If hemoptysis is significant, bronchial artery
embolization is recommended and should be
performed by an experienced interventional
radiologist. Recurrence of hemoptysis is
common if antifungal therapy is not given and
optimized and may be a sign of antifungal
failure.37
CONCLUSIONS
By reviewing these cases, we have come
to understand that normal pregnancy is a
physiologic state. During this time, the
respiratory tract undergoes profound changes as
a result of maternal adaptation to pregnancy. It
was shown that a variety of these changes are
important to recognize whether part of the
normal physiologic adaptation to pregnancy to
correlate with the pregnant patient’s symptoms.
It was also highlighted that caring for a
pregnant mother also entails care for the
patient’s fetus, therefore both benefits and risks
must be weighed to ensure a beneficial
environment for both patients.
A lot of pulmonary cases plague our
pregnant patients and it is indeed important to
review them and take into consideration each
little intricacy that is unique.
REFERENCES
1. Nelson-Piercy C, Waldron M, Moore-
Gillon J. Respiratory disease in pregnancy.
Br J Hosp Med. 1994 Apr 20-May
3;51(8):398-401.
2. Vatti R, Teuber S. Asthma and pregnancy.
Clinic Rev Allerg Immunol. 2012
Aug;43(1-2):45-56.
3. Hardy-Fairbanks AJ, Baker ER. Asthma in
11 Philipp J Chest Dis 2017
pregnancy: pathophysiology, diagnosis and
management. Obstet Gynecol Clin North Am.
2010 Jun;37(2):159-72.
4. Hanania NA, Belfort MA. Acute asthma in
pregnancy. Crit Care Med. 2005;33(10
Suppl):S319-24.
5. Ivancso, I, Bohacs, A, Ezes, N, Losonczy, G,
Tamasi, L. Asthma in Pregnancy. EMJ Respir.
2013
6. Schatz M, Dombrowski MP, Wise R, et al.
Asthma morbidity during pregnancy can be
predicted by severity classification. J Allergy
Clin Immunol. 2003 Aug;112(2):283-8.
7. Murphy VE, Gibson P, Smith R, Clifton VL.
Asthma during pregnancy: mechanisms and
treatment implications. Eur Respir J. 2005
Apr;25(4):731-50.
8. Delos Reyes G, Espino ME, Wang A.
Maternal and Infant Outcomes in the
Pregnancy of Asthmatic Women:
Retrospective Cohort Analysis. Chest 2001
9. Murphy VE. Managing asthma in pregnancy.
Breathe 2015 Dec;11(4):258-67.
10. Global Initiative for Asthma. Global Strategy
for Asthma Management and Prevention,
2016.
11. Wanderer JP, Leffert LR, Mhyre JM, Kuklina,
EV, Callaghan, WM, Bateman, B.T.
Epidemiology of obstetric related ICU
admissions in Maryland: 1999-2008. Crit Care
Med. 2013 Aug;41(8):1844-52.
12. Bhatia P, Biyani G, Mohammed S. Acute
respiratory failure and mechanical ventilation
in pregnant patient: A narrative review of
literature. J Anaesthesiol Clin Pharmacol.
2016 Oct-Dec;32(4):431-439.
13. Catanzarite V, Wims D, Landers C. Acute
respiratory distress syndrome in pregnancy
and the puerperium: Causes, courses and
outcome. Obstet Gynecol. 2001 May;97(5 Pt
1):760-4.
14. Elsayegh, D, Shapiro, J.M. Management of
the obstetric patient with status asthmaticus. J

Intensive Care Med. 2008 Nov-
Dec;23(6):396-402.
15. Liccardi, G, Cazzola, M, Canonica, G.W,
D’Amato, M, D’Amato, G, Passalacqua, G.
General Strategy for the management of
bronchial asthma in pregnancy. Respir Med.
2003 Jul;97(7):778-89.
16. World Health Organization 2012 Report
17. Sugarman J, Colvin C, Moran AC, Oxlade O.
Tuberculosis in pregnancy: an estimate of the
global burden of disease. Lancet Glob
Health. 2014 Dec;2(12):e710-6.
18. Say L, et. al. A WHO systematic review and
meta-analysis on the cause of maternal
deaths. 2014.
19. World Health Organization 2010 Updates on
Tuberculosis Management.
20. Zenner D, Kruijshaar ME, Andrews N,
Abubakar I. Risk of Tuberculosis in
Pregnancy A National, Primary Care–based
Cohort and Self-controlled Case Series
Study. Am J Respir Crit Care Med. 2012 Apr
1;185(7):779-84.
21. Wilsher ML. Human in vitro immune
responses to Mycobacterium tuberculosis.
Tuber Lung Dis. (1999)
22. Mathad JS, Gupta A.Tuberculosis in
pregnant and postpartum women:
epidemiology, management and research
gaps. Clin Infect Dis 2012 Dec;55(11):1532-
49.
23. Bates M, Ahmed Y, Chilukutu L, et. al. Use
of the Xpert® MTB/RIF assay for
diagnosing pulmonary tuberculosis
comorbidity and multidrug-resistant TB in
obstetrics and gynaecology inpatient wards at
the University Teaching Hospital, Lusaka,
Zambia. Trop Med Int Health. 2013
Sep;18(9):1134-1140.
24. Toppenberg KS, Hill DA, Miller DP. Safety
of radiographic imaging during pregnancy.
Am Fam Physician 1999 Apr 1;59(7):1813-8,
Dela Cruz, et al
1820.
25. Nahid P, Dorman SE, Alipanah N, et al.
Official ATS/CDC/IDSA Clinical Practice
Guidelines: Treatment of Drug-Susceptible
Tuberculosis. Clin Infect Dis. 2016 Oct
1;63(7):e147-e195.
26. WHO Treatment of Tuberculosis Guidelines
Fourth Edition (2010).
27. Franks AL, Binkin NJ, Snider DE Jr, Rokaw
WM, Becker S. Isoniazid hepatitis among
pregnant and postpartum Hispanic patients.
Public Health Rep. 1989 Mar-Apr;104(2):151-
5.
28. 2016 Philippine CPG on the Diagnosis,
Treatment and Management of Tuberculosis.
29. Segal H, Walsh T. Current approaches to
diagnosis and treatment of invasive
aspergillosis. Am J Respir Crit Care Med Vol
173, pp 707-717, 2006.
30. Kousha M, et. al. Pulmonary Aspergillosis: a
clinical review. Eur Respir Rev 2011; 20:
121,156-174
31. Munoz P, et al. Update on invasive
aspergillosis: clinical and diagnostic aspects.
Clin Microbiol Infect 2006;12(suppl 7):24-39.
32. Toppenburg KS, et. al., Safety of Radiographic
Imaging During Pregnancy. American Family
Physician 1999;59(7):1813-1818.
33. Melnick D, et al. Management of general
surgical problems in the pregnant patient. The
American Journal of Surgery 187 (2004) 170-
180.
34. M. Rosen. Management of Anesthesia for the
Pregnant Surgical Patient. Anesthesiology
1999; 91:1159-63
35. Tarnoff J, et.al. Major thoracic surgery during
pregnancy. Am Rev Respir Dis. 1967
Dec;96(6):1169-72.
36. Pilmis B, et.al. Antifungal drugs dring
pregnancy: an updated review. J Antimicrob
Chemother 2015;70(1):14-22.
Vol. 18 | Issue 03 | September 2017 12
 Overlap syndrome with ILD

CASE REPORT

Overlapping Overlaps: A Case Report

Maria Cristina A. Maranion, MD; Shariff Amiloari S. Manibpel, MD; Sonde Cris A. Punay, MD
Center for Respiratory Medicine, University of Santo Tomas Hospital, Manila

ABSTRACT
Chronic respiratory diseases such as interstitial lung disease (ILD), chronic obstructive pulmonary
disease (COPD) and obstructive sleep apnea (OSA) have been known to overlap. In fact, the co-
existence of COPD and OSA in a patient has been described as Overlap syndrome. Overlapping
pulmonary problems increase morbidity and mortality and usually require close monitoring, prompt
therapy and a multidisciplinary approach to management. Furthermore, the co-existence of these three
conditions in a patient is rare. Here we report the case of a patient with Overlap syndrome with
overlapping ILD due to autoimmune disease.

THE CASE right atrium (RA) were noted--all points to RA

History
This is the case of a 30-year-old female,
unmarried, from Quezon City, who was admitted
due to dyspnea.
In 2013, she was initially diagnosed with
pulmonary hypertension (PH) after complaining of
dyspnea and bipedal edema on routine check-up.
On physical examination, there was note of a PA
lift and fixed split S2. Chest radiograph revealed a
prominent right pulmonary artery.
Echocardiography revealed preserved left
ventricular (LV) function with a LV ejection
fraction (LVEF) of 67%, good wall motion and
contractility and normal resting systolic function.
However, there was an elevated tricuspid
regurgitation (TR) jet at 39 mmHg, with no atrial
dilatation and pericardial effusion. The diagnosis
was mild PH and she was treated with
phosphodiesterase (PDE)-5 inhibitor, to which she
was compliant.
On annual surveillance echocardiography, a
decrease in LVEF from 67% to 59%, worsening of
PH with increasing TR jet from 39 mmHg to
81mmHg, a dilated right ventricle, flattening of the
interventricular septum during systole and dilated
volume overload seen in PH. She was advised to
undergo right heart catheterization, but she
refused. The PDE-5 inhibitor was shifted to an
endothelin receptor antagonist, which improved
her symptoms.
Furthermore, high-resolution computerized
tomography (HRCT) of the chest done in 2014
revealed findings suggestive of interstitial lung
disease (ILD) (Figure 1).
One week prior, she experienced easy
fatigability accompanied by non-productive cough.
Symptoms were aggravated by movement and
relieved by rest. She did not note any fever,
bipedal edema, orthopnea or chest pain. She
consulted a private physician, and a complete
blood count (CBC) revealed a hemoglobin of 147
mg/dL, hematocrit of 46, platelet count of 239
cells/mm3, and a white blood cell (WBC) count of
7.91 cells/mm3 (with normal differential counts).
Urinalysis revealed proteinuria (+4), 6 red blood
cells/high power field (hpf) and 1 WBC/hpf. Chest
x-ray was done and signed out as bibasal
pneumonia (Figure 2). She was given cefuroxime
and azithromycin for 5 days, which afforded relief
of the cough.
However, 3 days prior, easy fatigability per-

13 Philipp J Chest Dis 2017

 Maranion et al

Figure 1. High-resolution computerized tomography of the chest. Top row: The parenchymal window reveals ground
glass opacities in the right upper lobe; beginning honeycomb changes on the left middle lung field up to the basal
segments; and pleural effusion. Bottom row: The mediastinal view shows cardiomegaly and dilated pulmonary
arteries (right-2.89 cm; left=2.60 cm).

sisted, now accompanied by increased lowing maintenance medications: hydroxychlo-

somnolence. Companions noted increase in
sleeping time accompanied by anorexia and body
malaise. She also experienced dyspnea on
exertion. There were no aggravating or relieving
factors, and she did not seek any consult nor took
any medications. Over the next few days, her
symptoms progressed, thus prompting consult.
Of note, she is hypertensive and was
diagnosed with systemic lupus erythematosus
(SLE) on July 2003, initially presenting as
alopecia, rash, arthritis, anemia, thrombocyte-
penia and proteinuria. Further work-up revealed
that she was positive for anti-nuclear antibody
(ANA), anti-double stranded DNA and anti-
ribonucleoprotein (anti-RNP). She was referred
to the National Kidney and Transplant Institute,
where a kidney biopsy done confirmed lupus
nephritis compatible with membranous
glomerulonephritis. She was treated with the fol-
roquine, prednisone, aspirin, supplemental
calcium and irbesartan.
She is a previous smoker with a 20-pack-
year smoking history, stopping in 2003.
Review of systems revealed no symptoms
attributable to a flare of SLE, but noted
unquantified weight gain.
Admission and hospital course
Upon admission, she was conscious,
coherent, stretcher borne, in cardiorespiratory
distress, with the following vital signs: blood
pressure of 140/80 mmHg, heart rate of 92
beats/min, regular respiration with a rate of 28
cycles/min, body temperature of 37⁰C, and an O2
saturation at room air of 92%. Her body mass
index was 37.
Examination of the chest revealed sym-
metric expansion, equal tactile and vocal fremiti,

Vol. 18 | Issue 03 | September 2017 14

 Overlap syndrome with ILD
resonant on percussion, bibasal crackles and
bilateral wheezes. The cardiac examination
showed a jugular vein pressure of 4.5 cm at a 30-
degree angle, adynamic precordium, apex beat at
the sixth intercostal space, left anterior axillary
line, RV heave, PA lift, no thrills, a loud P2 and
no murmurs. The abdomen was flabby and had
non-bulging flanks, normoactive bowel sounds,
tympanitic on percussion, soft and non-tender with
no hepatosplenomegaly. She had grade 1 bipedal
pitting edema but no cyanosis.
On admission, the initial diagnosis was
community-acquired pneumonia, moderate risk;
cor pulmonale; to rule out acute coronary
syndrome (ACS); chronic obstructive pulmonary
disease (COPD), in acute exacerbation;
obstructive sleep apnea (OSA) risk; to consider
overlap syndrome; SLE, not in flare; ILD probably
due to connective tissue disease (CTD); obesity
class II; hypertension stage II.
The patient was immediately given
supplemental oxygen (4 L/min). Arterial blood gas
(ABG) revealed partially compensated respiratory
Figure 2. Chest radiograph on admission revealed no significant change from her previous films. Widening of the hilar
structures and persistent lower lobe infiltrates are evident.
15 Philipp J Chest Dis 2017
acidosis with inadequate oxygenation with
supplemental oxygen.
Troponin I was not elevated, and 12-lead
electrocardiography showed a normal sinus rhythm
with no ischemic changes, thus ruling out ACS. CBC
showed leukocytosis (12 WBC/mm3), with 90%
segmenters. Serum sodium, potassium and creatinine
were all normal.
She was treated with broad spectrum
intravenous antibiotics to address the pneumonia;
diuretics to relieve pulmonary congestion; and
systemic steroids and short-acting bronchodilators to
address the obstructive airway disease. The patient was
unable to provide a good sputum specimen for
examination despite sputum induction.
During her hospital stay, her dyspnea persisted
and sleeping time and bibasal wheezes increased.
Serial ABGs showed uncompensated respiratory
acidosis with more than adequate oxygenation with
supplemental oxygen. She was then placed on non-
invasive mechanical ventilation (NIMV), which
improved her ventilatory status (ABG showing
uncompensated respiratory alkalosis with more than

adequate oxygenation with supplemental oxygen).
She improved over the next few days and she was
eventually weaned off from ventilator support and
discharged stable and improved on the 5th hospital
day. Home medications included a combined long-
acting beta-agonist (LABA) and long-acting
muscarinic antagonist (LAMA) and PDE-5
inhibitor. She was also advised surveillance of
ILD and PH through chest CT scan and 2D
echocardiography.
Outpatient assessments and follow-up
The underwent spirometry and sleep
polysomnography on follow-up. Spirometry
revealed a scooped-out pattern on the expiratory
limb of the flow-volume loop.
FEV1/FVC was 90.7%, with decreased
FEV1 (1.07 L) and FVC (1.18 L). FEF 25-75 was
low at 1.91 L/s. The low FVC was interpreted as
due to a restrictive ventilatory defect or residual
volume hyperinflation. The exaggerated concavity
of the expiratory part of the flow volume loop and
low FEF 25-75% were interpreted as suggestive of
obstructive ventilatory defect. The patient was not
able to tolerate post-bronchodilator studies, lung
volume studies and diffusing capacity of the lungs
for carbon monoxide (DLCO) studies; hence, were
not conducted. The final spirometry reading was
“suspect very severe underlying obstructive
ventilatory defect, cannot rule out restrictive
ventilatory defect.”
Polysomnography revealed multiple
hypopneic and apneic episodes, with a respiratory
disturbance index of 7/hour. These episodes were
accompanied by desaturations of up to 92%,
which resolved with continuous positive airway
pressure (CPAP). During pressure titration,
resolution of hypopnea with improvement of
oxygen saturation to 98% and decrease in the
frequency of desaturations were noted at a CPAP
level of 8-9 cm H2O. This was interpreted as “mild
OSA with effective CPAP level at 9 cmH2O”.
With the confirmation of COPD and OSA,
the patient was diagnosed with Overlap Syndrome
was confirmed. She was advised to initiate correct-
Maranion et al
ive therapy by using CPAP at starting pressure of 9
cmH2O with oxygen supplementation, which
improved her symptoms. Medically guided weight
reduction and sleep hygiene measures were also
recommended.
DISCUSSION
According to Murray, PH is seen in 12-28%
of patients with SLE.1 The clinical presentation is
the same as with other PH patients, with the most
common symptom being dyspnea. It is strongly
associated with Raynaud’s phenomenon, elevated
rheumatoid factor titre, anti-phospholipid anti-
bodies, and as found in this patient, anti-RNP.
The patient also had underlying ILD, as
diagnosed by HRCT. In these patients, ILD usually
presents as reticular infiltrates on chest radiograph,
but is best diagnosed via HRCT, being non-
invasive and more sensitive for mild or early
disease.2 Common patterns seen in ILD caused by
SLE are ground glass opacities, septal thickening,
fine reticular interstitial markings and honey-
combing changes prominent on the posterior and
basal segments of the lung. Patterns seen on HRCT
can help qualify disease severity and prognosticate
natural course.
Using the scoring system by Assayag et al,
there was presence of all patterns of ILD in our
patient with more than 75% lung involvement.3
These connote an increased risk of morbidity and
mortality due to a rapid decline in lung function,
increased decline in exercise tolerance, and
progressive hypoxia.
The presence of ILD also predisposes the
patient to other pulmonary conditions, including
pulmonary embolism, lung cancer, OSA, and
COPD.1 COPD was highly considered also
because of the presence of autoimmune disease.
Due to chronic inflammation and T cell activation,
around 2%-5% of patients with SLE develop
COPD, with around 5% developing COPD within
the first year of SLE diagnosis.4,5 The usual age at
diagnosis is between the second and fourth decade
of life.6
The patient also had OSA and was advised
Vol. 18 | Issue 03 | September 2017 16
 Overlap syndrome with ILD
corrective therapy using CPAP with oxygen
supplementation. Medically guided weight
reduction and bariatric procedures may also be
considered for such patients. Sleep hygiene such as
a regular sleep schedule and avoidance of
sedatives must also be advised. For such patients,
future surgeries with sedation may require
perioperative CPAP.
Pulmonary conditions are known to overlap,
as in this patient, who had ILD, PH, COPD and
OSA. However, most literature document only the
overlap of COPD with either OSA or ILD.7-20
Literature on the triumvirate of ILD, COPD and
OSA is scant.
Patients with ILD are at risk of hypoxemia
due to the architectural changes in the lungs, and
up to 88% of ILD patients have a form of
nocturnal desaturation and sleep disturbance,
mainly attributable to symptoms such as cough.7
Sleep disturbance is correlated with the FEV1 and
FVC, and symptoms usually resolve with
supplementation with CPAP. Patients with ILD
who develop OSA are likewise at higher risk of
developing PH.8
ILD and COPD syndrome was first
described by Auerbach 30 years ago.21 COPD is
seen in 5%-10% of patients with ILD, commonly
in those with idiopathic pulmonary fibrosis, and is
alternatively known as combined pulmonary
fibrosis emphysema.18 The exact correlation is
unknown but is believed to be due to chronic
inflammation in the interstitium, later affecting the
airways. The overlap is usually seen in younger
females with rheumatoid arthritis over scleroderma
and mixed CTD. Literature on ILD and COPD in
SLE is scarce. Treatment of COPD in ILD is
geared towards treatment of the underlying disease
contributing to ILD.10 In this case, administration
of immunomodulators and oxygen therapy will
provide relief of symptoms.
The co-existence of COPD and OSA is
termed by Dr David Flenley in 1985 as Overlap
syndrome.22 OSA usually develops in the later
stage of COPD. Overlap syndrome has since been
17 Philipp J Chest Dis 2017
used regardless of the relative burden to one
condition with the other. Carratu et al observed
that 15% of COPD patients have some form of
OSA, with prevalence rising to 43% among those
with Stage IV disease.12 Conversely, Greenberg
et al noted that patients with OSA has a COPD
prevalence of 7.6%.13 It is important to recognize
Overlap syndrome, as it increases the risk of
morbidities such as hypoventilation and
respiratory failure, as we as mortality.
Overlap of ILD, COPD and OSA
In patients with ILD and COPD, there is
increased fibrosis, disruption of normal lung
architecture, and decrease in lung compliance
leading to increased ventilation/perfusion
mismatch. These changes increase minute
ventilation and work of breathing, which is
constant both in the wake and sleep state. In the
presence of OSA, sleep may serve as an
additional stressor to respiration. Oxygen
desaturation may be more profound during sleep
because of muscle atonia. These changes may
worsen concomitant PH.
Additionally, hyperinflation due to air
trapping in COPD contributes to impaired
contractile function of the diaphragm. Patients
with COPD have increased minute ventilation
and frequently rely on accessory muscles to aid
ventilation. Thus, ventilation can fall dramatically
during sleep and particularly in rapid eye
movement (REM) sleep when muscle activity
decreases. In studies, desaturations are frequent
among patients with FEV1/FVC <65%, and
increasing severity of obstructive disease is
associated with more severe desaturations during
sleep.11-15,19,20
Since Overlap syndrome is rare, no
diagnostic algorithm or guideline. However,
Zamarron et al recommended that Overlap
syndrome should be suspected in COPD patients
complain of headache upon awakening, excessive
daytime sleepiness, snoring and breathing pauses,
and obesity.19 In patients with OSA, one should

suspect overlap COPD when one presents with
signs and symptoms of cor pulmonale and
polycythemia vera. OSA screening may be done
using the STOPBANG, Epworth and Berlin
questionnaires, with STOPBANG and Epworth
having the highest sensitivity. The diagnosis of
OSA must be confirmed by full polysomnography.
Other pulmonary function tests such as ABG,
spirometry with lung volume study and DLCO can
help prognosticate outcome. Cardiopulmonary
exercise test can also predict morbidity and
mortality outcomes.
The optimal treatment of overlap syndrome
is unknown. Few clinical trials have been
undertaken, and no large studies have compared
long-term outcomes between randomized
therapies. Medications to control COPD
exacerbation are still a mainstay. Inhaled
LABA/LAMA with or without inhaled
corticosteroids are important to keep the airways
open. Oxygen therapy for at least 18 hours is
advocated especially in the presence of severe PH.
Nocturnal oxygen supplementation can likewise
correct nocturnal desaturation in mild to moderate
COPD and OSA.
Hypnotics or sedatives to help patient
achieve REM sleep are advocated especially in
severely symptomatic patients. Cognitive
behavioral therapy, weight reduction and lifestyle
modification are mainstays of therapy in Overlap
syndrome. Smoking cessation and decrease in
alcohol consumption must be emphasized and
adherence to therapy must be stressed. Pulmonary
rehabilitation to improve exercise tolerance may
also help in improving FEV1 of these patients.
Positive airway pressure (PAP) in the form
of CPAP, biphasic PAP (BIPAP), and NIMV.
CPAP remains the gold standard of treatment for
OSA and Overlap Syndrome, as it could increase
in upper-airway resistance that occurs during sleep,
potentially unload the respiratory muscles, and
decrease hypoventilation, oxygen consumption or
carbon dioxide production by the respiratory
muscles. Alternatively, CPAP may offset intrinsic
Maranion et al
positive end-expiratory pressure in severe COPD.
The 5-year survival of among patients with
Overlap syndrome who use CPAP is 71% as
compared to 34% in those who do not use
CPAP.19,20
A subset of patients with stable COPD
who may benefit from NIMV include those with
daytime hypercapnia and super-imposed
nocturnal hypoventilation. The effects of BIPAP
have not been specifically evaluated since there is
a difference between inspiration PAP and
expiration PAP in maintaining alveolar
ventilation and reducing carbon dioxide partial
pressure.
There is little literature on the
epidemiology of Overlap syndrome. However, it
must be noted that all three disease entities share
a common pathophysiology of hypoxemia, which
can accelerate the disease process and decline in
respiratory function of the patient, leading to
higher cardiac events and respiratory failure.
In summary, we discussed the overlap of
ILD, COPD and OSA in a patient with SLE. It is
important to know the correlation of these
diseases and to recognize signs and symptoms
early for the timely institution of appropriate
treatment.
REFERENCES:
1. Broaddus C, Mason RJ, Ernst JD, et al.
Murray & Nadel’s Textbook of Respiratory
Medicine 19th edition 2010. Philadelphia, PA:
Elsevier; 2010.
2. Doyle TJ, Hunninghake GM, Rosas IO.
Subclinical interstitial lung disease: why you
should care. Am J Respir Crit Care Med.
2012;185:1147–53.
3. Assayag D, Kaduri S, Hudson M, Hirsch A,
Baron B. HRCT Scoring System to Evaluate
ILD in Systemic Sclerosis Patients.
Rheumatol Res 2012;S1:003.
Vol. 18 | Issue 03 | September 2017 18
 Overlap syndrome with ILD
4. Hemminki K, Liu X, Ji J, Sundquist K,
Sundquist J. Subsequent COPD and lung
cancer in patients with autoimmune disease.
Eur Respir J. 2011 Feb;37(2):463-5.
5. Avina-Zubieta A, Sadatsafavi M, Sayre EC,
Esdaile J. Elevated risk of chronic obstructive
pulmonary disease in systemic lupus
erythematosus: a population-based study.
Arthritis Research & Therapy. 2014;16(Suppl
1):A34.
6. Shen TC, Lin CL, Chen CH, et al. Increased
risk of chronic obstructive pulmonary disease
in patients with systemic lupus erythematosus:
a population-based cohort study. PLoS One.
2014 Mar 12;9(3):e91821.
7. Lancaster LH, Mason WR, Parnell JA, Rice
TW, Loyd JE, Milstone AP, Collard HR,
Malow BA. Obstructive sleep apnea is
common in idiopathic pulmonary fibrosis.
Chest. 2009 Sep;136(3):772-778.
8. Won CHK, Purvis TE, Bennett A, Chun HJ.
An Overlap Phenomenon Exists with
Interstitial Lung Disease and Obstructive Sleep
Apnea. Am J Respir Crit Care Med.
2011;183:A5272.
9. Cottin V, Nunes H, Brillet PY, et al.
Combined pulmonary fibrosis and
emphysema: a distinct underrecognised entity.
Eur Respir J. 2005;26:586–593.
10. Portillo K, Morera J. Combined Pulmonary
Fibrosis and Emphysema Syndrome: A New
Phenotype within the Spectrum of Smoking-
Related Interstitial Lung Disease. Pulmonary
Medicine. 2012;2012:867870.
11. Khatri SB, Ioachimescu OC. The intersection
of obstructive lung disease and sleep apnea.
Cleve Clin J Med. 2016 Feb;83(2):127-40.
12. Carratu P, Resta O. Is Obstructive sleep apnea
a comorbidity of COPD? Eur Respir J.
2008;31:1381-1382.
13. Greenberg-Dotan S. Increased Prevalence of
COPD in patients with OSA. Sleep Breath
2014;18 (1):69-75.
19 Philipp J Chest Dis 2017
14. Areias V, et al. Comorbidities in patients
with GOLD Stage 4 COPD. Rev Port
Pneumol. 2014:20(1):5-11.
15. Weitzenblum E, et al. Sleep and Chronic
Obstructive Sleep Apnea. Sleep Medicine
Reviews. 2004;8:281-294.
16. Gan WQ, et al. Association between COPD
and Systemic Inflammation: A systematic
review and meta analysis. Thorax
2004;59(7):574-80.
17. Mohsenin, V. Sleep in COPD. Semin Respir
Crit Care Med 2005;26(1):109-16.
18. Schiza S. et al. Idiopathic Pulmonary Fibrosis
and Sleep: no longer strangers in the night.
Eur Respir Rev 2015;24:327–339.
19. Zamarron,C. et al. Association of COPD and
OSA consequences. Int J COPD
2008:3(4):671-682
20. Hiestand D, Phillips B. The overlap
syndrome: chronic obstructive pulmonary
disease and obstructive sleep apnea. Crit Care
Clin. 2008 Jul;24(3):551-63, vii.
21. Auerbach O, Garfinkel L, Hammond EC.
Relation of smoking and age to findings in
lung parenchyma: a microscopic study. Chest
1974;65:29–35.
22. Flenley DC. Sleep in chronic obstructive lung
disease. Clin Chest Med. 1985 Dec;6(4):651-
61.
 Araneta-Cuňada et al

CROSS-SECTIONAL STUDY

Prevalence of Asthma-COPD Overlap Syndrome (ACOS) in

Patients Presenting with Asthma or COPD in the OPD of the UP-
PGH Section of Pulmonary Medicine: A Pilot Study
Mariella Macrina Araneta-Cuňada, MD; Ralph Elvi Villalobos, MD; Lenora C. Fernandez,
FPCP, FPCCP

ABSTRACT
A
Background: Asthma and COPD has significant overlap, which is known as Asthma-COPD
Overlap Syndrome (ACOS). The exact prevalence of ACOS is still unknown. ACOS patients have a
higher risk of exacerbation; thus, they must be identified.

Methodology: This was a single-center cross-sectional study. Asthma and COPD patients at the
OPD were identified and included until the computed sample size of 54 COPD patients and 53
asthma patients was reached. Demographic profile of patients were determined. Spirometry done
and patient was classified as having asthma, COPD or ACOS. The prevalence of ACOS was also
computed.

Results: Asthma and COPD patients had a mean age of 56.42 + 11.74 years and 66.63 + 9.53
years, respectively. The mean age of ACOS patients was 65.32 + 8.58 years. All patients were
above age 40 years. Majority with asthma were females (69.44%), while majority with COPD
(92.5%) and ACOS (63.64%) were males. Pulmonary tuberculosis (PTB) prevalence was 5%
(asthma), 41% (COPD) and 48% (ACOS). Only 13.9% with asthma smoked, while 97.5% of COPD
and 62.2% of ACOS patients smoked. Mean smoking history was 4.72 + 14.67, 50.6 + 30.28 and
32.23 + 37.65 pack-years, respectively. The overall prevalence of ACOS was 22.45%. Those with
asthma had a higher prevalence of ACOS (26.53%) compared to those with COPD (18.37%).
ACOS was most common in those aged 50-59 years old.

INTRODUCTION COPD Overlap Syndrome or ACOS.3 This

Asthma is defined as a heterogeneous
disease characterized by chronic airway
inflammation with a history of wheeze, shortness
of breath, chest tightness and cough that vary
over time and intensity, with variable expiratory
airflow limitation.1 Chronic obstructive
pulmonary disease (COPD), on the other hand, is
defined as enhanced chronic inflammatory
response in the airways and lungs to noxious
particles or gases.2 Although asthma and COPD
are different entities, it has been increasingly
recognized that these two diseases have
significant overlap and is now known as Asthma-
subset of patients is reported to have a higher risk
of exacerbations and hospitalization; thus, they
have to be identified as more aggressive
management is recommended for patients with
ACOS.
The exact prevalence of ACOS in our
country has not yet been determined but is said to
be approximately 15-25% worldwide among
patients diagnosed with obstructive airways
disease.4 Patients with ACOS have worse
outcomes and greater health care utilization.3,5
There have been several arguments whether this
overlap really exists or it is just a phenotype of

Vol. 18 | Issue 03 | September 2017 20

 ACOS prevalence in asthma and COPD cohorts
COPD. Although the British Hypothesis states that
asthma and COPD are two different disease
entities, the Dutch Hypothesis supports the
increasingly observed overlap between these two
diseases stating that asthma and bronchial hyper-
responsiveness predispose to COPD later in life
and that asthma, COPD, chronic bronchitis and
emphysema are different expressions of a single
airway disease.
Several methods to diagnose ACOS have
been proposed. Soler-Cataluňa et al diagnosed
ACOS based on three major and 2 minor criteria.6
The major criteria included a very positive
bronchodilator test with increase in FEV1 ≥ 15%
and ≥ 400 mL, eosinophilia in sputum, and
personal history of asthma. Minor criteria
included high total IgE, personal history of atopy,
and positive bronchodilator test with increase in
FEV1 ≥ 12% and ≥ 200 mL on two or more
occasions. However, these major and minor
criteria were not sensitive nor specific. Another
study done by Louie et al used the following major
criteria for ACOS: a physician diagnosis of asthma
and COPD in the same patient; history or evidence
of atopy such as hay fever, elevated total IgE; age
40 years or more; smoking >10-pack years; and,
postbronchodilator FEV1 < 80% predicted and
FEV1/FVC < 70%.6 Minor criteria used in their
study included ≥ 15% increase in FEV1 or ≥ 12%
and ≥ 200 mL increase in postbronchodilator
treatment with albuterol. Other studies have
attempted to diagnose ACOS among patients with
asthma or COPD, but their diagnostic criteria have
not been validated.
The prevalence of ACOS has also been a
topic of debate since it is highly variable if
categorized based on age group. A cohort study
by Amir et al reported the prevalence of ACOS at
19.9%, and that prevalence increases with
increasing age: 3.4% in patients 30 to 39 years old,
17.2% in patients 50 to 59 years old, and 37.9% in
patients 60 years old and above.7
The Global Initiative for Asthma (GINA)
and Global Initiative for Chronic Obstructive
Lung Disease (GOLD) has come together to come
21 Philipp J Chest Dis 2017
up with a report on ACOS which is intended as a
general guide for health professionals on
diagnosis and management approach.3 The aim of
the consensus-based report on ACOS was made
to assist clinicians to identify those patients who
have chronic airflow limitation and distinguish
asthma from COPD and ACOS. A stepwise and
syndromic approach to diagnose patients with
chronic airways disease is recommended. There
are several features that would favor one
diagnosis over the other. For instance, the age of
onset of asthma is usually during childhood,
symptoms may vary over time and lung function
may be normal between symptoms.1 On the other
hand, COPD is usually diagnosed in patients >40
years of age, with chronic and usually continuous
symptoms, and with persistent airflow limitation
even between symptoms.2 The usual age of
diagnosis of patients with ACOS is ≥ 40 years
but many had symptoms in adulthood.3
Respiratory symptoms are persistent but
variability in some patients may be prominent
and as with COPD, lung function between
symptoms is usually characterized by persistent
airflow limitation.
Although spirometry is essential for
diagnosis or exclusion of chronic airflow
limitation, it may have a more limited value in
distinguishing between asthma with fixed airflow
limitation, COPD and ACOS.3 Spirometric
variables that are consistent with ACOS are as
follows: post-bronchodilator FEV1/FVC < 0.7 is
usually present; FEV1 ≥ 80% predicted is
compatible with diagnosis of mild ACOS; FEV1
< 80% predicted is an indicator of severity of
airflow limitation and risk of future events such
as mortality and exacerbations; post-
bronchodilator increase in FEV1 ≥ 12% and 200
mL from baseline consistent with reversible
airflow limitation is common and more likely
when FEV1 is low; and, post-bronchodilator
increase in FEV1 > 12% and 400 mL from
baseline consistent with marked reversibility is
compatible with ACOS.3
It was said that ACOS is not a single dis-

ease but rather includes patients with different
phenotypes and shares features of both asthma and
COPD. There is a wide agreement that patients
with features of asthma and COPD have more
frequent exacerbations, with poor quality of life,
more rapid decline in lung function and high
mortality; thus, the importance of the identification
of patients with ACOS should be emphasized.8
METHODS
This was a single-center cross-sectional
study that included newly diagnosed patients and
patients on follow-up visit who have been
previously diagnosed to have asthma or COPD in
the outpatient department of the University of the
Philippines-Philippine General Hospital Section of
Pulmonary Medicine from December 2015 until
the computed sample size of 54 COPD patients
and 53 asthma patients was reached. This sample
size assumed an ACOS prevalence of 20 ± 10%
with 90% level of confidence.
For those with asthma, the following
patients were included: all patients 30 years old
and above who were diagnosed to have bronchial
asthma, either confirmed by spirometry or
clinically diagnosed, including those with
presumptive tuberculosis on chest x-ray and were
determined to be sputum smear negative. Among
those with COPD, the following patients were
included: all patients 30 years old and above who
were diagnosed to have COPD, either confirmed
by spirometry or clinically diagnosed, including
those with presumptive TB on chest x-ray and
were determined to be sputum smear negative.
Those with concomitant congestive heart failure,
recent myocardial infarction, recent eye or
abdominal surgery, pregnant, those who are
mentally incapacitated who will not be able to
follow instructions to perform spirometry, and
those who were sputum smear positive and/or TB
bronchiectasis were excluded.
Informed consent was solicited by the
primary or sub-investigator and a thorough history
and physical examination was performed on the
day of study inclusion. A chest x-ray was perform-
Araneta-Cuňada et al
ed and spirometry was done if there were no
suspicious densities suggestive of pulmonary
tuberculosis (PTB). On patients with suspicious
densities on chest x-ray suggestive of PTB, two
sputum specimens for examination was taken one
hour apart. Spirometry was done on patients with
negative sputum examination.
A syndromic diagnosis of airways disease
was done using Box 5-2b found in the ACOS
consensus-based document.6 Patients were class-
ified as: “more likely to be asthma” or “more likely
to be COPD” if 3 or more boxes were checked for
either asthma or COPD respectively. Patient were
classified as “diagnosis of ACOS should be
considered” if there were similar numbers of
checked boxes in each column. If a patient was
diagnosed to have ACOS, his or her attending
physician was notified as more close follow-up is
needed in patients with ACOS.
Specifically, a diagnosis of ACOS was
considered if a patient had the following features:
usually age ≥ 40 but may have had symptoms in
childhood or early adulthood; respiratory
symptoms including exertional dyspnea which are
persistent but may have prominent variability;
airflow limitation not fully reversible but often
with current or historical variability; persistent
airflow limitation; frequently a history of doctor-
diagnosed asthma (current or previous), allergies,
and a family history of asthma, and/or noxious
exposures; symptoms are partly but significantly
reduced by treatment which usually progress and
treatment needs are high; chest x-ray similar to
COPD; exacerbations may be more common than
in COPD but are reduced by treatment; and,
comorbidities are reduced by treatment and can
contribute to impairment.3
Spirometric variables that that were used to
support the diagnosis of ACOS were as follows:
(1) normal FEV1/FVC pre- or post-bronchodilator
(BD) not compatible with ACOS unless with other
evidence of chronic airflow limitation; (2) post-BD
FEV1/FVC < 0.7 usually present; (3) FEV1 ≥ 80%
predicted compatible with diagnosis of mild
ACOS: (4) FEV1 < 80% predicted as an indicator
Vol. 18 | Issue 03 | September 2017 22
 ACOS prevalence in asthma and COPD cohorts
of severity of airflow limitation and risk of future
events such as mortality and exacerbations; (5)
post-BD increase in FEV1 >12% and 200 mL from
baseline suggestive of reversible airflow limitation
common and more likely when FEV1 is low and
ACOS should be considered; and, (6) post-BD
increase in FEV1 >12% and 400 mL from baseline
suggestive of marked reversibility as compatible
with ACOS.
RESULTS AND DISCUSSION
Of the 53 asthma patients and 54 COPD
patients who were included, four and five patients,
respectively, were lost to follow up. Hence, they
were not able to complete the pulmonary function
test and was thus excluded from the study. Forty-
nine patients with asthma and 49 patients with
COPD were included in the statistical analysis.
Out of the 49 patients with asthma, 36
patients were identified to have purely asthma and
13 patients had ACOS (Table 1). On the other
hand, 40 COPD patients had purely COPD and 9
patients were found to have ACOS. Among
ACOS patients, there were more asthma patients
(59.09%) compared to COPD patients (40.91%).
The demographic profile of patients are
shown in Table 2.
As to age, asthma patients had a mean age
of 56.42 years old and was more variable (SD
11.74 years); while COPD patients had a mean age
of 66.63 + 9.53 years. There were no patients with
ACOS below 40 years of age and only one patient
younger than 50 years old. ACOS patients had a
mean age of 65.32 + 8.58 years.
There were more male patients identified to
have chronic disease of the airways. However,
majority of asthma patients were females (69.4%)
Table 1. Patients with Chronic Disease of the Airways
Pure
Number % Number
Asthma 36 47.37
COPD 40 52.63
Total 76 100.00
23 Philipp J Chest Dis 2017
while majority of COPD (92.5%) and ACOS
(63.64%) patients were males.
Only 33.67% of patients had history of
previous PTB infection regardless of treatment
status. Of note, 47.5% of COPD patients and
40.91% of ACOS patients had previous PTB
infection, while only 5% of asthma patients had
previous PTB. Previous PTB infection has not
been implicated to increase risk of development of
ACOS but it has been found that it increases the
overall prevalence of airflow obstruction.9
Only five patients (13.9%) with asthma
smoked or were previous smokers. In contrast,
97.5% of COPD and 62.2% of ACOS patients
smoked or were previous smokers. Asthma
patients had a mean smoking history of 4.72 +
14.67 pack-years; COPD patients, a mean of 50.60
+ 30.28 pack-years; and ACOS patients, a mean of
32.23 + 37.65 pack-years.
The prevalence of ACOS in this study was
22.45% (Table 3), which is similar to the
worldwide average of 22% (p=0.545). Although
the exact prevalence of ACOS among asthma
patients has not yet been studied, it was noted that
the prevalence of ACOS in the asthma group was
higher (26.53%) as compared to the COPD group
(18.37%, Table 4).
As expected, the prevalence of ACOS
increased with increasing age and was noted to be
highest in those aged 50-59 years old and was not
present in patients less than 40 years old.
CONCLUSION
There is still debate as to the existence of
Asthma-COPD Overlap Syndrome and to date it is
still not defined. It was noted in this study that
there were more asthma patients noted to have
ACOS Total
% Number %
13 59.09 49 50.00
9 40.91 49 50.00
22 100.00 98 100.00
 Araneta-Cuňada et al

Vol. 18 | Issue 03 | September 2017 24

 ACOS prevalence in asthma and COPD cohorts

7. Louie S, Zeki AA, Schivo M, et al. The

asthma-chronic obstructive pulmonary disease
overlap syndrome: pharmacotherapeutic
considerations. Expert Rev Clin Pharmacol
2013;6:197-219.
8. Gibson PG, Simpson JL. The overlap
syndrome of asthma and COPD: what are its
features and how important is it? Thorax
2009;64:728-35.
9. Menezes AM, Hallal PC, Perez-Padilla R,
Jardim JR, Muiño A, Lopez MV, Valdivia G,
ACOS which may represent a severe form of Montes de Oca M, Talamo C, Pertuze J,
asthma in adults.5 These patients should be Victora CG; Latin American Project for the
identified and more closely followed up as they are Investigation of Obstructive Lung Disease
more difficult to treat and have more frequent (PLATINO) Team. Tuberculosis and airflow
exacerbations. obstruction: evidence from the PLATINO
This study showed that the prevalence of study in Latin America. Eur Respir J. 2007
ACOS is our setting is similar to the worldwide Dec;30(6):1180-5.
prevalence, but a study with a larger population
may be done to validate these findings.

REFERENCES:
1. Global Strategy for Asthma Management and
Prevention, Global Initiative for Asthma
(GINA) 2015. Available from www.ginasthma.
org.
2. Global Strategy for Diagnosis, Management
and Prevention of COPD, Global Initiative for
Chronic Obstructive Lung Disease (GOLD)
2015. Available from www.goldcopd.org.
3. Asthma, COPD, and Asthma-COPD Overlap
Syndrome. Global Initiative for Chronic
Obstructive Lung Disease (GOLD) 2015.
4. Papaiwannou A, Zarogoulidis P, Porpodis K, et
al. Asthma-chronic obstructive pulmonary
disease overlap syndrome (ACOS): current
literature review. J Thoracic Dis 2014;6(Suppl
1):S146-S151.
5. De Marie S, et. al. Approach to ACOS.
Presented at ERS 2013.
6. Soler-Cataluña JJ, Cosío B, Izquierdo JL, et al.
Consensus document on the overlap phenotype
COPD-asthma in COPD. Arch Bronconeumol.
2012;48:331-7.

25 Philipp J Chest Dis 2017

 Bumanglag-Dela Cruz and Ladrera

PROSPECTIVE COHORT STUDY

Clinical Correlation of the Radiologic Findings and

Pulmonary Function of Patients with Bronchiectasis: a
Lung Center of the Philippines Experience
Joice Bumanglag-Dela Cruz, MD; Guia Elena Imelda R. Ladrera, MD, FPCP, FCCP
Department of Pulmonary Medicine, Lung Center of the Philippines

ABSTRACT
Objective: To describe the clinical characteristics and evaluate the high-resolution computed
tomography (HRCT) findings of patients with bronchiectasis in correlation with their pulmonary
function test (PFT) and their functional capacity

Methodology: This prospective study was conducted on stable patients with bronchiectasis
diagnosed by HRCT at the Lung Center of the Philippines outpatient department from April 2014
through September 2014. Pulmonary function test and HRCT scores were taken, and dyspnea was
assessed using the modified Borg scale (MBS).

Results: Fifty-eight patients were evaluated. Majority (75.9%) were female, mean age was 50.9
years, and most were non-smokers (87.9%). Fifty percent presented with mixed types of
bronchiectasis. Post-tuberculosis infection was the most common etiology (94.8%). PFT results
showed mostly probable restrictive type. FVC, FEV1 and MBS score were significantly correlated to
CT score, bronchial dilatation, bronchial wall thickening, and number of bronchiectatic segments
(p<0.001). No significant correlation was found between the number of bullae (p=0.190) and
emphysematous segments (p=0.718).

Conclusion: Patients with cystic and mixed types of bronchiectasis, high CT score, bronchial
dilatation, bronchial thickening and a higher number of bronchiectatic segments have more
functional impairment. CT score is a predictor of FVC, FEV1 and dyspnea.
Keywords: bronchiectasis, HRCT score, pulmonary function

INTRODUCTION of bronchiectasis patients founf that the most

Bronchiectasis is defined as a localized
permanent abnormal dilatation of an airway,1,2
characterized by airflow obstruction, with
symptoms including cough, sputum production,
wheeze, dyspnea and decreased exercise
tolerance. Most patients with bronchiectasis
have an obstructive pulmonary function defect,
although mixed-obstructive-restrictive or
restrictive patterns of lung function can be
found in a minority of patients.3 A local study
common finding on spirometry was an
obstructive ventilatory pattern.4 The severity of
airflow was related to the extent of bronchiectatic
segments, as demonstrated on high-resolution
computed tomography (HRCT).2 Extensive
bronchiectatic changes result in a reduction in
vital capacity leading to a restrictive defect,
whereas productive sputum causes obstruction by
mucosal thickening and sputum retention.
However, the mechanism of airway obstruction is

Vol. 18 | Issue 03 | September 2017 26

 HRCT and PFT in bronchiectasis
not certain. Previous studies have found it might be
associated with the collapse of large airways at
expiration, the retention of endobronchial
secretion, bronchial wall thickening, sputum
proteases, obliterative bronchitis, airway hyper-
reactivity or accompanying asthma, and
emphysema.1,3 The causes of dyspnea and reduced
exercise capacity are multifactorial—these include
altered pulmonary mechanics, inefficient gas
exchange, decreased muscle mass and confounding
psychological morbidity, all of which lead to a
progressive detraining effect. Koulouris et al
demonstrated that the presence of tidal expiratory
flow limitation in patients with bronchiectasis
related to an increase in dyspnea and a reduced
tolerance for exercise.5
Currently, HRCT of the chest is a
confirmatory test for bronchiectasis and is
commonly used to grade bronchiectatic severity
and extent.2 The computed tomography (CT)
scoring system modified from the one described by
Bhalla et al6 is used to quantify the severity and
extent of bronchiectasis. CT scoring consists of the
following parameters: bronchial dilatation,
peribronchial wall thickening, number of
bronchiectatic segments, number of bulla and
number of emphysematous segments.2
Several studies have demonstrated the
correlation between HRCT score and forced
expiratory volume in 1 second (FEV1) and the
extent of physiological impairment.3,7,8 In a
retrospective study, Lee et al found that patients
with cystic bronchiectasis had higher CT scores,
more dilated lumen, and lower forced vital
capacity (FVC), FEV1, and FEV1/FVC than
patients with cylindrical bronchiectasis.2 They also
found that CT score is the most important predictor
of lung function.
One study found that dyspnea perception,
FEV1, and the daily amount of produced mucus
independently affected the health status of
bronchiectasis patients. Psychological depression
was related to exercise performance and perception
of dyspnea was related to exercise capacity.9 There
is little published data concerning the assessment
27
19 Philipp J Chest Dis 2017
of physiologic status with respect to the radiologic
degree of bronchiectasis and the exercise capacity
of patients.2 We have found no published data
correlating the severity of bronchiectasis with the
functional status of patients as determined by their
dyspnea score.
This study aims to describe the clinical
characteristics of bronchiectasis patients and
correlate the extent and severity of their
bronchiectasis on HRCT with their pulmonary
function test (PFT) and functional capacity.
METHODS
This prospective study was conducted at the
general outpatient department (OPD) of the Lung
Center of the Philippines (LCP) from April 2014
through September 2014. The recruited patients
were 18 years old and above; with on-and-off
chronic cough for 3 months or more, sputum
production and easy fatigability; radiographic
evidence of bronchiectasis on chest radiograph
using the criteria of Gudbjerg et al (increased
pulmonary markings, honeycomb-like structures,
atelectasis and pleural changes)10 or HRCT scan of
the chest (bronchial wall dilatation and wall
thickening)17 done ≤6 months prior; clinically
stable disease with no history of change in the
medications or oxygen supplementation within 1
month; and no signs of acute exacerbation.
Returning patients with previous records and new
patients with available chest radiographs or CT
scan with a diagnosis of bronchiectasis were
included. Plain HRCT of the chest was done for
those with chest X-rays only or whose chest CT
scans had been done >6 months prior.
Excluded from the study were patients with
exacerbation of bronchiectasis (increased sputum
production, increased cough, increased dyspnea,
change in the color of the sputum, changes in chest
sounds, radiographic changes consistent with a
new pulmonary process and presence of fever);
patients with features of active pulmonary
tuberculosis (TB) on thoracic imaging (chest
radiography showing heterogeneous consolidation
involving apical and posterior segment of upper

lobes and superior segment of lower lobes, often
with cystic or cavitary changes, with nodular and
fibrotic infiltrates, or CT scan showing tree-in-bud
sign, patchy or lobular areas of consolidation and
cavitation, and microscopy showing sputum acid-
fast bacilli [AFB] smear or TB culture positive);
current smokers or those who have smoked ≥10
years; pregnant women; patients with cystic
fibrosis; and those with a history of hemoptysis
within the past 2 weeks. Informed consent was
collected from the participants. The study
protocols were approved by the hospital’s Ethics
Review Committee.
Patients had their PFT and plain HRCT of
the chest done either on the day of recruitment or
within a week from consultation. Single-visit
protocol was used to characterize the clinical and
radiologic phenotypes of bronchiectasis, where
physical features and radiographic patterns were
assessed. Functional capacity was assessed by
evaluating FEV1 and FVC results on PFT and by
using the modified Borg’s dyspnea scoring. This
study had no natural history of disease course
follow-up.
PFT (simple spirometry without postbron-
chodilator test) was performed in compliance with
American Thoracic Society (ATS)/European
Respiratory Society (ERS) standards, using the
Viasys Vmax Encore 22. The degree of ventilatory
impairment was based on Morris-Polgar class-
ification. FVC, FEV1, and FEV1/FVC ratio were
measured and indicated as percentage values in
accordance with the age, sex and height of the
patients.
HRCT of the chest was done using multi-
detector CT scanner Hitachi Pronto. All images
were obtained with the patient in supine position,
in full inspiration and without contrast medium.
CT images were evaluated and CT scoring was
done by 2 in-house radiologists. Bronchiectasis
was categorized as “cylindrical” (tubular) when the
bronchial lumen had a smooth tubular outline;
“varicose” when the lumen had a variable diameter
producing a beaded appearance; and “cystic”
(saccular) when the dilated bronchi had the appear-
Bumanglag-Dela Cruz and Ladrera
ance of rings or clusters of cysts.
The extent of bronchiectasis, severity of
bronchial dilatation, bronchial wall thickness
(BWT), presence of mucus plugging in large and
small airways, and decrease in parenchymal
attenuation were scored separately for each lung
lobe according to the modified Bhalla system:
extent of bronchiectasis (0=none, 1=one or partial
bronchopulmonary segment involved, 2=two or
more bronchopulmonary segments involved,
3=generalized cystic bronchiectasis); severity of
bronchial dilatation (0=normal, 1=less than twice
the diameter of the adjacent pulmonary artery,
2=more than twice the diameter of adjacent
pulmonary artery); severity of bronchial wall
thickening (0=normal, 1=0.5 times the diameter of
the adjacent pulmonary artery, 2=0.5 to 1.0 times
the diameter of the adjacent pulmonary artery, 3=at
least 1.0 times the diameter of the adjacent
pulmonary artery); presence of mucus plugging in
large airways (0=none, 1=present); presence of
mucus plugging in small airways (0=none,
1=present); and extent of decreased attenuation
(0=normal, 1=at most 50% of lobar volume,
2=more than50% of lobar volume).1,3
The functional status of the patients was
assessed by grading their dyspnea severity through
the modified Borg scale (MBS), written in English,
with a Filipino translation. The scale was shown to
the patients, who were then asked to point to the
number on the scale that corresponded with their
degree of dyspnea.
We analyzed the data based on distribution,
demographic profile, patient features, PFT
parameters, HRCT results and score, and grade of
dyspnea using the SPSS statistical software for
Windows. Scores were expressed as means,
standard deviations or medians with ranges.
Associations between PFT result, HRCT score and
functional status were determined using
Spearman’s rank correlation. Chi-squared test was
used to evaluate the association between
categorical variables.
Vol. 18 | Issue 03 | September 2017 28
 HRCT and PFT in bronchiectasis

RESULTS of the patients had increased sputum production,

Fifty-eight patients with diagnosed and 13% had dyspnea, usually during exertion.
bronchiectasis, confirmed by HRCT of the chest, The common findings on physical examination
were included in the study. Females made up the were crackles/rhonchi (12%). Three percent had
majority (76%). The mean age was 50.9±12.1 decreased breath sounds, wheezes and clubbing
years; range was 38 to 63. Fifty-one (88%) were (Table 2).
non-smokers. Twenty-six percent had tubular The most common radiologic finding of
(cylindrical) bronchiectasis; 24%, cystic (saccular); bronchiectasis was multilobar (76%); the most
and 50%, mixed. The underlying etiology for all commonly involved lobes, the right upper (67%)
was post-infection: 95% post TB infection and 5% and the left upper (50%) (Table 3).
post recurrent pneumonia. The mean FVC was The mean bronchial dilatation of the tubular
46% of the predicted value; FEV1, 53%; and group (1.2) was significantly lower than that of
FEV1/FVC ratio, 80% (Table 1). both the cystic (2.1) and the mixed groups (2.0)
Cough (86%) and easy fatigability (71%) (p=0.004). Tubular-type bronchiectasis also
were the most common complaints. Twenty (35%) displayed the least wall-thickening patterns
(p=0.045) on chest CT scan. There was significant
Table 1. Clinical Profile of Stable Bronchiectasis difference between the mean extent of
bronchiectasis of the tubular group (1.3) compared
Patients (N=58)
to the cystic (1.9) and mixed groups (1.9)
Parameter n (%) (p=0.027) (Table 4).
Age, y* 50.9±2.1 There were no significant differences
Sex between tubular, cystic and mixed bronchiectasis
Male 14 (24.1) in terms of FVC% predicted, FEV1% predicted
Female 44 (75.9) and FEV1/FVC (Table 5). No significant
Smoking history differences were found among the 3 groups in
terms of bronchial dilatation (0.121), bronchial
Ex-smoker 7 (12.1)
wall thickening (0.538), extent of bronchiectasis
Non-smoker 51 (87.9) (0.051), number of bullae (0.730) and number of
Etiology of bronchiectasis emphysematous segments (0.264) (Table 6).
Childhood disease 0 (0.0) The radiologic severity according to
Tuberculosis 55 (94.8) ventilatory impairment showed no significant
Pneumonia 3 (5.2) difference (p=0.078), suggesting that the
Types of bronchiectasis distribution of radiologic severity according to
lung impairment was similar among normal,
Tubular/cylindrical 15 (25.9)
restrictive and mixed types of ventilatory defect
Cystic/saccular 14 (24.1)
(Table 7).
Mixed (tubular and cystic) 29 (50.0) Probable restrictive type of ventilatory
Varicose 0 (0.0) pattern was detected in most of our patients
Lung function parameter* (tubular, 73%; cystic, 93%; and mixed type, 83%).
FVC % predicted 45.9±17.8 No obstructive ventilatory pattern was observed in
FEV1 % predicted 53.3±17.2 this study.
FEV1/FVC 80.3±9.2 FVC and FEV1 demonstrated significant
*Mean ± standard deviation. difference in all HRCT scores in an inversely
FEV = forced expiratory volume in 1 second; FVC = related fashion, per negative Pearson’s correlation
forced vital capacity. coefficient (Figure 1). The FEV1/FVC ratio was

29 Philipp J Chest Dis 2017

 Bumanglag-Dela Cruz and Ladrera

Table 2. Symptoms and Signs of Bronchiectasis rhonchi/crackles, and occasionally wheezes, as

were seen in our patients. Our study showed that
Symptom/Sign n (%) there are more females with bronchiectasis than
males; this data is consistent with the findings of
Cough 50 (86.2)
previous studies.2,3,4,13 We had more females than
Increased sputum 20 (34.5)
males in our study, perhaps because we excluded
Dyspnea 13 (22.4) patients who were at risk for chronic obstructive
Easy fatigability 41 (70.7) pulmonary disorder (COPD), ie, current smokers
Blood-streaked sputum 0 (0.0) and those with 10 years’ smoking history, who
Chest pain 3 (5.2) were more commonly males.
Crackles 7 (12.1) According to literature, in 30% to 74% of
patients with bronchiectasis, etiology could not be
Rhonchi 7 (12.1)
Decreased breath sounds 2 (3.4)
determined, but post-infection has been regarded as
Wheezes 2 (3.4) the most common cause.14 We came up with a
similar finding, specifically noting tuberculosis
Clubbing 2 (3.4)
infection as a significant factor in the history of
almost all of our patients, like in the local
not significantly associated with HRCT scores prospective study done by Ramos et al.4 Our study
(Table 8). showed that bronchiectasis involvement was
MBS score was significantly correlated to multilobar in majority, like in the study done by
total CT score, bronchial dilatation, bronchial wall Habesoglu et al13; however, unlike them who
thickening and number of bronchiectatic segments. found the right and left lower lobes as the most
There was no significant correlation between common location, we found the right and left upper
dyspnea score, number of bullae (p=0.190) and lobes as the most commonly involved. This
emphysematous segments (p=0.718) (Table 9). involvement of the upper lobes of the lungs was
There was a positive correlation (r=0.261) between consistent among our participants, the majority of
the CT score and the MBS (Figure 2). whom developed bronchiectasis post tuberculosis
FEV1 and CT score were significantly infection, which often involves the apical lobes.
dependent (p=0.007). A mild CT score tended to
have higher FEV1 (FEV1 ≥80% predicted), while a
moderate-to-severe CT score tended to have lower Table 3. Radiologic Distribution of Bronchiectasis
FEV1 (<79% predicted) (Table 10). Based on HRCT Findings
FVC and CT score were significantly Localization n (%)
dependent (p=0.01). Moreover, mild CT scores
Multilobar 44 (75.9)
tended to have higher FVCs, while those with a
Single lobe 8 (13.8)
moderate-to-severe CT scores tended to have
Right upper lobe 39 (67.2)
lower FVCs (FVC <80% predicted) (Table 11).
Left upper lobe 29 (50.0)
DISCUSSION Right middle lobe 27 (46.6)
Bronchiectasis is generally an anatomic Lingula 2 (3.4)
abnormality resulting from many different factors. Right lower lobe 13 (22.4)
It is defined pathologically as an irreversible Left lower lobe 21 (36.2)
dilatation of bronchi usually related to airway
HRCT=high-resolution computed tomography.
infection.2 It is typically characterized by chronic
Note: Frequency of each lobe involvement was calculated
productive cough, easy fatigability, dyspnea, separately.

Vol. 18 | Issue 03 | September 2017 30

 HRCT and PFT in bronchiectasis

Table 4. CT Scores According to Type of Bronchiectasis

Tubular Cystic Mixed
P-value
Bhalla's CT Score (n=15) (n=14 ) (n=29)
n (%) Mean±SD n (%) Mean±SD n (%) Mean±SD
Bronchial
dilatation
0 1 (6.7) 1.2±0.7* 0 (0.0) 2.1±0.8** 0 (0.0) 2.0±0.9** 0.004
1 11 (73.3) 4 (28.6) 10 (34.5)
2 2 (13.3) 5 (35.7) 8 (27.6)
3 1 (6.7) 5 (35.7) 11 (37.9)
Bronchial wall
thickening
0 0 (0.0) 1.2±0.6** 0 (0.0) 1.7±0.7 1 (3.4) 1.8±0.9** 0.045
1 13 (86.7) 6 (42.9) 11 (37.9)
2 1 (6.7) 6 (42.9) 9 (31.0)
3 1 (6.7) 2 (14.3) 8 (27.6)
Extent of
bronchiectasis
0 0 (0.0) 1.3±0.5* 0 (0.0) 1.9±0.9** 0 (0.0) 1.9±0.8** 0.027
1 11 (73.3) 6 (42.9) 11 (37.9)
2 4 (26.7) 3 (21.4) 10 (34.5)
3 0 (0.0) 5 (35.7) 8 (27.6)
Number of bullae
0 10 (66.7) 0.3±0.5 8 (57.1) 0.6±0.9 16 (55.2) 0.6±0.8 0.482
1 5 (33.3) 4 (28.6) 10 (34.5)
2 0 (0.0) 1 (7.1) 2 (6.9)
3 0 (0.0) 1 (7.1) 1 (3.4)
Number of
emphysematous
segments
0 9 (60.0) 0.4±0.5 5 (35.7) 0.8±0.7 14 (48.3) 0.6±0.7 0.275
1 6 (40.0) 7 (50.0) 12 (41.4)
2 0 (0.0) 2 (14.3) 3 (10.3)
3 0 (0.0)
CT=computed tomography. 0 (0.0) 0 (0.0)
*Mixed tubular and cystic type of bronchiectasis.
**Mixed obstructive and restrictive ventilatory defect.

We scored morphologic changes of the obstructive pulmonary defect in the majority of

lungs using the CT scoring system developed by
Bhalla et al.6 As a consequence of airway
infection, there was structural destruction of lung
tissues followed by functional deterioration.2 The
degree of anatomical change that can be assessed
radiographically may reflect pulmonary functional
limitation. We correlated the CT scores, types of
bronchiectasis, pulmonary functional status and
dyspnea perception of patients in our study. In
contrast to previous studies, which reported
bronchiectasis patients,2,13 our study showed that
most of our patients had probable restrictive type
of ventilatory defect, and a few had mixed
obstructive/restrictive ventilatory defect, which is
uncommon.14,15 However, pulmonary function
parameters may still be normal in minimal degree
of bronchiectasis,2 which was observed in some of
our patients. However, Lee et al have reported that
most of their patients had mixed type of ventilatory
defect, followed by obstructive defect.2

31 Philipp J Chest Dis 2017

 Bumanglag-Dela Cruz and Ladrera

Table 5. Pulmonary Function Test Results According to Type of Bronchiectasis (Mean ± SD)

Tubular/ Cylindrical Cystic/Saccular Mixed*

P-value
(n=15) (n=14) (n=29)
Lung function parameter
FVC % predicted 47.8±17.1 50.1±22.2 43.0±15.7 0.428
FEV1 % predicted 45.9±17.8 54.4±19.4 50.0±17.3 0.287

FEV1/FVC 79.7±6.7 85.4±4.8 78.2±11.1 0.054

Impairment of lung function
Normal 2±13.3 1±7.1 1±3.4 0.456
Restrictive type 11±73.3 13±92.9 24±82.8
Mixed type** 2±13.3 0±0.0 4±13.8
FEV1=forced expiratory volume in 1 second; FVC=forced vital capacity; SD=standard deviation.
*Mixed tubular and cystic type of bronchiectasis.
**Mixed obstructive and restrictive ventilatory defect.

The likely reason for this finding may be
because we excluded patients who were at risk of
COPD, specifically, current smokers and those
with significant smoking history ≥10 years. We
have noted that COPD and asthma were the
coexisting diseases or comorbidities of the patients
in other studies.2,4,13,16 Nicotra et al found that
obstructive lung disease was common in
bronchiectatic patients who were cigarette
smokers, while Lynch et al reported that airway
obstruction was seen more in cylindric type of
bronchiectasis, which was associated with a
greater number of current and previous smokers.12
In most of our patients, chest CT scan findings
showed fibrosis.
Habesoglu et al found a strong inverse
correlation between the extent of bronchiectasis,
the degree of bronchial dilatation, BWT, decrease
of attenuation in lung parenchyma, and PFT
parameters in patients with pure bronchiectasis,1
but the extent of bronchiectasis and the decrease in
the attenuation in the lung parenchyma were the
main determinants of the reduction of FVC and
FEV1; this suggests that morphologic changes in
patients with pure bronchiectasis could lead to both
restrictive and obstructive functional impairment.1
Sheehan et al8 stated that the mucus load
of airways varies over time, and this could be a
reason for some fluctuation in pulmonary
function. Reports have suggested that the
obstructive component of bronchiectasis is
caused by a combination of structural damage to
the airways, secretions in the airways,
bronchiolitis, bronchial hyperreactivity,12
obliterative bronchitis accompanied by
bronchiectasis,1 bronchial wall thickening, and
decreased attenuation of the lung parenchyma.8
Habesoglu et al found that the degree of
bronchial dilatation was the main independent
variable associated with a decrease in FEV1/FVC
ratio. Lee et al reported that the degree of
bronchial dilatation correlated with airway
obstruction.2 Roberts et al suggested that the
increase in the degree of bronchial dilatation
correlated with the amount of airway obstruction
at lower levels.17 In parallel, the increase in
airway obstruction can be associated with
morphologic changes in small airways, which
cannot be radiologically demonstrated with
HRCT.1
Roberts et al found that decreased
attenuation of the lung parenchyma on the expi-

Vol. 18 | Issue 03 | September 2017 32

 HRCT and PFT in bronchiectasis

Table 6. CT scores According to Type of Ventilatory Defect

Bhalla's CT Normal (n=4) Restrictive (n=48) Mixed (n=6)

P-value
Parameters n (%) Mean±SD n (%) Mean±SD n (%) Mean±SD
Bronchial
dilatation
0 1 (25) 0 (0) 0 (0)

1 2 (50) 19 (39.6) 4 (66.7)

1±0.8 1.9±0.8 1.7±1.0 0.121
2 1 (25) 14 (29.2) 0 (0)

3 0 (0) 15 (31.3) 2 (33.3)

Bronchial wall
thickening
0 0 (0) 1 (2.1) 0 (0)

1 3 (75) 23 (47.9) 4 (66.7)

1.3±0.5 1.7±0.8 1.5±0.8 0.538
2 1 (25) 14 (29.2) 1 (16.7)

3 0 (0) 10 (20.8) 1 (16.7)

Extent of
bronchiectasis
0 0 (0) 0 (0) 0 (0)

1 4 (100) 20 (41.7) 4 (66.7)

1.0±0.0 1.9±0.8 1.3±0.5 0.051
2 0 (0) 15 (31.3) 2 (33.3)

3 0 (0) 13 (27.1) 0 (0)

Number of bullae

0 3 (75) 28 (58.3) 3 (50.0)

1 1 (25) 15 (31.3) 3 (50.0)

0.3±0.5 0.6±0.8 0.5±0.8 0.73
2 0 (0) 3 (6.3) 0 (0)

3 0 (0) 2 (4.2) 0 (0)

Number of
emphysematous
segments

0 3 (75) 21 (43.8) 4 (66.7)

1 1 (25) 22 (45.8) 2 (33.3)

0.3±0.5 0.7±0.7 0.3±0.5 0.264
2 0 (0) 5 (10.4) 0 (0)

3 0 (0) 0 (0) 0 (0)

33 Philipp J Chest Dis 2017

 Bumanglag-Dela Cruz and Ladrera

Table 7. Radiologic Severity According to Ventilatory Impairment

Normal Restrictive Mixed
Radiologic P-value
(n=4) (n=48 ) (n=6)
Severity
n % n % n %
Normal 0 0 0 0 0 0.0
Mild 4 100 19 40 3 50
0.078
Moderate 0 0 26 54 3 50
Severe 0 0 3 6 0 0.0
*Radiologic severity based on HRCT score: normal=0, mild=1 to 10, moderate=11 to 21, severe=22 to 31.

Figure 1. FEV1 vs CT score (left) shows inverse correlation (r=–0.625), and FVC vs CT score (right) shows inverse
relationship (r=–0.609)

Table 8. Correlation Between HRCT Scores and Lung Function Parameters

FVC FEV1 FEV1/FVC

Pearson r P-value Pearson r P-value Pearson r P-value
HRCT score -0.609 <0.001 -0.625 <0.001 0.210 0.114

Bronchial dilatation -0.664 <0.001 -0.512 <0.001 0.252 0.056

Bronchial wall thickening -0.507 <0.001 -0.571 <0.001 0.170 0.202

No. of bronchiectatic
-0.570 <0.001 -0.516 <0.001 0.193 0.148
segments

No. of bullae -0.473 <0.001 -0.522 <0.001 0.129 0.333

No. of emphysematous
-0.185 0.165 -0.376 0.004 0.154 0.248
segments

HRCT=high-resolution computed tomography; FEV1=forced expiratory volume in 1 second; FVC=forced vital capacity.

Vol. 18 | Issue 03 | September 2017 34

 HRCT and PFT in bronchiectasis

Table 9. Correlation Between CT Score and Although restrictive lung impairment is a

Functional Status of Patients Using Modified Borg feature of previous studies of bronchiectasis and
Scale (MBS) was a significant finding in our patients, we found
MBS Score no satisfactory explanation for this finding.
Pearson r P-value* Possible mechanisms for lung restriction include
CT score 0.261 0.048 atelectasis, pleural disease, and parenchymal
Bronchial dilatation 0.334 0.010 scarring and peribronchial fibrosis that accompany
Bronchial wall thickening 0.273 0.038
bronchiectasis secondary to previous infection,
No of bronchiectatic segments 0.260 0.049 particularly, tuberculosis,1,17 Evolution of peri-
No. of bulla 0.175 0.190 bronchial inflammation to fibrotic disease might
No. of emphysematous account for a restrictive functional element and
0.048 0.718 might also lessen gas trapping by a traction effect
segments
on partially obstructed airways.17
Among the different types of bronchiectasis,
ratory CT scan was a major determinant of airflow the cystic and mixed types showed more bronchial
obstruction. In bronchiectasis, this phenomenon dilatation and bronchial wall thickening than the
represents inflammatory or obliterative tubular type. This may reflect more pronounced
bronchiolitis, which is an integral histologic distortion of the lung architecture and airways
feature. Obliterative bronchiolitis is believed to be inflammation. However, there was no difference in
a key early event in the pathogenesis of terms of the number of bullae and emphysematous
bronchiectasis in cystic fibrosis, and others have segments both in the cystic and mixed (cystic and
argued that obliteration of peripheral bronchi and tubular) types of bronchiectasis. In other studies,
bronchioles results from the spread of chronic patients with cystic bronchiectasis also showed a
infection from bronchiectatic airways.17 Thus, decrease in the individual parameters of lung
bronchial wall thickening in small airways is a function compared to patients with cylindrical
pathophysiologic event in airflow obstruction. bronchiectasis.2,12
We found no significant differences in type
Figure 2. Relationship Between CT Score and of bronchiectasis in relation to the FEV1, FVC and
Dyspnea Score FEV1/FVC ratio. In contrast, Alzeer et al7 and
Lynch et al12 found FVC and FEV1 to be
significantly lower in cystic patients than in
cylindrical patients.
We observed that the radiologic severity of
bronchiectasis is the same in all types of lung
impairment. The FVC% and FEV1% predicted
were significantly correlated to CT scores:
bronchial dilatation, bronchial wall thickening, and
the number of bronchiectatic segments. However,
there was no significant difference with FEV1/FVC
ratio. FVC and HRCT scores were inversely
related to each other. CT score includes severity,
extent and associated findings in bronchiectasis; it
reflects functional changes.
CT=high-resolution computed tomography; There was significant correlation between
MBS=modified Borg scale.

35 Philipp J Chest Dis 2017

 Bumanglag-Dela Cruz and Ladrera

Table 10. Correlation Between Severity of Bronchiectasis (CT Score) and FEV 1
FEV1 (% predicted)
CT Score P-value
≥80% 50–79% 30–49% <30%
0 (normal) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
1–10 (mild) 3 (100) 13 (72.2) 5 (41.7) 5 (20.0)
0.007
11–20 (moderate) 0 (0.0) 4 (22.2) 7 (58.3) 15 (60.0)
21–30 (severe) 0 (0.0) 1 (5.6) 0 (0.0) 5 (20.0)
CT=computed tomography; FEV1=forced expiratory volume in 1 second.

Table 11. Correlation Between Severity of Bronchiectasis (CT Score) and FVC
FVC (% predicted)
Total CT Score P-value
≥80% 50–79% 30–49% <30%
0 (normal) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
1–10 (mild) 4 (100.0) 18 (60.0) 2 (20.0) 2 (14.3)
0.010
11–20 (moderate) 0 (0.0) 11 (36.7) 6 (60.0) 9 (64.3)
21–30 (severe) 0 (0.0) 1 (3.3) 2 (20.0) 3 (21.4)
CT=computed tomography; FVC=forced vital capacity.

the dyspnea score (MBS score) and the total CT
score, bronchial dilatation, bronchial wall
thickening and the number of bronchiectatic
segments. A higher CT score would correlate to
a higher MBS; thus, CT score could be a
predictor of dyspnea.
CONCLUSION
We conclude that radiologic findings
such as cystic and mixed (tubular and cystic)
type, high CT score, bronchial dilatation,
bronchial thickening and the number of
bronchiectatic segments were highly relevant to
functional impairment in our patients with
stable bronchiectasis. CT score appeared to be
the most important predictor of FVC and FEV1.
As a prospective investigation of stable
bronchiectasis patients, our study was limited in
that it did not measure total lung capacity
through helium dilution or body
plethysmograph to confirm restrictive pulmo-
nary impairment. In addition, the CT scans
were interpreted by different in-house
radiologists who were unaware of the clinical
conditions of the patients, and 2 different in-
house radiologists did the CT scoring.
We recommend further studies to verify
these clinical, functional and radiologic
relationships in a bigger population. Investigators
could do complete lung volume studies using
body pletysmograph. Future studies could also
correlate CT scan with long-term outcome and
find its role in acute exacerbations.
REFERENCES
1. Habesoglu MA, Tercan F, Ozkan U, Fusun
EO. Effect of radiological extent and severity
of bronchiectasis on pulmonary function.
Multidiscip Respir Med. 2011;6:284–290.
2. Lee JH, Kim YK, Kwah HJ, Chang JH.
Relationships between high-resolution
computed tomography, lung function and
bacteriology in stable bronchiectasis. J
Korean Med Sci. 2004;19:62–68.

Vol. 18 | Issue 03 | September 2017 36

 HRCT and PFT in bronchiectasis

3. Ooi GS, Khong PL, Chan-Yeung M, et al. 13. Habesoglu MA, Ugurlu AO, Eyuboglu FO.
High-resolution CT quantification of Clinical, radiologic, and functional
bronchiectasis: clinical and functional evaluation of 304 patients with
correlation. Radiology. 2002;225:663–672. bronchiectasis. Ann Thorac Med.
4. Ramos RE, et al. A prospective study on the 2011;6:131–136.
relationship between the extent and severity of 14. Pande JN, Jain BP, Gupta RG, Guleria JS.
bronchiectasis on CT and clinical symptoms Pulmonary ventilation and gas exchange in
and PFT results. Lung Center of the bronchiectasis. Thorax. 1971;26:727-733.
Philippines. 2002. 15. Ip M, Lauder IJ, Wong WY, Lam WK, So
5. Koulouris NG, Retsou S, Kosmas E, Dimakou SY. Multivariate analysis of factors affecting
K, Malagari K, Mantzikopoulos G, pulmonary function in bronchiectasis.
Koutsoukou A, Milic-Emili J, Jordanoglou J. Respiration. 1993;60:45–50.
Tidal expiratory flow limitation, dyspnea and 16. Baig IM, Saeed W, Khalil KF. Post-
exercise capacity in patients with bilateral tuberculous chronic obstructive pulmonary
bronchiectasis. Eur Respir J. 2003;21:743– disease. J Coll Physicians Surg Pak.
748. 2010;20:542–524.
6. Bhalla M, Turcios N, Aponte V, Jenkins M, 17. Roberts HR, Wells AU, Milne DG, et al.
Leitman BS, McCauley DI, Naidich DP. Airflow obstruction in bronchiectasis:
Cystic fibrosis: scoring system with thin- correlation between computed tomography
section CT. Radiology. 1991;179:783–788 features and pulmonary function tests.
7. Alzeer AH. HRCT score in bronchiectasis: Thorax. 2000;55:198–204.
correlation with pulmonary function tests and
pulmonary artery pressure. Ann Thorac Med.
2008;3:82–86.
8. Sheehan RE, Wells AU, Copley SJ, Desai SR,
Howling SJ, Cole PJ, Wilson R, Hansell DM.
A comparison of serial computed tomography
and functional change in bronchiectasis. Eur
Respir J. 2002;20:581–587.
9. Ozalp O, Inal-Ince D, Calik E, et al.
Extrapulmonary features of bronchiectasis:
muscle function, exercise capacity, fatigue,
and health status. Multidiscip Respir Med.
2012;7:3.
10. Gudbjerg CE. Roentgenologic diagnosis of
bronchiectasis: an analysis of 112 cases. Acta
Radiol. 1955;43:210–226.
11. Ogbeide O. The radiological management of
tuberculosis. Benin J Postgrad Med.
2009;11:74–78.
12. Lynch DA, Newell J, Hale V, et al. Correlation
of CT findings with clinical evaluations in 261
patients with symptomatic bronchiectasis. AJR
Am J Roentgenol. 1999;173:53–58.

37 Philipp J Chest Dis 2017

 Sabando and Idolor

RETROSPECTIVE STUDY

Prevalence and Characteristics of the Three Clinical

Phenotypes of COPD at Lung Center of the Philippines
May N. Sabando, MD; Luisito Idolor, MD, FPCCP
Department of Pulmonary Medicine, Lung Center of the Philippines

ABSTRACT
Objectives: To determine the prevalence and analyze the most relevant clinical characteristics of
chronic obstructive pulmonary disease (COPD) in patients seen at a tertiary hospital’s COPD
outpatient clinic
Methods: This retrospective study stratified the characteristics of COPD into three phenotypes (ie,
chronic bronchitis, emphysematous and COPD asthma) based on imaging tests, pulmonary
functions and reported symptoms.
Results: Out of 165 patients, 60% were chronic bronchitic (phenotype 1); 27%, emphysematous
(phenotype 2); and 13% showed mixed characteristics with asthma (phenotype 3) (p=0.09). There
was no significant difference in level of smoking among the groups. Type 2 patients showed lower
forced expiratory volume in one second (FEV1) compared to types 1 and 3 (p<0.001). No significant
differences were observed in the proportion of patients who experienced any exacerbations in the
past.
Conclusions: In a general population of COPD patients, three patient profiles can be seen in
clinical practice. Most fall under the chronic bronchitis or emphysematous phenotype.
Emphysematous patients normally show worse pulmonary functions than the other two groups, with
no differences in exacerbations and use of hospital health care resources.
Keywords: COPD, phenotype, clinical phenotypes

INTRODUCTION bronchodilator forced expiratory volume in 1 sec

Chronic obstructive pulmonary disease
(COPD) is a preventable and treatable disease
state characterized by airflow limitation that is
not fully reversible. The airflow limitation is
usually progressive and associated with the
lungs’ abnormal inflammatory response to
noxious particles or gasses, primarily caused by
cigarette smoking. COPD is a leading cause of
morbidity and mortality worldwide and results
in an economic and social burden that is both
substantial and increasing.1 Current clinical
guidelines define COPD by the presence of
chronic, almost irreversible, airflow obstruction,
confirmed by spirometry, with a ratio of post-
to forced vital capacity (FEV1/FVC) <70 in the
absence of a defined pathology, such as
bronchiectasis or tuberculosis, to otherwise
explain the airflow obstruction.2 The main
problem with these guidelines is that they ponder
too much on the value of forced spirometry in the
diagnosis and assessment of the severity of
COPD, thereby preventing the adequate
assessment of the “various faces of the disease”.3
It is now widely accepted that COPD is a
complex syndrome with numerous pulmonary
and extra-pulmonary components.4
Since the Ciba symposium in 1959, COPD
has been considered an overlap between chronic

Vol. 18 | Issue 03 | September 2017 38

 Three COPD phenotypes in Filipinos
bronchitis, emphysema and subtypes of asthma
associated with chronic airflow limitation.5 This
was first represented in a non-proportional Venn
diagram by Snider.2 In the 1960s, Burrows6
further defined the emphysematous phenotype to
differentiate it from the bronchitic phenotype.
Since then, various observational studies have
confirmed the existence of groups of patients
with peculiar characteristics such as the presence
of emphysema in imaging techniques and a
decrease in the diffusion test, low sputum
production, low body mass index (BMI), normal
arterial blood gases and greater dyspnea; chronic
bronchitis with no evidence of emphysema in
chest x-rays and with normal diffusing capacities;
and patients with characteristics similar to
bronchial asthma, which have generally been
excluded from clinical trials but actually
constitute a phenotype with greater concentration
of eosinophils in their secretions and bronchial
mucosa.3
As a result of these studies, there is
consensus that FEV1 by itself does not adequately
describe the complexity of COPD and cannot be
used in isolation for the optimal diagnosis,
assessment and management of the disease. A
clear alternative has not yet been defined, but
identification and subsequent grouping of key
elements of the COPD syndrome into clinically
significant subgroups can guide therapy more
effectively.4 In recent years, the term “COPD
phenotype” has been used to refer to the clinical
types of patients with COPD. The term
“phenotype” is defined as a single disease
attribute or a combination of attributes that
describe differences between individuals with
COPD as they relate to clinically meaningful
outcomes.4 These recent pieces of information on
different phenotypes of COPD indicate that we
are not justified in continuing to assume that a
classification based exclusively on spirometric
criteria is a good classification.7
Recognizing the different phenotypes
within COPD is important in understanding the
underlying disease processes. Each phenotype
39 Philipp J Chest Dis 2017
may have a different pathophysiology, and the
identification of biological mechanisms specific
to some phenotypes may lead to the development
of biomarkers aimed at the diagnosis of
phenotypes and the identification of candidates to
specific and more targeted treatments. It is,
therefore, from the clinical point of view,
possible to identify thee different COPD
phenotypes, the assessment of which could
facilitate a better understanding and management
of the disease.8
The objective of this study is to determine
the prevalence of each phenotype in a population
of COPD patients seen at a tertiary hospital’s
COPD outpatient clinic and to analyze the most
relevant clinical characteristics in each of the
three described COPD phenotypes.
METHODS
This is a retrospective, descriptive study
performed at a tertiary hospital COPD outpatient
clinic. Charts were included for reviewed if the
patient was aged ≥40 years, consulted at the
clinic from January 2013 through December
2013, had a >10 pack-year index (PYI) smoking
history, and was diagnosed with COPD according
to Global Initiative for Chronic Obstructive
Pulmonary Disease 2014 criteria (post-
bronchodilator FEV1/FVC <0.70). Charts were
excluded if the patient had a current diagnosis of
asthma, bronchiectasis or pulmonary
tuberculosis.
A sample size of 165 was computed based
on the report of a local study, that the estimated
prevalence of COPD in the Philippines was
around 12.5% to 13.8% and an alpha of 0.05.
Demographics, BMI, comorbidities,
smoking status, exacerbations and hospital-
izations, treatment, dyspnea score in daily living
and results from pulmonary function tests/chest
radiography/chest CT scan were collected.
Patients were then categorized into different
subgroups according to the following criteria3,7:
• Phenotype 1. Chronic Bronchitis - cough
and sputum production on most days for at

3 months per year, for ≥2 years; absence of
pulmonary emphysema, demonstrated
through imaging technique (ie, CT scan or
thorax radiography); and absence of asthma
antecedents.
• Phenotype 2: Emphysema - pulmonary
emphysema proved by CT scan, or diffusion
test with transfer factor for carbon
monoxide/alveolar volume (TLCO/VA)
values inferior to 80% and thorax
radiography suggesting emphysema.
• Phenotype 3. Asthma overlap - personal
history or physician diagnosis of asthma
before the age of 40; and absence of
pulmonary emphysema demonstrated
through imaging techniques, CT scan or
thorax radiography.
Descriptive analysis was performed on all
the variables: absolute and relative frequencies
for qualitative variables, mean with standard
deviation for continuous variables.
Pearson’s chi-squared test was used to
compare independent samples for quantitative
variables; ANOVA for qualitative variables.
Tukey’s honest significant difference (HSD)
was used for analysis between groups. In all
statistical tests performed, the level of statistical
significance was set at <0.05. SPSS Statistics v.
17.0 statistical package was used.
RESULTS
Out of the 400 charts reviewed, 180 met
the inclusion criteria and 165 were randomly
selected to be analyzed in the study. Of the 165
included patients, 60% (n=98) presented as
chronic bronchitic (type 1); 27% (n=45) were
emphysematous (type 2); and the remaining
showed mixed characteristics with asthma (type
3). The proportion of male patients was
significantly higher in type 1 and type 2; the
proportions of females was significantly higher
in type 3 (p=0.009). No significant differences
were noted in smoking level, age, BMI, and
Sabando and Idolor
level of dyspnea. The emphysematous group
showed lower FEV1 than the chronic bronchitic
group (p<0.001). FVC and FEV1/FVC were also
significantly lower in type 2 than in type 3. The
mean height in type 2 was significantly higher
than in type 3 (163.0 cm vs 157.5 cm; p<0.05)
(Table 1).
The proportions of patients with any
exacerbation in the past year were the same for
the three groups (34%, 33%, 52%; p=0.234).
There was no significant difference among the
three groups in proportion of patients with only
one exacerbation (p=0.282) and with two or more
(p=0.767). No significant differences were
observed in the numbers of visits to the
emergency room (p=0.333), hospital admittances
(p=0.487), and ICU admittances (p=0.405)
(Table 2).
Common comorbidities observed in the
study group were hypertension, diabetes mellitus,
cardiovascular disease and cerebrovascular
diseases. There were no noted significant
differences among the three groups in terms of
these observed comorbidities (Table 3).
Long-acting beta-agonist (LABA) plus
inhaled corticosteroid (ICS) was the most
frequently used medication (92%), followed by
doxofylline, and then tiotropium, excluding the
use of the short-acting bronchodilator salbutamol,
which was mainly used as rescue medication
(Table 4). There were no significant differences
in the use of LABA+ICS and salbutamol among
the three groups. Doxofylline use was
significantly higher in the emphysema group
(p<0.001). Among the medications used for the
cardiovascular sphere, statins were most
frequently used in the chronic bronchitic group
(p=0.003) (Table 4).
DISCUSSION
The results of this study show that, for an
equal degree of smoking, three patient profiles
can be identified in clinical practice: Patients
with pulmonary emphysema, phenotype 1, show
Vol. 18 | Issue 03 | September 2017 40
 Three COPD phenotypes in Filipinos

Table 1. Baseline characteristics of included patients according to COPD phenotype

Chronic Bronchitis Emphysema Asthma Overlap
p-value
(n=97) (n=44) (n=21)
Age 66.8±8.9 68.1±8.6 67.2±9.5 0.682
Height 160.9 ±6.6 163±6.1 157.5±8.1 0.009*
BMI 21.6±5.9 20.8±5.4 19.8±5.0 0.343
FEV1 (% predicted) 53.5±19.0 39.9±16.1 45.0±19.3 <0.001**
FVC (% predicted) 72.6±17.4 64.8±19.0 67.9±12.6 0.040**
FEV1/FVC 51.8±13.2 45.6±13.1 45.4±12.3 0.018**
Dyspnea (mMRC)
0 28.6 28.9 31.8 0.978
1 53.1 48.9 50.0
2 15.3 15.6 13.6
3 3.1 6.7 4.5
4 0.0 0.0 0.0
Smoking 37.2±24.3 37.6±16.0 25.8±24.7 0.090
Gender
Male 90 (92.8%) 41 (93.2%) 15 (71.4%) 0.009
Female 7 (7.2%) 3 (6.8%) 6 (28.6%)
*Significant difference between types 2 and 3.
**Significant difference between types 1 and 2.
mMRC=Modified Medical Research Council Dyspnea Scale.

Table 2. Exacerbation frequency in the past year

Chronic Bronchitis Emphysema Asthma Overlap p-value

Exacerbations, % 0.5 0.4 0.7 0.479

34.1 33.0 52.4 0.234

Patient with any exacerbations, %
1 exacerbation
25.0 26.8 42.9 0.282
≥2 exacerbations
9.1 6.2 9.5 0.767

Visits to the emergency due to

0.45 0.40 0.67 0.333
exacerbation, %
Hospital admittances due to
0.3 0.2 0.4 0.487
exacerbation, %
ICU admittances due to
0.022 0.04 0.10 0.405
exacerbation, %

41 Philipp J Chest Dis 2017

 Sabando and Idolor

Table 3. Comorbidities per COPD phenotype

Chronic
Emphysema Asthma Overlap p-value
Bronchitis

Hypertension, % 44.3 29.5 52.4 0.140

Diabetes mellitus, % 5.2 4.5 4.8 0.987

Cardiovascular
2.1 2.3 0 0.793
disease, %
Cerebrovascular
1.0 0 0 0.999
accident, %

Table 4. Cardiorespiratory medications per COPD phenotype

Chronic Asthma
Emphysema p-value
Bronchitis Overlap
Respiratory medications
LABA+ICS 93 93 91 0.960
Salbutamol 60 60 73 0.581
Tiotropium 36 32 41 0.609
Doxofylline 36 79 64 0.000
Comorbidities medications
Calcium channel blocker 13 24 14 0.302
Statins 22 4 9 0.003
Angiotensin receptor blocker 16 19 27 0.446
Anticoagulants 4 7 5 0.796
Anti-diabetics 2 4 9 0.400
ICS=inhaled corticosteroid; LABA=long-acting beta-agonist..

worse pulmonary functions and are associated with
greater mean height. The chronic bronchitic group,
phenotype 2, has better pulmonary function. The
third group, phenotype 3, is not large in general
population of COPD and is more prevalent among
women. The prevalence in this group may vary
notably when diagnostic criteria are modified.9
The term COPD phenotype is used as a
characteristic of the disease, establishing difference
in clinical relevance, but it still generates
discrepancy of criteria within the scientific
community.10 This is important because previous
studies confirm that for the same FEV1, COPD
patients can be very different in terms of clinical,
functional, imaging, and evolution course point
of view. The ECLIPSE study recently
demonstrated that these differences may also
extend to exacerbations and FEV1 deterioration.11
Approaches to phenotype identification in COPD
have been very varied. Some studies try to
identify all the possible phenotype features and
establish groups after performing statistical
analysis. But in most of these studies, most of the
phenotype characteristics lack clinical meaning
and their relevance has not been established. On
the other hand, using predefined clinical
phenotypes for COPD in clinical practice is very
easy—they are based on theories that are solid,

Vol. 18 | Issue 03 | September 2017 42

 Three COPD phenotypes in Filipinos
and they represent groups of patients with clinical
characteristics differentiated regardless of their
functional stage.12
Garcia-Aymerich et al have identified three
types of patients by means of cluster analysis:
group 1 represented a greater functional severity
and worse clinical situation; group 2, less overall
respiratory impairment; and group 3, lower
functional deterioration, like group 2 but with
greater obesity prevalence, cardiovascular
disorder, diabetes and systemic inflammation.13
That study’s results are consistent with our study
in that, for equal degree of smoking, they also
identified a group showing worse lung function
than others.
In a separate study, Izquerdo-Alonzo et al
recruited patients from different pulmonary
outpatient services and used the same criteria as
our study to stratify patients into subgroups. They
found that the emphysema group showed lower
BMI, worse pulmonary function and a greater
degree of dyspnea; in the chronic bronchitic group,
greater concentration of comorbidity and high
BMI; and in the third group, greater prevalence
among women.3 Their data are consistent with our
results in that the emphysematous group showed
worse pulmonary function and the asthma overlap
showed greater prevalence in women and the
lowest proportion among the three groups.
The asthma overlap group was the
predominant COPD phenotype in the study of
Marsh et al—they represented more than 50% of
the study population.7 Conversely, this overlap
group was not seen by Garcia-Aymerich et al;
patients who had certain characteristics with
asthma could have been excluded from their study.
This could also be the same reason why the asthma
overlap group comprised the lowest proportion of
patients in our study, because patients with post-
bronchodilator characteristics of asthma were not
enrolled in the COPD clinic.
Increased reversibility is one of the key
differential aspects of the overlap-asthma COPD
phenotype. Welte et al observed frequent signifi-
43 Philipp J Chest Dis 2017
cant reversibility in COPD patients. Recently, by
consensus, a group of experts established the
diagnosis of an overlap phenotype14: the patient
must meet three major criteria or two major and
two minor among the following: Major criteria:
very positive bronchodilator response (>400ml
and >15% in FEV1), sputum eosinophilia or
previous diagnosis of asthma; and minor
criteria: increased total serum IgE, previous
history of atopy or positive bronchodilator test
(>200ml and >12%) on at least 2 occasions.15
Previous literature suggests that part of
phenotypic heterogeneity in COPD is due to
divergent distribution of bronchial airway
(chronic bronchitis) and parenchymal disease
(emphysema). Another characterization has been
Type A (Pink Puffer) and Type B (Blue Bloater)
COPD, clinico-pathophysiologic syndromes that
clustered together and were thought to represent
points on a continuum representing different
pathophysiology. Subsequently, certain authors
considered this classification obsolete and of
poor clinical usefulness, promoting a uniform
vision of COPD classified based on FEV1 values.
After the publication of the Global Initiative for
Obstructive Lung Disease (GOLD) in 2001, key
aspects in the disease’s heterogeneity gave
priority to the simplicity of spirometric values.
But as stated earlier, focusing solely on FEV1
poses a barrier in dealing with the disease,
because FEV1 does not adequately reflect all the
multiple clinical and systemic manifestations of
the disease.16
As seen in this study, despite differences
in the clinical characteristics of patients, the
amount of exacerbation was similar in the three
groups. Acute exacerbation of COPD is currently
defined as “a sustained worsening of the patient’s
condition, from the stable state and beyond
normal day-to-day variations, that is acute in
onset and necessitates a change in regular
medication in a patient with underlying
COPD.”17 But the numeric assessment of
exacerbation has limited value, because there are

important limitations in this current definition of
COPD exacerbation. The general description poses
numerous operational challenges for use in the
clinical phenotyping. It remains unclear whether
these changes are quantitative or if there is a
qualitative element.4 The study also does not allow
for the identification of the characteristics of all
exacerbations. Numerous data associate the
presence of chronic bronchitis with greater
exacerbation. The absence of differences in the
study may be, at the very least, conditioned by a
greater efficiency of the treatment in those patients
with a greater risk of exacerbations.3 Also, the
patient-recorded increases in symptoms that appear
to be exacerbations outnumber those that cause
them to present for medical attention.4 These
findings pose different phenotypes of exacerbation,
the treatment and prevention of which should be
individualized according to the baseline
characteristics of each patient.18
Patients with COPD often present with
comorbid diseases. Crisafulli et al found that
metabolic (systemic hypertension, diabetes and/or
dyslipidemia) and heart disease (chronic heart
failure and/or coronary heart disease) were the
most frequently reported comorbid combinations
among the diseases associated with COPD.19 This
was also observed in our study. In another study by
Mannino et al, the presence of respiratory
impairment, as determined using both lung
function measurement and the presence of
respiratory symptoms, was associated with a
higher risk of having comorbid hypertension,
cardiovascular disease and diabetes.20 The reason
for this association was unclear but it was
theorized that systemic inflammation, chronic
infections, shared risk factors or undefined factors
may contribute to the development of comorbid
conditions, and these disorders can be seen as
manifestations of COPD or vice versa. The
presence of many of these comorbidities appears to
have deleterious effects on several outcomes in
COPD.18 Izquerdo et al have reported that the
chronic bronchitis group showed a greater concen-
Sabando and Idolor
tration of comorbidity and cardiovascular risk
factors.3 This finding was further supported by
Hassan et al, who also found that the chronic
bronchitis group showed a greater concentration
of comorbidity.21 However, our study did not
show significant differences among the three
groups in terms of these comorbidities.
Whether treatment of comorbid conditions
alters the natural history of COPD, or whether
treatment of COPD is altered by the presence of
a concomitant comorbidity, awaits further study.4
Currently, only smoking cessation and long-term
oxygen therapy in patients with resting
hypoxemia while awake clearly alter prognosis
for survival or decline in lung function.22,23
Mancini et al found that statins, ace-converting
enzyme inhibitors and angiotensin-receptor
blockers reduced both the cardiovascular and
pulmonary outcomes of COPD patients.24 This
may be due to mitigation of pulmonary injury by
the statins and drugs affecting angiotensin II.25,26
Dobler et al found statins may have beneficial
effects by reducing all-cause mortality, deaths
from COPD, respiratory-related urgent care,
COPD exacerbations and lung function decline;
and by improving exercise capacity.27 Soyseth et
al hypothesized that statins might improve all-
cause disease mortality in COPD because many
COPD patients probably have unrecognized
ischemic disease.28 However, Keddissi et al
associated the use of statins with an attenuated
decline in lung function and a lower incidence of
respiratory-related emergency room visits and/or
hospitalization in COPD, which imply that
statins may have a direct disease-modifying
effect on COPD.29 In our study, statin use is
significantly different among the three groups,
with the chronic bronchitic group predominantly
using this drug. The question of whether this
group’s use of statin could have contributed to
the observed better pulmonary function and
relatively less number of hospitalizations
compared to the other two groups needs further
investigation and follow-up.
Vol. 18 | Issue 03 | September 2017 44
 Three COPD phenotypes in Filipinos
One salient feature noted in this study is that
despite the significant differences in their airflow
limitation, the three groups did not show
significant differences in numbers of exacerbation
and hospitalizations. One possibility is that patients
in the emphysematous group, who have the worst
pulmonary function, might be poor perceivers of
dyspnea. This hypothesis is well established in
asthma but has not been formally explored in
COPD.30 Also worth noting is that the chronic
bronchitic and asthma overlap groups are, on the
average, 4 cm shorter than the emphysematous
group, and the previous two groups show better
pulmonary function. The shorter height in the
asthma overlap group is attributable to the fact that
most subjects were women. Kjensil et al have
noted that lung functions were overestimated in
COPD patients with relatively modest height
reductions, and height reduction depends on the
number and severity of vertebral deformities.31
Patients that were included in the study may be
followed up to further evaluate for any co-existing
vertebral deformities.
The prescription pattern observed is not
surprising as current clinical current guidelines
recommend that pharmacological treatment should
be used mainly on FEV1 values and on symptoms.
But such an approach may no longer be correct,
based on recent experience in the development of
roflumilast, the first drug developed specifically
for the treatment of COPD associated with chronic
bronchitis. Clinical trials have shown that, among
patients with chronic bronchitis–associated COPD
and a history of exacerbations, roflumilast
improves lung function and reduces the frequency
of exacerbations that require medical
interventions.32 This shows that identification of a
patient’s profile allows greater benefit, as the drug
is administered to the most adequate patient and
withheld from those who are unlikely to benefit
from it. This can be a key in the development of
new drugs that may be effective in certain groups
of patients but may look inefficacious when a
nontargeted COPD population is analyzed.3
45 Philipp J Chest Dis 2017
The main limitation of this study is that it is
retrospective and used cluster analysis to group
patients according to key variables. The clinical
relevance of these data would still require
longitudinal validation to determine how such
clustered subjects differ with respect to important
clinical outcomes. Also the criteria established to
define the groups may seem arbitrary. Lastly, the
population comes from the pulmonary outpatient
clinic; therefore, the results may not necessarily
be extrapolated to the general population.
REFERENCES
1. Qureshi H, Sharafkhaneh A, Hanania NA.
Chronic obstructive pulmonary disease
exacerbations: latest evidence and clinical
implications. Ther Adv Chronic Dis. 2014;
5(5):212-27.
2. Celli B, MacNee W; ATS/ERS Task Force.
Standards for the diagnosis and treatment of
patients with COPD: a summary of the
ATS/ERS position paper. Eur Respir J. 2004;
23:932-46.
3. Izquierdo-Alonso JL, Rodriguez-
Gonzálezmoro JM, de Lucas-Ramos P, et al.
Prevalence and characteristics of three
clinical phenotypes of chronic obstructive
pulmonary disease. Respir Med. 2013;107
(5):724-31.
4. Han MK, Agusti A, Calverley P, et al.
Chronic obstructive pulmonary disease
phenotypes: the future of COPD. Am J
Respir Crit Care Med. 2010;182(5):598-604.
5. Fletcher CM. Terminology, definitions and
classifications of chronic pulmonary
emphysema and related conditions (a report
of the conclusions of a Ciba guest sympo-
sium). Thorax. 1959;14:286-99.
6. Burrows B, Fletcher CM, Heard BE, et al.
The emphysematous and bronchial types of
chronic airways obstruction. A clinic-
pathological study of patients in London and
Chicago. Lancet 1966;1:830-5.
7. Marsh SE, Travers J, Weatherall M, et al.

Proportional classifications of COPD
phenotypes. Thorax. 2008;63(9):761-7.
8. Burgel PR, Paillasseur JL, Roche N.
Identification of clinical phenotypes using
cluster analyses in COPD patients with
multiple comorbidities. Biomed Res Int.
2014;2014:420134.
9. Hardin M, Silverman EK, Barr RG, et al. The
clinical features of the overlap between COPD
and asthma. Respir Res. 2011;12:127.
10. Agusti A, Calverly PM, Celli B, et al.
Characterization of COPD heterogeneity in the
ECLIPSE cohort. Respir Res. 2010;10
(11):122.
11. Hurst JR, Vestbo J, Anzueto A, et al.
Susceptibility to exacerbation in chronic
obstructive pulmonary disease. N Engl J Med.
2010;363(12):1128-38.
12. Hurst JR. Exacerbation phenotyping in
chroniobstructive pulmonary disease. Am J
Respir Crit Care Med. 2011;184(6):625-6.
13. Garcia-Aymerich J, Gomez FP, Benet M, et al.
Identification and prospective validation of
clinically relevant chronic obstructive pulmo-
nary disease (COPD) subtypes. Thorax.
2011;66(5):430-7.
14. Welte T. Miravitlles M, Hernandez P, et al.
Efficacy and tolerability of budesonide/
formoterol added to tiotropium in patients with
chronic obstructive pulmonary disease. Am J
Respir Crit Care Med. 2009;180(8):741-50.
15. Soler-Cataluna JJ, Cosio B, Izquierdo JL, et al.
Consensus document on the overlap phenotype
COPD-asthma in COPD. Arch Bronconeumol.
2012;48(9):331-7.
16. Bafadhel M, McKenna S, Terry S, et al. Acute
exacerbations of chronic obstructive pulmo-
nary disease: identification of biologic clusters
and their biomarkers. Am J Respir Crit Care
Med. 2011;184(6):662-71.
17. Rodrigues-Roisin R. Towards a consensus
definition for COPD exacerbation. Chest.
2000;117:398-401.
Sabando and Idolor
18. Celli B, Cote C, Marin J, et al. The Body
mass index, airflow obstruction, and exercise
capacity index in chronic obstructive
pulmonary disease. N Engl J Med. 2004;350:
1005-12.
19. Crisafulli E, Costi S, Luppi F, et al. Role of
comorbidities in a cohort of patients with
COPD undergoing pulmonary rehabilitation.
Thorax. 2008;63:487-92.
20. Mannino DM, Thorn D, Swensen A,
Holguin F. Prevalence and outcomes of
diabetes, hypertension and cardiovascular
disease in COPD. Eur Respir J. 2008;32:962-
9.
21. Hassan WA, Abo-Elhamd E. Emphysema
versus chronic bronchitis in COPD: clinical
and radiologic characteristics. Open J Radiol.
2014;4(2):155-62.
22. Anthonnisen NR, Skeans MA, Wise RA, et
al. The effects of smoking cessation
intervention on 14.5-year mortality: a
randomized clinical trial. Ann Intern Med.
2005;142:233-39.
23. Long term domiciliary oxygen therapy in
chronic hypoxic cor pulmonale complicating
chronic bronchitis and emphysema. Report
of the Medical Research Council Working
Party. Lancet. 1981;1(8222):681-6.
24. Mancini GB, Etminam M, Levesque L et al.
Reduction of morbidity and mortality by
statins, angiotensin-converting enzyme
inhibitors in patients with chronic obstructive
pulmonary disease. J Am Coll Cardiol.
2006;47:2554-60.
25. Mancini GB. The 'double dip' hypothesis:
simultaneous prevention of cardiovascular
and pulmonary morbidity and mortality using
angiotensin II type 1 receptor blockers. Can J
CardioL. 2005;21:519-23.
26. Mancini GB, Khalil N. Angiotensin II type 1
receptor blocker inhibits pulmonary injury.
Clin Invest Med. 2005;28(3):118-26.
27. Dobler CC, Wong KK, Marks GB. Associa-
Vol. 18 | Issue 03 | September 2017 46
 Three COPD phenotypes in Filipinos

tion between statins and COPD: a systematic

review. BMC Pulm Med. 2009;9:32.
28. Soyseth V, Brekke PH, Smith P, Omland T.
Statin use is associated with reduced mortality
in COPD. Eur Respir J. 2007;29:279-83.
29. Keddissi JI, Younis WG, Chbeir EA, et al. The
use of statins and lung function in current and
former smokers. Chest. 2007;132(6):1764-71.
30. Miravitlles M, Anzueto A, Legnani D, et al.
Patient’s perception of exacerbations of
COPD—the PERCEIVE study. Respir Med.
2007;101(3):453-60.
31. Kjensil A, Ryg M, Flach JA, et al. Does body
height reduction influence interpretation of
lung function in COPD patients? Eur Respir J.
2010;36(3): 540-8.
32. Izquierdo JL, Aparicio J. Roflumilast for
COPD. Drugs Today (Barc). 2010;46(11):823-
31.

47 Philipp J Chest Dis 2017

 Girado and Bate

RETROSPECTIVE STUDY

Clinical Profile and Outcome of Lung Cancer Patients with

Pneumonia Admitted at Lung Center of the Philippines: A
5-year Retrospective Study
Tuesday N. Girado, MD, FPCP, FPCCP; Daphne D. Bate, MD, FPCP, FPCCP
Department of Pulmonary Medicine, Lung Center of the Philippines

ABSTRACT
Objective: To determine the clinical profile and outcome of lung cancer patients with pneumonia
admitted at a tertiary hospital over a 5-year period.

Methodology: This was a retrospective cohort study that included 312 lung cancer patients
admitted due to a tertiary hospital for pneumonia from January 1, 2009 to December 31, 2013.
Study data were extracted from patient records and analyzed through descriptive statistics.
Correlation between patient outcomes and patient characteristics were also statistically analyzed.

Results: In total, 312 lung cancer patients admitted due to pneumonia were included. Age ranged
from 29 to 86 years, with a mean age of 61.23 years. Majority of patients were male (68.6%), had
non-small cell adenocarcinoma (88.5%), and stage IV/extensive disease (78.2%). Almost half
(45.3%) of patients opted supportive treatment. Around a third (32.7%) had Candida spp as the
predominant organism grown in sputum culture. Overall, 74% patients were discharged improved
while 26% died. Clinical stage and patient age were found to be significantly associated with
patients outcome (p<0.05). All deaths occurred in patients with stage IV/extensive disease.

Conclusion: Pneumonia is life-threatening in lung cancer patients. It can shorten survival

especially those with advanced age and cancer stage, in which mortality is high. These two factors
are reliable predictors of mortality that can be used to prognosticate patients.

INTRODUCTION cer patients may develop due to local or systemic

The main causes of death in patients with
lung cancer are local progression of the disease,
metastases to remote organs and respiratory
infections, particularly pneumonia.1 Pneumonia
is considered as a secondary cause of death,
which is caused not only by the progression of
the disease but also by the applied treatment
negatively influencing the immunity of
patients.2 In a study done by Zieba etal (2003)
in Poland, pneumonia was diagnosed in 58.5%
as the secondary cause of death among lung
cancer patients.3
Severe pulmonary infections in lung can-
immunological disorders, primarily affecting
cellular immunity.4,5 This can be compounded by
an impaired cough reflex, which may take place
against the background of applied treatment or as
a result of neoplastic metastases to the brain.6
Moreover, metastases to bone marrow may lead
to leukopenia and anemia.4,7,8 Studies would
show that the main causes of pneumonia were
atelectasis and dysfunction of phagocytes and
lymphocytes, especially in non-small cell lung
cancer (NSCLC).4
Another group of factors predisposing to
the occurrence of the respiratory system infection

Vol. 18 | Issue 03 | September 2017 48

 Pneumonia in lung cancer

includes those related to the radical and palliative Department of Pulmonary Medicine was acquired
treatment of lung cancer. Most anti-neoplastic for this study.
drugs have a suppressive effect on the function of
the immune system.9 By the suppressive RESULTS
influence on the cellular immunity, they In total, 312 lung cancer patients who were
contribute to the increase of susceptibility to admitted from January 1, 2009 to December 31,
infections.10 The syndrome produced by 2013 secondary to pneumonia were included in
radiotherapy depends on the size of irradiated our study. Demographic characteristics of these
area and the amount of a total dose. Developing patients are reflected in the Table. The age range
inflammatory changes in lungs may be is from 29 to 86 years old with a mean age of
responsible for the occurrence of respiratory 61.23 years. Majority of patients were males with
failure and death, especially if complicated by a total rate of 68.6% while 31.4% were females
respiratory system infection.7,11,12 as shown in the table.
This study aimed to investigate the clinical Most patients had NSCLC (Table 1).
profile and outcome of lung cancer patients with Adenocarcinoma predominated the histologic
pneumonia admitted at a tertiary hospital in the type in 88.5% of cases. Squamous non-small cell
Philippines over a 5-year period, and to identify carcinoma was seen in 3.8% of patients while the
patient characteristics that could prognosticate
outcomes.
Table 1. Characteristics of included patients
METHODS
This was a retrospective cohort study that Characteristic Value (n=312)
included lung cancer patients, treated or Age (mean) 61.23 + 11.87 years
untreated, with pneumonia admitted at a tertiary Frequency %
hospital in the Philippines from January 1, 2009 Gender
to December 31, 2013. Patients admitted for Female 98 31.4%
reasons other than pneumonia, those who did not Male 214 68.6%
undergo culture and sensitivity testing on Type of cancer
admission, and those who died due to conditions Non-small cell
other than pneumonia, were all excluded. carcinoma
Data were collected retrospectively from Adenocarcinoma 276 88.5%
patient records. For those who fulfilled the Squamous 12 3.8%
inclusion/exclusion criteria, patient demographic Small cell carcinoma 24 7.7%
data, cancer type, clinical stage, treatment Cancer Stage
modalities received, microbiologic data and Stage I 0 0
patient outcomes during hospital stay were Stage II 4 1.3%
collected, summarized and analyzed statistically. Stage III 64 20.5%
Data were presented as means and standard
Stage IV/extensive 244 78.2%
deviations (SD) or frequencies and percentages, Treatment
as appropriate. Cramers V and Chi-Square tests Surgical resection +
were employed to establish statistical correlation 13 4.1%
chemotherapy
between clinical variables and patient outcome. A Radiation Therapy +
p-value of less than 0.05 was considered 30 9.6%
chemotherapy
statistically significant. Chemotherapy 128 41.0%
Institutional review and approval from the Supportive treatment 141 45.3%

49 Philipp J Chest Dis 2017

 Girado and Bate

Table 2. Organisms isolated in blood culture DISCUSSION

To our knowledge, this is the first local
Organism N Percent
study to examine pneumonia in lung cancer
Coagulase negative patients. Our retrospective study indicates that
6 6.5%
Staphylococcus pneumonia among lung cancer patients is indeed
No growth 87 93.5% life threatening mainly because of their
Total 93 100.0 underlying condition. Based on the data gathered,
majority of these patients are males (68.6%) with
a mean age of 61.23 years.
remaining 7.7% had small cell carcinoma. Male predominance is consistent with
On admission, 78.2% had stage IV/ several studies worldwide in which lung cancer is
extensive lung cancer (patients with small cell- considered as the most common cancer in this
extensive disease was categorized as stage IV) group secondary to high incidence of smoking.13
and 20.5 % had stage III. Most patients opted for In terms of age, lung cancer peaks in persons
supportive treatment (45.3%) or chemotherapy between 60-80 years old and becoming common
(41%). among those below 40 years old according to
Table 2 shows the organisms isolated in latest statistics.1 Therefore, the demographic
blood culture of patients included in the study. profile of lung cancer patients with pneumonia
Out of the 312 patients, only 93 had blood gathered from our study still reflects the
culture. Coagulase-negative Staphylococcus was demography of lung cancer patients in general.
isolated in 6.5% of patients while the rest This study also revealed that greater
(93.5%) had no growth. In sputum culture, number of patients had adenocarcinoma (88.5%),
Candida spp (32.7%) was the predominant compared to other histologic types like small cell
organism while 23.4% of the specimen had no carcinoma (7.7%) and squamous cell carcinoma
growth. Other common organisms isolated from
sputum culture include Moraxellla catarrhalis
(9.0%), alpha-hemolytic streptococci (8.3%), Table 3. Organisms isolated in sputum culture
Pseudomonas aeruginosa (8.0%), coagulase- Organism N %
negative staphylococci (6.4%) and Acinetobacter
baumanii (6.1%). Candida spp. 102 32.7
The outcome of patients during No growth 73 23.4
hospitalization is shown in Table 3 and Figure 1. Moraxella catarrhalis 28 9
In total, 74% were discharged improved while Alpha-hemolytic streptococcus 26 8.3
26% died. Cancer stage was found to be Pseudomonas aeruginosa 25 8
correlated with outcomes (p<0.001). No mortality
Coagulase-negative 20 6.4
was noted in patients with stage II and III lung
staphyloccocus
cancer; all 81 patients who died had stage
IV/extensive disease. Acinetobacter baumanii 19 6.1
Advancing age was also correlated with Enterobacter aerogenes 9 2.9
poorer patient outcomes (p=0.025) (Table 4). Staphyloccoccus aureus 5 1.6
However, the correlation of outcomes with Stenotrophonas maltophila 3 1
gender or cancer treatment modality was not Pantoea agglomerans 2 0.6
statistically significant (Table 5 and 6,
Total 312 100
respectively).

Vol. 18 | Issue 03 | September 2017 50

 Pneumonia in lung cancer

Table 4. Cramer’s V: Relationship of Cancer stage and outcome

OUTCOME
Total Value P-value
Cancer stage Improved expired
Stage II 4 0 4
Stage III 64 0 64
Stage IV/ 0.313 <0.001
163 81(33.2%) 244
extensive
Total 231 81 312

Table 5. Cramer’s V: Relationship of patient’s age and outcome

OUTCOME
Age (years) Total Value P-value
Improved Died

29-47 31 8 (20.5%) 39

48-66 132 40 (23.2%) 172

0.153 0.025
67-86 68 33 (32.6%) 101

Total 231 81 312

Table 6. Chi-square: Relationship of Gender and Outcome

OUTCOME 2-sided
Gender Total Value df
Improved Died P-value

Female 77 21 98
Male 154 60 214 1.203 1 0.273
Total 231 81 312

Table 7. Chi -Square: Relationship of cancer treatment modalities and outcome

Treatment OUTCOME Total 2-sided

Value df
modalities Improved Died P-value
Supportive
107 34 141
treatment

Chemotherapy 38 128
90
Radiotherapy + 3.364 2 0.067
9 30
Chemotherapy 21
Surgery +
13 0 13
Chemotherapy
Total 231 81 312

51 Philipp J Chest Dis 2017


(3.8%). This finding is contrary to what many
investigators have noted that patients with
squamous cell lung cancer tend to contract
pneumonia more readily than patients with cancer
of other histopathological types.12 However, the
predominance of adenocarcinoma in this study is
not reflective of those lung cancer patients who
acquired pneumonia but rather based on the fact
that adenocarcinoma is the most common cancer
worldwide.13
With regards to clinical stage, most patients
in our review had stage IV/extensive lung cancer
(78.4%) while the rest had stage III (20.5%), and
stage II (1.3%). Majority opted supportive
treatment (45.3%) while others received
chemotherapy (41%), concurrent radiation therapy
and chemotherapy (9.6%), and for patients with
early stage lung cancer, surgical resection plus
adjuvant chemotherapy (4.1%) were offered. Their
underlying condition, location of metastasis and
the treatment received were contributory to the
degree of immunosuppression leading to the
development of several infections particularly
pneumonia based on several studies.4,5
Our study also demonstrated that Candida
sp. (32.7%) was the predominant organism grown
in sputum cultures of these patients. Other isolates
include Moraxella catarrhalis (9.0%) alpha-
hemolytic streptococcus (8.3%), P. aeruginosa
(8.0%), coagulase-negative staphylococcus (6.4%),
A. baumanii (6.1%), Enterobacter aerogenes
(2.9%), S. aureus (1.6%), Stenotrophomonas
maltophila (1%) and Pantoea agglomerans
(0.6%). Data also revealed that significant number
of patients had no growth (23.4%) in their sputum
as well as in blood culture (93.5%). Coagulase-
negative staphylococcus was isolated in blood
culture of the remaining patients (6.5%). A study
done by Zeiba in Poland showed that
Streptococcus and Proteus species as well as
Mycobacterium tuberculosis were the predominant
organisms isolated in this group of patients.
Putinati et al indicated Gram-negative rods
(usually Haemophilus at 45.2%) as the most
Girado and Bate
frequent cause. S. aureus (33.3%), Pneumocystis
carinii and Chlamydia trachomatis (16.7%) as
well as Gram-negative cocci (4.8%.) were also
seen in this group of patients.9 Japanese
investigations, on the other hand, noted frequent
involvement of S. aureus, Enterococcus faecalis,
and various Gram-negative organisms such as
Pseudomonas, Acinetobacter, Enterobacter, and
Klebsiella species on lung cancer patients who
had pneumonia.14 Variability of results gathered
from different countries may depend on the
setting as well as the predominant organism in
that particular area.15
According to a local study done by
Handog and Dayrit in 2005 at the Research
Institute of Tropical Medicine, the warm tropical
climate in our country and its interplay with age,
occupation, genetic susceptibilities and immune
responsiveness contribute to the high prevalence
of fungal infections among Filipinos.16 In their
paper, it was also noted that although fungal
culture yield is low, Candida sp. is the most
common isolate obtained predominantly from
specimens taken from the oral mucosa and nails.
This opportunistic organism may become
pathologic once the immune system is impaired,
as in the case of patients with lung cancer.
This study reported that 74% of patients
recovered from pneumonia. All deaths occurred
in those with stage IV/extensive disease
(p<0.001). Likewise, a significant relationship
between age and outcome was also established,
(p=0.025) in which increasing age parallels with
increasing mortality. Therefore, these factors can
be used to prognosticate lung cancer patients
with pneumonia. However, gender and cancer
treatment modalities did not significantly
correlate with patient outcomes.
This study was limited in the variables
examined in relation to patient outcomes. Future
studies may provide more in-depth analysis into
functional status, presenting signs and symptoms,
co-morbidities and duration. Treatment for
pneumonia should also be explored in further
Vol. 18 | Issue 03 | September 2017 52
 Pneumonia in lung cancer
studies. Nonetheless, the high clinical response
rate suggests that prompt diagnosis and treatment
of pneumonia may yield high clinical success
rates. Additionally, the prevalence of Candida sp.
indicates that physicians should have a high index
of suspicion for Candida pneumonia in these
patients, and should consider anti-fungal coverage
when necessary.
CONCLUSION
Pneumonia is common among lung cancer
patients, and this study demonstrated that
pneumonia can be life-threatening in these
patients, especially in those with stage IV disease
(33.2%). Advanced age was also correlated with
increased mortality. Thus, age and cancer stage
can be used to prognosticate patients. Prompt
identification and immediate proper management
are also necessary to lessen morbidity and
mortality.
REFERENCES
1. World Cancer Report 2014. Geneva: World
Health Organization. 2014.
2. Zych J, Szymańska D, Drozd I, Słupek A,
Rowińska-Zakrzewska E. Infections as a cause
of death in patients with lung cancer.
Pneumonol Pol 1984; 52 (1):11-17.
3. Zieba M, et al. Pneumonia and lung cancer.
Radiol Oncol 2003; 37(3): 167-74.
4. Remiszewski P, Słodkowska J, Wiatr E, Zych
J, Załęska J, Radzikowska E, et al. Infections
as a main and additional cause of death in
patients treated due to small cell lung cancer.
Pneumonol Alergol Pol 1999;67:347-53.
5. Van Meerten E, Verweij J, Schellens JHM.
Antineoplastic agents. Drug interaction of
clinical significance. Drug Staf 1995;12:168-
82.
6. Law A, Karp DD, Dipetrillo T, Daly BT.
Emergence of increased cerebral metastasis
after high dose preoperative radiotherapy with
chemotherapy in patients with locally advance-
ed nonsmall cell lung carcinoma. Cancer 2001;
53 Philipp J Chest Dis 2017
92:160-4.
7. Remiszewski P. Supporting care in lung
cancer. Nowa Klinika 1999;6:324-28.
8. Varthalitis I, Aoun M, Daneau D, Meunier F.
Pneumocystis carinii Pneumonia in patients
with cancer. An increasing incidence. Cancer
1993;71:481-5.
9. Putinati S, Trevisani L, Gualandi M, Guerra
G, Rossi MR, Sartori S, et al. Pulmonary
infections in lung cancer patients at
diagnosis. Lung Cancer 1994;11:243-9.
10. Maschmeyer G, Link H, Hiddemann W,
Meyer P, Helmerking H, Eisenmann E, et al.
Pulmonary Infiltrations in Febrile Patients
with Neutropenia. Risk factors and outcome
under empirical antimicrobial therapy in a
randomized multicenter study. Cancer
1994;73:2296-304.
11. Spiro SG. Lung cancer. Eur Respir Monogr
2001;17:22-48.
12. Ali MA, Kraut MJ, Valdivieso M, Merskovic
AM, Du W, Kalemkerian GP. Phase II study
of hyperfractionated radiotherapy and
concurrent weekly alternating chemotherapy
in limited-stage small cell lung cancer. Lung
Cancer 1998;22:39-44.
13. Mechanisms in Medicine, March 2012.
14. Nagata N, Nikaido Y, Kido M, Ishibashi T,
Sueishi K. Terminal pulmonary infections in
patients with lung cancer. Chest
1993;103:1739-42.
15. Rikimaru T, Matsumoto K, Koga T, Ichiki
M, Kinosita M, Oizumi K.Nihon Kokyuki
Gakkai Zasshi. Clinical features and outcome
of pneumonia in patients with lung cancer
1999;37(4):282-6.
16. Handog E, Dayrit J. Mycology in the
Philippines, revisited. Muntinlupa: DOH-
RITM; 2005.
 NOTES

____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________

Vol. 18 | Issue 03 | September 2017 54

 NOTES

____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________

55 Philipp J Chest Dis 2017

 OUTSIDE BACK COVER

The Philippine Journal of Chest Diseases

An official publication of:
Philippine College of Chest Physicians
84-A Malakas St., Pinyahan, Quezon City, Philippines
Email: secretariat@philchest.org
Phone: (+632) 924 9204
 Volume 18 Number 2
April-June 2017

• PCCP Position Statement on E- Cigarettes

• OSI in ARDS assessment
•• MDMA-induced
Turnaround timepneumothorax
in smear-negative TB
• Long-term cognitive impairment in ICU delirium
• TB in cancer patients
• Prediction of pneumonia among patients with
cough
• Primary lung cancer: young vs old patients
 PHILIPPINE JOURNAL OF CHEST DISEASES
AN OFFICIAL PUBLICATION OF THE
PHILIPPINE COLLEGE OF CHEST PHYSICIANS

Editor-in-Chief
Evelyn Victoria E. Reside, MD, FPCCP

Managing Editor
Camilo C. Roa, Jr., MD, FPCCP

Reviewers
Richmond. B. Ceniza, MD, FPCCP Sigrid Marie F. Marquez, MD, FAPA
Ria Edwina Gripaldo, MD, FACP Albert L. Rafanan, MD, FPCCP

Copy Editor
Blesilda O. Adlaon

Editorial Assistant
Ivan Noel G. Olegario, MD, MDC

PHILIPPINE COLLEGE OF CHEST PHYSICIANS OFFICERS 2017-2018

Charles Y. Yu, MD, FPCCP

President

Lenora C. Fernandez, MD, FPCCP

Vice President

Malbar G. Ferrer, MD, FPCCP

Secretary

Ivan N. Villespin, MD, FPCCP

Treasurer

Gregorio P. Ocampo, MD, FPCCP

Imelda M. Mateo, MD, FPCCP
Eileen G. Aniceto, MD, FPCCP
Ma. Janeth T. Samson, MD, FPCCP
Jubert P. Benedicto, MD, FPCCP
Board Members

Vincent M. Balanag Jr., MD, FPCCP

Immediate Past President

The opinions and data expressed in the Philippine Journal of Chest Diseases (PJCD) are those of the individual authors. They are not
attributable to the editors or editorial board of the PJCD and should not be regarded as the official stand of/or endorsement by the
Philippine College of Chest Physicians. References may be made in the articles regarding drug usage, which may not be included in the
current prescribing information. The reader is, thus, urged to check the full prescribing information of drugs. No part of the PJCD may be
reproduced without the written permission of the publisher.

Address all communication and manuscripts for publication to the following: The Editor, Philippine Journal of Chest Diseases, 84-A Malakas
St., Pinyahan, Quezon City. Email: secretariat@philchest.org. Phone: (+632) 924 9204.
 INSTRUCTIONS TO AUTHORS
The Philippine Journal of Chest Diseases
publishes scientific papers in the field of
pulmonary medicine. These papers may be in the
form of collective and current reviews (state of the
art, meta-analyses), original investigations, case
reports, editorials or letters to the editor. All
manuscripts must be submitted electronically to
secretariat@philchest.org. Manuscripts should be
single spaced and left-justified, including
references. Use 10-point type, approximately 1-
inch margins, and format for 8 ½ x 11 paper. The
editorial staff requires files that can be opened and
manipulated in Word 2004-2009, PowerPoint or
Excel.
Accepted manuscripts become the property of the
Philippine College of Chest Physicians and are
published with the understanding that they are not
for publication elsewhere without approval.
These manuscripts are subject to editorial
modification.
Generally, write using the first person, active
voice; for example, “We analyzed data,” not
“Data were analyzed.” The Abstract
and acknowledgments or disclaimers are the
exceptions to this guideline, and should be written
in the third person, active voice; “The authors
analyzed,” “The authors wish to thank.”
Supply a title page as the first page of the
manuscript with the following information:
1. The manuscript’s full title which should
provide sufficient information regarding the
contents of the manuscript.
2. All authors should provide their complete
names, professional titles, and institutional
affiliations. Include an author byline that lists
all authors’ full names and academic degrees
above a Masters; for example, “Juana Cruz,
MD, PhD, and Juan Ramos, MD”. Also
include sentence-style bios for each author
than list position(s) or title(s) and institutional
affiliation(s); for example, “Dr. Cruz is
assistant professor, Section of Pulmonary
Medicine, Department of Internal Medicine,
State University College of Medicine”.
3. Contact information (address and email
address, plus telephone and/or fax) for the
corresponding author.
4. Disclosure of funding received for this work
from any organization or company.
5. State if the paper has been presented in any
convention and whether any awards have
been conferred on the paper.
Abstract. The abstract should not be longer than
250 words. It should contain a summary of what
was done in the study, including objectives, study
design, important results and conclusions. Only
findings restricted to the study should be
mentioned in the abstract. For research reports
only, abstracts must be in the structured form of
four paragraphs, with headings Purpose,
Methods, Results, and Conclusions; and must
include the year of the study. The authors should
also provide three key words under which the
article can be indexed.
Headings
For all manuscripts. Use main headings and
short subheadings as needed. Do not create a
heading at the very top of the manuscript (e.g.,
“Introduction”), since layout constraints make
such headings unworkable. Text should be set in
Times New Roman font, 10 point in size, and
single-spaced. The main heading of the online-
only text should be in 12 point and boldface;
subheadings should be in 10-point and boldface.
If subheadings are used, two or more such
headings must be used, as in outline style.
For research reports. Structure the body of the
manuscript using the headings Introduction,
Methods, Results, and Conclusions. At least a full
paragraph of text must precede the Introduction
heading, for layout reasons.
For articles. Create headings that are substantive
and interesting and that will give readers a sense
of the article’s organization. Make headings as
short as is feasible. At least a full paragraph of
text must precede the initial heading, for layout
reasons.
Text. Formal scientific or technical style shall be
followed in writing the manuscripts. All
abbreviations should be spelled out when used
for the first time. For standard terminology,
such as chronic obstructive pulmonary disease
 INSTRUCTIONS TO AUTHORS
(COPD) or forced vital capacity (FVC), only
standard abbreviations should be used. Information
or data that is best described in tables should be
presented as such. Tables which duplicate
information provided in the text shall be removed.
Generic names of drugs shall be used except in
instances where trade names are vital, such as in
clinical trials.
Tables and Figures. Only tables cited in the text
should be included. All tables should be called out
in the text and shall be numbered in ascending
order depending on the sequence they were
referred to in the text. A different order for tables
and figures is to be used. Symbols are * † ‡ § ¶.
A single table or figure with the appropriate labels
should be printed on a single page. The text and
data in online tables should be Arial font, 10 point
in size, and single-spaced. The table title should be
set in Arial font 12 point, and bold. Headings
within tables should be set in 10 point bold.
Explanatory notes or legends should be written
at bottom of the table or figure. Table titles should
make the table sufficiently understandable
independent of the manuscript. Typically, include
type of data, number and type of respondents, place
of study, year of study. Titles should be placed
directly above the table, not in a data cell. Columns
should be clearly labeled, including unit of
measure.
Footnotes: If information is needed to make the
table understandable that won’t easily fit into the
table title or data cells, create one or more
footnotes. Table footnotes should be set in 8 point
and single-spaced. Place footnotes at the bottom of
the table, not in a data cell. All abbreviations
should also be explained.
Figures. Only figures (or pictures) cited in the text
should be included. All figures should be called out
in the text and shall be numbered in ascending
order depending on the sequence they were
referred to in the text. A different order for tables
and figures is to be used.
Figures are acceptable as Excel, PowerPoint
or Word 2004-2009 files. All files supplied must be
“live” figures that can be opened and formatted.
PDFs and JPGs are not accepted. Figures should
be two-dimensional; black-and-white or
grayscale; and without gridlines or background
shading. X and Y axes, if present, must be
labeled.
Figure legends should make the figure
sufficiently understandable independent of the
manuscript. Legends should be placed on the last
page in the manuscript. All figures should be
separated from the text file, yet bundled into a
common file, if possible, with individual figures
separated by page breaks.
The editorial staff reserves the right to determine
whether the graphical instruments are appropriate
for the information being imparted and modify or
request modification/s for inappropriate
illustrations. The editorial staff reserves the right
to generate illustrations compatible with the
professional standards of the journal.
References. Authors are responsible for the
accuracy and completeness of their references and
for correct text citations. All references should be
identified at the appropriate parts of the text using
Arabic numerals enclosed in parentheses. All
references should then be typed double-spaced at
the end of the manuscript and numbered
according to the order they were cited in the text.
Journal references should include the names of all
the authors and inclusive page numbers.
Abbreviations of names of journals should
conform to those used in the Index Medicus.
For world wide web citations, follow the
following format: <author’s name> <title of
document> <<URL>> <date of document>
(accessed <date accessed>). You may break
URLS across lines, but if possible, arrange for
breaks to occur only at punctuation separators
(but not on hyphens, and don’t ever add hyphens).
Samples of the style to be followed in the listing
references are enumerated below:
JOURNAL ARTICLE: Tanchuco JQ, Young J.
Normal standards for spirometric tests in Filipino
children. Chest Dis J 1989. 16:93-100.
 INSTRUCTIONS TO AUTHORS
BOOK: Kelley MA, Fishman AP. Exercise
Testing. In: Pulmonary Diseases. 2 edition.
Fishman AP, (ed.). McGraw-Hill Book Co.; 1989.
pp.2525-2532.
WORLD WIDE WEB: Horton M, Adams R.
Standard for interchange of USENET messages
Request for comment s 1036, Network Working
Group. <ftp://ftp.demon.co.uk/pub/doc/rfc/rfc1036.
txt> Dec.1987 (Accessed 19 June 1995)
Personal communications, unpublished data or
manuscripts in preparation should not be used as
numbered reference. Instead, these may be cited in
parentheses or as a footnote on the page where they
are mentioned. Authors assume responsibility for
verifying the accuracy of their cited reference.
Advertisements. All requests for rates should be
add-ressed to: The Business Manager, Philippine
Journal of Chest Diseases, PCCP Secretariat, 84-A
Malakas St., Brgy. Pinyahan, Diliman, Quezon
City (Telephone No. 924-9204 and Fax No. 924-
0144). The journal also accepts announcements
from institutions or professional
invitations to forthcoming symposia or convention
for publication at minimal cost depending on
available space.
Reprints. Requests for additional reprints of
individual articles should be addressed to: The
Editor-In-Chief, Philippine Journal of Chest
Diseases, PCCP Secretariat, 84-A Malakas St.,
Brgy. Pinyahan, Diliman, Quezon City (Telephone
No. 924-9204 and Fax No. 924-0144). Author/s of
each manuscript are entitled to 25 copies of the
article. These shall be sent to the major author.
Requests for reprints should be addressed to the
senior author. Reprints of entire issues may be
provided at cost, depending on availability of
copies.
Subscriptions. All requests for subscriptions should
be addressed to: The Business Manager, Philippine
Journal of Chest Diseases, PCCP Secretariat, 84-A
Malakas St., Brgy. Pinyahan, Diliman, Quezon City
(Telephone No. 9249204 and Fax No. 924-0144. E-
mail address secretariat@philchest.org. One issue
(P120.00). Back issues (depending on availability
P120.00).
 APRIL-JUNE 2017 VOLUME 18 NUMBER 2

1 EDITORIAL

3 Oxygen Saturation Index as a Surrogate of PaO2/FiO2 Ratio in Acute

Respiratory Distress Syndrome
Caroline Bernadette O. King Kay, MD; Patrick Gerard L. Moral, MD, FPCP,
FPCCP

9 Turnaround Time for Smear-negative Category I Cases to Initiation of

Treatment in District IV of Manila from January 2014 to December 2014
Radha Marie M. Sillano, MD; Caroline Bernadette O. King Kay, MD; Jose Hesron
D. Morfe, MD

14 Neurocognitive outcome of patients with delirium in the intensive care units at a

tertiary government hospital
Coleen Gulay, MD; Gerard Saranza, MD; Genevieve Tuble, MD; Derick Erl
Sumalapao; Albert Albay Jr., MD, FPCCP; Veeda Michelle Anlacan, MD; Lourdes
Ledesma, MD

22 Prevalence of tuberculosis infection in cancer patients at Veterans Memorial

Medical Center
Maryanne Cristy T Dadulla, MD, DPCP; Teresita Aquino MD, FPCCP

31 Prediction of Pneumonia Based on Signs and Symptoms in Patients Presenting

with Cough at the Veterans Memorial Medical Center
Marco Gil S. Veracruz, MD, FPCP, Arnold G. Germar, MD, FPCP, FPCCP

36 A Retrospective Study Comparing Young and Old Patients Diagnosed with

Primary Lung Cancer
Rossini Abbie Pasanting-Lim, MD
EDITORIAL
Simple Approaches Yielding
High Impact Changes
Evelyn Victoria E. Reside, MD, FPCCP
Editor-in-Chief
“There is always one more thing to learn.”
- Steve Jobs. Apple
As the Philippine Journal of Chest Diseases
continues its quest to help inform its members of
the latest research endeavors of the College, it is
clear that the PJCD contributes to member
learning and development as well. Moreover, it
is hoped that the PJCD’s featured articles
motivate others to ask more significant
questions, and drive them to pursue more
relevant research. After all, to quote from Steve
Jobs, a master of forward thinking and
innovation, “There is always one more thing to
learn”.
And indeed, there is always one more thing to
learn … and another. And a next.
Such is the beauty of learning – there seems to
be no end to it. And when somebody,
somewhere, develops an easier way of doing
things (and for things that matter, more
importantly) then its value escalates. In this issue
of the PJCD, we highlight articles which help
demonstrate how perhaps new, or different,
approaches to assessing and managing patients,
are able to enhance patient care.
Our first article by King Kay and Moral shows
us that oxygen saturation can be a useful alter-
1 Philipp J Chest Dis 2017
native to the PF ratio in evaluating patients with
respiratory failure. This is important since not all
healthcare facilities have immediate access to
arterial blood gas determination, and not all
patients are able to afford it, even if the test is
available. This opportunity to provide appropriate
yet more affordable care greatly impacts the way
the less fortunate are able to receive medical care;
instead of resorting to the usual “clinical eye” as
the only means of validating diagnoses and
monitoring progress, the simpler way of using
oxygen saturation is now shown to be a viable
alternative.
The second article by Sillano et al emphasizes the
value of the simple question that responds to the
current government’s appeal to eliminate or
decrease waiting time for services. “How long do
patients wait prior to the start of TB treatment?”.
Indeed, such is not the stuff of which award-
winning papers or clinical trials are made of, but
such is research which positively impacts patient
care in public health facilities. Clearly, the issue of
appropriate and efficient health care cannot be
considered separately. Imagine a TB patient who
needs to wait for almost a month prior to
initiating treatment, and all the time continuing to
be a public health threat.
The papers of Gulay, et al., and Dadulla and
Aquino provide a glimpse of outcomes among
critically ill patients. According to Gulay, et
al, the early detection of delirium among ICU
patients may allow for early interventions in
order to prevent neurocognitive impairment
such as memory and processing speed. This
clearly emphasizes the holistic approach to
patient care to include mental health. In the
same way, the paper of Dadulla and Aquino
sheds light on two very common conditions
facing pulmonary specialists: tuberculosis
(TB) and cancer. Based on their retrospective
data, TB and malignancy do not only mimic
each other, but they also occur together in
many instances, making their diagnosis more
challenging.
Moreover, the study of Veracruz and Germar,
is a timely reminder of the value of the chest
radiograph as a diagnostic tool for
pneumonia. The paper validates the
importance of clinical findings such as fever
and sputum production as the cornerstones of
diagnosis, with the x-ray providing support.
This is not new information for us, but the
study sends a clear message to clinicians: the
chest x-ray should not be considered routine
for all patients with cough; rather, it is best
requested for patients demonstrating signs and
symptoms highly suggestive of pneumonia.
To complete this issue of the PJCD, Pasanting-
Lim describes the characteristics of patients
with primary bronchogenic carcinoma among
the young and the old. Although oftentimes we
declare that “age is but a number”, it can be
considered, in one way or another, among
those factors which can contribute to illness.
However, despite how often we clinicians
attribute age as a potential confounder, this
retrospective review tells us otherwise: that
comparing young and old patients with lung
cancer, there appears to be no significant
difference in treatment and, more importantly,
survival. This is one aspect of lung cancer with
may benefit from analysis of prospective data.
Yes, Steve Jobs’ message is clear: that “There
is always one more thing to learn”. And as
every passionate researcher knows, this
translates into “there is always one more study
to do”. And knowing that research is not for
the faint-hearted, nor is it for anyone and
everyone, a pat on the back to all those who
continue to contribute to the growth of the
PJCD.
Mabuhay ang PCCP researcher!
Vol. 18 | Issue 02 | June 2017 2
OSI in ARDS assessment

RETROSPECTIVE COHORT STUDY

Oxygen Saturation Index as a Surrogate of PaO2/FiO2 Ratio

in Acute Respiratory Distress Syndrome
Caroline Bernadette O. King Kay, MD; Patrick Gerard L. Moral, MD, FPCP, FPCCP
University of Santo Tomas Hospital, Manila

ABSTRACT

Background: Acute respiratory distress syndrome (ARDS) is characterized by noncardiogenic

pulmonary edema, lung inflammation, hypoxemia and decreased lung compliance. It is diagnosed by
using the Berlin criteria, which considers PaO2/FiO2 Ratio. Recently, oxygenation index (OI), another
measure of oxygenation dysfunction, has been suggested as a more accurate means of determining
severity of respiratory failure. Other studies showed that oxygen saturation index (OSI), which is the
result of (MAP x FiO2)/SPO2, has a strong linear association with OI and PaO2/FiO2 ratio in patients with
type 1 respiratory failure. This study aimed to determine the performance of oxygen saturation index
(OSI), as a surrogate of PaO2/FiO2 ratio in the diagnosis of ARDS.

Methods: Review of records was done on patients diagnosed with ARDS from January 2012 to
December 2015 at the University of Santo Tomas Hospital, Philippines. Simultaneous arterial blood gas,
pulse oximetry and ventilator settings were recorded during the first 1, 24, 48 and 72 hour of mechanical
ventilation. PaO2/FiO2 Ratio, OI and OSI were then calculated. Descriptive statistics and two-way
scatterplots were used to describe the correlation of PaO2/FiO2 Ratio, OI and OSI. A linear modeling was
used to derive predictive equation for PaO2/FiO2 Ratio using OSI, oxygen saturation (SpO2), respiratory
rate (f) and MAP.

Results: Eighty-five arterial blood gas, SpO2 and MAP values from 27 patients (mean age of 57 years;
55% males) were included. Analysis showed that PaO2/FiO2 ratio was inversely related to OI and OSI,
with stronger linear correlation with OI than OSI. OI and OSI were directly related. The following
predictive equation of PaO2/FiO2 ratio was derived: PaO2/FiO2 ratio=exp (3.33 + 0.03*[SpO2] – 9.92*[OSI]
– 0.02*[f] + 0.06*[MAP]) (R2=61.41%).

Conclusion: OSI may be a noninvasive surrogate measure of oxygen dysfunction in patients with ARDS.

INTRODUCTION genesis is still unclear; hence no gold standard

Acute respiratory distress syndrome (ARDS) is
a constellation of clinical and physiologic
observations characterized by noncardiogenic
pulmonary edema, lung inflammation, hypoxemia
and decreased lung compliance.1 It is often fatal if
not recognized and managed in a timely manner. It
evolves through a number of different phases, from
alveolar capillary damage to lung resolution to a
fibroproliferative phase.2 However, the exact patho-
diagnostic test is currently available.
According to the most recent consensus
initiated by the European Society of Intensive Care
Medicine and endorsed by the American Thoracic
Society and the Society of Critical Care Medicine,
the Berlin Definition of ARDS includes the
following: 1) within one week of known clinical
insult or new or worsening respiratory symptoms;
2) chest radiograph or computed tomography scan

3 Philipp J Chest Dis 2017


finding of bilateral opacities not fully explained by
effusions, lobar/lung collapse, or nodules; 3)
respiratory failure not fully explained by cardiac
failure or fluid overload, excluded by objective
assessment (e.g., echocardiography); 4)
oxygenation dysfunction classified as mild,
moderate or severe based on PaO2 (partial pressure
of oxygen)/fio2 (fraction of inspired oxygen) ratio
with Positive End Expiratory Pressure (PEEP) or
continuous positive airway pressure (CPAP)
≥5cmH2O.3
PaO2/FiO2 ratio is an arterial blood gas-derived
oxygenation criteria. It is a simplified and reliable
method for estimating the degree of intrapulmonary
shunting.4,5 Evidence shows that a PaO2/FiO2 ratio
of ≥150mmHg suggests acceptable physiologic
shunt and compatible to successful weaning trial.4
Oxygenation index (OI) is another measure of
oxygenation and is determined as follows: (Mean
Airway Pressure [MAP] x FiO2)/PaO2. It was
originally used as a criterion in identifying neonates
who would benefit from extracorporeal membrane
oxygenation (ECMO). However, in adults, it has
recently been suggested as a more accurate means
of determining severity of respiratory failure
compared to PaO2/FiO2 ratio, and is a statistically
significant predictor of death, failure of
conventional ventilation, and need for rescue
therapies such as inhaled epoprostenol, paralytics,
airway pressure release ventilation and ECMO.6-8
As the parameter involves MAP, any change in
PEEP, peak inspiratory pressure (PIP), inspiratory
time, and respiratory rate, which can all affect
MAP, is reflected in the OI.
However, both the PaO2/FiO2 Ratio and OI
require arterial blood gas determination, which can
be technically difficult to perform, and is costly and
not readily available in some centers. The pulse
oximeter is an alternative, reliable, and inexpensive
means of monitoring hypoxemia by measuring the
approximate oxyhemoglobin saturation (SpO2). It
has a good correlation with arterial oxygen
saturation (SaO2) when the SaO2 is 95% or
greater.9 In an attempt to find other non-invasive
King Kay and Moral
invasive means of determining oxygenation in
type 1 respiratory failure patients, Otekeiwebia et
al studied the performance of oxygen saturation
index (OSI), which is the result of (MAP x
FiO2)/SPO2, and found it to have a strong linear
association with OI and PaO2/FiO2 ratio in patients
with type 1 respiratory failure.10
Currently, there is no published data in
adults regarding the use of OSI as a surrogate to
PaO2/FiO2 Ratio in patients with ARDS. This
study aimed determine the performance of OSI as
compared with PaO2/FiO2 ratio in the diagnosis of
ARDS in patients at the University of Santo
Tomas Hospital (USTH) Intensive Care Unit from
January 2012 to December 2015.
METHODOLOGY
All patients, of any age and gender,
diagnosed with ARDS based on the Berlin criteria,
admitted at the USTH Intensive Care Unit from
January 2012 to December 2015 were included in
the study. Patients with incomplete data and those
with ARDS admitted at the regular ward were
excluded. Request for permission to review the
medical charts were done. The name, age, gender,
co-morbidities and outcome of each patient were
recorded.
Simultaneous arterial blood gas, pulse
oximetry and mechanical ventilator setting were
extracted from the ventilator flowsheet during the
first 1, 24, 48 and 72 hour of mechanical
ventilation. The PaO2/FiO2 Ratio, OI and OSI
were calculated from the given data.
Measures of central tendency were used to
describe continuous numerical variables and
percentage frequency distribution for categorical
data. Descriptive statistics and two-way
scatterplots were used to characterize the
relationship between PaO2/FiO2 Ratio, OI and
OSI. A linear modeling was used to derive the
predictive equation for OSI between PaO2/FiO2
ratio and OSI.
Vol. 18 | Issue 02 | June 2017 4
 OSI in ARDS assessment

RESULTS years old (20 to 90 years). Forty-eight percent of

Out of the 43 records reviewed, 27 patients the patients were eventually discharged, with an
fulfilled the inclusion and exclusion criteria, 56% average of 27 days of confinement. Most
(n=15) of which were males, with a mean age of 57 common co-morbidities included pneumonia,
chronic kidney disease, urinary tract infection and
Table 1. Clinical profile of included parients pulmonary congestion. There was an almost
Age (mean, range) 57 years old (20-90) equal distribution between ARDS severity classes
Gender (n,%) (Table 1).
Male 15 (56%) Eighty-five arterial blood gas, SpO2 and
Female 12 (44%) MAP values from these patients were recorded.
The averages for the three tests for the four time
Outcome (n,%)
Discharged 13 (48%)
interval have no significant differences (Table 2).
Expired 11 (41%)
Correlation matrix showed that the
Transferred 3 (11%) PaO2/FiO2 ratio was inversely related to OI and
Length of stay (days, range) 27 (1-74) OSI (Tables 3 and 4), but the correlation was
Comorbidities (n) stronger with OI than with OSI.
HAP 7 OI was also found to be a significant
CAP 7 indicator of PaO2/FiO2 Ratio (R2=73.2%) (Figure
CKD 6 1), with an increase in OI corresponding to a
UTI 6
5
584.59 decrease in PaO2/FiO2 Ratio.
Pulmonary congestion
VAP 5
PCP 5 Table 2. Average PaO2/FiO2 Ratio, OI and OSI for
Hypertension 4
each time interval
HCAP 4
PTB 4 Test ABG Mean (95% CI)
Bronchial asthma 3
3 1 hr 154.94 (112.97-196.91)
Myocardial infarction
AKI 3 24 hrs 231.21 (168.92-293.5)
COPD 3 PaO2/
48 hrs 209.62 (161.27-257.98)
CAD 2 FiO2
Diabetes mellitus 2 72 hrs 277.58 (155.8-399.36)
SLE 2 Total 218.34 (181.46-255.22)
CHF 2
Pulmonary contusion 2 1 hr 0.11 (0.07-0.14)
AML 2 24 hrs 0.09 (0.05-0.12)
Febrile neutropenia 2
2 OI 48 hrs 0.09 (0.06-0.12)
Septic shock
Candidiasis 2 72 hrs 0.11 (0.07-0.15)
Others 23
Total 0.1 (0.08-0.12)
ARDS severity (n,%)
Mild 29 (34%) 1 hr 0.11 (0.09-0.13)
Moderate 32 (38%) 24 hrs 0.09 (0.07-0.11)
Severe 24 (28%)
OSI 48 hrs 0.09 (0.07-0.11)
HAP, hospital-acquired pneumonia; CAP, community-acquired pneumonia; CKD,
chronic kidney disease; UTI, urinary tract infection; VAP, ventilator-associated 72 hrs 0.11 (0.08-0.13)
pneumonia; PCP, Pneumocystis carinii pneumonia; HCAP, health care-associated
pneumonia; PTB, pulmonary tuberculosis; AKI, acute kidney injury; COPD, chronic Total 0.1 (0.09-0.11)
obstructive pulmonary disease; CAD, coronary artery disease; SLE, systemic lupus
erythematosus; CHF, congestive heart failure; AML, acute myelogenous leukemia; ABG, arterial blood gas; PaO2, arterial partial pressure of oxygen; FiO2, fraction of
ARDS, acute respiratory distress syndrome. inspired oxygen; OI, oxygenation index; OSI, oxygen saturation index.

5 Philipp J Chest Dis 2017

 King Kay and Moral

OSI was also a significant indicator of Figure 1. Scatterplot of PaO2/FiO2 ratio values
PaO2/FiO2 Ratio (R2=58.5%) (Figure 2), but to a versus OI
lesser degree than OI, with an increase in OSI 0.600
corresponding to a 683.23 decrease in
PaO2/FiO2 Ratio. Likewise, OI and OSI are 0.500
directly correlated with each other, with OI
being a significant indicator of OSI (R2=88.4%). 0.400
An increase in OI corresponded to a 0.604

OI
increase in PaO2/FiO2. The following predictive 0.300
equation of PaO2/FiO2 ratio was derived:
PaO2/FiO2 Ratio = exp (3.33 + 0.03*[SpO2] – 0.200
9.92*[OSI] – 0.02*[f] + 0.06*[MAP]) (R2 =
61.41%). Figure 3 shows good correlation 0.100

between actual and predicted PaO2/FiO2 ratio

0.000
using this formula. 0 100 200 300 400
P/F Ratio
DISCUSSION
ARDS is a critical illness that needs not
only constant clinical assessment, but serial
arterial blood gas extractions as well. And the This study has shown that OSI can be an
importance of oxygenation monitoring cannot acceptable alternative to the more expensive
be overemphasized. Unfortunately, due to its PaO2/FiO2 Ratio and OSI in determining the
financial burden and technical difficulty, oxygenation status of ARDS patients. Of course, it
particularly in resource limited areas, this is not has certain limitations. Artifacts, sunlight, nail
always practical. polish, improper placement, low perfusion states
and presence of dyshemoglobin can give
inaccurate OSI results.10
Table 3. Correlation Matrix (ratio) between PaO2/FiO2
Likewise, factors which affect oxygen
Ratio, OI and OSI.
affinity to hemoglobin, such as changes in carbon
PaO2/FiO2 OI OSI
dioxide, hydrogen ions, 2-3-diphosphoglycerate
PaO2/FiO2 1 -0.732* -0.585* and temperature, and presence of carbon
monoxide, can influence oxygen saturation.11
OI -0.732* 1 0.884*
These factors can occur in combination, especially
OSI -0.585* 0.884* 1 in critically ill patients. Hence, use of the
*Correlation is significant at 1% level.

Table 4. Correlation Matrix (ratio) between PaO2/FiO2 Ratio, OI and OSI for each time period.
After 1 hour After 24 hours After 36 hours After 72 hours
P/F OI OSI P/F OI OSI P/F OI OSI P/F OI OSI

PaO2/FiO2 1 -0.667* -0.514* 1 -0.631* -0.552* 1 -0.748* -0.534* 1 -0.528* -0.500*

OI -0.667* 1 0.890* -0.631* 1 0.922* -0.748* 1 0.859* -0.528* 1 0.869*
OSI -0.514* 0.890* 1 -0.552* 0.922* 1 -0.534* 0.859* 1 -0.500* 0.869* 1

*Correlation is significant at 1% level.

Vol. 18 | Issue 02 | June 2017 6

 OSI in ARDS assessment

Figure 2. Scatterplot of PaO2/FiO2 ratio values Figure 3. Scatterplot of actual versus predicted
versus OSI PaO2/FiO2 Ratios

0.300 1800

1600
0.250
1400

0.200 1200

Actual P/F
1000
OSI

0.150
800

600
0.100
400

0.050 200

0
0.000 0.00 100.00 200.00 300.00 400.00
0 100 200 300 400 -200
Estimated PaO2/FiO2
PaO2/FiO2

predictive equation must be interpreted with due
consideration of each patient’s comorbidities.
Since this is a retrospective study, a
prospective study assessing the clinical
application of OSI as an alternative to PaO2/FiO2
Ratio is recommended.
CONCLUSION
OSI may be a noninvasive surrogate
measure of oxygen dysfunction in patients with
ARDS. A prospective study is recommended to
further assess its clinical application.
REFERENCES
1. Lee WL, Slutsky AS. Acute Hypoxemic
Respiratory Failure and ARDS. Murray and
Nadel’s Textbook of Respiratory Medicine,
6th edition, Edited by Broaddus VC, et al.
Philadelphia, Elsevier Saunders, 2015. p
1742.
2. Fanelli V, Vlachou A, Zhang H, et al. Acute
respiratory distress syndrome: new definition,
current and future therapeutic options. J Tho-
cic Dis., 2013; 5(3):326-334.
3. Ranieri VM, Rubenfeld GD, Thompson BT et
al. Acute respiratory distress syndrome: the
Berlin Definition. J Am Med Assoc 2012;
307(23):2526-2533.
4. Chang DW, Hiers JH. Weaning from
Mechanical Ventilation. Clinical Application of
Mechanical Ventilation, 4th edition, Edited by
Chang D. New York, Delmar Cengage
Learning, 2014. p522.
5. El-Khatib MF, Jamaleddine GW. A new
oxygenation index for reflecting intrapulmonary
shunting in patients undergoing open-heart
surgery. Chest 2004; 125:592-596.
6. Davies K, Bourdeaux, Gould T, et al.
Oxygenation index outperforms the P/F ratio
for mortality prediction. Crit Care 2014;
18(Suppl 1): p266.
7. Seeley E, McAuley DF, Kallet RH et al.
Predictors of mortality in acute lung injury
during the era of lung protective ventilation.
Thorax 2008; 63(11):994-998.
8. Agarwal V, Almeida R, Gaurav K, et al. Oxy-

7 Philipp J Chest Dis 2017

 King Kay and Moral

genation Index as a predictor of failure of

conventional ventilation and mortality in
Acute Respiratory Distress Syndrome. Am J
Respir Crit Care Med 2013; 187:A2215.
9. Niehoff J, Delguercio C, LaMorte W, et al.
Efficacy of pulse oximetry and capnometry in
postoperative ventilator weaning. Crit Care
Med 1999; 16(7):701-705.
10. Chop W, Chang D. Monitoring in Mechanical
Ventilation. Clinical Application of
Mechanical Ventilation, 4th edition, Edited by
Chang D. New York, Delmar Cengage
Learning, 2014. P259.
11. Powell FL, Wagner PD, West JB. Ventilation
Blood Flow, and Gas Exchange. Murray and
Nadel’s Textbook of Respiratory Medicine,
6th edition, Edited by Broaddus VC, et al.
Philadelphia, Elsevier Saunders, 2015. p59.
12. Otekeiwebia A, Ajao O, Ingrid P, et al.
Performance of oxygen saturation index
among adults with type 1 respiratory failure.
Crit Care Med 2014; 42(12 Supp 1): pA1521.

Vol. 18 | Issue 02 | June 2017 8

Turnaround time in smear-negative TB

RETROSPECTIVE COHORT STUDY

Turnaround Time for Smear-negative Category I Cases to

Initiation of Treatment in District IV of Manila from January
2014 to December 2014
Radha Marie M. Sillano, MD; Caroline Bernadette O. King Kay, MD; Jose Hesron D. Morfe, MD
University of Santo Tomas Hospital, Manila

ABSTRACT
Background: The diagnosis of tuberculosis (TB) requires bacteriologic confirmation through direct
sputum smear microscopy to allow early access to treatment. However, smear-negative cases are a
commonly experienced diagnostic dilemma. Certification of disease activity from TB Diagnostic
Committee (TBDC) is needed to curb unnecessary treatment. Turnaround time starts from the collection
of the first sputum sample to the initiation of treatment—this should be within 5 working days based on
local guidelines.

Objectives: To determine the mean turnaround time for new smear-negative pulmonary TB (PTB) cases
in District IV of Manila referred to the USTH TBDC from January to December 2014.

Methods: A retrospective descriptive study was done to determine the number of days it took for new
smear-negative PTB cases to initiate treatment. Demographic data was noted. The intervals between
submission of sputum, TBDC certification and the first dose of anti-TB medication were obtained and
used for the calculation of turnaround time.

Results: There were 153 patients in the study. The mean total turnaround time was 37.78 + 24.62 days,
with a mean of 14.30 + 18.58 days from sputum collection to follow-up at the health care facility (return of
results and referral to TBDC); 12.74 + 10.15 days thereafter to TBDC decision to treat; and another 10.69
+ 15.18 days to initiation of treatment at the health care facility.

Conclusion: There was significant delay in the initiation of treatment among smear-negative PTB cases,
mostly observed between sputum collection and TBDC referral. This reflects a poorly functioning default
tracing mechanism among Directly Observed Treatment Strategy facilities even at the diagnostic phase,
which has negative implications for infection prevention and control.

INTRODUCTION of morbidity and mortality, the country ranks ninth

Tuberculosis (TB) is a major global health
problem, ranking as the second leading cause of
death from an infectious cause worldwide after the
human immunodeficiency virus. Among 9.0 million
new TB cases in 2013, there have been 1.5 million
associated deaths. Globally, TB mortality rate has
fallen by 45% since 1990 and incidence rates have
decreased in most parts of the world.1 However, in
the Philippines where TB is the sixth leading cause
out of the 22 highest TB-burden countries in the
world.2,3
Identification and diagnosis of TB cases
among individuals with signs and symptoms
suggestive of TB entails direct sputum smear
microscopy. The National TB Program (NTP)
adopts this primary diagnostic method because it
provides definitive diagnosis of active TB, it is
simple and economical to do, and a microscopy

9 Philipp J Chest Dis 2017


center could easily be put up in remote areas.
The chest x-ray is used to complement
bacteriologic testing to arrive at a diagnosis.
However, it has low specificity and is unable to
differentiate drug-susceptible from drug-
resistant disease.4
Any person with signs and/or symptoms
suggestive of TB or those with chest x-ray
findings suggestive of active TB is referred to
as Presumptive TB. These patients should
undergo direct sputum smear microscopy for
two determinations unless he/she is in a
situation that prohibits this requirement. If at
least one sputum smear is positive for acid-fast
bacilli (AFB), the patient is classified as
bacteriologically-confirmed pulmonary TB
(PTB) and should start treatment. However, if
both sputum smears are negative for AFB, the
patient may be referred to a Xpert MTB/RIF
site for testing. If the patient has no access to
Xpert MTB/RIF or could not expectorate, the
Directly Observed Treatment, Short-course
(DOTS) physician will use his best clinical
judgment to decide if a diagnosis of active TB
is warranted. Referral to a specialist or a TB
Diagnostic Committee (TBDC) may be done to
confirm active TB diagnosis. In either case, the
patient is classified as clinically-diagnosed
TB.4,5
In District IV of Manila, patients with
two negative sputum AFB smears and chest
radiograph findings suggestive of PTB are
referred by their respective health centers to the
TBDC Center at the University of Santo Tomas
Hospital. This committee meets twice a month
to discuss each case prior to arriving at a
consensus on whether a patient would warrant
anti-TB treatment.
Providers must recognize that early and
accurate diagnosis is critical in TB care and
control.6 Diagnostic delays result in ongoing
transmission in the community and more
severe, progressive disease in the affected
person.7
Sillano et al
Turnaround time refers to the time from
collection of the first sputum sample to
initiation of treatment for TB, which is desired
to be within 5 working days.4 In a systematic
review of time delays in the diagnosis of PTB,
the average patient delay was 31.7 days and
health system delay was 28.5 days for low-
income countries.9 However, there is no
published data on the actual turnaround time for
patients belonging to smear-negative category 1
up to initiation of treatment. The Philippines,
being a high TB burden country, needs to
achieve the desired turnaround time to prevent
transmission and achieve disease control. This
study aimed to determine the turnaround time
specifically for smear-negative category 1 cases
to initiation of treatment in District IV of
Manila.
METHODS
This study included all patients of any
age and gender from District IV of Manila who
are suspected of having presumptive PTB based
on chest radiograph findings and had negative
sputum AFB smear results and referred to the
TBDC of USTH for Category I treatment from
January 2014 to December 2014. Patients with
incomplete data were excluded.
The following data were then requested
from the appropriate health centers of Distric IV
of Manila: date of first sputum collection, date
the sputum results were brought back to the
health center, date the patient was referred to
the USTH TBDC, date of TBDC decision to
start Category 1 treatment, and date anti-TB
medications were initiated at the health center.
Demographic data were also obtained. Each
patient was then assigned a case number for
confidentiality purposes.
Based on the retrieved information, the
following information were calculated: the
number of days from first sputum collection to
the time sputum results were brought back to
the health center (N1); the number of days from
Vol. 18 | Issue 02 | June 2017 10
 Turnaround time in smear-negative TB
Figure. Schema of time intervals assessed in
the study
Presumptive TB (PTB on chest x-ray)
N1 (number of days)
Referral to health center
N2 (number of days)
Referral to TBDC
N3 (number of days)
TBDC decision to start Category 1 treatment
N4 (number of days)
Initiation of TB treatment at the health center
TB, tuberculosis; PTB, pulmonary TB; TBDC, TB
Diagnostic Committee.
the return of sputum results to the time of
referral to USTH TBDC (N2); the number of
days from the time the health center referred the
patient to the USTH TBDC to the time the
TBDC decides to start Category 1 treatment
(N3); and the number of days from TBDC
output to the time anti-TB medications were
initiated at the health center (N4) (Figure).
The data obtained was listed and
tabulated using Microsoft Xcel and the data
analyzed using descriptive statistics. Measures
of central tendency were used for continuous
numerical variables and percentage frequency
distribution for categorical data.
11 Philipp J Chest Dis 2017
RESULTS
There were 153 patients included in the
study (55% male and 44% female). The mean age
of the population was 36.87 years.
The mean total turnaround time was 37.78 ±
24.62 days, with a mean of 14.30 ± 18.58 days
from the first sputum collection to follow-up at the
health care facility and TBDC referral (N1+N2);
12.74 ± 10.15 days thereafter to TBDC referral
and decision to start treatment (N3) and another
10.69 ± 15.18 days to initiation of treatment (N4)
(Table).
Table. Mean turnaround times
Time interval Time (days)
N1 + N2: From 1st sputum sample
to health care facility follow-up 14.36 ± 18.58
(return of results and referral to days
TBDC)
N3: From health care facility
12.47 ± 10.15
follow-up to TBDC decision to start
days
treatment
N4: From treatment decision of
10.69 ± 15.18
TBDC to initiation of treatment at
days
health care facility
37.78 ± 24.62
Total turnaround time
days
TBDC, Tuberculosis Diagnostic Committee.
DISCUSSION
The TBDC was originally set up by the
Department of Health NTP with the advice of the
World Health Organisation-Western Pacific
Regional Office to help prevent over-diagnosis of
PTB using chest x-ray. Its main function is to
review symptomatic smear-negative cases with
chest x-ray findings suggestive of PTB or referred
cases with such radiologic features that may
warrant anti-TB treatment. It is composed of an
NTP coordinator, a radiologist, a clinician or
internist often represented by a pulmonologist or

an infectious disease specialist, and an NTP
nurse. Each case is discussed and a consensus
among the members is reached regarding the
proper management. This decision is mainly
recommendatory and is forwarded to the
referring physician or unit; however, it must be
adhered to if the DOTS services provided by the
health center is to be availed.5
The turnaround time determined by this
study (37.78 + 24.62 days) exceeds what has
been set by the local guidelines (5 working days).
Significant delay of the initiation of treatment
among smear-negative PTB cases was mostly
observed between the first sputum collection to
follow-up at the health care facility and TBDC
referral.
In previous studies, the three main reasons
for the delay in diagnosing TB are the following:
the affected person either does not seek or does
not have access to healthcare; the provider does
not suspect the disease; and the most commonly
available diagnostic test, sputum smear
microscopy, lacks sensitivity.6,8,9 In the study,
contributing factors include prolonged processing
of direct sputum smear microscopy, poor patient
follow-up, and reliance on the TBDC decision for
smear-negative cases.
Reducing delay on the part of the person
entails providing accessible health care facilities,
enhancing community and individual awareness,
and active case-finding in high-risk
populations.10 Provider delay is best reduced by
increasing provider awareness of the risks and
symptoms of TB and of the appropriate and
available WHO-approved diagnostic tests in their
communities. Rapid molecular tests such as
GeneXpert MTB/RIF that increase both the speed
and sensitivity of identifying Mycobacterium
tuberculosis are increasingly available.7
Providers must recognize that early and
accurate diagnosis is critical in TB care and
control.6 Diagnostic delays result in ongoing
transmission in the community and more severe,
progressive disease in the affected person.7
Sillano et al
Patients with sputum smears negative for AFB
are considered less infectious than patients
who are smear positive. However, they also
contribute to TB transmission. In the
Netherlands, patients with smear-negative
culture-positive TB are responsible for 13%
of TB transmission.11 In the United States,
these patients are responsible for 17% of TB
transmission.12 Thus, early diagnosis and
initiation of treatment of sputum smear-
negative patients is crucial to prevent
transmission.
Based on the results of this study, we recommend
the improvement in patient follow-up,
increased provisions for direct sputum smear
microscopy, and training of primary care
physicians in the diagnosis of PTB based on
clinical and chest radiograph findings. These
measures may decrease the turnaround time
for the prompt diagnosis and treatment of
the disease and prevention of disease
progression and transmission.
CONCLUSION
There was significant delay in the initiation of
treatment among smear-negative PTB cases,
mostly observed during the follow-up visits
after sputum collection and interval time to
TBDC referral. This reflects a poorly
functioning default tracing mechanism
among DOTS facilities even at the
diagnostic phase, which has negative
implications for infection prevention and
control.
REFERENCES
1. World Health Organization Global
Tuberculosis Report 2014. Geneva: World
Health Organization; 2014.
2. Vianzon R, et al. The Tuberculosis Profile
of the Philippines, 2003-2011: Advancing
DOTS and beyond. Western Pac Surveill
Resonse J. 2013 Apr-Jun: 4(2): 11-16.
Vol. 18 | Issue 02 | June 2017 12
 Turnaround time in smear-negative TB

3. National Tuberculosis Control Program.

Manila: Department of Health; 2011.
4. National Tuberculosis Program Manual of
Procedures 5th edition: 2014. Manila:
Department of Health; 2014.
5. Diagnosis, Treatment, Prevention & Control
of Tuberculosis in Adult Filipinos: 2006
Update. Manila: Department of Health; 2006.
6. World Health Organization. Early detection
of tuberculosis: An overview of approaches,
guidelines and tools. Geneva: World Health
Organization; 2011.
7. International Standards for Tuberculosis Care
Diagnosis, Treatment, Public Health, 3rd
edition; 2014. Geneva: World Health
Organization; 2014.
8. Storla DG, et al. A systematic review of delay
in the diagnosis and treatment of tuberculosis.
BMC Public Health. 2008; 8:15.
9. Sreeramareddy CT, et al. Time delays in
diagnosis of pulmonary tuberculosis: a
systematic review of literature. BMC Infect
Dis. 2009; 9:91.
10. World Health Organization. Integrating
community-based tuberculosis activities into
the work of nongovernmental and other civil
society organization. Geneva: World Health
Organization; 2012.
11. Totsmann A, et al. Tuberculosis Transmission
by Patients with Smear-Negative Pulmonary
Tuberculosis in a Large Cohort in The
Netherlands. Clinical Infectious Diseases
2008;47:1135-42.
12. Behr M, et al. Transmission of Myco-
bacterium tuberculosis from patients smear
negative for acid-fast bacilli. Lancet 1999;
353;444-449.

13 Philipp J Chest Dis 2017

 Gulay et al

LONGITUDINAL DESCRIPTIVE STUDY

Neurocognitive outcome of patients with delirium in the

intensive care units at a tertiary government hospital
Coleen Gulay, MD1; Gerard Saranza, MD2; Genevieve Tuble, MD1; Derick Erl Sumalapao3;
Albert Albay Jr., MD1; Veeda Michelle Anlacan, MD2; Lourdes Ledesma, MD2
1Section of Pulmonary Medicine, Department of Medicine, Philippine General Hospital
2Department of Neurosciences, Philippine General Hospital
3Department of Biology, College of Science, De La Salle University

Introduction: Delirium among patients admitted in intensive care units (ICU) is associated with
impairment of cognitive function. This study aims to describe the development of cognitive impairment
among patients who developed ICU delirium.

Methods: This is a non-interventional, descriptive, longitudinal study that included patients with ICU
delirium. The Montreal Cognitive Assessment Philippine Version (MoCA-P) was used to assess cognitive
function. Visual Reproduction (VR) and Logical Memory (LM) subtests of the Wechsler Memory Scale-
Fourth Edition (WMS-IV) and the Symbol Search (SS) subtest of the Wechsler Adult Intelligence Scale-
Fourth Edition (WAIS-IV) were also performed to further assess the cognitive profile of the subjects.

Results: Out of 39 patients diagnosed to have ICU delirium from November 2014 to February 2015, only
8 subjects were available for evaluation in this follow-up study due to high mortality rate. 6 out of 8
patients (75%) developed cognitive impairment (MoCA-P score <20) 18 months after hospital discharge.
Together with the VR and LM subtests of WMS-IV and the SS subtest of WAIS-IV, item analysis showed
that the cognitive domains affected are memory, executive function and processing speed.

Conclusions: Critically ill patients who developed delirium during their ICU admission are at high risk for
development of long-term cognitive impairment. These findings underline the importance of detection and
treatment of ICU delirium as it leads to a high risk of mortality and poor cognitive outcome among
survivors.

Keywords: cognitive outcome, dementia, delirium, intensive care unit, critical illness

INTRODUCTION Delirium is an acute brain dysfunction that

Current advances in critical care medicine
have greatly improved survival in patients
admitted to the intensive care unit (ICU).1
However, cognitive and psychiatric impairments
frequently occurs among survivors of critical
illness and are associated with development of
long-term cognitive complications.2 Among
patients admitted in the ICU, delirium is found to
be common during critical illness and is
associated with cognitive decline and mortality.3
affects approximately 20% to 80% of ICU
patients, depending on the severity of illness.4
Patients who developed delirium during their
ICU admission were three times more likely to
have cognitive dysfunction 3 years after
discharge.5 Several other studies report varying
incidences of long-term cognitive dysfunction
after ICU discharge.3,6,7 Cognitive impairment
among ICU survivors is associated with poor
outcomes from rehabilitation and increased risk

Vol. 18 | Issue 02 | June 2017 14

 Long-term cognitive impairment in ICU delirium
of institutionalization, mostly because of inability
to fully participate in rehabilitation activities due
to impairment in executive function, inability to
remember therapy instructions, or deranged
implicit and explicit learning ability.8 In contrast,
improvement of cognition may directly improve
rehabilitation outcomes.9
Currently, most studies focus on the
prevalence and risk factors of ICU delirium, with
only few studies on the neuropsychological profile
of patients with cognitive decline after delirium.
This study aimed to describe long-term (18
months) cognitive impairment in critically ill
patients who developed ICU delirium at a tertiary
government hospital.
METHODOLOGY
This is a non-interventional, descriptive,
longitudinal study which included participants
who were previously admitted in the medical,
neurological, and surgical ICUs of a tertiary
government hospital. This is the second part of a
prior study that detected delirium in ICU patients.
Only patients who developed delirium in the first
part of the study were evaluated.
Study Population and Setting
Out of the 196 ICU patients observed in the
first part of the study, 39 patients were diagnosed
with delirium. Only 20 patients were discharged
alive, and of these, two patients died within 6
months of hospital discharge. Of the 18 patients
eligible for long-term follow-up, 10 patients were
lost to follow-up. Hence, only 8 patients were
included in the analysis for the presence of
cognitive decline 18 months from hospital
discharge.
Informed consent was acquired from the
patient or a legal representative before the conduct
of any study intervention. Chart review of the 8
patients was done to obtain information related to
their admission in the ICU, such as the reason for
admission, number of hospital days prior to onset
of delirium, onset and duration of delirium, use of
15 Philipp J Chest Dis 2017
sedation, use of mechanical ventilation, number of
days on mechanical ventilation, and date of discharge.
Assessment of Cognitive Function
A trained and experienced psychologist who
was unaware of the patient’s hospital course evaluated
the patients in a clinic in our institution to avoid
interrater variability in the assessment of cognitive
function of the participants. The primary investigators
were not allowed to enter the examination room so as
not to influence the psychologist in the conduct of the
examination.
The Montreal Cognitive Assessment test,
Philippine version (MoCA-P) was the standard test
used to assess cognitive function. The core domains
assessed in this tool include Orientation, Visuo-graphic
or visuo-spatial function, Registration, Semantic
memory, Sustained attention, Language, and Executive
functions. Executive functions were divided into
Mental tracking, Cognitive flexibility, Concept
formation and Abstract reasoning. A MoCA-P cutoff
of 20 was used as a cut-off for the presence of
cognitive impairment.
The following tests were also conducted to
assess the full cognitive profile of the patients:
1. Visual Reproduction I (Immediate Recall) [VR-1].
This test assessed memory for visual stimuli. The
examinee was shown a series of 5 designs one at a
time for 10 seconds each. After each design was
presented, the examinee was asked to draw this
from memory.
2. Logical memory I (Immediate Recall) [LM-1].
This assessed narrative memory under a free recall
condition. Two short stories, both of which are
Filipino adaptations of the Logical Memory
subtest of the Wechsler Memory Scale, 4th Edition
(WMS-IV), were presented orally one at a time.
The patient was then asked to retell each story
from memory immediately after.
3. Visual Reproduction II (Delayed Recall) [VR-2].
The delayed condition assessed long-term visuo-
spatial memory with free recall. The examinee was
asked to draw the 5 designs shown during the
immediate recall phase in any order.
 Gulay et al

4. Visual Reproduction-Recognition Phase [VR- Table 1. Demographic and clinical characteristics of

Rec]. The examinee was asked to choose study participants
which of 6 designs on a page matches the Variable Value
original design shown during the immediate Age (years), (mean, range) 59 (36-78)
recall phase. Gender (n)
5. Logical Memory II (Delayed Recall) [LM-2]. Male 5
The delayed condition assessed long-term Female 3
narrative memory with free recall. The Level of education (years) 10.88 (3.18)
examinee was asked to retell both stories from (mean, SD)
the immediate recall phase. Diagnosis at ICU admission (n)
6. Logical Memory-Recognition Phase [LM- Neurologic 6
Rec]. The examinee was asked yes/no Post-operative care
questions about both stories. monitoring 2
7. Montreal Cognitive Assessment-Philippines Length of ICU stay (days) 8.62 (6.05)
(MoCA-P) test for Visuospatial/Executive (mean, SD)
Functioning. No. of days in ICU before onset 2.00 (2.00)
8. The Symbol Search [SS] subtest of the of delirium (mean, SD)
Wechsler Adult Intelligence Scale – Fourth Duration of ICU delirium (days) 4.25 (2.82)
Edition (WAIS-IV) is designed to assess (mean, SD)
processing speed, short-term visual memory, MV on admission
visual-motor coordination, visual Yes 4
discrimination, psychomotor speed, speed of No 4
mental operation, attention, and concentration. Days on MV (mean, SD) (n=4) 2.62 (3.78)
Working within a specified time limit (i.e., ICU, intensive care unit; MV, mechanical ventilation.
120 seconds), the examinee scanned a group
of symbols and indicated whether one of these
matches either of 2 target symbols by marking pective study have cognitive impairment 18
either the “yes” or “no” box. months after hospital discharge, with total MoCA-
The protocol was approved by the P scores < 20 (Table 2). Given the small number of
institutional technical and ethical review board. participants in the study, the scores of each patient
in the different domains of MOCA-P were
RESULTS analyzed using a Boston Process Approach which
The study population had a mean age of 59 used an error analysis of their performance per
years, with more males than females, and with an cognitive domain. In this analysis, the participants
average of 10 years of education (Table 1). were classified into three categories (Table 2 and
Majority of the patients were admitted in the ICU Figure) based on the number of errors committed
due to neurological diseases, with an average in the battery: (1) High Performers (n=2), patients
length of ICU stay of 8.62 days. Delirium was who did comparatively better than others in the
diagnosed mostly on the second ICU day with study group, (2) Typical Performers (n=4), patients
duration of approximately 4 days. There is an who performed like most of the other participants,
equal number of participants who were previously and lastly (3) Atypical Performers (n=2) who can
on mechanical ventilation and those who were not be regarded as outliers when compared to the rest
during their ICU admission. in the group.
Based on the patients’ total MoCA-P scores, Two participants classified as atypical
6 out of the 8 patients (75%) included in this pros- performers committed errors in 16/17 components

Vol. 18 | Issue 02 | June 2017 16

 Long-term cognitive impairment in ICU delirium

Table 2. Patient performance on neuropsychological battery

Px No. MOCA-P MOCA-P Visual Reproduction Interpretation Logical Memory Interpretation Symbol
Total Interpre- Search
Score tation Interpre-
Imme- Delayed Repro- Recall Delayed Repro- tation
diate Recall duction (LM-1) Recall duction (SS)
Recall (VR-2) Phase (LM-2) Phase
(VR-1) (VR-Rec) (LM-Rec)

High Performer*
5 25 N VS S A A HA A A
8 24 N A HA A A A B I
Typical Performer*
1 19 I LA LA I B B A I
2 12 I I I I I I I LA
3 13 I I I I I I B I
4 14 I I B B B B B I
Atypical Performer*
6 4 I I I I I I I I
7 5 I I B I I I LA I

N=Normal; I=Impaired; VS=Very Satisfactory; S=Satisfactory; HA=High Average; A=Average; LA=Low Average
B=Borderline.

of MoCA-P. One of these atypical performers
presented with aphasia, while the other one
presented with florid frontal features. The aphasic
patient committed many mistakes, especially on
items that required a verbal response. Qualitative
analysis revealed that he committed several
verbal/semantic paraphasing but seemed to know
more than he could display based on the
standardized way of administering the MoCA-P.
The patient with florid frontal features was
difficult to test because words within an instruction
or test item would lead the participant to digress.
This affected the manner the participant stored the
new information on delayed recall. The
tangentiality of though also contributed to
forgetting more complex instructions. Given these
features, the atypical performers were not included
in the item analysis for MoCA-P as their inclusion
could have an impact on trends that emerged with
this small group of patients.
Based on the performance of the high and
the typical performers, the components of
cognitive function reasonably compromised were
memory, executive function and processing speed
(Table 3). Specifically, the patients had problems
with working memory (i.e., storage/registration,
praxis and visual memory, semantic memory and
executive functions such as mental tracking,
cognitive flexibility and abstract reasoning). On
the other hand, the cognitive domains of visuo-
graphic/visuo-spatial abilities, sustained attention,
naming, concept formation and orientation to
place were preserved (Table 4).
Qualitative analysis reveals that storage
and retrieval of new visual information (i.e.,
geometric designs) was more compromised than
that with new and complex verbal material (i.e.,
stories), in part perhaps because the latter is
readily meaningful.

17 Philipp J Chest Dis 2017

 Gulay et al

Figure. Number of patients with impairment for each neuropsychological test.

100%

80%
% Patients

60%

40%

20%

0%
MoCA VR- LM-
VR-1 VR-2 LM-1 LM-2 SS
-P Rec Rec
Normal/At least average or
2 3 5 3 3 4 6 2
Borderline
Impaired 6 5 3 5 5 4 2 6

Table 3. Compromised cognitive domains among high and typical performers (n=6)
Cognitive Domain
Working Memory: Storage
/ Registration
Praxis & Visual Memory
Semantic Memory
a. Verbal, simple
b. Verbal, complex
Executive Function
a. Mental Tracking
b. Cognitive Flexibility
c. Abstract Reasoning
Processing Speed
Neuropsychological Test
MoCA-P: Digits Forward
MoCA-P: Word List
(Immediate Recall)
Visual Reproduction: VR-1,
VR-2, VR-Rec
MoCA-P: Word List (Delayed
Recall)
Logical Memory: LM-1, LM-2,
LM-Rec
MoCA-P: Serial 7 (plus math
computation)
MoCA-P: Trails
MoCA-P: Digits Backwards
MoCA-P: Verbal Fluency
MoCA-P: Similarities
WAIS-IV: Symbol Search
Remarks
• Half of the patients committed mistakes by
interchanging the numbers.
• No one was able to succeed during the first
learning trial. Only 3/6 were able to mention
all 5 words by the second learning trial
• Most patients (4/6) had low average,
borderline and impaired scores.
• The patients needed cueing in remembering
the words on the list, especially when the
multiple choice format (vs. category cueing)
was used.
• Most patients (4/6) had low average,
borderline and impaired scores but with better
scores compared to VR tests.
• Most patients made 2-4 mistakes.
• 4/6 did not do well on this, largely due to difficulty
switching from one category (i.e., numbers) to
the other (i.e., letters).
• Half of the patients committed mistakes.
• No one was able to generate the minimum 11
words in order to pass. Most patients generated
only 3 – 6 words.
• 4/6 patients committed mistakes on these
items. They instead stated the differences of
the objects they were being asked to compare.
• Most patients (5/6) had low average and
impaired scores.

Vol. 18 | Issue 02 | June 2017 18

 Long-term cognitive impairment in ICU delirium
Table 4. Preserved cognitive domains
Cognitive domain Neuropsychological Test
Visuo-spatial Abilities MoCA-P: copying of a
cube, clock face and
numbers
Sustained attention MoCA-P: Tap “A”
Language MoCA-P: Picture Naming
Concept Formation MoCA-P: Clock drawing
DISCUSSION
Several studies have shown that delirium in
the ICU is associated with mortality and long-term
cognitive impairment. In this study, 6 out of 8
patients (75%) had cognitive impairment 18
months after hospital discharge. This finding
complements those of earlier cohort studies
wherein 40% of the patients has cognitive decline
after 3 months, while 70% with severe cognitive
impairment has persistent cognitive impairment
one year after their critical illness.3,6 One strength
in this study is that we evaluated patients from all
adult ICUs in our hospital, giving us a diverse
population of critically ill patients. Most published
studies are small cohort studies limited to a
specific disease entity (e.g., post-stroke or post-
operative patients).
In a study done by Pandharipande et al.,
delirium increased the risk of long-term cognitive
impairment affecting patients across all ages
regardless of the severity of disease at baseline.6
However, other prospective cohort studies showed
that older adults who developed delirium during
19 Philipp J Chest Dis 2017
Remarks
• No gross distortions or fragmentations seen.
• All patients drew the clock face accurately.
• Half of the patients drew some numbers in the wrong
quadrant
• Half of the patients did this perfectly while 2/6 patients
committed only 1 – 2 mistakes.
• 5/6 patients named all 3 pictures. The other patient
could just not name the camel but she knew it is found
in Saudi Arabia.
• There does not seem to be a problem telling time with
this group; they know what the short and hands signify
• Clock hands: 3/6 patients had errors, usually because
they drew hands of equal length. The errors with the
clock hands suggest that they are not attuned enough
to the significance of hand length as they were
drawing
• Clock time: only 1/6 committed an error.
hospitalization were at 2.4-fold more at risk in
developing cognitive impairment.10,11 In our
study, the youngest patient at 36 years old was
already noted to have cognitive impairment.
Furthermore, more severe illness and longer
hospital stay were also associated with faster
cognitive decline after hospitalization.11 In line
with previous studies, duration of ICU delirium
has significant association with cognitive decline,
wherein those with longer duration of delirium
were found to have increased risk for long-term
cognitive decline. The average length of ICU stay
in this group of patients is at 8.62 days, with
onset of delirium mostly on the second ICU day
with duration of an average of 4.25 days.
While most studies on cognitive decline
after critical illness are mainly epidemiologic,
focusing on prevalence and the associated risk
factors, this study presents a more in-depth
analysis on the type of cognitive impairment
manifested in this population, which makes it
possible to determine a cognitive profile unique
to this subset of patients. There are only a few

published papers that thoroughly examined this
group of patients using an extensive
neuropsychological battery; most studies use only
short cognitive screening tools such as Mini-
Mental State Exam (MMSE) and MoCA.
In our study, we found that patients with
delirium after critical illness show difficulty in
memory and executive functions. Problems with
sustained attention were also felt to account for
poor performance on a speeded clerical task,
resulting in subjects working at a slower pace than
expected. This is consistent with other studies
where they have also shown that attention,
memory, executive function, mental processing
speed spatial abilities, and general intelligence
were most affected.11 Wilson et al. found that there
is a 3.3-fold increase in the rate of cognitive
decline on measures of episodic memory while
there is a 1.7-fold increase in cognitive impairment
on measures of executive function.10 Multiple
cognitive domains are affected, unlike in
Alzheimer’s disease where delayed memory is
usually affected. In another similar on post-stroke
patients who developed delirium, the cognitive
domains affected were memory, language, visual
construction and executive functioning.12 In our
study, language and visuo-spatial abilities were
relatively spared.
Impairment on memory tests are always
accompanied by impairment in other domains such
as semantic fluency and executive function since
both domains involve the frontal lobes, frontal
subcortical areas and limbic lobe. Frontal features
were also evidenced which impacted on semantic
memory. These included inattention to details
(which led to inaccurate recognition on multiple-
choice formats) and cognitive inflexibility (which
led to perseverative errors). Studies have shown
that neurotransmitter abnormalities, such as
reduction in cholinergic activity leading to relative
dopamine excess in the central nervous system,
and occult diffuse brain injury are important
mechanisms that underlies critical illness associa-
Gulay et al
ted cognitive decline.13 There is still a need for
further neurophysiologic studies to better
understand the underlying mechanism behind
cognitive decline after ICU delirium and possibly,
to determine the effect of early intervention on the
cognitive impairment seen in these patients.
There are a number of limitations to our
study. First, only a relatively small percentage of
patients were evaluated, mainly due to the high
mortality during the follow-up period. This
underlies the fact that ICU delirium is associated
with a high risk of mortality. Second, we only
tested the patients at one follow-up period (18
months) without any intermediate assessment.
There might be other confounding factors during
the time interval which may have affected the
patients’ cognitive functioning. In addition, we do
not know exactly when the cognitive impairment
developed in this group of patients. The authors
recommend re-assessment of the patients after 6
months to see if there is further decline in the
patients’ cognition.
CONCLUSION
Long-term cognitive impairment is found in
a large proportion of survivors of critical illness
who developed ICU delirium during their hospital
admission. Patients with longer duration of
delirium are more likely to develop cognitive
decline which may persist even a year after their
critical illness. The components of cognitive
function reasonably compromised include
memory, executive function and processing speed
while visuo-graphic/visuo-spatial abilities, sustain-
ed attention, naming, concept formation and
orientation to place were relatively spared. These
findings underline the importance of detection and
treatment of ICU delirium as it leads to cognitive
decline. Further periodic evaluation is
recommended to monitor the progression of
cognitive impairment.
Vol. 18 | Issue 02 | June 2017 20
 Long-term cognitive impairment in ICU delirium

REFERENCES
1. Adhikari NK, Fowler RA, Bhagwanjee S, 11. Wilson R, Hebert L, Scherr P, Dong X,
Rubenfeld GD. Critical care and the global Leurgens S, Evans D. Cognitive decline after
burden of critical illness in adults. Lancet hospitalization in a community population of
2010;376:1339-1346. older persons. Neurology 2012;78(13): 950-
2. Karnatovskaia L, Benzo R, Gajic O. The 956.
Spectrum of psychocognitive morbidity in the 12. van Rijsbergen M, Oldenbeuving A,
critical ill: A review of the literature and call Nieuwenhuis-Mark R, et al. Delirium in
for improvement. J Crit Care 2015;30:130-137. acute stroke: A predictor of subsequent
3. Girard TD, Jackson JC, Pandharipande PP, et cognitive impairment? A two-year follow-up
al. Delirium as a predictor of long-term study. J Neurol Sci 2011; 306:138-142.
cognitive impairment in survivors of critical 13. Milbrandt E, Angus D. Bench to bedside
illness. Crit Care Med 2010;38:1513-1520. review: Critical illness-associated cognitive
4. Girard TD, Ely W. Delirium in the intensive dysfunction - mechanisms, markers, and
care unit. Critical Care 2008;12(Suppl 3):S3. emerging therapeutics. Critical Care
5. Ely E, Jackson J, Tomason J, Truman B, 2006;10:238.
Gordon S, Dittus R, Bernard G. Current
opinions regarding the importance, diagnosis,
and management of delirium in the intensive
care unit: a survey of 912 healthcare
professionals. Crit Care Med 2004;32:106-112.
6. Pandharipande P, Jackson J, et al. Delirium as
a predictor of long-term cognitive impairment
after critical illness. New Engl J Med
2013;369:1306-1316.
7. Hopkins R. Long-term Neurocognitive
Function after Critical Illness. Chest
2006;130(3):869–878.
8. Wergin R, Modrykamien A. Cognitive
impairment in ICU survivors: Assessment and
therapy. Cleveland Clinic J Med
2012;79(10):705-712.
9. Whyte E, Aizenstein H, Ricker J, Butters M.
Cognitive impairment in acquired brain injury:
a predictor of rehabilitation outcomes and an
opportunity for novel interventions. PM R
2011;3 (suppl 1):S45-S51.
10.Hsieh SJ, Madahar P, Hope A, Zapata J, Gong
M. Clinical deterioration in older adults with
delirium during early hospitalization: a
prospective cohort study. BMJ Open 2015; 5:
e007496.

21 Philipp J Chest Dis 2017

 Dadulla and Aquino

RETROSPECTIVE COHORT STUDY

Prevalence of tuberculosis infection in cancer patients at Veterans

Memorial Medical Center
Maryanne Cristy T Dadulla, MD, DPCP; Teresita Aquino MD, FPCCP
Veterans Memorial Medical Center, Quezon City

ABSTRACT
Cancer patients have depressed adaptive cellular immunity, which predisposes them to
infections associated with cell-mediated immunity deficiencies such as tuberculosis (TB). Cancer
therapy also adds to adaptive cellular immunity dysfunction, further increasing the risk of TB or TB
A
reactivation.
This study retrospectively reviewed charts of histologically diagnosed cancer patients and
assessed for TB or TB reactivation prior, during and after cancer specific therapies. The overall
computed period prevalence of TB infection in cancer patients was 2.3% or 6 cases per person-
years. TB infection developed in 67% of patients prior to cancer-specific therapies, 5% during the
duration of cancer-specific therapy and 28% after cancer-specific therapy completion. Cancer
therapy was associated with an odds ratio of 15 for TB infection (95% CI 3.10, 77.74; p=0.0009).
Among the different cancer types, 12.5% of TB patients developed in lung cancer patients (OR
5.96; 95% CI 1.25, 28.41; p=0.0252). Six percent developed in patients with hematologic and bone
malignancy, 2.8% in those with head and neck malignancies, 2.5% in breast cancer patients, 2% in
patients with gastrointestinal malignancy and 1.3% in genitourinary malignancy patients. Factors
associated with increased odds of TB infections include pulmonary manifestations (OR 4.92; 95%
CI 1.52, 15.91; p=0.0077) and history of previous TB infection and treatment (OR 5.80; 95% CI
2.00, 16.66; p<0.0012).
These results show that proper assessment for concurrent TB infection should be done upon
cancer diagnosis and prior to initiation, during and after cancer-specific therapies.

Key words: prevalence, cancer, tuberculosis

INTRODUCTION higher incidence of TB than solid organ tumors.

Patients with depressed adaptive cellular
immunity such as those with cancer are at
increased risk of tuberculosis (TB) infection or
reactivation.1 Chemotherapy and radiation
therapy can further amplify the risk of primary
infections and reactivation of chronic indolent
infection.2
A comprehensive review of TB in cancer
patients done from 1989 to 1994 in the US
revealed a significant difference from previous
years in terms of demographics and cancer
therapy. Hematologic malignancies, such as
acute leukemia and Hodgkin’s lymphoma have
Leukemia tends to present with disseminated or
extrapulmonary disease. Hodgkin’s lymphoma
appears as focal extrapulmonary disease than
disseminated. This is due to the disease itself and
its treatment which included radiotherapy,
chemotherapy, high dose corticosteroids and
bone marrow transplant. Tumor cachexia is also a
contributory factor.3
Among the solid organ tumors, head and
neck, lung cancer and gastrointestinal cancer
have the highest incidence of TB infection. It was
also found out that cancer patients with
comorbidities such as TB and diabetes have high-

Vol. 18 | Issue 02 | June 2017 22

 TB in cancer patients
er risk of mortality.3 It has to be noted that since
1970 cancer care has improved with new and
more-intensive treatment modalities such as purine
analogues, antilymphocyte monoclonal antibodies
and hematopoietic stem cell transplantation.4 These
new ways of cancer treatment may have influence
the increased risk of TB infection.
From a 1989 to 1994 data, there is an
incidence of 90 per 100,000 populations in the
United States but most are foreign-born patients
(126 per 100,000 population vs. 33 per 100,000
populations).3 From a 2006 to 2014 data, there is
an incidence of 61 per 100,000 populations in
India, which is known to have the highest TB
burden worldwide.5
The Philippines is ranked 9th of 22 countries
in the world with the highest TB burden. TB is the
6th leading cause of mortality and morbidity in the
country.6 However, while several studies7-18 have
already described the relationship of TB and
cancer, there paucity of local literatures on the
frequency of TB infection in cancer patients and its
association with cancer therapy in the Philippines
and in our institutioe. Therefore, this study was
conducted determine the prevalence of active TB
infection among diagnosed case of cancer patients
at Veterans Memorial Medical Center from
January 1, 2011 to December 31, 2013 prior to
initiation, during and after cancer-specific therapy
METHODS
This is a retrospective cross-sectional study
that included patients with histopathologically
diagnosed cancer of any form admitted from
January 1, 2011 to December 31, 2013 at Veterans
Memorial Medical Center (VMMC). Patients
should have histopathologic result released by the
VMMC Histopathology Section; had undergone
work-up or treatment for pulmonary or
extrapulmonary TB prior to initiation of cancer-
specific therapy, during cancer-specific therapy, or
after cancer-specific therapy completion; and
consented to and received cancer-specific therapy.
Patients with concomitant human immuno-
deficiency virus infection or acquired immunode-
23 Philipp J Chest Dis 2017
ficiency syndrome were excluded. Patient charts of
all included patients were reviewed, and the
following relevant information were extracted:
age, sex, co-morbidities, smoking history; history
and outcomes of previous TB diagnosis and
treatment; and history and outcomes of previous
cancer diagnosis and treatment.
Descriptive statistics were used to describe
the population, using means and standard
deviations for continuous variables, and
frequencies and percentages for standard
deviations. The incidence of TB was computed per
1,000 new cancer diagnoses. Cancer-specific TB
frequency rate was also computed. Odds ratios
were computed to show associated odds.
This study followed the standard operating
procedures and guidelines for health research of
VMMC. Ethical approval was obtained from the
Ethics Committee of VMMC. Confidentiality of
patient information were maintained through the
use of patient codes.
RESULTS AND DISCUSSION
There were 793 histologically diagnosed
cancer patients in VMMC from 2011 to 2013
(Table). Only 63 patients were admitted with a
diagnosis of bacteriologically confirmed or
clinically diagnosed pulmonary TB (new cases on
ongoing intensive or maintenance phase TB
treatment; n=10); previously treated TB with
work-up for probable TB relapse (n=40), or
presumptive TB with work-up to rule out TB
(n=13). The rest of the patients either did not
receive cancer-specific treatment (n=7), did not
receive TB work-up or treatment (n=65), neither
TB work-up or treatment nor cancer-specific
treatment (n=655), or missing or incomplete data
(n=3).
Table 2 summarizes the demographic profile
of the 63 patients included in the study, and the
computed odds of these characteristics on the
development of TB infection. Seventy percent
were males. The mean age was 68  15 years and
52% were  65 years old. Fifty-nine percent had
no compounding comorbidities. For patients with
 Dadulla and Aquino

Table 1. Number of admitted patients histologically diagnosed with cancer and cancer types in VMMC from
2011 to 2013
Year 2011 2012 2013 Total
Total number of cancer cases 260 284 249 793
Type of Cancer
Breast cancer 35 38 46 119
Gastrointestinal malignancy 69 62 72 203
Genitourinary malignancy 56 49 45 150
Gynaecological malignancy 20 43 26 89
Head and neck malignancy 59 69 50 178
Hematologic and bone malignancy 10 17 6 33
Lung and pleura malignancy 9 5 2 16
Skin and soft tissue malignancy 2 1 2 5

Table 2. Baseline demographic and clinical profile of included patients

Variable Frequency (%) Mean  SD Odds ratio (95% CI) P value
Sex 1.17 (0.35-3.93) 0.7946
Male 44 (70)
Female 19 (30)
Age (years) 68  15 2.15 (0.70-6.57) 0.1792
< 65 years old 30 (48)
 65 years old 33 (52)
With comorbidities 26 (51) 0.44 (0.42-1.34) 0.1495
COPD 13 9.10 (2.61-31.70) 0.0005
Diabetes mellitus 10 1.86 (0.46-7.57) 0.3878
ESRD/CKD 3 0.33 (0.02-6.68) 0.4686
Hypertension 32 0.96 (0.32-2.85) 0.9365
With no comorbidities 37 (59)
Smoking history 0.55 (0.18-1.67) 0.2925
Non-smoker 25 (40)
Passive smoker 0
Smoker or previous smoker 38 (60) 3.36 (0.16-68.38) 0.4316
<10-pack years 4 (10)
>10-pack years 34 (90)
COPD, chronic obstructive pulmonary disease; ESRD, end-stage renal disease; CKD, chronic kidney disease.

comorbidities, chronic obstructive pulmonary
disease, diabetes mellitus, chronic kidney disease
or end-stage renal disease, and hypertension were
the commonly associated diseases. Sixty percent
were previous or current smokers, and 90% had a
smoking history of 10 pack years.
Sixty percent of patients had no pulmonary
symptoms but were worked up due to a history of
previous TB treatment (Table 3). Of those who
had pulmonary symptoms, cough, dyspnea, ano-
rexia, fever and weight loss were the common
manifestations. Only one patient presented with
extrapulmonary TB in the form of tuberculous
adenitis. All patients underwent sputum acid-fast
bacilli (AFB) smear and chest radiography in the
diagnosis of TB. Most TB diagnosis were based
clinically but three patients had positive sputum
AFB smears (two cases of TB relapse and one
new case). Of the bacteriologically confirmed
cases, one was diagnosed with TB and cancer

Vol. 18 | Issue 02 | June 2017 24

 TB in cancer patients

Table 3. Tuberculosis-related factors of included patients

Variable Frequency (%) Odds ratio (95% CI) P value
TB diagnosis upon cancer diagnosis
Probable TB relapse 37 (59)
Presumptive TB 13 (21)
New case, on-going treatment 10 (16)
Retreatment, on-going treatment 3 (4)
Clinical manifestations 25 (40) 4.92 (1.52-15.91) 0.0077
Fever 4 (6) 0.82 (0.08-8.48) 0.8704
Anorexia 7 (11) 22.00 (2.41-200.78) 0.0061
Cough 19 (30) 3.50 (1.0963-11.1744) 0.0344
Dyspnea 6 (10) 0.47 (0.05-4.34) 0.5059
Weight loss 12 (19) 14.00 (3.15-62.24) 0.0005
Hemoptysis 0
Night sweats 0
None consistent with TB 38 (60)
Site of TB infection
Pulmonary TB 62 (98)
Extrapulmonary TB 1 (2)
TB Diagnostic modality used
Sputum AFB 63 (100)
Bronchoscopy 2 (3)
Chest radiography 63 (100)
Chest CT scan 4 (6)
Sputum Gene Xpert 1 (2)
PCR 0
PPD 1 (2)
Tissue biopsy 3 (4)
Pleural fluid analysis 1 (2)
Sputum AFB result
Smear negative 60 (95)
Smear positive 3 (5)
TB treatment regimen received
Previous treatment received (40) 5.80 (2.00-16.66) 0.0012
CAT I 40 (63)
CAT II 0
New case, PTB relapse, On-going treatment (15)
CAT I, intensive 10 (16)
CAT I, maintenance 4 (6)
CAT Ia, intensive 0
CAT Ia, maintenance 1 (2)
CAT II, intensive 3 (5)
TB treatment outcome
Previous treatment received (40)
Completed 38 (60)
Defaulted 2 (3)
New case, PTB relapse, On-going treatment (15)
Completed 13 (21)
Defaulted 0
Treatment outcome unknown 1 (2)
On-going 1 (2)
TB, tuberculosis; AFB, acid-fast bacilli; CT, computerized tomography; CAT, category; PTB, pulmonary tuberculosis.

25 Philipp J Chest Dis 2017

 Dadulla and Aquino

concurrently, and two were diagnosed after cancer-
specific therapy. All patients were treated with
anti-TB regimen and all but one completed
therapy.
The most common cancer type in the cohort
was head and neck malignancy (32%); the least
common was gynaecological malignancy (3%)
(Table 4). The common histologic type was
adenocarcinoma (46%) and most patients were in
stage II disease (38%). Eighty-four percent (84%)
of patients underwent surgery coupled with
radiation and/or chemotherapy. Ninety-nine
percent (99%) of the patients completed their
cancer specific therapy. However, two patients
(1%) died prior to completion of cancer-specific
therapy; these patients did not develop TB
infection.
Overall prevalence. The calculated TB
period prevalence from 2011 to 2013 in a
population of 793 newly diagnosed cancer patients

Table 4. Cancer-related factors of included patients

Variable Frequency (%) Odds ratio (95% CI) P value
History of previous cancer diagnosis
Yes 4 (6)
None 59 (94)
Type of Cancer
Breast cancer 5 (8) 0.97 (0.28-3.42) 0.9674
Gastrointestinal malignancy 11 (17) 1.16 (0.37-3.59) 0.7971
Genitourinary malignancy 18 (29) 0.45 (0.10-1.98) 0.2909
Gynaecological malignancy 2 (3) 0.21 (0.01-3.47) 0.2737
Head and neck malignancy 20 (32) 1.13 (0.40-3.21) 0.8196
Hematologic and bone malignancy 3 (5) 2.62 (0.58-11.91) 0.2121
Lung and pleura malignancy 4 (6) 5.96 (1.25-28.41) 0.0252
Histologic type
Adenocarcinoma 29 (46)
Squamous cell carcinoma 13 (21)
Others 21 (33)
Stage of cancer
I 5 (8) 1.75 (0.27-11.46) 0.5595
II 24 (38) 0.65 (0.20-2.10) 0.4698
III 17 (27) 0.70 (0.19-2.54) 0.5913
IV 16 (25) 1.75 (0.52-5.84) 0.3631
Grading 1 (2)
Cancer specific intervention
Chemotherapy 36 (57)
Chronic steroid use 0
Radiation 31 (49)
Surgery 53 (84)
Others: Immunotherapy 4 (6)
Cancer therapy outcome
Completed 61 (99)
Interrupted 2 (1)
Reason for cancer therapy interruption
Drug adverse effects 0
Lost to follow up 0
Death of any cause 2

Vol. 18 | Issue 02 | June 2017 26

 TB in cancer patients
in Veterans Memorial Medical Center was 2.3% or
rate of 6 cases per 1000 person-years. A bigger
study by Kaamboj and Sepkowitz (2006)11 from
1980 to 2004 with 186,843 population of cancer
patients, the computed rate was 55 cases per
100,000 persons. Cancer itself is indeed a risk
factor for the development of active TB.18,19
Demographic analysis. Pertinent demo-
graphic characteristics were noted to have
influenced occurrence of TB infection in cancer
patients. Patients with concomitant COPD had 9
times increased odds for TB infection (OR 9.10;
95% CI 2.61, 31.70; p=0.0005). Chronic illnesses
had long been proven to increase infection risk in
cancer patients.19 Cancer patients with smoking
history of  10 pack had 3 times odds for TB
infection but was not statistically significant and
with wide range of heterogeneity.
Cancer patients with clinical manifestations
like cough, weight loss and anorexia had 5 times
odds for TB infection than those without
pulmonary clinical manifestations (OR 4.92; 95%
CI 1.52, 15.91; p=0.0077). Weight loss and
anorexia were manifestations of the malignancy
itself that it was noted with wide range of
heterogeneity. TB should be included in the
differentials of diagnosis in cancer patients with
pulmonary manifestations during the course of
diagnosis or cancer therapy.
Cancer type and TB infection. The cancer
type also is a risk factor for the development of
active TB that acute and chronic leukemic, solid
organ tumors such as breast, lung, brain,
gastrointestinal tract and genitourinary tract
malignancies are associated with cellular immune
dysfunctions that is why they are predominantly
vulnerable to intracellular pathogens associated
with cell-mediated immunity deficiencies like
Listeria monocytogenes, Salmonella spp.,
Nocardia asteroids, Legionella, Cryptococcus
neoformans, Histoplasma capsulatum, Coccidio-
ides immitis, Pneumocystis jiroveci, Varicella
zoster, Cytomegalovirus, Epstein-Barr virus,
Herpes simplex, adenoviruses, Toxoplasma gondii,
Cryptosporidium, Strongyloides stercoralis and
27
19 Philipp J Chest Dis 2017
mycobacteria including both Mycobacterium
tuberculosis and the non-tuberculous
mycobacteria.19
In this study, among the total number of
lung cancer patients, 12.5% developed TB, being
the highest among other cancer types. Lung cancer
had 6 times odds of TB infection than other cancer
type (OR 5.9; 95% CI 1.25, 28.41; p=0.0252). Six
percent had TB among the hematologic and bone
malignancy patients, 2.8% in patients with head
and neck malignancy, 2.5% in breast cancer
patients, 2% in patients with gastrointestinal
malignancy and 1.3% in genitourinary malignancy
patients. Studies had shown that hematologic
diseases were the most common malignancy
associated with TB infection like Hodgkin’s
lymphoma. 11,18,20 In this study a case of Non-
Hodgkin lymphoma and Ewing sarcoma developed
active TB. Among the solid tumors, lung cancer
was the most common underlying malignancy and
was consistent with the result of this study.11,18,20
History of previous TB infection and TB
reactivation in cancer patients. In this study, of
the 40 patients who had history of previous TB
treatment, 37 patients were ruled out for TB
reactivation and three had TB reactivation. The
mean age was 71  13 years, 75% are males, and
55% had comorbidities of COPD, CKD, diabetes
mellitus and hypertension. Forty percent of
patients had genitourinary malignancy, 35% had
head and neck malignancy, 18% had
gastrointestinal malignancy, 5% had breast cancer
and 2% had hematologic and bone malignancy.
Fifty percent of patients were in the Stage II
disease, 20% were in the Stage III and Stage IV
disease and 10% were in the Stage I disease.
Ninety-five percent of patients completed
treatment of previous TB therapy and 5%
defaulted. Of the 3 patients that were assessed for
TB relapse, two were diagnosed prior to initiation
of cancer specific therapy. One patient was
bacteriologically confirmed and was considered
cured after completing Category II regimen. One
other patient was clinically diagnosed and also
completed category II treatment. The third patient

was assessed to have bacteriologically confirmed
PTB relapse during the duration of cancer-specific
therapy, and was considered cured after
completing Category II regimen.
Cancer patients previously infected by
organisms like M tuberculosis are at increased risk
of TB reactivation. In a case series, most solid
organ malignancy patients had healed scars in their
chest radiographs suggesting previous TB,
regardless of whether they had anti-TB treatment.
The study concluded that the disease was caused
by reactivation of latent TB infection. It was
observed in the same study that patients not
receiving cancer specific therapy were also found
to have healed scars and this reactivation may be
caused by the immunodeficiency effect of the
malignancy itself.22
In this study, history of previous TB
infection poses a 6 times increased odds for TB
reactivation in cancer patients (OR 5.8; 95% CI
2.00, 16.66; p<0.0012). Gastrointestinal
malignancy with previous TB treatment has 39
times odds for TB reactivation than head and neck
malignancies (OR 38.8; 95% CI 4.51, 333.65;
p=0.0009). However, there was a wide range of
heterogeneity which may be influenced by many
other risk factors. The addition of
immunosuppressive therapies should further
increase the risk of reactivation. This could explain
the fate of the patient who developed
bacteriologically confirmed PTB relapse during the
course of cancer specific therapy.
Concurrent TB and cancer diagnosis. In
this study, 67% had TB diagnosis prior to cancer
specific therapies, 5% developed TB during the
duration of cancer-specific therapy and 28%
developed TB after cancer-specific therapy
completion. Of the patients diagnosed with TB
prior to cancer-specific therapies, 83% had the TB
diagnosis concurrent with cancer diagnosis and
17% were TB relapse cases. The common
underlying malignancy were gastrointestinal
(25%), followed by genitourinary (17%), breast
(17%), lung (17%), hematologic malignancy
(17%) and head and neck malignancy (8%).
Dadulla and Aquino
Of the 10 patients with TB treatment or
concurrent TB diagnosis upon cancer diagnosis,
80% in this group were <65 years old, 70% were
males and 60% were associated with hypertension,
diabetes mellitus and COPD. There were two
(20%) cases each of genitourinary malignancy,
breast cancer, lung and pleura malignancy and
hematologic and bone malignancy. There was one
(10%) case each of gastrointestinal malignancy
and head and neck malignancy. There were three
(30%) cases each of Stage II and Stage IV diseases
and two (20%) cases each of Stage I and Stage III
diseases. All were pulmonary TB except for one
with TB of the lymph nodes. Two were
bacteriologically confirmed and the rest were
clinically diagnosed PTB cases. Two were already
in the maintenance phase of TB treatment upon
cancer diagnosis and the rest were in the intensive
phase. All cancer patients on TB treatment or
concurrent TB infection completed their treatment
and the 2 bacteriologically confirmed cases were
declared cured after TB treatment completion.
In a study by Kaplan, Armstrong and
Rosen,20 TB developed during the development of
the neoplasm in patients with lung and head and
neck malignancy as compared to breast and
hematologic malignancies. This was seen in our
present study, and poses a diagnostic dilemma in
lung cancer patients because TB may mimic lung
cancer.
Cancer specific therapy and the risk of
TB infection in cancer patients. In a series study
by Say and Donehan (1974),21 radiation therapy
during the preoperative period increases the risk of
infection of two folds in breast cancer patients
while postoperative irradiation was not associated
with an increased risk. It is theorized that fistula
formation, impaired wound healing, and local
tissue damage are the negative effects of radiation
that predisposes cancer patients to infection and
this phenomenon was well described in rectal
cancer patients receiving radiation therapy.
Chemotherapy predisposes cancer patients
to infection in many ways. It damages anatomical
barriers; it causes bone marrow suppression, neut-
Vol. 18 | Issue 02 | June 2017 28
 TB in cancer patients
ropenia, inhibits bactericidal activity, and alters
humoral immunity.19
In this study, there is an overall 15 times
increased odds for TB infection in cancer patients
who underwent cancer specific therapy
(chemotherapy and/or radiation therapy and/or
immunotherapy) (OR 15; 95% CI 3.10, 77.74;
p=0.0009).
The patient that developed TB infection
during the duration of cancer therapy was a
microbiologically confirmed TB relapse case. The
factor that the patient had history of TB infection
and the addition of immunosuppressive therapy
made him more vulnerable to TB reactivation.
Thirteen patients with no history of previous
PTB treatment were worked up upon cancer
diagnosis as presumptive TB cases prior or during
or post cancer specific therapy. Five patients were
diagnosed and treated for active TB infection after
cancer specific therapy; four were clinically
diagnosed and one was bacteriologically
confirmed. Active TB was ruled out in the eight
other cancer patients.
In this group, 80% were 65 years old, 60%
were males, and 80% were associated with
hypertension and diabetes mellitus. There were
three cases (60%) of head and neck malignancy,
one case of gastrointestinal malignancy and one
case of breast cancer. Two patients were in Stage
IV disease, two in Stage II disease and one in
Stage 3 disease. Three patients were diagnosed to
have TB infection 2 years after completion of
cancer specific therapy, one patient developed TB
after 3 years of completion, and one patient
developed TB just after completion of cancer-
specific therapy.
TB occurring after cancer specific therapy
usually occurs in patients with breast or ovarian
cancer or hematologic malignancy, while TB
occurring during the development of cancer are
lung and head and neck malignany.20 The result of
the study is quite different from generalities for
head and neck tumors and this maybe a venue for
further clinical research.
Mortality rate. There were no reported
deaths among cancer patients with TB in the study
29 Philipp J Chest Dis 2017
period. Two deaths were noted in patients without
TB infection, and these patients were not able to
finish their cancer therapy.
CONCLUSION AND RECOMMENDATION
The overall computed period prevalence of
TB infection in cancer patients was 2.3% or 6
cases per person-years. TB infection developed in
67% of patients prior to cancer-specific therapies,
5% during the duration of cancer-specific therapy
and 28% after cancer-specific therapy completion.
Cancer therapy was associated with an odds ratio
of 15 for TB infection (95% CI 3.10, 77.74;
p=0.0009). Among the different cancer types,
12.5% of TB patients developed in lung cancer
patients (OR 5.96; 95% CI 1.25, 28.41; p=0.0252).
Six percent developed in patients with hematologic
and bone malignancy, 2.8% in those with head and
neck malignancies, 2.5% in breast cancer patients,
2% in patients with gastrointestinal malignancy
and 1.3% in genitourinary malignancy patients.
Factors associated with increased odds of TB
infections include pulmonary manifestations (OR
4.92; 95% CI 1.52, 15.91; p=0.0077) and history
of previous TB infection and treatment (OR 5.80;
95% CI 2.00, 16.66; p<0.0012).
The characteristics of cancer patients with
TB in this study could serve as guide in the risk
stratifications of cancer patients for TB infection.
Patients with lung cancer and hematologic
malignancy, patients with pulmonary symptoms
that may mimic the cancer itself or other bacterial
infections, patients with chronic illness like COPD,
and patients with previous PTB infection should be
screened for concurrent TB infection prior, during
and after cancer specific therapy initiation and
course. Breast, ovarian, hematologic and head and
neck malignancies should be closely monitored for
TB infection along and after the course of cancer
specific therapies. This study therefore concludes
that cancer patients should be carefully assessed
for TB infection before, during and after cancer
specific therapies.
The use of newer diagnostic modalities like
Gene Xpert or interferon-gamma release assays
(IGRA) may have an added value in the evaluation

and monitoring of cancer patients with history of
previous TB treatment, but this needs further
study. The treatment of latent TB in cancer patients
with a previous history of TB infection also
remains unclear. Due to the limitations of
retrospective, single-center studies with limited
number of patients, a prospective multicenter study
is also recommended to fully characterize the TB
risk of cancer patients in the Philippines.
REFERENCES
1. De La Rosa, K., et al. Mycobacterium
tuberculosis at a comprehensive cancer centre:
active disease in patients with underlying
malignancy during 1990-2000. European Society
of Clinical Microbiology and Infectious
Diseases. 2004; 10: 749-772.
2. Ramon AE Jacobs, Ping Gu and Abraham
Chachoua. Reactivation of pulmonary
tuberculosis during cancer treatment. Int J
Mycobacteriol. 2015; 4: 337-340.
3. Libshitz HI et al. Tuberculosis in cancer patients:
an update. J Thoracic Imaging. 1997; 12(1): 41-
6.
4. Hadir A. El-Mahallawy et al. Tuberculosis in
cancer patients: Role of new techniques in
relation to conventional diagnostic methods.
Journal of Advanced Research. 2010.
5. Amupama Dutt Mane et al. Clinical
characteristics and outcome of cancer patients
with tuberculosis. J Clin Oncology. 2015; 33.
6. Manual of Procedures for the National TB
Control Program. 5th Edition. 2013. Department
of Health.
7. ME Falagas et al. Tuberculosis and malignancy.
Quarterly J Med. 2010; 103: 461-487.
8. Luis Anibarro and Alberto Pena. Tuberculosis in
patients with hematologic malignancies.
Mediterranean J Hematol Infect Dis. 2014; 6(1).
9. Silva FA et al. Risk factors for and attributable
mortality from tuberculosis in patients with
hematologic malignancies. Haematologica. 2005;
90:1110-5.
10. Chen CY et al. Clinical characteristics and
outcomes of Mycobacterium tuberculosis disease
in adult patients with haematological malig-
nancies. BMC Infect Dis 2011; 11:324.
Dadulla and Aquino
11. Mini Kamboj and Kent A Sepkowitz. The risk of
tuberculosis in patients with cancer. Clinical
Infectious Disease. 2006; 42: 1592-5.
12. Antonis Christopoulos et al. Epidemiology of
active tuberculosis in lung cancer patients: a
systematic review. Clin Respir J 2014;8:375-381.
13. Lonnroth K et al. Systematic screening for active
tuberculosis: rationale, definitions and key
considerations. Int J Tuberc Lung Dis. 2013;
17(3):289-98.
14. Canadian Tuberculosis Standards. 7th edition.
Quebec: Public Health Agency of Canada; 2013.
15. NICE Clinical Guidelines CG117. London:
NICE; March 2011.
16. Barbara Rybacka-Chabros, Beata Gryglicka and
Janusz Milanowski. Coexistennce of lung cancer
and active pulmonary tuberculosis. 2013.
National Cancer Research Institutute.
17. Chia-Jen Liu et al. Risk and impact of
tuberculoiss in patients with chronic myeloid
leukemia: A nationwide population-based study
in Taiwan. International Journal of Cancer. 2015:
136; 1881-1887.
18. Fujita T, et al. Mycobacterium tuberculosis
infection in cancer patients at a tertiary care
center in Japan. J Infect Chemother. 2013: 1-4.
19. Teresa R. Zembower. Epidemiology of infections
in cancer patients. Cancer Treatment and
Research 2014; 161:43-89.
20. Kaplan M, Armstrong D, Rosen P. Tuberculosis
complicating neoplastic disease. A review of 201
cases. Cancer. 1974;3:850-858.
21. Say CC, Donegan W. A biostatistical evaluation
of complications from mastectomy. Surg Gynecol
Obstet 1974;138(3):370–376.
22. Kim HR, et al. Solid-organ malignancy as a risk
factor for tuberculosis. Respirology 2008; 13:
413-419.
Vol. 18 | Issue 02 | June 2017 30
 Predictors of pneumonia in patients with cough

CROSS-SECTIONAL STUDY

Prediction of Pneumonia Based on Signs and Symptoms in Patients

Presenting with Cough at the Veterans Memorial Medical Center
Marco Gil S. Veracruz, MD, FPCP, Arnold G. Germar, MD, FPCP, FPCCP
Department of Internal Medicine, Section of Pulmonary Disease, Veterans Memorial Medical
Center, North Avenue, Diliman, Quezon City

ABSTRACT
Objective: This study aims to identify the association between pneumonia’s signs and symptoms
and its radiographic findings among patients with cough.

Method: All adult patients (18 years old and above) who consented for the study; coming from the
outpatient department, Medical Ambulatory Care Clinic, and emergency room of the Veterans
Memorial Medical Center from 2013 to 2014; complaining of cough were interviewed by their
attending physicians who utilized the standardized history and physical examination checklist. All
patients underwent chest radiography, posteroanterior view.

Results: Gender distributions were the same among the patients with and without pneumonia.
Most of the patients with pneumonia were around the ages of 50 to 69. Among the symptoms,
sputum production obtained the highest sensitivity (89%) and bloody sputum obtained the highest
specificity (100%). Rhinorrhea and sore throat turned out to be negative predictors of pneumonia.
Among the different physical examination findings, rales showed the highest sensitivity (75%) and
local dullness had the highest specificity (97%). A pulse rate >100 beats per minute, a respiratory
rate >25 cycles per minute, or a temperature >37.8°C were also associated with an increased
probability of pneumonia.

Conclusion: Chest radiography should not be requested for all patients presenting with cough. It
should be reserved for patients with signs and symptoms associated with a high probability of
pneumonia.

INTRODUCTION must rely on the patient's medical history and

A 2010 report from the US Centers for
Disease Control and Prevention states that the
third most common reason for physician visits is
cough.1 Among the distinguishable diseases that
present with acute cough, pneumonia represents
5% of consultations, and it is the fifth most
common diagnosis following bronchitis, upper
respiratory tract infection, asthma, and sinusitis.2
Pneumonia entails a specific course of treatment
and follow-up, unlike other types of acute
respiratory infections, which only require
expectant management. Primary care physicians
physical examination, with or without a radiologic
evaluation, to diagnose pneumonia.
Accurate diagnosis of pneumonia in primary
care is difficult because it is not feasible to obtain
chest radiographs from all patients with lower
respiratory tract infection. The British Thoracic
Society guidelines discourage performing a chest
radiograph on every patient presenting with cough,
because the cost of the procedure can be high and
patients may be exposed to unnecessary
radiation.3,4
The physician’s concern about the possibili-

31 Philipp J Chest Dis 2017


ty of pneumonia (ie, the presence of acute
infiltrate on chest radiographs) appears to be the
chief reason for obtaining chest radiography and
prescribing unnecessary antibacterial drugs that
cause the worldwide problem of antibiotic
resistance.5
A disease-specific checklist that measures
the probability of pneumonia may facilitate the
diagnosis and treatment of such patients.
This paper aims to determine—through the
combination of symptoms, patient history,
physical examination results, and radiologic
evidence—the statistical likelihood of diagnosing
pneumonia in patients who present with acute
cough. We sought to identify the correlation
between symptoms in a patient presenting with
acute cough and findings of pneumonia on chest
radiography.
METHODOLOGY
This is a cross-sectional study that included
all adult patients (18 years old and above) who
came from December 2013 to December 2014 to
the Veterans Memorial Medical Center outpatient
department, MACC, and emergency room with a
cough less than 2 weeks in duration and who
consented to participate the study. Patients with a
pulse rate ≥160 bpm, a temperature ≥40 °C, or a
systolic blood pressure <90 mmHg were excluded
from the study.
Patients were interviewed by the attending
physician using the standardized history and
physical examination checklist (Appendix A). All
patients underwent chest radiography, postero-
anterior view.
Radiology residents or staff radiologist
consultants who interpreted the chest radiographs
were not allowed any access to the patients’
history except for history of cough less than 2
weeks in duration.
The principal investigator secured the
patients’ accomplished forms and correlated the
findings with the chest radiography results (as
Veracruz and Germar
interpreted by the radiologist for the confirmation
of presence or absence of pneumonia). Data used
for statistical analysis were descriptive (ie,
frequency, proportion, sensitivity, and specificity)
as well as inferential (ie, logistic regression).
We used Power Analysis and Sample Size
(PASS) 2008 software to compute the minimum
sample size requirement with the following
parameters for logistic regression analysis: alpha
(α)=0.05, power (1-β)=80%, P0 (percent of
pneumonia among patients without
tachypnea)=0.26, and P1 (percent of pneumonia
among patients with tachypnea)=0.02. Except for
alpha and power levels, which were set by the
researchers, all the parameters were taken from
literature. The computed 161 minimum sample
size was increased to 194 to account for a possible
20% nonresponse.
RESULTS AND DISCUSSION
Gender distribution overall was 48% for
males and 52% for females. Among patients
without pneumonia, the gender distribution was
54% male and 46% female. In terms of age, the
average for patients with pneumonia was 68 years
old; for those without pneumonia, 65 years old.
Most of the patients were within the age bracket of
50 to 69; specifically, 55% of those with
pneumonia and 63% of those without pneumonia
63% fell within this age group (Table 1).
Among the different symptoms that were
presented, sputum production obtained the highest
sensitivity (89%), while sore throats and night
sweats turned out to be the least sensitive. Bloody
sputum obtained the highest specificity scores of
100%, while sputum production and chronic cough
has the lowest of specificity of 57% (Table 2).
Only the following symptoms significantly
affected the presence or absence of pneumonia:
rhinorrhea (p<0.001), sore throat (p<0.001),
sputum production (p<0.001), and fever (p<0.001).
The relative risks of rhinorrhea and sore throat
were both <1. This suggests that the presence of
Vol. 18 | Issue 02 | June 2017 32
 Predictors of pneumonia in patients with cough

rhinorrhea or sore throat is a negative predictor for significantly affected the presence or absence of
pneumonia. However, as indicated by these pneumonia: pulse rate >100 bpm (p<0.001),
factors’ low sensitivities, very few patients had respiratory rate >25 cpm (p<0.001), temperature
findings with these two factors, suggesting that this >37.8°C (<0.001), rales (<0.001), and local
may be a chance result. On the other hand, the dullness (p=0.02). The relative risk of all these 4
resulting relative risks >1 for sputum production significant factors exceeds 1. This denotes that
and fever suggest that the presence of these presence of any of them increases the probability
symptoms increase the probability pneumonia. of pneumonia (Table 3).
Results also showed that the other acceptable When a patient presents with cough
predictors of pneumonia were not significantly associated with fever and sputum production
related to the occurrence of pneumonia. together with clinical findings of tachycardia,
Among the different physical examination tachypnea, and rales, the probability of
findings, rales obtained the highest sensitivity diagnosing pneumonia is high. In this study,
(75%), while cachexia turned out to be the least however, 45% of our 161 patients with cough did
sensitive (1%). Local dullness obtained the highest not have pneumonia, and we found that those
specificity score (97%) while temperature, rales, with rhinorrhea and sore throat were less likely to
and rhonchi had the lowest (86%). have the disease. Differential diagnosis can save
Among the different possible clinical patients from unnecessary exposure to radiation,
findings, results showed that only the following as well as reduce healthcare costs that come from
the prescription of empiric antibacterial
Table 3. Physical Examination Findings Associated treatments given for pneumonia.
with Pneumonia One limitation of this study is that it
observed mostly elderly patients, many of whom
Without
With had comorbidities that may have predisposed
Pneumonia
Pneumonia them to pneumonia. These comorbidities include
(%)
(%) n=92
n=69 chronic obstructive pulmonary disease, which
Sex were not among the parameters we analyzed.
Furthermore, the association between signs and
Male 44 (48) 37 (55)
symptoms and atypical pneumonia were not
Female 48 (52) 32 (46) included in this data analysis; these can be
Age (years)
included in a future study.
Based on our observations, we recommend
Mean, SD 67.9 (14) 64.9 (14) that chest radiography be reserved for patients
13–19 0 0 with cough associated with signs and symptoms
that seem to be significant predictors for the
20–29 0 0
occurrence of pneumonia. It is for this group,
30–39 1 (1) 1 (1) too, that more aggressive management, such as
40–49 5 (5) 5 (7) (empirical) antibiotic treatment for pneumonia,
should be considered.
50–59 24 (26) 20 (29)

60–69 27 (29) 24 (35) CONCLUSION

70–79 10 (11) 5 (7) Chest radiography should not be requested
for all patients presenting with cough. It should
≥80 25 (27) 14 (20)
be reserved for patients with signs and symptoms

33 Philipp J Chest Dis 2017

 Veracruz and Germar

associated with a high probability of pneumonia. tion and clinical findings of tachycardia,
These include those with fever and sputum produc- tachypnea and rales.

Table 2. History Findings Associated with Pneumonia

History Findings Sensitivity Specificity Relative Risk P-value

Chronic cough 53.26 56.52 1.18 0.219

Pleuritic chest pain 11.96 95.65 1.43 0.076

Night sweats 2.17 92.75 0.49 0.121

Rhinorrhea 5.43 65.22 0.26 <0.001

Sore throat 2.17 72.46 0.15 <0.001

Sputum production 89.13 56.52 3.59 <0.001

Smoker 29.35 75.36 1.10 0.507

Chills 3.26 89.86 0.51 0.073

Alcoholic 8.70 92.75 1.08 0.738

Bloody sputum 3.26 100.00 1.78 0.488

Fever 51.09 76.81 1.62 <0.001

Table 3. Physical Examination Findings Associated with Pneumonia

Physical Findings Sensitivity Specificity Relative Risk P-value

Pulse rate >100 22.83 95.65 1.69 <0.001

Respiratory rate > 25 51.09 88.41 2.01 <0.001

Temperature >37.8°C 54.35 85.51 2.00 <0.001

Local dullness 13.04 97.10 1.58 0.020

Rales 75.00 85.51 3.11 <0.001

Asymmetric
2.17 94.20 0.57 0.217
respiration

Cachexia 1.09 92.75 0.28 0.052

Rhonchi 9.78 85.51 0.81 0.250

Vol. 18 | Issue 02 | June 2017 34

 Predictors of pneumonia in patients with cough

REFERENCES
1. Center for Diseases Control and Prevention.
National ambulatory medical care survey:
2010 summary tables. Available at:
https://www.cdc.gov/nchs/data/ahcd/namcs_s
ummary/2010_namcs_web_tables.pdf.
2. Metlay JP, Kapoor WN, Fine MJ. Does this
patient have community-acquired pneumonia?
Diagnosing pneumonia by history and
physical examination. JAMA.
1997;278(17):1440–5.
3. Paula Diehr, Robert Wood, James Bushyhead.
Prediction of pneumonia in outpatients with
acute cough—a statistical approach. J Chronic
Dis. 1984;37(3):215–25.
4. Lim WS, Baudouin SV, George RC, et al.
British Thoracic Society guidelines for the
management of community acquired
pneumonia in adults: update 2009. Thorax.
2009;64(Suppl 3):iii1–55.
5. Costelloe C, Metcalfe C, Lovering A, et al.
Effect of antibiotic prescribing in primary care
on antimicrobial resistance in individual
patients: systematic review and meta-analysis.
BMJ. 2010;340:c2096.

35 Philipp J Chest Dis 2017

 Pasanting-Lim

PROSPECTIVE COHORT STUDY

A Retrospective Study Comparing Young and Old

Patients Diagnosed with Primary Lung Cancer
Rossini Abbie Pasanting-Lim, MD
Chong Hua Hospital, Cebu City

ABSTRACT
Background: Lung cancer is the second most common cause of cancer-related deaths in the
Philippines. While lung cancer is predominantly a disease of the elderly, an increasing trend among
young patients has been reported. Nevertheless, local data comparing the characteristics of young
and old lung cancer patients are sparse. This study aims to determine whether the demographic
and clinicopathologic characteristics of Filipino lung cancer patients <50 years old differ from those
of older patients.

Methodology: This retrospective study includes all patients admitted at a tertiary hospital, from
January 2011 to December 2013, with a histologic or cytologic diagnosis of primary lung cancer.
The participants, identified by chart review, were grouped into young (<50 years old) and old (≥50
years old). Demographic and clinicopathologic data were obtained. Comparisons were made using
the chi-squared test.

Results: Two hundred fifty-one patients had a diagnosis of primary lung cancer. Twenty-eight
(11%) patients were <50 years old, with a median age of 44; 223 (89%) were ≥50 years old, with a
median age of 65. The gender (p=0.336) and smoking habits (p=0.310) of the 2 groups did not
significantly differ. Coughing was the most frequent initial symptom, and majority of the patients
(69%) were at stage 4 at the time of diagnosis. Adenocarcinoma was the most common histologic
type observed in both groups. The overall 1-year survival rate was 79%. No significant differences
appeared in clinicopathologic characteristics between the young and old patient groups.

Conclusion: While lung cancer patients in the young group were mostly females, nonsmokers, with
advanced-stage adenocarcinoma, and presented with cough and upper lobe lesions, their profile,
including treatment modalities and survival, did not differ significantly from the older group.

INTRODUCTION
Lung cancer is a modern-day disease
afflicting a steady number of men and women
worldwide since the turn of the twentieth
century. Today, it has become the second most
commonly diagnosed cancer for both sexes and
the most common cause of cancer death. It is
projected to claim 1.67 million lives by year
2015 and 2.2 million by the year 2030.1,2 In the
Philippines, the age-standardized incidence and
mortality rates for the world population of lung
cancer are 50.2 and 46.4, respectively, per
100,000 males; 13.2 and 12.6, respectively, per
100,000 females.3
Predominantly considered as a disease of
the elderly (with median age-at-diagnosis of 70
years old), lung cancer is rare among young
adults. It has a reported incidence of 1.2% to
6.2% for those under 40 years,4,5 5.3% for those
under 45 years,6 and 13.4% for those under 50
years old.7 However, other studies have shown

Vol. 18 | Issue 02 | June 2017 36

 Primary lung cancer: young vs old patients

trends of increasing incidence rates among young
patients.8,9 Recent studies suggest that younger
patients with lung cancer are often female
nonsmokers who (1) present with advanced-stage
disease that is predominantly adenocarcinoma, (2)
are more likely to receive aggressive treatment,
and (3) have survival rates similar to older
patients.10,11,12 However, other reports have shown
different results with regard to responses to
treatment. Also, survival rates vary depending on
the regions the studies were made and the
ethnicities of the patients involved.13
This study aims to describe the clinical
characteristics of young and old lung cancer
patients admitted at a tertiary hospital. The results
of this study could establish baseline local clinical
data that would improve our understanding of the
Filipino lung cancer patient.
METHODS
This retrospective study covering the period
of January 2011 to December 2013 was conducted
in a 660-bed privately owned tertiary care facility.
It included all Filipino patients admitted into the
hospital with a diagnosis of primary lung cancer
based on (1) histologic examination of surgical or
biopsy specimens or (2) cytologic examination of
bronchial washing or brushing, lymph node
aspiration, or pleural effusion. Non-Filipino
patients and patients whose clinical diagnosis of
lung cancer was not proven by histologic or
cytologic examinations were excluded.
Patients with a diagnosis of primary lung
cancer, lung mass, or malignant pleural effusion
were identified from charts in the Medical Records
section using the International Classification of
Diseases version 10 coding system. Patients <50
years old were classified as “young,” while those
≥50 years old were classified as “old.” Clinical
data—including age, gender, smoking habits,
comorbid illnesses, family history of cancer,
presenting symptoms, radiologic findings,
cytologic or histologic diagnosis, treatment
modalities and 1-year survival—were recorded.
For categorizing according to smoking
habits, current smokers were defined as patients
who reported smoking ≥100 cigarettes in their
lifetime and who, at the time of admission,
smoked either every day or some days; former
smokers were those who reported smoking ≥100
cigarettes in their lifetime but did not smoke at
time of admission; and never smokers were those
who reported smoking <100 cigarettes in their
entire lifetime.14
Data were recorded using Microsoft Excel
and analyzed using MedCalc statistical software.
Qualitative variables were summarized as
proportions. A 2-tailed chi-squared test
determined whether there was significant
difference between the 2 groups. P-value ≤0.05
was deemed statistically significant.
RESULTS
Review of charts at the Medical Records
section generated 326 patient charts that
contained diagnoses of lung cancer, lung mass,
and malignant pleural effusion. After applying
the criteria for inclusion and exclusion, 75 charts
were excluded and 251 were included in the
study (Figure 1).
Figure 1. Flowchart of included and excluded
patients

37 Philipp J Chest Dis 2017

 Pasanting-Lim

The 251 included patients represented a 3%
incidence of lung cancer among admitted patients.
Twenty-eight patients (11% of cohort) were <50
years old, and 17 (61%) of this subcohort were
females (Table 1). Two hundred twenty-three
(89%) patients were ≥50 years old; this group was
predominantly male. The young group had a
median age of 44, while the old group had a
median age of 65.
One hundred thirty-seven (55%) of the lung
cancer patients were never smokers. The
differences in gender and smoking habits between
the two groups were not statistically significant
(Table 1).
Hypertension was the most common
comorbid condition identified in each group. Six
patients in the old group (3%) and 1 in the young
group (4%) had a prior history of cancer
elsewhere. A family history of gastrointestinal
cancer was identified in 17 (7%) of all included
patients, while lung cancer was identified in only
5 (2%). Most of the patients (87%) did not have a
family history of cancer (Table 1).
Adenocarcinoma was identified in 130 pat-

Table 1. Clinical and demographic profile of included patients

Young (<50 years) Old (>50 years) P-value

No. of patients 28 (11%) 223 (89%)
Median age, y (range) 44 (31–49) 65 (50–98)
Gender 0.336
Male 11 (39%) 125 (56%)
Female 17 (61%) 98 (44%)
Smoking status 0.310
Current 8 (28.6%) 97 (43.5%)
Former 1 (3.6%) 8 (3.6%)
Never 19 (67.8%) 118 (52.9%)
Comorbidities 0.382
Hypertension 9 (32.1%) 107 (48.0%)
Diabetes mellitus 2 (7.1%) 60 (26.9%)
Asthma 3 (10.7%) 17 (7.6%)
COPD 0 12 (5.4%)
Pulmonary TB 2 (7.1%) 15 (6.7%)
Cancer 1 (3.6%) 6 (2.7%)
Family history of cancer 0.196
Lung 2 (7.1%) 3 (1.3%)
Gastrointestinal 1 (3.6%) 16 (7.2%)
Breast 1 (3.6%) 10 (4.5%)
Genitourinary 1 (3.6%) 2
Hematologic 1 (3.6%) 1 (0.4%)
Thyroid 1 (3.6%) 1 (0.4%)
None 25 (89.3%) 194 (87.0%)

Vol. 18 | Issue 02 | June 2017 38

 Primary lung cancer: young vs old patients
Figure 2. Histologic type of lung cancer (%)
AdenoCA
Squamous cell
Large cell
Small cell
Undiff NSCLC
Others
0% 20% 40% 60% 80%
Old Young
ients (52%) and was the most common histologic
type of lung cancer in both the young and old
groups. It was followed by undifferentiated non–
small cell lung cancer (NSCLC), found in 64
(25%) patients (Figure 2). Of those with NSCLC,
174 (75%) were at stage 4 upon diagnosis.
Sixteen (70%) of those with small cell lung
cancer presented with extensive disease (Table
2).
The three most common symptoms at time
of diagnosis for both age groups were cough,
dyspnea, and back pain. Younger patients did not
present with hemoptysis, lymphadenopathy, body
malaise, or weight loss. Radiologic findings
showed that the upper lobe was the most common
location of primary lesions in both age groups
(Table 2).
Patients with metastatic disease mostly had
involvement of one metastatic site at the time of
diagnosis. The three most common sites for
metastases were the pleura, bone, and lymph
nodes (Table 3).
One hundred thirty-three (53%) patients
did not undergo treatment at the time of
diagnosis. Most of those who underwent single-
treatment modality were subjected to
chemotherapy. There was no significant
difference between the 2 groups in terms of initial
treatment approach (Table 4).
One hundred ninety eight (79%) patients
39 Philipp J Chest Dis 2017
were alive one year after the diagnosis of lung
cancer. The 1-year survival rate for patients
diagnosed with small cell lung cancer was 100%
(Table 5).
DISCUSSION
This study showed a 3% incidence of lung
cancer among admitted patients at our institution.
Eleven percent of those with the disease were
<50 years old at the time of diagnosis. Lung
cancer in the young is considered rare, with
incidence rates ranging from 1% to 12%, as in
this study.4,5,15,16,17,18 Other reports, however,
have shown increasing incidence trends.8,9,19 It is
difficult to make interstudy comparisons because
there is no definite age cutoff to define young
patients: some investigators set the cutoff at <40
years old,4,5 while others set it as <45 years old or
<50 years old. 6,7,13,20-23 Since the incidence of
lung cancer has been shown to increase rapidly
after 50 years of age, we used 50 years as cutoff
age in our study.24
The Surveillance, Epidemiology, and End-
Results (SEER) Cancer Statistics Review shows
that the median age for the diagnosis of cancers
of the lung and bronchus is 70 years.24 In this
paper, the young group had a median age of 44,
while the old group had a median age of 65. A
similar pattern was noted in the study of Gadgeel
et al.23
Females dominated the young group, while
56% of the old group were males. This is
comparable to other studies, which observed a
higher female-to-male ratio in younger lung
cancer patients, thus suggesting a probable higher
susceptibility to lung carcinogens among
women.4,6,25
The association between cigarette smoking
and the development of lung cancer has long
been established. While the predominant cause of
this disease is now known, other factors that may
independently or synergistically increase risk—
such as air pollutants, human occupational
causes, micronutrients in the diet, and
preexisting lung disease (eg, tuberculosis)—are
 Pasanting-Lim

Table 2. Cancer-related baseline characteristics (time of diagnosis)

Variable Young (<50 years) Old (>50 years) P-value

Disease stage
Non-small cell lung cancer 0.617
1 0 7 (3.1%)
2 0 1 (0.4%)
3 3 (10.7%) 47 (21.1%)
4 25 (89.3%) 149 (66.8%)
Small cell lung cancer 0.296
Limited 0 7 (3.1%)
Extensive 0 16 (7.2%)
Presenting symptom 0.795
Cough 18 (64.3%) 131 (58.7%)
Dyspnea 4 (14.3%) 44 (19.7%)
Back pain 5 (17.9%) 27 (12.1%)
Neurologic 1 (3.6%) 15 (6.7%)
Hemoptysis 0 14 (6.3%)
Body malaise 0 5 (2.2%)
Weight loss 0 5 (2.2%)
Lymphadenopathy 0 3 (1.3%)
Superior vena cava syndrome 0 1 (0.4%)
Asymptomatic 1 (3.6%) 11 (4.9%)
Radiologic finding 0.651
Upper lobe 8 (28.6%) 78 (35.0%)
Lower lobe 7 (25%) 56 (25.1%)
Right middle lobe 3 (10.7%) 31 (13.9%)
Hilar 5 (17.9%) 38 (17.0%)
Massive effusion 5 (17.9%) 20 (9.0%)

also being investigated.26 play in the development of the disease.

A case control study in the Philippines by
Ngelangel et al associated lung cancer with
smoking and a positive family history of lung
cancer.27 Interestingly, in this study, only 5
patients had a positive family history of lung
cancer, and 137 (55%) patients were never
smokers. These findings suggest that other
environmental and genetic factors may be at
Adenocarcinoma is the most common
histologic type of lung cancer worldwide.24 Data
also show that it is the most common subtype
found among younger patients.10-13,28 This study
found adenocarcinoma to be the most
predominant subtype in both groups. Although
the incidences of each histologic type do not
significantly differ between the young and old

Vol. 18 | Issue 02 | June 2017 40

 Primary lung cancer: young vs old patients

Table 3. Metastatic sites

Variable Young (<50 years) Old (>50 years) P-value

No. of sites 0.127
1 20 (71.4%) 141 (63.2%)
2 5 (17.9%) 34 (15.2%)
>2 3 (10.7%) 5 (2.2%)

Specific sites 0.671

Pleura (effusion) 12 (42.9%) 64 (28.7%)
Bone 8 (28.6%) 53 (23.8%)
Lymph nodes 14 (50%) 46 (20.6%)
Brain 6 (21.4%) 26 (11.7%)
Lung (nodules) 5 (17.9%) 11 (4.9%)
Liver 1 (3.6%) 11 (4.9%)
Adrenal 2 (7.1%) 9 (4.0%)
Pancreas 0 1 (0.4%)
Peritoneum 0 1 (0.4%)
Spinal cord 0 2 (0.9%)

Table 4. Treatment strategy

Treatment Young (<50 years) Old (>50 years) P-value

Single 0.244
Surgery 1 (3.6%) 16 (7.2%)
Chemotherapy 11 (39.3%) 49 (22.0%)
Radiotherapy 1 (3.6%) 16 (7.2%)

Combined 3 (10.7%) 21 (9.4%) 0.514

None 12 (42.9%) 121 (54.3%)

Table 5. One-year survival

Variable Young (<50 years) Old (>50 years) P-value

Overall 24 (85.7%) 174 (78.0%) 0.464

By stage 0.415

Non-small cell 0.234

1 - 5 (2.2%)
2 - 1 (0.4%)
3 3 (10.7%) 38 (17.0%)
4 21 (75%) 113 (50.7%)

Small cell
Limited - 6 (2.7%)
Extensive - 11 (4.9%)

By cell type
NSCLC 24 (85.7%) 157 (70.4%)
Small cell - 17 (7.6%)

41 Philipp J Chest Dis 2017


patient groups, large cell and small cell cancer
were not found to occur in the young group in this
small study.
Symptoms associated with lung cancer are
usually nonspecific and occur late. As a result,
majority of patients are diagnosed during the
advanced stage of the disease. In the United States,
for instance, only 16% of patients have localized
disease at the time of diagnosis.24 In this study, 174
(75%) patients with NSCLC were at stage 4 by the
time their cancer was diagnosed, while 16 (70%)
of those with small cell lung cancer presented with
extensive disease. No significant difference in
terms of staging was noted between the 2 groups,
in contrast to the claims of several reports that
younger patients present with more advanced
disease than older patients.13,18,29,30
Most of those with metastatic disease had
involvement of 1 metastatic site at the time of
diagnosis. The 3 most common sites for metastases
were the pleura, bone, and lymph nodes.
Patients commonly presented with cough,
dyspnea, and back pain in both groups.
Hemoptysis, weight loss, and body malaise were
not noted in the young patients on presentation. A
number of older patients were also noted to be
asymptomatic at the time of diagnosis. This is
similar to the findings of Bourke et al, who noted
that younger patients had less hemoptysis and
fewer of them were asymptomatic upon
presentation. However, Bourke et al observed that
younger patients had higher incidences of chest
and shoulder pain, fever, and neurologic
symptoms.13
Lung cancer occurs most frequently in the
upper lobes,31 and radiologic findings reveal that
the upper zone is the most involved area, followed
by the middle lobe, and then the lower lobes.
Lower lobe lesions were more frequently noted
among younger patients.13 In this study, the
primary tumor was most commonly observed in
the upper lobe, followed by the lower lobe, and
then the right middle lobe in both age groups.
Data from the SEER registry and other prev-
Pasanting-Lim
ious studies have shown that younger patients
with lung cancer were more likely than older
patients to receive anticancer treatment,
including combined-modality therapy. In
addition, despite presenting with more advanced-
stage disease, younger patients were more likely
to undergo cancer-directed surgery.13,23,24 These,
however, were not noted in this study as we
found no significant difference between the old
and young patient groups in terms of initial
treatment approach. This study also showed that
133 (53%) of the patients did not undergo
treatment at the time of diagnosis, while most of
those who underwent single-treatment modality
were subjected to chemotherapy. This is in
conjunction with the finding of a high percentage
of patients presenting with stage 4 upon
admission.
The 1-year relative survival rate for lung
cancer is currently estimated at 44%, which is
higher than the 37% of 1975–1979, perhaps
largely due to improvements in surgical
techniques and combined therapies. However,
the 5-year survival rate for all stages combined is
only 16%. The 5-year survival for small cell lung
cancer (6%) is lower than that for NSCLC
(18%).2
In this study, 194 (79%) of all patients
were alive 1 year after the diagnosis was made,
and patients with small cell lung cancer had a
100% 1-year survival rate. Other studies have
shown varying survival rates according to tumour
histology,2 which was not made in this study.
In summary, lung cancer still remains a
significant global health burden, accounting for
the most number of cancer-related deaths. Most
epidemiologic studies have shown that although
lung cancer is predominantly a disease of the
elderly, younger patients may also be affected.
Reports show that patients aged <50 years old
are more commonly female, nonsmokers; they
more often have adenocarcinoma than squamous
cell carcinoma, present with advanced disease,
and have better or similar overall survival rates
Vol. 18 | Issue 02 | June 2017 42
 Primary lung cancer: young vs old patients
when compared with older patients.10,11,12,23 In this
study, patients in the young group were mostly
females, nonsmokers, with advanced-stage
adenocarcinoma, and presented with cough and
upper lobe lesions. However, the characteristics of
this group—including treatment modalities and
survival—did not differ significantly from the
older group.
This being a retrospective study, one must
take into account the limitations inherent to the
study design when interpreting the findings. The
results reported here should be validated using a
prospective study design.
CONCLUSION
The incidence of lung cancer among
admitted patients in a tertiary hospital was 3%.
Eleven percent of the patients were <50 years old.
Females dominated the young group, while more
males were noted in the older group. Most of the
patients were nonsmokers; presented with cough,
dyspnea, and back pain; and had a primary tumor
located in the upper lung zone on radiologic
imaging. Adenocarcinoma was the most common
histologic type observed in both groups. Seventy-
five percent of the patients had advanced-stage
disease, often with metastatic lesions to the pleura,
bone, and lymph nodes. Most of the patients did
not undergo treatment at the time of admission.
The 1-year relative survival rate was 79%.
REFERENCES
1. World Health Organization. Projections of
mortality and burden of disease, 2002–2030.
http://www.who.int/healthinfo/global_burden_
disease/projections2002/en/. Accessed on
September 18, 2013.
2. American Cancer Society. Cancer Facts &
Figures 2013. Atlanta: American Cancer
Society; 2013.
3. Medina V, Laudico A, Redaniel MTM, et al.
Incidence trends 1980–2002. In: Cancer in the
Philippines, vol. IV, part 2. Manila: Philippine
Cancer Society; 2011.
43 Philipp J Chest Dis 2017
4. Subramanian J, Morgensztern D, Goodgame
B, et al. Distinctive characteristics of non-
small cell lung cancer (NSCLC) in
the young: a surveillance, epidemiology, and
end results (SEER) analysis. J Thorac Oncol.
2010;5(1):23–8.
5. Liam CK, Lim KH, Wong CM. Lung cancer
in patients younger than 40 years in a
multiracial Asian country. Respirology.
2000;5(4):355–61.
6. Zhang J, Chen SF, Zhen Y, Xiang J, Wu C,
Bao P, Luketich J, Hu H, Zhou X, Yao S, et
al: Multicenter analysis of lung cancer
patients younger than 45 years in Shanghai.
Cancer. 2010;116(15):3656–62.
7. Ak G, Metintas M, Metintas S, Yildirim H,
Erginel S, Alatas F. Lung cancer in
individuals less than 50 years of age. Lung.
2007;185(5):279–86.
8. Strand TE, Malayeri C, Eskonsipo PK,
Grimsrud TK, Norstein J, Grotmol T.
Adolescent smoking and trends in lung
cancer incidence among young adults in
Norway 1954–1998. Cancer Causes Control.
2004;15(1):27–33.
9. Marugame T, Yoshimi I, Kamo K, et al.
Trends in lung cancer mortality among
young adults in Japan. Jpn J Clin Oncol.
2005;35(4):177–80.
10. Chen KY, Chang CH, Yu CJ, Kuo SH, Yang
PC. Distribution according to histologic type
and outcome by gender and age group in
Taiwanese patients with lung carcinoma.
Cancer. 2005;103(12):2566–74.
11. Capewell S, Wathen CG, Sankaran R,
Sudlow MF. Lung cancer in young patients.
Respir Med. 1992;86(6):499–502.
12. Skarin AT, Herbst RS, Leong TL, Bailey A,
Sugarbaker D. Lung cancer in patients under
age 40. Lung Cancer. 2001;32(3):255–64.
13. Bourke W, Milstein D, Giura R, et al. Lung
cancer in young adults. Chest.
1992;102(6):1723–9.

14. Centers for Disease Control and Prevention.
State-specific secondhand smoke exposure and
current cigarette smoking among adults –
United States, 2008. MMWR Morb Mortal
Wkly Rep. 2009;58(44):1232–5.
15. Schottenfeld D. Epidemiology of lung cancer.
In: Pass HI, Mitchell JB, Johnson DH, et al
(Eds). Lung Cancer: Principles and Practice.
Philadelphia, PA: Lippincott-Raven,
1996;305–21.
16. Jung KW, Park S, Kong HJ, et al. Cancer
statistics in Korea: incidence, mortality and
survival in 2006–2007. J Korean Med Sci.
2010;25(8):1113–21.
17. Liu NS, Spitz MR, Kemp BL, et al.
Adenocarcinoma of the lung in young patients.
Cancer. 2000;88(8):1837–41.
18. Green LS, Fortoul TI, Ponciano G, et al.
Bronchogenic cancer in patients under 40
years old. The experience of a Latin American
country. Chest. 1993;104(5):1477–81.
19. Kim L, Kim KH, Yoon YH, et al.
Clinicopathologic and molecular
characteristics of lung adenocarcinoma arising
in young patients. J Korean Med Sci.
2012;27(9):1027–36.
20. Roviaro GC, Varoli F, Zannini P, Fascianella
A, Pezzuoli G. Lung cancer in the young.
Chest. 1985;87(4):456–9.
21. Kyriakos M, Webber B. Cancer of the lung in
young men. J Thorac Cardiovasc Surg.
1974;67(4):634–48.
22. Kreuzer M, Kreienbrock L, Gerken M, et al.
Risk factors for lung cancer in young adults.
Am J Epidemiol. 1998;147(11):1028–37.
23. Gadgeel S, Ramalingam S, Cummings G, et al.
Lung cancer in patients < 50 years of age: the
experience of an academic multidisciplinary
program. Chest. 1999;115(5):1232–6.
Pasanting-Lim
24. Howlader N, Noone AM, Krapcho M, et al
(Eds). SEER Cancer Statistics Review, 1975-
2010, National Cancer Institute. Bethesda,
MD; 2013.
25. Kuo CW, Chen YM, Chao JY, Tsai CM,
Perng RP. Non-small cell lung cancer in very
young and very old patients. Chest.
2000;117(2):354–7.
26. Youlden D, Cramb S, Baade P. The
international epidemiology of lung cancer:
geographical distribution and secular trends.
J Thorac Oncol. 2008;3(8):819–31.
27. Ngelangel CA, Javelosa MA, Cutiongco-de
la Paz EM; Philippine Cancer Genetics Study
Group. Epidemiological risk factors for
cancers of the lung, breast, colon-rectum &
oral cavity: a case-control study in the
Philippines. Acta Medica Philippina.
2009;43(4):29–34.
28. Hsu CK, Chen KY, Shih JY, et al. Advanced
non-small cell lung cancer in patients aged
45 years or younger: outcomes and
prognostic factors. BMC Cancer. 2012;
12:241.
29. Neuman HW, Ellis FH Jr, McDonald JR.
Bronchogenic carcinoma in persons under
forty years of age. N Engl J Med. 1956;
254(11):502–7.
30. Antkowiak JG, Regal AM, Takita H.
Bronchogenic carcinoma in patients under
age 40. Ann Thorac Surg. 1989;47(3):391–
93.
31. Byrd RB, Carr DT, Miller WE, Payne WS,
Woolner LB. Radiographic abnormalities in
carcinoma of the lung as related to
histological cell type. Thorax. 1969;24(5):
573–5.
Vol. 18 | Issue 02 | June 2017 44
 NOTES

____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________

45 Philipp J Chest Dis 2017

 OUTSIDE BACK COVER

The Philippine Journal of Chest Diseases

An official publication of:
Philippine College of Chest Physicians
84-A Malakas St., Pinyahan, Quezon City, Philippines
Email: secretariat@philchest.org
Phone: (+632) 924 9204
 Volume 18 Number 1
January-March 2017

“PEPTALKS: Pursuing Excellence in Pulmonology—

Trends, Advances and Latest Knowledge in Sleep”

36th Annual Chest Convention &

4th ASEAN Sleep Congress
March 07-10, 2017 • Manila, Philippines

Scientific Program • Faculty Abstracts •

Posters and Researches
 PHILIPPINE JOURNAL OF CHEST DISEASES
AN OFFICIAL PUBLICATION OF THE
PHILIPPINE COLLEGE OF CHEST PHYSICIANS

Editor-in-Chief
Evelyn Victoria E. Reside, MD, FPCCP

Managing Editor
Camilo C. Roa, Jr., MD, FPCCP

Copy Editor
Blesilda O. Adlaon

Editorial Assistant
Ivan Noel G. Olegario, MD, MDC

PHILIPPINE COLLEGE OF CHEST PHYSICIANS OFFICERS 2016-2017

Vincent M. Balanag Jr., MD, FPCCP

President

Charles Y. Yu, MD, FPCCP

Vice President

Lenora C. Fernandez, MD, FPCCP

Secretary

Malbar G. Ferrer, MD, FPCCP

Treasurer

Ivan N. Villespin, MD, FPCCP

Gregorio P. Ocampo, MD, FPCCP
Imelda M. Mateo, MD, FPCCP
Eileen G. Aniceto, MD, FPCCP
Ma. Janeth T. Samson, MD, FPCCP
Board Members

Patrick Gerard L. Moral, MD, FPCCP

Immediate Past President

The opinions and data expressed in the Philippine Journal of Chest Diseases (PJCD) are those of the individual authors. They are not
attributable to the editors or editorial board of the PJCD and should not be regarded as the official stand of/or endorsement by the
Philippine College of Chest Physicians. References may be made in the articles regarding drug usage, which may not be included in the
current prescribing information. The reader is, thus, urged to check the full prescribing information of drugs. No part of the PJCD may be
reproduced without the written permission of the publisher.

Address all communication and manuscripts for publication to the following: The Editor, Philippine Journal of Chest Diseases, 84-A Malakas
St., Pinyahan, Quezon City. Email: secretariat@philchest.org. Phone: (+632) 924 9204.
 JANUARY-MARCH VOLUME 18 NUMBER 1

3 Programme Overview

5 Detailed Scientific Programme

5 Day 0 -- Pre-convention
9 Day 1 – Convention Proper
16 Day 2 – Convention Proper
24 Day 3 – Convention Proper

27 Faculty Abstracts: Pulmonary Medicine

28 The New TB National Strategic Plan 2017-2022
Anna Marie Celina G. Garfin, MD

29 The Pulmonary Physical Exams … Dying or Adopting?

Errol O. Ozdalga, MD

30 Removing Simple Barriers to Asthma Control

Matthew Peters, MD

31 The New Staging of Lung Cancer

Saeed Mirsadraee, MD

32 High-Flow Nasal Oxygen (HFNO) and Non-invasive Ventilation (NIV) in Respiratory

Failure
Mark Elliott, MD, FERS

33 Issues in the Management of Idiopathic Pulmonary Fibrosis

Philip Eng, MBBS, MMed (Int. Med.)

33 Non-tuberculous mycobacteria infections in bronchiectasis

Eva Polverino, MD, PhD

34 Faculty Abstracts: Sleep Medicine

36 Sleep Medicine: Promise and Directions
Christian Guilleminault, MD

38 Principles of PAP Titration for Sleep Disordered Breathing

Teofilo Lee-Chiong, MD

38 Must Know: Sleep Essentials Overcoming Insomnia

Teofilo Lee-Chiong, MD
 JANUARY-MARCH VOLUME 18 NUMBER 1

39 Science of Non-invasive Ventilation

Teofilo Lee-Chiong, MD

39 Overlap Syndrome: Obstructive Sleep Apnea and COPD

Teofilo Lee-Chiong, MD

40 Research collaboration across Asian countries

Yun Kwok Wing, MD

41 Home Sleep Testing in Remote Areas in ASEAN region

Tripat Deep Singh, MD

41 Sleep in the ICU

Tripat Deep Singh, MD

42 Late use of electronic media and its association with sleep, depression, and
suicidality among Korean adolescents
Seung Bong Hong, MD

43 Adolescent sleep habits and their impact on school life

Joshua J. Gooley, MD

44 Oral Appliances for Obstructive Sleep Apnea: An Update

Yu-Fang Liao, DDS, PhD

45 Beyond CPAP: Ventilation in Sleep Disordered breathing

Mark Elliot, MD, FERS

45 Obstructive Sleep Apnea and Stroke

Rimawati Tedjasukmana, MD

46 Renal Disease in OSA

Ning-Hung Chen, MD

46 OSA Matters for Asians: Improving CPAP Acceptability among your patients
Naricha Chirakalwasan, MD

47 Obstructive Sleep Apnea and Cardiovascular Disease

Albert L. Rafanan, MD

48 Sudden Death in Sleep Among Asians

Maria Felicidad Soto, MD
 JANUARY-MARCH VOLUME 18 NUMBER 1

48 Solving the snore: From medical to surgical management

Michael Alexius Sarte, MD

49 Preoperative Evaluation of OSA Patients

Agnes Remulla, MD

49 Movement Disorders in Sleep: Restless and Sleepless

Rosalina Espiritu-Picar, MD

50 Sleep and Pregnancy

Ruth Divinagracia, MD

51 Chronobiology and sleep research and the design of shift work routines
Gayline F. Manalang Jr., PTRP, MOH

52 Weight Management Strategies in Obstructive Sleep Apnea

Gabriel Jasul, Jr., MD

53 Cognitive Behavioral Therapy for Insomnia (CBT-I)

Wynette Marie Solis, MA

54 Personalizing Treatments for Shift Work Disorder

Manuel Jorge II, MD

55 Poster presentation: Sleep Medicine

56 Clinical Characteristics of Obstructive Sleep Apnea Syndrome in Indonesian Adults
Telly Kamelia, SpPD

57 Sleep, slipping away…

Leong Lai Kuan, MBBS

58 Prevalence of Restless Legs Syndrome and Sleep Related Disorders in Filipino

Hemodialysis Patients
Kristine Mae Vega-Alava, MD; Rodolfo Dizon, Jr, MD

59 Association of Excessive Daytime Somnolence and Metabolic Profile in Newly

Diagnosed Hypertensive OPD Patients seen in Ospital ng Makati
Marie Menette I. Agapito, MD; Rodolfo Dizon Jr, MD
 JANUARY-MARCH VOLUME 18 NUMBER 1

60 Anthropometric Measurements as a Screening for Obstructive Sleep Apnea among

Employees of Philippine Heart Center
Mander L. Cambonga, MD; Aileen G. Banzon, MD; Ma. Encarnita B. Limpin, MD

61 Association of Sleep Quality with Glucose Control in Filipino Adults with Type 2 Diabetes
Mellitus
Abigail C. Zaraspe, MD; Virginia S. Delos Reyes, MD; Cecilia A. Jimeno, MD

62 General Research Paper Submissions from Pulmonary Medicine Training Institutions

63 Utility of DECAF score in Hospitalized Patients with COPD in Acute Exacerbation
Dennis Mark N. Santos, MD; Guinevere Dy-Agra, MD

64 Phenotyping of Adult Patients with Bronchial Asthma at the Lung Center of the Philippines
OPD Asthma Clinic: A 6-month Pilot Study
Maria Jennifer A. Apurillo, MD; Paul Rilhelm M. Evangelista, MD; Glynna O. Cabrera, MD;
Vincent M. Balanag, MD

65 Association of Serum Uric Acid Levels and Outcomes of Patients with Chronic Obstructive
Pulmonary Disease: A Prospective Cohort Study
John Ray T. Galamay, MD; Ma. Encarnita Limpin, MD; Fernando G. Ayuayo, MD

66 Blood Eosinophilia as Predictor for Outcomes in Chronic Obstructive Pulmonary Disease

Exacerbations: A Systematic Review And Meta-Analysis
Ralph Elvi M. Villalobos, MD; Aileen Wang, MD

67 Efficacy and Safety of Long-Acting Beta-Agonists (LABA) Plus Long-Acting Muscarinic

Antagonists versus LABA Plus Inhaled Corticosteroids in Chronic Obstructive Pulmonary
Disease: A Meta-Analysis
Ralph Elvi M. Villalobos, MD; Aileen Wang, MD

68 Prevalence of Asthma-COPD Overlap Syndrome (ACOS) Among Patients Presenting with

Asthma of COPD in the OPD of the UP-PGH Section of Pulmonary Medicine: A Pilot Study
Mariella Macrina Araneta-Cunada, MD; Ralph Elvi M. Villalobos, MD; Lenora C. Fernandez,
MD

69 Comparison of Glycopyrronium plus Indacaterol compared to Inhaled Corticosteroids plus

Long-Acting Beta-Agonists in Patients with Chronic Obstructive Pulmonary Disease: A Meta-
Analysis
Jim Paulo Pantas, MD; Krislyn Panugayan, MD; Cristeta Perez, MD

70 Knowledge and Use of Spirometry for the Diagnosis of Chronic Obstructive Pulmonary
Disease Among Senior Medical Residents in Metro Manila
Erlyn D. Lopez, MD; Bernice Ong-Dela Cruz, MD
 JANUARY-MARCH VOLUME 18 NUMBER 1

71 Correlation of Fractional Exhaled Nitric Oxide Level with Severity of Chronic Obstructive
Pulmonary Disease
Johnson O. See, MD; Rommel Bayot, MD; Ma. Encarnita Blanco-Limpin, MD; Fernando G.
Ayuyao, MD

72 Validity of the LENT Prognostic Score for Predicting Survival in Malignant Pleural Effusion
Rylene A. Baquilod, MD

73 LENT Prognostic Score in Malignant Pleural Effusion at Veterans Memorial Medical Center
Mary Jane A. Cadiente MD; Tito C. Atienza MD

74 Clinical Profiles and Survival of Female Patients Diagnosed with Primary Lung Cancer
Registered at the Lung Cancer Registry of St. Luke’s Medical Center
Sheilla Mae C. Jalandra, MD; Windfield Tan, MD

75 The Association between Implementation of Bundles of Care and Possible Ventilator

Associated Pneumonia Among Mechanically Ventilated Patients in the Intensive Care Unit: A
Quasi-Experimental Study
Anna Francesca Abarquez, MD-MBA; Patricia Ann Estrella, MD; Mary Claire Orden, MD-
MBA; Marissa Alejandria, MD; Evelyn Victoria Reside, MD

76 Neurocognitive Outcome of Patients with Delirium in the Intensive Care Units at a Tertiary
Government Hospital
Coleen Gulay, MD; Gerard Saranza, MD, Genevieve Tuble, MD; Derick Erl Sumalapao;
Albert Albay Jr., MD; Veeda Michelle Anlacan, MD; Lourdes Ledesma, MD

77 Non-invasive Ventilation versus Conventional Oxygen Therapy in Immuno-compromised

Patients: A Meta-analysis
Ralph Elvi Villalobos, MD; Ulysses King, Gopez, MD; Karen Flores, MD; Norman Maghuyop,
MD

78 A Preliminary Study on the Nutritional Intake and Clinical Outcomes of Patients Admitted at
the Medical Intensive Care Unit
Aiza Chrysan C Blanco-Estabillo, MD; Albert B. Albay Jr., MD

79 Oxygen Saturation Index as a Surrogate of PaO2/FiO2 Ratio in Acute Respiratory Distress

Syndrome
Caroline Bernadette O. King Kay, MD; Patrick Gerard L. Moral, MD

80 Clinical Outcomes of Mechanically Ventilated Patients in the Intensive Care Unit Referred to
Clinical Nutrition Services
Jenet B. Lim, MD; Joyce B. Bernardino, MD; Ma. Janeth Samson, MD
 JANUARY-MARCH VOLUME 18 NUMBER 1

81 Cohort Study on the Applicability of the Updated 2015 LCP Algorithm on Preoperative Risk
Assessment as a Predictor of Postoperative Pulmonary Complications
Randy Joseph D.T. Castillo, MD; Glynna O. Cabrera, MD

Pre-operative Nutritional Assessment in Surgical Lung Resection and Occurrence of Post-

82 operative Pulmonary Complication: A Prospective Cohort Study
Rely Ann Ronquillo, MD; Virginia Delos Reyes MD; Marianna Ramona Sioson, MD

Adherence, Enablers and Barriers to the Implementation of the Ventilator-Associated

83 Pneumonia Bundle in the Intensive Care Units at the Makati Medical Center
Cyrus Gerald P. Pasaporte, MD; Norman L. Maghuyop, MD

Yield Pattern of Three Sputum Smears in the Case Detection of Pulmonary Tuberculosis in a
84 Tertiary Hospital (2012-2014)
Lowell N. Bascara II, MD; Gwendolyn D. Pepito, MD; John Clifford E. Aranas, MD

Adherence to the National Tuberculosis Control Program Guidelines 2013 and Outcome of
85 Treatment on People Living With HIV Co-Infected with Tuberculosis Enrolled in the Philippine
General Hospital Treatment Hub (SAGIP)
Rhea Joy P. Tabujara, MD; Ellan Lyll B. Sallada, MD; Jubert P. Benedicto, MD

86 Assessment of the Utilization of Gene Xpert MTB/RIF in Philippine Tuberculosis Society, Inc.
Rianne L. de la Cruz, MD; Michelle B. Recana; Jubert P. Benedicto, MD

Validity study of Gene Xpert MTB/Rif Assay in the Diagnosis of Tuberculous Pleural Effusion
among Adult Patients at the Lung Center of the Philippines
87 Ronel G. Sario, MD; Joven Roque V. Gonong, MD

Performance of TB Diagnostic Committee in Certifying Disease Activity of Smear Negative

88 Category II Cases in District IV of Manila
Caroline Bernadette O. King Kay, MD; Julie Christie G. Visperas, MD; Jose Hesron D. Morfe,
MD

89 Turnaround Time for Smear Negative Category I Cases to Initiation of Treatment in District IV
of Manila
Radha Marie M. Sillano, MD; Caroline Bernadette O. King Kay, MD; Jose Hesron D. Morfe,
MD

90 Risk Factors for Development of Secondary Spontaneous Pneumothorax in Patients with

Pulmonary Tuberculosis Admitted to the Lung Center of the Philippines: A 10-year
Experience
Reya S. Domingo MD; Guia Elena Imelda Ladrera, MD
 JANUARY-MARCH VOLUME 18 NUMBER 1

91 Outcomes of Multi Drug Resistant Tuberculosis Contacts who received Category I

Treatment for Clinically Diagnosed Pulmonary Tuberculosis under DOTS
Pamela Joy V. Dionisio, MD; Joven Roque V. Gonong MD

92 Prevalence of Tuberculosis Infection in Cancer Patients at Veterans Memorial Medical

Center
Maryanne Cristy T Dadulla, MD; Teresita Aquino, MD

93 Clinical Profile and Outcome of Patients Presenting with Hemoptysis Admitted in a Tertiary
Hospital
Profile and Outcome of Patients Presenting with Hemoptysis Admitted in a Tertiary Hospital
Jan Sydiongco-Fernando, MD; Ralph Elvi Villalobos, MD; Jubert Benedicto, MD

94 Validity of Pleural Fluid Cholesterol in Differentiating Exudative from Transudative Pleural

Effusions of Pleural Fluid Cholesterol in Differentiating Exudative from Transudative Pleural
Effusions
Cynthia M. Buhain, MD; Sergio S. Andres, Jr., MD

95 Effectiveness of Mechanical Cough Assist (Insufflator-Exsufflator) among Hospitalized

Patients: An Open-Label Randomized Control Study of Mechanical Cough Assist
(Insufflator-Exsufflator) among Hospitalized Patients: An Open-Label Randomized Control
Study
Joyce T. Manalo, MD; Virginia Delos Reyes, MD; Glynna Ong-Cabrera, MD

96 Diagnostic Accuracy of Berlin, Sleep Apnea Clinical Score, and St. Luke’Accuracy of Berlin,
Sleep Apnea Clinical Score, and St. Luke’s Medical Center-Obstructive Sleep Apnea (OSA)
Clinical Score Questionnaires for OSA Screening Among Filipinos: A 4-Year Retrospective
Study
Babyleen E. Macaraig, MD; Mercy Antoinette S. Gappi, MD

97 Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration in the Philippines: A

Preliminary Retrospective Cohort Study on Diagnostic Performance
Fatima Antonia F. Ponte, MD; Christine L. Chavez, MD; Regina Elena M. Bisnar, MD; Maria
Katrina R. Rivera, MD
 INSTRUCTIONS TO AUTHORS
The Philippine Journal of Chest Diseases
publishes scientific papers in the field of
pulmonary medicine. These papers may be in the
form of collective and current reviews (state of the
art, meta-analyses), original investigations, case
reports, editorials or letters to the editor. All
manuscripts must be submitted electronically to
secretariat@philchest.org. Manuscripts should be
single spaced and left-justified, including
references. Use 10-point type, approximately 1-
inch margins, and format for 8 ½ x 11 paper. The
editorial staff requires files that can be opened and
manipulated in Word 2004-2009, PowerPoint or
Excel.
Accepted manuscripts become the property of the
Philippine College of Chest Physicians and are
published with the understanding that they are not
for publication elsewhere without approval.
These manuscripts are subject to editorial
modification.
Generally, write using the first person, active
voice; for example, “We analyzed data,” not
“Data were analyzed.” The Abstract
and acknowledgments or disclaimers are the
exceptions to this guideline, and should be written
in the third person, active voice; “The authors
analyzed,” “The authors wish to thank.”
Supply a title page as the first page of the
manuscript with the following information:
1. The manuscript’s full title which should
provide sufficient information regarding the
contents of the manuscript.
2. All authors should provide their complete
names, professional titles, and institutional
affiliations. Include an author byline that lists
all authors’ full names and academic degrees
above a Masters; for example, “Juana Cruz,
MD, PhD, and Juan Ramos, MD”. Also
include sentence-style bios for each author
than list position(s) or title(s) and institutional
affiliation(s); for example, “Dr. Cruz is
assistant professor, Section of Pulmonary
Medicine, Department of Internal Medicine,
State University College of Medicine”.
3. Contact information (address and email
address, plus telephone and/or fax) for the
corresponding author.
4. Disclosure of funding received for this work
from any organization or company.
5. State if the paper has been presented in any
convention and whether any awards have
been conferred on the paper.
Abstract. The abstract should not be longer than
250 words. It should contain a summary of what
was done in the study, including objectives, study
design, important results and conclusions. Only
findings restricted to the study should be
mentioned in the abstract. For research reports
only, abstracts must be in the structured form of
four paragraphs, with headings Purpose,
Methods, Results, and Conclusions; and must
include the year of the study. The authors should
also provide three key words under which the
article can be indexed.
Headings
For all manuscripts. Use main headings and
short subheadings as needed. Do not create a
heading at the very top of the manuscript (e.g.,
“Introduction”), since layout constraints make
such headings unworkable. Text should be set in
Times New Roman font, 10 point in size, and
single-spaced. The main heading of the online-
only text should be in 12 point and boldface;
subheadings should be in 10-point and boldface.
If subheadings are used, two or more such
headings must be used, as in outline style.
For research reports. Structure the body of the
manuscript using the headings Introduction,
Methods, Results, and Conclusions. At least a full
paragraph of text must precede the Introduction
heading, for layout reasons.
For articles. Create headings that are substantive
and interesting and that will give readers a sense
of the article’s organization. Make headings as
short as is feasible. At least a full paragraph of
text must precede the initial heading, for layout
reasons.
Text. Formal scientific or technical style shall be
followed in writing the manuscripts. All
abbreviations should be spelled out when used
for the first time. For standard terminology,
such as chronic obstructive pulmonary disease
 INSTRUCTIONS TO AUTHORS
(COPD) or forced vital capacity (FVC), only
standard abbreviations should be used. Information
or data that is best described in tables should be
presented as such. Tables which duplicate
information provided in the text shall be removed.
Generic names of drugs shall be used except in
instances where trade names are vital, such as in
clinical trials.
Tables and Figures. Only tables cited in the text
should be included. All tables should be called out
in the text and shall be numbered in ascending
order depending on the sequence they were
referred to in the text. A different order for tables
and figures is to be used. Symbols are * † ‡ § ¶.
A single table or figure with the appropriate labels
should be printed on a single page. The text and
data in online tables should be Arial font, 10 point
in size, and single-spaced. The table title should be
set in Arial font 12 point, and bold. Headings
within tables should be set in 10 point bold.
Explanatory notes or legends should be written
at bottom of the table or figure. Table titles should
make the table sufficiently understandable
independent of the manuscript. Typically, include
type of data, number and type of respondents, place
of study, year of study. Titles should be placed
directly above the table, not in a data cell. Columns
should be clearly labeled, including unit of
measure.
Footnotes: If information is needed to make the
table understandable that won’t easily fit into the
table title or data cells, create one or more
footnotes. Table footnotes should be set in 8 point
and single-spaced. Place footnotes at the bottom of
the table, not in a data cell. All abbreviations
should also be explained.
Figures. Only figures (or pictures) cited in the text
should be included. All figures should be called out
in the text and shall be numbered in ascending
order depending on the sequence they were
referred to in the text. A different order for tables
and figures is to be used.
Figures are acceptable as Excel, PowerPoint
or Word 2004-2009 files. All files supplied must be
“live” figures that can be opened and formatted.
PDFs and JPGs are not accepted. Figures should
be two-dimensional; black-and-white or
grayscale; and without gridlines or background
shading. X and Y axes, if present, must be
labeled.
Figure legends should make the figure
sufficiently understandable independent of the
manuscript. Legends should be placed on the last
page in the manuscript. All figures should be
separated from the text file, yet bundled into a
common file, if possible, with individual figures
separated by page breaks.
The editorial staff reserves the right to determine
whether the graphical instruments are appropriate
for the information being imparted and modify or
request modification/s for inappropriate
illustrations. The editorial staff reserves the right
to generate illustrations compatible with the
professional standards of the journal.
References. Authors are responsible for the
accuracy and completeness of their references and
for correct text citations. All references should be
identified at the appropriate parts of the text using
Arabic numerals enclosed in parentheses. All
references should then be typed double-spaced at
the end of the manuscript and numbered
according to the order they were cited in the text.
Journal references should include the names of all
the authors and inclusive page numbers.
Abbreviations of names of journals should
conform to those used in the Index Medicus.
For world wide web citations, follow the
following format: <author’s name> <title of
document> <<URL>> <date of document>
(accessed <date accessed>). You may break
URLS across lines, but if possible, arrange for
breaks to occur only at punctuation separators
(but not on hyphens, and don’t ever add hyphens).
Samples of the style to be followed in the listing
references are enumerated below:
JOURNAL ARTICLE: Tanchuco JQ, Young J.
Normal standards for spirometric tests in Filipino
children. Chest Dis J 1989. 16:93-100.
 INSTRUCTIONS TO AUTHORS
BOOK: Kelley MA, Fishman AP. Exercise
Testing. In: Pulmonary Diseases. 2 edition.
Fishman AP, (ed.). McGraw-Hill Book Co.; 1989.
pp.2525-2532.
WORLD WIDE WEB: Horton M, Adams R.
Standard for interchange of USENET messages
Request for comment s 1036, Network Working
Group. <ftp://ftp.demon.co.uk/pub/doc/rfc/rfc1036.
txt> Dec.1987 (Accessed 19 June 1995)
Personal communications, unpublished data or
manuscripts in preparation should not be used as
numbered reference. Instead, these may be cited in
parentheses or as a footnote on the page where they
are mentioned. Authors assume responsibility for
verifying the accuracy of their cited reference.
Advertisements. All requests for rates should be
add-ressed to: The Business Manager, Philippine
Journal of Chest Diseases, PCCP Secretariat, 84-A
Malakas St., Brgy. Pinyahan, Diliman, Quezon
City (Telephone No. 924-9204 and Fax No. 924-
0144). The journal also accepts announcements
from institutions or professional
invitations to forthcoming symposia or convention
for publication at minimal cost depending on
available space.
Reprints. Requests for additional reprints of
individual articles should be addressed to: The
Editor-In-Chief, Philippine Journal of Chest
Diseases, PCCP Secretariat, 84-A Malakas St.,
Brgy. Pinyahan, Diliman, Quezon City (Telephone
No. 924-9204 and Fax No. 924-0144). Author/s of
each manuscript are entitled to 25 copies of the
article. These shall be sent to the major author.
Requests for reprints should be addressed to the
senior author. Reprints of entire issues may be
provided at cost, depending on availability of
copies.
Subscriptions. All requests for subscriptions should
be addressed to: The Business Manager, Philippine
Journal of Chest Diseases, PCCP Secretariat, 84-A
Malakas St., Brgy. Pinyahan, Diliman, Quezon City
(Telephone No. 9249204 and Fax No. 924-0144. E-
mail address secretariat@philchest.org. One issue
(P120.00). Back issues (depending on availability
P120.00).
 TIME Day 0 (March 7, 2017 -Tuesday) Day 1 (March 8, 2017 - Wednesday)
07:00 Sunrise Symposium 1
QUIZ CONTEST
(Banquet Hall 2 & 3)
08:15
PSG Interpretation and Multidisciplinary Management of Sleep Apnea

08:30 PLENARY SESSION 1

The New TB National Strategic Plan 2017-2022
Dr. Anna Marie Celina Garfin
09:00 Post-Graduate Course 2 - P.E.T. Scan

CT/MRI/PET Imaging for Chest Physicians)

(Reception Hall)

(Pursuing Excellence in Thoracic Scan:

09:15 PLENARY SESSION 2
Post-Graduate Course 1

Sleep Medicine: Promise and Directions

(Summit Hall D)
(Summit Hall C)

Dr. Christian Guilleminault

(Reception Hall)
10:00 OPENING OF EXHIBITS

10:30 PLENARY SESSION 3

CS1
Lung CA: Personalized Medicine: Options 10:20 am–11:30 am

in Cancer Therapy Level up:

Dr. Chong Kin Liam Interactive
Sleep Cases
New Members
Orientation of

(Summit Hall E/F)

11:15 (Reception Hall)

PLENARY SESSION 4 (Meeting Room 4)
N

11:30 Non-TB Mycobacterium (NTM) in Non- CS2

O

11:30am - 12:00nn
Cystic Fibrosis (Non-CF) Bronchiectasis:
Consolidating ASEAN
I

Diagnosis & Management Sleep Medicine

12:00nn Dr. Eva Polverino
T

(Concurrent Discussions)
(MR 4, 7 & 8)
A

(Reception Hall)
R

LS LS LS 1 LS 2 LS 3
T

PHILIPS RESPIRONICS OEP

ASTRAZENECA SANDOZ GSK
S

(Summit Hall C)
(Summit Hall D)
Research Oral Presentation

(Meeting Room 1) (Summit Hall C/D) (Summit Hall E/F)

I
G

(Summit Hall E/F)

R E

01:30 Visit the EXHIBITS

Post-Graduate Course 1
02:00 Post-Graduate Course 2 PLENARY SESSION 5 CS3
P. E. T. 1:20 pm-2:30pm
PSG The Pulmonary Physical Exams… Sleep in the ICU
Dying or Adopting? (MR 4)
(Summit Hall C) Dr. Errol Ommar Ozdalga
(Summit Hall D)
02:30 (Meeting Room 1)

VISIT THE EXHIBITS

02:45 2:30 pm-2:50 pm

03.:00 Visit the EXHIBITS

CS4 CS5 CS6 CS7
New TB Beyond COPD: 2:50 pm – 4:00 pm
Asthma in Dx Tools for The Unmet Sleep & the
Digital Age Improved Needs of the Specialist I
Case Findings Elderly
04:00 (Summit Hall C/D)
(Summit Hall E/F)
(Meeting Room 4)
(Meeting Room
1)
04:30 OPENING CEREMONIES CS8
4:00 pm – 5:10 pm
Generation Gap: Age
INDUCTION OF NEW MEMBERS Related Sleep
Disorders
DR. DINA V. DIAZ
Honor Lecture (Meeting Room 4)

(Meeting Room 1)
05:00

PLENARY SESSION 6
Removing Simple Barriers
to Asthma Control
Dr. Matthew Peters
(Meeting Room 1)

1 Phil
07:00 J Chest Dis 2017 PRESIDENTS HONOR BANQUET
(Summit Hall D)
FELLOWSHIP NIGHT
(Reception Hall)
 TIME Day 2 (March 9, 2017 - Thursday) Day 3 (March 10, 2017 -Friday)
07:00 Sunrise Symposium 2
INTER-HOSPITAL DEBATE CS9 Sunrise Symposium 3
7:50 am-9:00 am
(In cooperation with TOHAP) MEDICAL ETHICS
(Banquet Hall 2 & 3) Sleep Disordered
08:15 Breathing Solutions Pulmonology & Social Media
(Meeting Room 4)
08:30 PLENARY SESSION 7
07:30am – 08:30am
The New Staging in Lung CA
Dr. Saeed Mirsadraee (Reception Hall)

09:00 (Reception Hall)

09:15 PLENARY SESSION 8 PLENARY SESSION 13

Sleep Forensics Issue in the Management of IPF
Dr. Michel A. Cramer Bornemann Dr. Philip Eng

(Reception Hall) (Reception Hall)

10:00 Visit the EXHIBITS Visit the EXHIBITS

10:30 PLENARY SESSION 9 PLENARY SESSION 14
CS10
The Call to Personal Leadership 10:20 am-11:30am State of the Art: COPD Exacerbations
Mr. Francis J. Kong Sleep Dr. Jadwiga Anna “Wisia” Wedzicha
and the Specialist II
(Reception Hall)
11:15 (Reception Hall) (Meeting Room 4)

PLENARY SESSION 10 PLENARY SESSION 15

FERMIN MANALO LECTURE
High Flow Nasal Oxygen (HFNO) & Non-Invasive
Ventilation (NIV) Sunrise, Sunset:
In Respiratory Failure Starting vs Retiring Pulmonologist
Dr. Mark Elliott MA MD FERS Dr. Parkash T. Mansukani & Dr. Radha Marie M. Sillano

(Reception Hall) (Reception Hall)

11:30 CS11
11:30 am-12:00nn
OSA Matters for Asians
12:00nn (Concurrent Discussions)

(MR 4, 6, 7 & 8)
LS 4 LS 5 LS 6 LS 7 LS 8 LS 9
NOVARTIS BOEHRINGER PFIZER PCCP & PSSM UAP CORBRIDGE
INGELHEIM
(Reception Hall) (Summit Hall C/D) (Summit Hall E/F) (Reception Hall) (Summit Hall C/D) (Summit Hall E/F)

01:30 Visit the EXHIBITS

02:00 PLENARY SESSION 11 CS12
COPD: The Role of Physicial Activity 1:20 pm-2:20 pm

Prof. Klaus F. Rabe, MD, PhD Sleep in the Workplace

(Meeting Room 4) PCCP BUSINESS
02:30 (Reception Hall) MEETING
VISIT THE EXHIBITS
02:45 2:30 pm-2:50 pm
02:00PM
03.:00 Visit the EXHIBITS
CS13 CS14 CS15 CS16
2:50 pm – 4:00 pm
GOLD Interactive Clinical Year Insomnia from the Bedroom to the
Clinic (Reception Hall)
2017 Discussion on Review in
(Meeting Room 4)
04:00 Pleural Effusions Critical Care
(Reception Hall) (Summit Hall C/D) (Summit Hall E/F)
04:30 CS17
4:00 pm – 5:10 pm

Bedroom Bumps & Grind

(Meeting Room 4)

05:00
PLENARY SESSION 12
HAP &VAP: IDSA and PCCP perspective
Dr. Isauro Q. Guiang Jr., Dr. Mario Panaligan CLOSING CEREMONIES
Dr. Rodolfo S. Pagcatipunan Jr.
FAREWELL DINNER

Vol. 18 | Issue 01 |(Summit

March 2017 2
(Reception Hall)
INDUCTION OF NEW OFFICERS
07:00 PSSM Business Meeting (5-7pm) Hall D)
TRAINING INSTITUTION’S REUNION (Meeting Room 8)
 The 36th Annual Chest Convention & 4th ASEAN Sleep Congress
March 07-10, 2017 Philippine International Convention Center

SCIENTIFIC PROGRAM

Day 0 - TUESDAY, 7TH MARCH – PRE CONVENTION

ASC POST GRADUATE COURSE 1:

“PSG Interpretation and Multidisciplinary Management of Sleep Apnea”

March 7, 2017 (Tuesday)  08:00am - 04:00pm
Summit Hall C, 4th/F PICC, CCP Complex Pasay City

The 4th ASEAN Sleep Congress Post-Graduate Course will be a whole day comprehensive program
targeting doctors, polysomnographers, respiratory technicians, nurses and other allied healthcare
providers. Its aims are to 1) reinforce knowledge in staging and scoring pediatric and adult
polysomnograms, 2) boost the skills in performing positive airway titration studies, 3) provide basic
competency in interpreting a sleep study result and compliance data, 4) provide exposure on the
available positive airway pressure devices, different types of masks and how to maximize the user’s
comfort, 5) expand the understanding on surgical management of obstructive sleep apnea and use
of oral appliances and 6) gain familiarity with the use of a portable monitoring device

MORNING SESSION
TIME ACTIVITY FACULTY
07:30 - 08:00 am Registration
08:00 - 08:05 am Welcome Remarks Virginia S. de Los Reyes, MD, FPCCP,
FPSSM
08:05 - 08:15 am Overview of Post-graduate Course Rodolfo V. Dizon, Jr., MD, FPCCP, FPSSM
08:15 - 09:00 am Adult Sleep Staging Mr. Glenn S. A. Roldan, RPSGT, RST, CSE
09:00 - 09:45 am Pediatric Staging and Scoring Jonalyn Chris A. Ang, MD, FPSSM
Challenges - How is it different from the
adult?
09:45 -10:15 am Visit the booths/Coffee break
10:15 -11:00 am Adult Scoring Tripat Deep Singh, MD, RPSGT
11:00 - 11:45 am Interpretation of a Sleep Study Result Emelie Bautista-Ojascastro, MD, FPCCP,
FPSSM

5
1 Phil J Chest Dis 2017
AFTERNOON SESSION (30 Minute Stations) - to start at 1:00pm to 4:00pm
TOPIC
Types of PAP devices
(CPAP/APAP/BPAP/ASV)
Proper Mask Fitting &
Ensuring Comfort while PAP
(Pap nap/ramp/management
of nasal congestion)
Interpreting Compliance Data
Upper airway evaluation for
CPAP failures (Surgical
management)
Oral Appliances
Portable monitoring
FACILITATORS
GROUP 1
Aileen Guzman-Banzon, MD,
FPCCP, FPSSM
Mr. Jonathan J. Rivera, RPSGT
Mary Warren E. Ilaga, MD,
FPSSM
Ms. Charmain Beatrice Atos,
RPSGT
Alexander Abe, MD, FPSSM
Romulus Instrella, MD, FPSSM
Colina Colina, MD
Jimmy V. Chang, MD, FPSSM
Emma Natividad, MD
Tripat Deep Singh, MD
GROUP 2
Teresita Celestina Fuentes, MD,
FPCCP, FPSSM
Mr. Glenn Roldan, RPSGT
Abigail Zaraspe, MD, FPCCP,
FPSSM
Cristito B. Alea, MD, FPSSM
Keith Romeo Aguilera, MD, FPSSM
Beverly Carbonell, MD
Maria Patricia T. Puno, MD, FPSSM
Pamela Mendoza, DMD
Duane L. Salud, MD, FPSSM
Mr. Khem Ballaho, RPSGT

PCCP POST GRADUATE COURSE 2:

P.E.T. Scan (Pursuing Excellence in Thoracic Scan:

CT/MRI/PET Imaging for Chest Physicians)
March 7, 2017 (Tuesday)  08:00am - 03:00pm
Summit Hall D, 4th/F PICC, CCP Complex Pasay City

PG Course Director: Roland M. Panaligan, MD, FPCCP

PG Course Member/s: Patrick Gerard L. Moral, MD, FPCCP
Ma. Janeth T. Samson, MD, FPCCP
Geraldine D.C. Garcia, MD, FPCCP
Julie Christie G. Visperas, MD, FPCCP
Ma. Ronila A. Santos, MD, FPCCP
Jude P. Guiang, MD, FPCCP
Irene Salve D. Joson-Vergara, MD, FPCCP
Earl Louis A. Sempio, MD, FPCCP
Aileen F. Zagala, MD

Objectives of the course:

1. To provide a comprehensive and structured learning opportunity regarding thoracic imaging as
applicable to chest physicians.
2. To provide learning activities from lecturettes to small group clinical case discussions that will
cover thoracic imaging anatomy, interpretation and clinical applications.

Vol. 18 | Issue 01 | March 2017 6

P.E.T. Scan (Pursuing Excellence in Thoracic Scan: CT/MRI/PET Imaging for Chest Physicians)
TIME TOPIC/ACTIVITY
07:00am – 07:30 Registration
Online Pre-Test
07:30 – 08:00 Welcome Address / Course Overview
Roland M. Panaligan, MD, FPCCP
Chair
08:00 – 08:30 CT Anatomy and Interpretation
Roy P. Vizcarra, MD (Radiologist) (St. Luke’s Medical Center, Philippines)
08:30 – 09:00 MRI Anatomy and Interpretation
Dr. Saeed Mirsadraee (University of Edinburgh, Scotland, United Kingdom)
09:00 – 09:30 Hands-on/Small Group Discussion
Facilitators
09:30 – 09:45 Working Break
09:45 – 10:15 Pulmonary Ultrasound (Ultrasound)
Dr. Errol Ommar Ozdalga (Stanford University, United States)
10:15 - 10:45 Imaging of Lung Infection (CT/MRI)
Roy P. Vizcarra, MD (Radiologist) (St. Luke’s Medical Center, Philippines)
10:45 – 11:15 Hands-on/Small Group Discussion
Facilitators
11:15 – 11:45 Imaging for Lung Cancer Screening
Dr. Saeed Mirsadraee (United Kingdom)
11:45am – 12:15nn Hands-on/ Small Group Discussion
Facilitators
1:30pm – 2:00 PET Scan Basic
Dr. Saeed Mirsadraee (University of Edinburgh, Scotland, United Kingdom)
2:00 – 2:30pm Online Post-Test
Closing

ORIENTATION OF NEW MEMBERS

Venue: Summit Hall E/F, 4th/F, PICC
Time: 10:30am-12:00nn

RESEARCH ORAL PRESENTATION

Venue: Summit Hall E/F, 4th/F, PICC
Time: 12:00nn – 03:00pm

7
1 Phil J Chest Dis 2017
 LUNCHEON SYMPOSIA

Luncheon Symposium
Date: March 7, 2017 (Tuesday)
Venue: Summit Hall C, 4th Floor, Time: 12:00nn – 1:30pm
Title & Speaker: “Principles of Positive Airway Pressure Titration for Sleep Related
Breathing Disorders” by Dr. Teofilo Lee-Chiong (USA)
(Through a CME grant from Philips Respironics)

Luncheon Symposium
Date: March 7, 2017 (Tuesday)
Venue: Summit Hall D, 4th Floor, Time: 12:00nn – 1:30pm
Title & Speaker: “New perspectives for mucoactive drugs in COPD treatment: The
RESTORE Study” by Prof. Roberto W. Dal Negro (Italy)
(Through a CME grant from OEP Philippines Inc.)

OPENING CEREMONIES
Induction of New Member
Honor Lecture: DINA V. DIAZ, MD, FPCCP
04:30pm at Meeting Room 1, 3rd/F PICC

PRESIDENT’S HONOR BANQUET

07:00pm at Summit Hall D, 4th/F, PICC

Vol. 18 | Issue 01 | March 2017 8

 Day 1 - WEDNESDAY, 8TH MARCH – CONVENTION PROPER

SUNRISE SESSION 1: QUIZ CONTEST

07:00am – 08:30am at Banquet Hall 2 & 3,
2nd/F Delegation Building, PICC

7th PCCP Quiz Challenge: “#PulmoKNOWlogy2017”

Judges: Ma. Bella R. Siasoco, MD, FPCCP; Manuel Hector U. Silos, MD, FPCCP; Aven-Kerr S.
Ubalde, MD, FPCCP
Quizmaster / Moderator: Mary Grace P. Quilloy-Arellano, MD, FPCCP; Gene Philip C. Louie
Ambrocio, MD
Session Chair: Joanne Kathleen B. Ginete-Garcia, MD, FPCCP
Session Co-Chair: Coleen B. Gulay, MD

INSTITUTIONS PULMONARY FELLOW

LCP Eva Christine O. Navales, MD
PHC John Ray T. Galamay, MD
VMMC Abigail D. David, MD
SLMC Raychelle Anne B. Yang-Nagaño, MD
USTH Maria Cristina A. Maranion, MD
CGH Archie E. Apostol, MD
MDH Cristina D. Roldan, MD
MMC Kenneth Jorge A. Lasafin, MD
TMC Patricia Ann T. Estrella, MD
CHH Kristoferson A. Catungal, MD
PSH Marlo P. Bagano, MD
UPHDMC Raissa Joyce Guarin, MD
UP-PGH Jonray R. Magallanes, MD

PCCP PLENARY SESSION 1

TOPIC: The New TB National Strategic Plan 2017-2022

Anna Marie Celina Garfin, MD (Philippines)
Date / Time / Venue: March 8, 2017 (Wednesday), 08:30 – 09:15am, Reception Hall
Chairman: Jose Hesron D. Morfe, MD, FPCCP

Objectives:
1. understand and list the strategies, performance targets and key activities of the Philippine
Strategic TB Elimination Plan Phase 1 (PhilSTEP 1)
2. apply strategies in eliminating TB in the country.

9
1 Phil J Chest Dis 2017
 Sleep Medicine ASC PLENARY SESSION 2
Session

TOPIC: Sleep Medicine: Promise and Directions

Dr. Christian Guilleminault (USA)

Date / Time / Venue: March 8, 2017 (Wednesday), 09:15 -10:00am, Reception Hall
Chairman: Virginia S. de Los Reyes, MD, FPCCP, FPSSM

OPENING OF EXHIBITS
March 8, 2017 (Wednesday)
10:00 – 10:30am at 3rd/F Delegation Building

PCCP PLENARY SESSION 3

TOPIC: Lung CA: Personalized Medicine Options in Cancer Therapy

Professor Chong Kin Liam (Malaysia)
Date / Time / Venue: March 8, 2017 (Wednesday), 10:30-11:15am, Reception Hall
Chairman: Guia Elena Imelda R. Ladrera, MD, FPCCP

Objectives:
At the end of the session, the participant will
• Outline the approach to utilization of markers for targeted cell therapy, such as EGFR, ALK,
and ROS-1 testing.
• List the available agents for targeted cell therapy-indications, potential benefits, common
adverse reactions and in dealing with T790 mutations and /or resistance.
• Discuss the role of screening for PDL1 and immunotherapy in the treatment of lung cancer.

Sleep Medicine
Session ASC CONVENTION SYMPOSIUM 1

TOPIC: Level up: Interactive Sleep Cases

March 8, 2017 (Wednesday), 10:20 – 11:30am, Meeting Room 4, 2nd/F Delegation Building

Title & Speaker/s:

Must Know: Sleep Essentials Overcoming Insomia by Dr. Teofilo Lee-Chiong (USA)

Usual and Beyond: Classic Cases Narcolepsy vs Idiopathic hypersomnia by Dr. Tayard
Desudchit (Thailand)

Master Specialist: Difficult Cases -- Unusual Parasomnias

Dr. Michel A. Cramer-Bornemann (USA)

Chairman: Patrick Gerard L. Moral, MD, FPCCP, FPSSM

Vol. 18 | Issue 01 | March 2017 10

 PCCP PLENARY SESSION 4

TOPIC: Non-TB Mycobacterium (NTM) in Non-Cystic Fibrosis (Non-CF) Bronchiectasis:

Diagnosis & Management by Eva Polverino, MD (Spain)

Date / Time / Venue: March 8, 2017 (Wednesday), 11:15am - 12:00nn, Reception Hall
Chairman: Rizal Alberto B. Nolido Jr., MD, FPCCP

Objectives: Sponsored and supported by:

At the end of the session, the participant will
• Apply the necessary clinical information
i. to diagnose NTM non-CF bronchiectasis
ii. to differentiate it from Tuberculosis
• Plan a management approach for the disease

Sleep Medicine
ASC CONVENTION SYMPOSIUM 2
Session
TOPIC: Consolidating ASEAN Sleep Medicine(Concurrent Discussions)
March 8, 2017 (Wednesday), 11:30am – 12:00nn
Meeting Room 4, 7 & 8, 2nd/F Delegation Building

Title & Speaker: ASEAN Sleep Legislation by Dr. Yap Yoke-Yeow (Malaysia) (Meeting Room 4)
Chairman: Ma. Encarnita Blanco-Limpin, MD, FPCCP, FPSSM

Title & Speaker: Areas for research collaboration in ASEAN sleep by Dr. Yun-Kwok Wing
(Hong Kong) (Meeting Room 7)
Chairman: Aileen Guzman-Banzon, MD, FPCCP, FPSSM

Title & Speaker: Truly Asian ideas on Sleep: Sudden Death in Sleep among Asians by
Dr. Felicidad Soto (Philippines) (Meeting Room 8)
Chairman: Mary Warren E. Ilaga, MD, FPSSM

LUNCHEON SYMPOSIA
Luncheon Symposium 1

Date: March 8, 2017 (Wednesday)

Venue: Meeting Room 1, Time: 12:00nn – 1:30pm
Title & Speaker: “Revisiting the Role of Device and its Impact in Asthma Outcomes” by Prof.
Matthew Peters, MD (Australia)
(Through a CME grant from AstraZeneca Philippines)

11
1 Phil J Chest Dis 2017
 Luncheon Symposium 2

Date: March 8, 2017 (Wednesday)

Venue: Summit Hall C/D, 4th Floor, Time: 12:00nn – 1:30pm
Title & Speaker: “Optimizing Control of Uncontrolled Chronic Airway Obstruction” by
Daniel T. Tan, MD, FPCCP (Philippines)
(Through a CME grant from Sandoz Philippines Corporation)

Luncheon Symposium 3

Date: March 8, 2017 (Wednesday)

Venue: Summit Hall E/F, 4th Floor, Time: 12:00nn – 1:30pm
Title & Speaker: “Shifting the Paradigm in Asthma & COPD: The Impact of 24 hour efficacy
and Clinically Important Deteriorations” by Celeste Mae L. Campomanes, MD, FPCCP
(Philippines)
(Through a CME grant from GlaxoSmithKline)

Visit the EXHIBITS

(01:30 – 2:00pm) at 3rd/F Delegation Building

PCCP PLENARY SESSION 5

TOPIC: The Pulmonary Physical Exams…Dying or Adopting? By Errol Ommar Ozdalga, MD

(USA)
Date / Time / Venue: March 8, 2017 (Tues), 02:00 – 02:45pm; Meeting Room 1, 3rd Floor
Summit Hall C/D, 4th Floor – live feed venue
Chairman: Abundio A. Balgos, MD, FPCCP

Objectives:
At the end of the session the participant will:
• Review the importance of history and PE in medical diagnosis
• Appraise the clinical usefulness of the stethoscope
• List the additional information provided with the use of ultrasound

Vol. 18 | Issue 01 | March 2017 12

 Sleep Medicine
Session ASC CONVENTION SYMPOSIUM 3

TOPIC: Sleep in ICU

March 8, 2017 (Wednesday), 01:20 – 02:30pm; Meeting Room 4, 2nd/Floor Delegation Building

Title & Speaker/s:

• Sleep in ICU by Dr. Tripat Deep Singh (Singapore)
• OSA and the Cardiovascular patient by Dr. Albert L. Rafanan (Philippines)
• NIV in the Critically ill sleep patient (Science of Non-invasive ventilation) by Dr. Teofilo
Lee-Chiong (USA)
Chairman: Dr. Ye Tun (Myanmar)

Visit the EXHIBITS

(02:45 – 03:00pm) at 3rd/F Delegation Building

PCCP CONVENTION SYMPOSIUM 4

TOPIC: Asthma in Digital Age

March 8, 2017 (Wednesday), 03:00 – 04:30pm
Meeting Room 1, 3rd/Floor Delegation Building

Title & Speaker: Digital Challenges and Opportunities for Asthma Management by Errol
Ommar Ozdalga, MD (USA)

Title & Speaker: The Digital Evolution and the Future of Mobile Apps in Asthma
Management by Chris Chen, MD

Objectives:
At the end of the session the participant will
• Discuss and describe the impact of developments in the use of the internet in general and
social media in particular on the management of asthma in the light of GINA
• Speculate on the digital technological future for asthma
• Review significant digital technological developments vis-à-vis asthma diagnosis and
management including: 1) the evolution of mobile apps for asthma; and 2) Electronic asthma
action plan tools

Chairman: Aileen David-Wang, MD, FPCCP

Moderator: Joven Roque V. Gonong, MD, FPCCP

13
1 Phil J Chest Dis 2017
 PCCP CONVENTION SYMPOSIUM 5

TOPIC: New TB Diagnostic Tools for Improved Case Findings

March 8, 2017 (Wednesday), 03:00 – 04:30pm
Summit Hall C/D, 4th Floor

Title & Speaker: PURE TB LAMP: The Use of Loop-mediated Isothermal Amplification for
TB Diagnosis by Ma. Cecilia Ama, MD

Title & Speaker: GENOSCHOLAR: A New Line Probe Assay (LPA) Kit for TB by Ramon
Basilio, MD

Objectives:
At the end of the session the participant will
• express the local experience on the TB Lamp as a possible first-line diagnostic tool
• trace back the role of LPA in programmatic management of Drug-resistant TB (PMDT
• evaluate the local experience with the new LPA kit.

Chairman: Joanne A. Apdol, MD, FPCCP

Moderator: Shelley A. Romero, MD, FPCCP

PCCP CONVENTION SYMPOSIUM 6

TOPIC: Beyond COPD: The Unmet Needs of the Elderly

March 8, 2017 (Wednesday), 03:00 – 04:30pm
Summit Hall E/F, 4th Floor

Panelists: Inocencio Alejandro, MD; Roy Cuison, MD; Patrick Gerard L. Moral, MD, FPCCP
Moderator / Presentor: Marilyn Ong-Mateo, MD, FPCCP

Objectives:
At the end of the session the participant will practice a holistic approach in the management of
COPD in the elderly.

Description: This will be an interactive session of an elderly COPD patient. The panelists will
be composed of 2 pulmonologists and 2 physicians specializing in Geriatric Medicine.
Aside from discussing COPD categorization, the session will expound on:
• cognitive and functional impairment of geriatric COPD patient
• other co-morbidities (malnutrition)
• polypharmacy
• vaccinations
• advance directives (end-of-life issues)

Vol. 18 | Issue 01 | March 2017 14

 Sleep Medicine
Session ASC CONVENTION SYMPOSIUM 7

TOPIC: Sleep and the Specialist I

March 8, 2017 (Wednesday), 02:00 – 04:00pm
Meeting Room 4, 2nd Floor Delegation Building

Title & Speaker/s:

Sleep and Depression by Dr. Christian Guilleminault (USA)
Sleep and Pregnancy by Dr. Ruth Marie D. Divinagracia (Philippines)
Overlap syndrome: Sleep and COPD by Dr. Teofilo Lee- Chiong (USA)

Chairman: Dr. Sy Duong-Quy (Vietnam)

Sleep Medicine ASC CONVENTION SYMPOSIUM 8

Session
TOPIC: Generation Gap: Age related sleep disorders
March 8, 2017 (Wednesday), 04:00 – 05:10pm
Meeting Room 4, 2nd Floor Delegation Building

Title & Speaker/s:

Sleep and senescence by Dr. Christian Guilleminault (USA)
Adolescent sleep habits and their impact on school life by Dr. Joshua Gooley (Singapore)
Late use of Electronic Media and Sleep by Dr. Seung Bong Hong (Korea)

Chairman: Dr. Fang Han (China)

PCCP PLENARY SESSION 6

TOPIC: Removing Simple Barriers to Asthma Control by Prof. Matthew Peters, MD (Australia)
Date / Time / Venue: March 8, 2017 (Tues), 04:45 – 05:30PM
Meeting Room 1, 3rd Floor
Summit Hall C/D, 4th Floor – live feed venue
Chairman: Ma. Bella R. Siasoco, MD, FPCCP

Objectives:
At the end of the session the participant will
• understand the background to poor asthma control
• identify key changes in emphasis in the new GINA guidelines
• understand why changes had to be made (rationale)
• gain confidence in applying the changes to achieve asthma control
• generate learning in his/her own clinical practice that will reward and reinforce this new
knowledge

FELLOWSHIP NIGHT
March 8, 2017 (Wednesday), 7:00pm
Reception Hall, PICC

15
1 Phil J Chest Dis 2017
 Day 2 - THURSDAY, 9TH MARCH – CONVENTION PROPER

SUNRISE SESSION 2: INTER-HOSPITAL DEBATE

07:00am – 08:30 am at Banquet Hall 2 & 3
2nd/F Delegation Building

16th PCCP Inter-Hospital Engagement: The Pulmonary and Critical Care Debate

Issue: Should e-cigarettes be used as a means for smoking cessation in a heavily dependent
smoker who is considering quitting smoking?

Background Setting: JT is a 45-year-old married man who smokes between 15 and 20

cigarettes per day since college. Recently, a friend was diagnosed with lung cancer, and JT
reports this is his motivation for quitting. He has tried several times to quit “cold turkey” without
success, saying he would sustain his efforts only for 2-3 weeks and then go back to his old
habits. He has no known co-morbids and allergies; no previous hospitalizations. He works as a
lawyer and consumes about 3-4 beers a week. He says he mostly smokes to keep him up while
working. He has a wife and 2 children.

On physical examination, his BP is 120/80, HR 78bpm RR18 O2sat 99% at room air. BMI 26.
Lungs are clear on auscultation. The rest of his physical examination findings are normal.
He consults you in the clinic and asks whether he can use e-cigarettes for smoking cessation.

PROPOSITION: E-cigarettes are an effective and safe aid in smoking cessation in a heavily
dependent smoker who is considering to quit.

PRO: E-cigarettes are an effective and safe CON: E-cigarettes are not an effective and safe
means for smoking cessation in this heavily means for smoking cessation in this heavily
dependent smoker. dependent smoker.

Katrina J. Villegas, MD (CHH)

Sayyid Ronron D. Datukon, MD (SLMC)
Kenneth Jorge A. Lasafin, MD ( MMC)
Ruby Rose S. Bisquera, MD (CGH)
Kenneth Jay-R Alberca, MD (PSH)
Sonde Cris Punay,MD (USTH)
Neil Angelo B. Tiangco, MD (TMC)

JUDGES: Imelda M. Mateo, MD, FPCCP; Lenora C. Fernandez, MD, FPCCP; Anthony C.
Leachon, MD, FPCP
MODERATOR: Lalaine M. Mortera, MD, FPCCP
HOST TEAM: Iandrof G. Patricio, MD (MDH); Dolores Joy Ocampo-Rillera, MD (UPHDMC);
Milraam L. Quinto, MD (UP-PGH)
DOCUMENTATION: Randy Joseph A. Castillo, MD (LCP); Mark Janiel I. Cacanindin, MD
(PHC); Emmylou Adamos, MD (VMMC)
SESSION CHAIR: Julie Christie G. Visperas, MD, FPCCP
SESSION CO-CHAIR: Mark Leonard C. Flores, MD, FPCCP

Vol. 18 | Issue 01 | March 2017 16

 PCCP PLENARY SESSION 7

TOPIC: The New Staging in Lung CA by Dr. Saeed Mirsadraee (United Kingdom)

Date / Time / Venue: March 9, 2017 (Thursday), 08:15 – 09:00am, Reception Hall, Ground floor
Chairman: Roland M. Panaligan, MD, FPCCP

Objectives:
At the end of the session the participant will
• apply the revisions in the new lung cancer staging
• identify the limitations of the new staging

Sleep Medicine ASC CONVENTION SYMPOSIUM 9

Session
TOPIC: Sleep Disordered Breathing Solutions
March 9, 2017 (Thursday), 07:50 – 09:00am
Meeting Room 4, 2nd Floor Delegation Building

Title & Speaker/s:

Oral appliance for OSA: an update by Dr. Liao Yu-Fang (Taiwan)
Beyond CPAP: ventilation in SDB by Dr. Mark Elliott (United Kingdom)
Minimally invasive surgery for OSA by Dr. Yap Yoke-Yeow (Malaysia)

Chairman: Keith Romeo S. Aguilera, MD, FPSSM

Sleep Medicine
ASC PLENARY SESSION 8
Session
TOPIC: Forensic Sleep Medicine by Dr. Michel A. Cramer-Bornemann (USA)
March 9, 2017 (Thursday), 09:15 – 10:00am
Reception Hall, Ground floor

Chairman:Albert L. Rafanan, MD, FPCCP, FPSSM

Objectives:
At the end of the session the participant will
• recognize the inherent clinical complexities associated with complex Parasomnias and
identify that these have potential far-reaching legal implications.
• briefly review the conceptual model based upon neuroscientific principles in which to better
understand the broad spectrum of Parasomnias.
• define Sleep Forensics- a rapidly growing forensics investigative field.
• identify those Parasomnias which are most likely to have forensic implications.

Visit the EXHIBITS

(10:00 – 10:30 am) at 3rd/F Delegation Building

17
1 Phil J Chest Dis 2017
 PCCP PLENARY SESSION 9

TOPIC: The Call to Personal Leadership by Mr. Francis J. Kong (Philippines)

Date / Time / Venue: March 9, 2017 (Thursday), 10:30 – 11:15am
Reception Hall, Ground floor

Chairman: Malbar G. Ferrer, MD, FPCCP

Objectives:
At the end of the session the participant will
• value their inherent talents to be leaders
• identify the levels of leadership

Sleep Medicine
Session ASC CONVENTION SYMPOSIUM 10

TOPIC: Sleep and the Specialist II

March 9, 2017 (Thursday), 10:20 – 11:30am
Meeting Room 4, 2nd floor Delegation Building

Title & Speaker/s:

Sleep and Public Health: Screening for Drowsy Driving by Dr. Tayard Desudchit (Thailand)
Sleep and Strokes by Dr. Rimawati Tedjasukmana (Indonesia)
Sleep and Renal Dysfunction by Dr. Ning-Hung Chen (Taiwan)

Chairman: Dr. Yotin Chinvarun (Thailand)

PCCP PLENARY SESSION 10

TOPIC: High Flow Nasal Oxygen (HFNO) & Non-Invasive Ventilation (NIV) in Respiratory
Failure by Dr. Mark Elliott MA MD FERS (United Kingdom)
March 9, 2017 (Wednesday), 11:15am – 12:00nn
Reception Hall, Ground floor

Chairman: Teresita S. de Guia, MD, FPCCP

Objectives: Sponsored and supported by:

At the end of the session the participant will
• determine the physiologic differences of
HFOT vs NIV
• evaluate the effectiveness of the 2 strategies
in managing hypoxemia.

Vol. 18 | Issue 01 | March 2017 18

 Sleep Medicine
Session ASC CONVENTION SYMPOSIUM 11

TOPIC: P2P2: OSA Matters for Asians (Concurrent Discussions)

March 9, 2017 (Thursday), 11:30am – 12:00nn
Meeting Room 4, 6, 7 & 8, 2nd/F Delegation Building

Title & Speaker: Improving CPAP acceptability among your patients by Dr. Naricha
Chirakalwasan (Thailand) (Meeting Room 4)
Chairman: Richmond B. Ceniza, MD, FPCCP, FPSSM

Title & Speaker: Preoperative evaluation of OSA patients by Dr. Agnes T. Remulla
(Philippines) (Meeting Room 6)
Chairman: Maria Patricia T. Puno, MD, FPSSM

Title & Speaker: Weight reduction strategies in OSA by Dr. Gabriel Jasul Jr. (Philippines)
(Meeting Room 7)
Chairman: Rosauro C. Cabana, MD, FPCCP, FPSSM

Title & Speaker: Portable PSGs for remote areas by Dr. Tripat Deep Singh (Singapore)
(Meeting Room 8)
Chairman: Teresita Celestina S. Fuentes, MD, FPCCP, FPSSM

LUNCHEON SYMPOSIA

Luncheon Symposium 4
Date: March 9, 2017 (Thursday)
Venue: Reception Hall, Time: 12:00nn – 1:30pm
Title & Speaker: “Updates in the Management of COPD” by Prof. Jadwiga Anna Wedzicha
(United Kingdom)
(Through a CME grant from Novartis Healthcare Philippines, Inc.)

Luncheon Symposium 5
Date: March 9, 2017 (Thursday)
Venue: Summit C/D, 4th Floor, Time: 12:00nn – 1:30pm
Title & Speaker: “The Emerging Role of LAMA/LABA in COPD Management”
Prof. Klaus F. Rabe, MD, PhD (Germany)
(Through a CME grant from Boehringer Ingelheim)

Luncheon Symposium 6
Date: March 9, 2017 (Thursday)
Venue: Summit E/F, 4th Floor, Time: 12:00nn – 1:30pm
Title & Speaker/s: “Bacteria in Respiratory Tract: Treat ot Not to Treat”
Ricardo C. Zotomayor, MD, FPCCP (Philippines)
Rontgene M. Solante, MD, FPSMID (Philippines)
(Through a CME grant from Pfizer Inc.)

19
1 Phil J Chest Dis 2017
 Visit the EXHIBITS
(10:00 – 10:30 am) at 3rd/F Delegation Building

PCCP PLENARY SESSION 11

TOPIC: COPD: The Role of Physical Activity by Prof. Klaus F. Rabe, MD, PhD (Germany)
Date / Time / Venue: March 9, 2017 (Thursday), 02:00 – 2:45pm; Reception Hall, G/ F, PICC

Chairman: Bernice T. Ong-de la Cruz, MD, FPCCP

Objectives:
At the end of the session the participant will
• Identify the current scientific evidences of the benefits of pulmonary rehabilitation
• understand the mechanisms on how pulmonary rehabilitation improve outcomes in COPD
• instruct a COPD patient on how to increase physical activity in places with no physical
rehabilitation facilities based on evidence

Sleep Medicine
Session ASC CONVENTION SYMPOSIUM 12

TOPIC: Sleep in the Workplace

March 9, 2017 (Thursday), 01:20 – 2:30pm
Meeting Room 4, 2nd floor, PICC

Title & Speaker/s:

• Chronobiology and Sleep Research and the Design of shift work routines by Prof.
Gayline F. Manalang Jr., PTRP, MOH (Philippines)
• Personalizing treatment for shiftwork sleep disorders by Manuel C. Jorge II, MD, FPCCP,
FPSSM (Philippines)

Chairman: Jimmy V. Chang, MD, FPSSM

PCCP CLINICAL SYMPOSIUM 13

TOPIC: GOLD 2017

March 9, 2017 (Thursday), 03:00 – 04:30pm
Reception Hall, G/F, PICC

Speaker & Topic: Does “Early COPD” diagnosis matter? By Tomas M. Realiza, MD, FPCCP
Objectives:
At the end of the session, the participant will
• recognize the importance of diagnosing early COPD
• practice the steps on how to diagnose early COPD
• enumerate the treatment options for early COPD

Vol. 18 | Issue 01 | March 2017 20

 Speaker & Topic: COPD therapy: Thoughts on De-escalation by Prof. Klaus F. Rabe, MD,
PhD
Objectives:
At the end of the session, the participant will
• understand the data on blood eosinophils as a biomarker for ICS responsiveness
• comprehend the rationale of the ICS (de-escalation) withdrawal therapy among COPD
patients
• adhere to guidelines on how to institute de-escalation therapy: Who? When? How?

Speaker & Topic: Pharmacologic Treatment Algorithm: Story Behind by Prof. Jadwiga
Anna Wedzicha
Objectives:
At the end of the session, the participant will
• apply the GOLD 2017 treatment algorithm
• comprehend the rationale and controversies for the preferred treatment pathway”
• in the GOLD 2017 pharmacologic treatment pathway algorithm

Speaker & Topic: Panel Discussion: GOLD 2017: Strengths and Future Directions by Prof.
Jadwiga Anna Wedzicha
Objectives:
At the end of the session, the participant will
• understand the merits of the revisions in the GOLD 2017
• enumerate suggestions on how to further improve the GOLD 2017

Chairman: Luisito F. Idolor, MD, FPCCP

Moderator: Joel M. Santiaguel, MD, FPCCP

PCCP CLINICAL SYMPOSIUM 14

TOPIC: Interactive Discussion on Pleural Effusions

March 9, 2017 (Thursday), 03:00 – 04:30pm
Summit Hall C/D, 4th floor, PICC

Speakers: Ariel A. Boongaling, MD (Pulmonology)

Edmund E. Villaroman, MD, FPATACSI (TCVS)
Elizabeth Ann S. Alcazaren, MD (Pathology)

Chairman: Julius Caesar J. Dalupang, MD, FPCCP

Co-chair & Moderator: Christine L. Chavez, MD, FPCCP

Objectives:
At the end of the session the participant will
• To present current knowledge and practice about the diagnostic and therapeutic modalities
for pleural effusion.
• To utilize the best clinical reasoning and decide on the best options in the management
pleural effusion.

21
1 Phil J Chest Dis 2017
Description:
This clinical symposium will be an interactive case discussion about two cases of pleural
effusion. The audience will be asked to answer three questions per case using individual
keypads. After each question or during the flow of discussion, the speakers will be asked for
their evidence-based and experience-based comments.

PCCP CLINICAL SYMPOSIUM 15

TOPIC: Clinical Year Review in Critical Care

March 9, 2017 (Thursday), 03:00 – 04:30pm
Summit Hall E/F, 4th floor, PICC

Title & Speaker/s:

New Oral Anticoagulants: The Good, the Bad and the Ugly by Ivan N. Villespin, MD, FPCCP
(Introduction & Rationale) and Maria Paz B. Mateo, MD, FPCCP
Objectives: At the end of the session the participant will discuss the role of the newer
anticoagulants in the management and prophylaxis in venous thromboembolism

Weaning by Rommel DLR Bayot, MD, FPCCP

Objectives:
At the end of the session the participant will
• Present the latest ATS/ACCP clinical practice guidelines on liberation from
mechanical ventilation
• Apply guidelines in local setting

Prone Positioning by Emily Tan-Aventura, MD, FPCCP

Objectives:
At the end of the session the participant will
• enumerate strategies for management of ARDS
• recognize the clear benefits of prone positioning as to oxygenation and lung mechanics.

Chairman: Ma. Encarnita Blanco-Limpin, MD, FPCCP

Moderator: Cesar Antonio O. Ligo, MD, FPCCP

Sleep Medicine ASC CONVENTION SYMPOSIUM 16

Session
TOPIC: Insomnia from the Bedroom to the Clinic
March 9, 2017 (Thursday), 02:50 – 04:00PM
Meeting Room 4, 2nd floor, PICC

Title & Speaker/s:

• Insomnia-proofing the bedroom by Dr. Deborah Bernardo (Philippines)
• Side Effects and Toxicity of Sedative Hypnotic Agents by Dr. Michel A. Cramer-
Bornemann (USA)
• Cognitive Behavioral Therapy by Dr. Wynette Marie Solis (Philippines)
Chairman: Dr. Rusdi Abd Rashid (Malaysia)

Vol. 18 | Issue 01 | March 2017 22

 Sleep Medicine
Session ASC CONVENTION SYMPOSIUM 17

TOPIC: Bedroom Bumps and Grind

March 9, 2017 (Thursday), 04:00 – 05:10pm
Meeting Room 4, 2nd floor, PICC

Title & Speaker/s:

Movement disorders of sleep by Dr. Rosalina Picar (Philippines)
Solving the snore: From medical to surgical management by Dr. Michael Alexius A. Sarte
(Philippines)

Chairman: Dr. Yuichi Inoue (Japan)

PCCP PLENARY SESSION 12

TOPIC: HAP & VAP: IDSA and PCCP perspective

Isauro Q. Guiang Jr., MD, FPCCP
Rodolfo S. Pagcatipunan Jr., MD, FPCCP
Mario M. Panaligan, MD, FPCP

Date / Time / Venue: March 9, 2017 (Thursday), 04:30 – 05:15pm

Reception Hall, G/ F, PICC

Chairman: Eloise Arabelle M. Caburnay, MD, FPCCP

Objectives:
At the end of the session the participant will
• evaluate the current IDS-ATS HAP and VAP guidelines as to diagnosis and management
• consider PCCP Lung Infection Council recommendations on diagnostics for applicability in
the local settings

PSSM Business Meeting

05:00 – 07:00pm, Meeting Room 8, 2nd floor, PICC

TRAINING INSTITUTION’S REUNION

March 9, 2017 (Thursday), 7:00pm

23
1 Phil J Chest Dis 2017
 Day 3 - FRIDAY, 10TH MARCH – CONVENTION PROPER

SUNRISE SESSION 3: MEDICAL ETHICS

07:00am – 09:00am at Reception Hall, G/F, PICC

Pulmonology & Social Media by Ma. Gia B. Sison, MD, DPCOM

Chairman: Roland M. Panaligan, MD, FPCCP
Objectives:
At the end of the session the participant will
• To present different practical applications of technology and social media in the practice of
medicine and pulmonology.
• To discuss the ethical approach of using online platforms and social media applicable in our
daily clinical practice.

PCCP PLENARY SESSION 13

TOPIC: Issue in the Management of IPF by Dr. Philip Eng (Singapore)
Date / Time / Venue: March 10, 2017 (Friday), 09:15 – 10:00am; Reception Hall, Ground floor

Chairman: Joven Jeremius Q. Tanchuco, MD, FPCCP

Objectives:
At the end of the session the participant will
• evaluate a patient with ILD according to the different clinical spectra of the disease
• decide on initial management plans
• analyze the issues on treatment

Visit the EXHIBITS

(10:00 – 10:30 am) at 3rd/F Delegation Building

PCCP PLENARY SESSION 14

TOPIC: State of the Art: COPD Exacerbations by Prof. Jadwiga Anna Wedzicha (United
Kingdom)
Date / Time / Venue: March 10, 2017 (Friday), 10:30 – 11:15am; Reception Hall, Ground floor

Chairman:Lenora C. Fernandez, MD, FPCCP

Objectives:
At the end of the session the participant will
• identify the limitations in the definition/diagnosis of COPD exacerbations
• analyze what is known and unknown about the COPD exacerbation pathogenesis and
therapy

Vol. 18 | Issue 01 | March 2017 24

 PCCP PLENARY SESSION 15

TOPIC: FERMIN MANALO LECTURE

Sunrise, Sunset: Starting vs Retiring Pulmonologist

Parkash T. Mansukani, MD, FPCCP & Radha Marie M. Sillano, MD

Date / Time / Venue: March 10, 2017 (Friday), 11:15am – 12:00nn

Reception Hall, Ground floor

Chairman: Earl Louis A. Sempio, MD, FPCCP

Objectives:
At the end of the session the participant will
• To present the insights of a starting and a retiring pulmonologist.
• To demonstrate the unique transition between training, medical practice and retirement.
• To present the academic and pharmaceutical/corporate tracks as alternatives to clinical
practice for a pulmonologist
• To correct misconceptions and validate truths in both the academic and pharmaceutical or
corporate lives

LUNCHEON SYMPOSIA
Sleep Medicine Luncheon Symposium 7
Session
Date: March 10, 2017 (Friday)
Venue: Reception Hall, Time: 12:00nn – 1:30pm
Title & Speaker: “The Implications of Sleep Disordered Breathing and Sleepiness on
Driving” by Dr. Mark Elliott MA MD FERS
(PCCP & PSSM sponsored CME session)

Luncheon Symposium 8
Date: March 10, 2017 (Friday)
Venue: Summit C/D, 4th Floor, Time: 12:00nn – 1:30pm
Title & Speaker: “Dual Facets of Methylxanthines in Airway Diseases” by Lenora C.
Fernandez, MD, FPCCP
(Through a CME grant from United American Pharmaceuticals, Inc.)

25
1 Phil J Chest Dis 2017
 Luncheon Symposium 9

Date: March 10, 2017 (Friday)

Venue: Summit E/F, 4th Floor, Time: 12:00nn – 1:30pm

Title & Speaker: “VTE TREATMENT: Anong Bago?...

Ivan N. Villespin, MD, FPCCP
Marie Simonette V. Ganzon, MD

(Through a CME grant from Corbridge Group Phils., Inc.)

PCCP BUSINESS MEETING

March 10, 2017 (Friday), 2:00pm
Reception Hall, Ground Level, PICC

CLOSING CEREMONIES

FAREWELL DINNER
INDUCTION OF NEW OFFICERS

March 10, 2017 (Friday), 06:00pm

Summit Hall D, 4th floor, PICC

Vol. 18 | Issue 01 | March 2017 26

 Faculty Abstracts: Pulmonary Medicine

Faculty abstracts:
PULMONARY MEDICINE
The New TB National Strategic Plan 2017-2012
Anna Marie Celina G. Garfin, MD

The Pulmonary Physical Exams … Dying or Adopting?

Errol O. Ozdalga, MD

Removing Simple Barriers to Asthma Control

Matthew Peters, MD

The New Staging of Lung Cancer

Saeed Mirsadraee, MD

High-Flow Nasal Oxygen (HFNO) and NIV in Respiratory Failure

Mark Elliott, MD

Issues in the Management of Idiopathic Pulmonary Fibrosis

Philip Eng, MBBS, MMed (Int. Med.)

Non-tuberculous mycobacteria infections in bronchiectasis

Eva Polverino, MD, PhD

27
1 Phil J Chest Dis 2017
 Faculty Abstracts: Pulmonary Medicine

The New TB National Strategic Plan 2017-2022

Anna Marie Celina G. Garfin, MD
National TB Control Program manager, Department of Health, Disease Prevention and Control
Bureau

ABSTRACT

2017-2022 Philippine Strategic TB Elimination Plan Phase 1 (PhilSTEP 1)

The Philippines is one of the 9 high tuberculosis (TB) burden countries that have reached the
Millennium Development Goals of decreasing by half the mortality and prevalence rates due to TB
based on the 1990 Guidelines and decrease the trend for the incidence rate. However, despite this
accomplishment, Philippines is still one of the 30 countries with high burden for drug susceptible and
drug resistant TB cases.

In 2016, the National TB Control Program (NTP) in preparation for the formulation of the 2017 to
2022 national Strategic Plan, conducted a joint Program review with partners. Achievements and
Challenges of the Program were presented and the main recommendations were the following:
1. Develop a roadmap towards sustainability
2. Act on the TB law once passed
3. Embrace and scale-up new technologies, medicines and approaches
4. Innovate and be bold to solve problems.

With these findings and recommendations, the Program will implement 7 strategies that are aligned
with the Philippine Health Agenda. The impact indicators will be reduction in TB burden as shown by
the decrease in TB mortality and TB incidence rates, zero catastrophic cost to TB families affected
and having a responsive delivery of TB services.

The 7 strategies (A.C.H.I.E.V.E.) to be implemented are the following:

1. Activate TB patient support groups and communities to access quality TB services
2. Collaborate with other government agencies and partners to reduce out-of-pocket expenses of
TB patients and expand social protection measures
3. Harmonize national and local efforts mobilize adequate and capable human resources for TB
elimination
4. Innovate TB surveillance, research and data generation for decision-making
5. Enforce NTP TB care and prevention standards and use of quality TB products and services
6. Value clients an patients through provision of integrated patient-centered services
7. Engage local government units to implement localized TB elimination plans through multi-
sectoral collaboration.

Vol. 18 | Issue 01 | March 2017 28

 Faculty Abstracts: Pulmonary Medicine

The Pulmonary Physical Exams … Dying or Adopting?

Errol O. Ozdalga, MD
Clinical Associate Professor and Director of Stanford Medicine 25, Department of Medicine,
Stanford School of Medicine, California, USA

ABSTRACT

As medicine evolves with the growth of technology and time for being with our patients gets attacked
by growing demands from other needs, questions are beginning to be asked … isn’t the physical
exam valuable anymore? Does the pulmonary exam have a purpose in medicine? This is partially
fueled by the fact that the physical exam is often not being taught in many schools in the United
States. While students learn basics, they are not taught at the bedside, where disease is found. It is
being argued by some that with the improvements of ultrasound and other technologies, combined
with the lack of this education, we cannot expect that the pulmonary exam, like other aspects of the
exam will be part of the future of medicine.

We will explore the reasons why medicine in the United States is leading to more time away from the
patient, and discuss some of the challenges related to that change with possible implications to
challenges that you may be facing or potentially will face in the future. We will review some aspects
of the evidence base for the pulmonary exam, and share the efforts of the Stanford Medicine 25: an
initiative at Stanford University, to revive the culture of bedside medicine and provide resources
online and in person.

29 Phil J Chest Dis 2017

 Faculty Abstracts: Pulmonary Medicine

Removing Simple Barriers to Asthma Control

Matthew Peters, MD
Professor of Respiratory Medicine, Macquarie University, Sydney, Australia

ABSTRACT

The pathological basis of asthma is now better, if imperfectly, understood as is the necessity to focus
on preventative therapy to achieve the twin goals of improving asthma symptom control and reducing
the future risk of severe asthma events. These most notably are asthma exacerbations but also the
longer term harms of poor current control; whether that be fixed airflow obstruction or systemic side
effects of repeated courses of oral corticosteroids.

Studies performed in many regions have demonstrated that good asthma control is not achieved in
many or the majority of those living with asthma. This is not because of the absence of effective
asthma treatments. Shifting attitudes amongst doctors and patients is essential. There is a strong
belief that hypertension and hypercholesterolemia should be treated to reduce risk of vascular events
that might never occur.

At the same time, there seems a remarkably permissive approach to the non-usage of preventer
therapy in asthma even though the disease is actually present and readily responsive. A key change
in the revised GINA guidelines is the new focus on attending to simple errors that might compromise
the effectiveness of preventer therapies. These, of course, include poor adherence and suboptimal
inhaler technique. In resource-poor countries, cost of preventer medication is important but a
potentially greater cost is generated by the use of ineffective treatments, such as oral
bronchodilators, and the loss of employment or trade income when poor asthma control impedes
capacity for work.

Vol. 18 | Issue 01 | March 2017 30

 Faculty Abstracts: Pulmonary Medicine

The New Staging of Lung Cancer

Saeed Mirsadraee, MD
Consultant Cardiothoracic Radiologist, Royal Brompton Hospital and Chelsea and Westminister
Hospital, London, United Kingdom

ABSTRACT

8th edition of the TNM classification of lung cancer

In 2012, there were 1.8 million new cases of lung cancer worldwide that resulted in over 1.5 million
deaths. Lung cancer is the number one cause of death from cancer in males and is most common in
Central and Eastern Europe and Eastern Asia.

Staging of cancer at the time of diagnosis is the most important predictor of survival, and treatments
options should be based on the disease stage. Since its introduction, the tumour, node, metastasis
(TNM) staging of lung cancer has undergone significant changes based on collected data.

In 2010, the International Association for the Study of Lung Cancer (IASLC) published a major
revision of the TNM staging system for lung cancer (7th edition) that was based on multicentre and
larger cohorts of patients being treated for lung cancer. Despite significant improvement, the data
had deficiencies in the global distribution of the data. The latest classification (8th edition) is based
on information from 77,156 patients with a new diagnosis of lung cancer between 1999 and 2010.

The highlight of the 8th edition is the sub/re-classifications of the TNM based on the survival
outcome. Based on the prognostic data, the main changes in the sub-classifications are related to
the tumour size and other T descriptors; number of the positive nodal stations; and the number of
distal organs involved. Despite its limitations, the new staging system is expected to positively impact
the management of patients with lung cancer.

31 Phil J Chest Dis 2017

 Faculty Abstracts: Pulmonary Medicine

High-Flow Nasal Oxygen (HFNO) and Non-invasive

Ventilation (NIV) in Respiratory Failure
Mark Elliott, MD
Senior Lecturer and Consultant Physician in Respiratory Medicine, University of Leeds
Department of Respiratory Medicine, United Kingdom

ABSTRACT

High flow nasal oxygen (HFNO) was initially developed to provide more accurate and more
consistent increased fractional oxygen concentrations, together with better humidification.
However HFNO also has other physiological effects which may be important in improving
outcomes in patients with respiratory failure. These include a small amount of PEEP and lavaging
of the dead space, reducing carbon dioxide rebreathing. As a result HFNO has been considered
as a potential alternative, or complementary, to non-invasive ventilation (NIV).

A large, multicenter, randomised controlled trial in patients with non-hypercapnic hypoxemic

respiratory failure showed no difference in intubation rates between NIV, standard oxygen and
high flow oxygen therapy. However there was a significant difference in favour of high flow oxygen
in 90 day mortality.

The role of HFNO in hypercapnic respiratory failure remains to be determined, but it may either be
a means of preventing some patients from requiring NIV at all or an alternative in those intolerant
of NIV.

Vol. 18 | Issue 01 | March 2017 32

 Faculty Abstracts: Pulmonary Medicine

Issues in the Management of Idiopathic Pulmonary

Fibrosis
Philip Eng, MBBS, MMed (Int. Med.)
Professor of Respiratory Medicine at the National Heart and Lung Institute, Imperial College,
UK

ABSTRACT

Interstitial lung disease is a broad group of diseases which affects the lung interstitium, resulting
in cough or shortness of breath. The prognosis depends on the cause, and a huge group of
patients have interstitial lung disease due to sarcoidosis, connective tissue or drugs. One of the
biggest difficulties is with Idiopathic Pulmonary Fibrosis, where the etiology remains unknown.
Over the past 3 years, recent advances have been made in the understanding of IPF, with better
diagnostic criteria and more available treatment.

Non-tuberculous mycobacteria infections in bronchiectasis

Eva Polverino, MD, PhD
Servei de Pneumologia, Hospital Universitari Vall d'Hebron (HUVH)

ABSTRACT

Bronchiectasis is an underestimated chronic respiratory disease that has raised increasing

interest worldwide in the last 5 years. Although it was considered an orphan disease up to recent
years, the more recent epidemiological estimations describe this heterogeneous condition as the
3rd most common chronic respiratory disease after asthma and COPD. The pathophysiology
bronchiectasis is mainly characterized by the presence of chronic airways inflammation, reduced
mucociliary clearance and recurrent or chronic infections.

Non-tubercoulous mycobacteria (NTM) infections are frequent infections in bronchiectatic

patients, particularly in middle age female patients. In fact, the presence of bronchiectasis is
described as a condition predisposing to NTM infections but also as a consequence of this
infection (pulmonary sequelae). NTM can have different clinical and radiological manifestations
and involve different tissues and organs. A correct microbiological identification is crucial in order
to define therapy and prognosis. ATS criteria (2007) set the diagnostic criteria to define when
NTM infections should be treated. Unfortunately adherence to guidelines has been quite poor
worldwide, leading to inappropriate management of these infections and potentially to increased
antibiotic resistance. Specific therapeutic recommendations are available today for different NTM
infections due to the fact that different microorganisms show different virulence, antimicrobial
susceptibility, risk factors and prognosis. The management of NTM infections in bronchiectasis is
very challenging and adherence to guidelines and strict follow-up are highly recommended.

33 Phil J Chest Dis 2017

 Faculty Abstracts: Sleep Medicine

Faculty abstracts:
SLEEP MEDICINE
Sleep Medicine: Promise and Directions
Christian Guilleminault, MD

Principles of PAP Titration for Sleep Disordered Breathing

Teofilo Lee-Chiong, MD

Must Know: Sleep Essentials Overcoming Insomnia

Teofilo Lee-Chiong, MD

Science of Non-invasive Ventilation

Teofilo Lee-Chiong, MD

Overlap Syndrome: Obstructive Sleep Apnea and COPD

Teofilo Lee-Chiong, MD

Research collaboration across Asian countries

Yun Kwok Wing, MD

Home Sleep Testing in Remote Areas in ASEAN region

Tripat Deep Singh, MD

Sleep in the ICU

Tripat Deep Singh, MD

Late use of electronic media and its association with sleep, depression, and
suicidality among Korean adolescents
Seung Bong Hong, MD

Adolescent sleep habits and their impact on school life

Joshua J. Gooley, MD

Oral Appliances for Obstructive Sleep Apnea: An Update

Yu-Fang Liao, DDS, PhD

Beyond CPAP: Ventilation in Sleep Disordered breathing

Mark Elliot, MD, FERS

Obstructive Sleep Apnea and Stroke

Rimawati Tedjasukmana, MD

Vol. 18 | Issue 01 | March 2017 34

 Faculty Abstracts: Sleep Medicine

Faculty abstracts:
SLEEP MEDICINE
Renal Disease in OSA
Ning-Hung Chen, MD

OSA Matters for Asians: Improving CPAP Acceptability among your patients
Naricha Chirakalwasan, MD

Obstructive Sleep Apnea and Cardiovascular Disease

Albert L. Rafanan, MD

Sudden Death in Sleep Among Asians

Maria Felicidad Soto, MD

Solving the snore: From medical to surgical management

Michael Alexius Sarte, MD

Preoperative Evaluation of OSA Patients

Agnes Remulla, MD

Movement Disorders in Sleep: Restless and Sleepless

Rosalina Espiritu-Picar, MD

Sleep and Pregnancy

Ruth Divinagracia, MD

Chronobiology and sleep research and the design of shift work routines
Gayline F. Manalang Jr., PTRP, MOH

Weight Management Strategies in Obstructive Sleep Apnea

Gabriel Jasul, Jr., MD

Cognitive Behavioral Therapy for Insomnia (CBT-I)

Wynette Marie Solis, MA

Personalizing Treatments for Shift Work Disorder

Manuel Jorge II, MD

35 Phil J Chest Dis 2017

 Faculty abstracts: Sleep Medicine

Sleep Medicine: Promise and Directions

Christian Guilleminault, MD
Director of Training, Stanford University Sleep Disorders Center, California, USA

ABSTRACT

Sleep Medicine has advanced throughout the world and congresses are on many continents. The
World congress in Sleep Medicine was in Seoul in 2015 and will be in Prague in 2017, and the
International Pediatric Sleep Association meeting was in Taipei in 2016 and will be in Lille (France) in
2018.

Advances have involved the “hypersomnias”: The ICSD 3rd ed. recognizes type-1 and type 2
narcoleptics and hypersomniacs. But many questions this subdivision: Type-1 narcoleptics (also
labelled narcolepsy-cataplexy) appears well defined. It is related to the des truction of the hypocretin
neurons in the lateral hypothalamus and destruction of the 5 bundles impinging on other structures.
Recent imaging (PET) and performance tests studies, indicate that many brain-structures affected by
the elimination of the 5 bundles show abnormal findings with hypometabolism in in the frontal lobe,
posterior cingulum, angular gyrus and part of the parietal lobe; these changes associated with more
errors on the performance test. There is also hypermetabolism in the fusiform gyrus, striatum,
hippocampus, thalamus, basal ganglia , and cerebellum than in type-2 narcoleptics.

But the type 2 narcoleptics are significantly less impaired at our different testing than type-1 patients,
they are different from controls, they even have significantly more hypometabolism in Heschl gyrus
and in the paracentral lobule than type-1 narcoleptics. They have much less impairment in the
learning and memory regions and perform better than the type-1 narcoleptics at cognitive testing and
have better maintenance of overall sleep and wakefulness cycles, but have daytime sleepiness
objectively. The question is again raised concerning the name ”narcolepsy” if such a term should not
be reserve only for the type-1 with cataplexy and absence of hypocretin in CSF. Such patients are
much more affected than any other ”hypersomniacs” and Ohayon et al recent morbidity study shows
that co-morbidity including reduction in life expectancy is shown.

The world of OSA has shown also advances: Abnormal breathing seems in many cases to begin in
childhood. The upper-airway, ie a collapsible tube during sleep due to disappearance of reflexes
during sleep, is also susceptible to minor anatomic changes that occur early in life due to absence of
normal functions: ie sucking, swallowing, chewing and nasal breathing: The inter-maxillary cartilage,
and the dento-alveolar ligament-both active growth center of the oral-facial region till about 14-15
years are not stimulated as it should be and normal oral facial growth do not occur leading to greater
risk of collapse during sleep. Fat that primary infiltrate the tongue muscles will also have a role by
again increasing the soft tissue mass and narrowing the upper-airway increasing its collapsibility.

Recognition of the above problems early in life should lead to functional reeducation through
myofunctional therapy (MFT) in association with orthodontic treatments, in children as adenotonsil-

Vol. 18 | Issue 01 | March 2017 36

 Faculty Abstracts: Sleep Medicine

lectomy (T&A) are not sufficient to eliminate risks of OSA. MFT have even been used in adults and
has shown to significantly reduce adult AHI, up to 50%, but compliance with treatment is important,
and at least 3/12 months every year, exercises to maintain normal UA muscle tone are need after the
initial 3 to 6 months re-education period.

Recognition early in life of risk factors and their treatment will decrease the development of OSA.
In adult without major obesity and AHI<55 and age to 60 years may benefit from XII nerve
implantation, but this treatment is still in its beginning phase despite the fact that progress has been
made in our understanding of where to stimulate (most anterior part of the XII nerve to avoid
stimulating retrusive fibers) and which stimulating frequencies to use. Hypoglossal nerve stimulation
has limitation, but has been an alternative treatment for patients that failed other treatment
particularly PAP therapy

Restless Leg Syndrome is still a major syndrome in sleep-medicine, the hypothesis is still that there
is an iron abnormality involved but not of the circulating iron, but of the brain iron, either related to
abnormality of the blood-brain barrier or other abnormalities. Dopamine agonists always lead to
“augmentation” if prescribe long term, Rotigotin patch may help but this long acting dopamine agonist
may not be the solution once augmentation is noted, but IV iron perfusion has been performed even
in patient with normal blood ferritin level wit good results. Perfusion in 1-L normal saline passed in 1
to 2 hours has been given good results for 6 to 18 months without complaints in chronic RLS
patients.

Cognitive Behavior Therapy for Insomnia (CBT-I) is more and more used in the treatment of chronic
insomnia and long term positive results have been confirmed in several studies with a long term
success rate of about 60%. The available hypocretin-antagonist Suvorexant (Belsomra; Merck) is not
a widely used medication. It is recommended for maintenance insomnia, but most commonly
maintenance insomnia is related to abnormal breathing during sleep, with “flow limitation” and mild
OSA [UARS] and secondary frustration related to waking up all the time; the association of CPAP,
Dental appliance and CBT-I usually give better results. The problem of the medication is its absence
of impact on sleep-onset insomnia with activity late in the night. But the mode of action seems to be
safer than for GABA-type drugs with no impact on memory and no residual sleepiness.

Efforts are made to study neuro-muscular patients early during sleep, as breathing abnormalities
during sleep largely precede changes in pulmonary function test performed awake. Systematic sleep
testing is more and more recommended when such disorder is suspected, with usage of bilevel
initially, that may give a better quality of life during wakeful ness to patients.

These are some of the recent advances in the field.

37 Phil J Chest Dis 2017

 Faculty abstracts: Sleep Medicine

Principles of PAP Titration for Sleep Disordered Breathing

Teofilo Lee-Chiong, MD
Professor of Medicine, University of Colorado, National Jewish Health, Colorado, USA

ABSTRACT

Positive airway pressure (PAP) therapy is the treatment of choice for most patients with sleep
disordered breathing. Selecting the proper modality and optimal settings guarantee the best
outcomes. This presentation will provide an overview of the different positive airway pressure
devices, including continuous PAP, automatic PAP, bilevel PAP, pressure control, volume-assured
pressure support, servo ventilation, and volume control, and recommendations on their use.

Must Know: Sleep Essentials Overcoming Insomnia

Teofilo Lee-Chiong, MD
Professor of Medicine, University of Colorado, National Jewish Health, Colorado, USA

ABSTRACT

Insomnia is the most common sleep-related disorder. It consists of difficulty falling asleep (sleep
onset insomnia), difficulty staying asleep (sleep maintenance insomnia) or earlier-than-desired
morning awakenings (terminal insomnia). These various sleep disturbances are associated with
impairments of daytime functioning. This presentation will discuss the major presenting features,
demographic characteristics, causes and complications of chronic insomnia, and provide guidelines
on evaluating and treating patients with this disorder.

Vol. 18 | Issue 01 | March 2017 38

 Faculty Abstracts: Sleep Medicine

Science of Non-invasive Ventilation

Teofilo Lee-Chiong, MD
Professor of Medicine, University of Colorado, National Jewish Health, Colorado, USA

ABSTRACT

Non-invasive ventilation is increasingly being used both in the hospital and home to manage patients
with acute and chronic respiratory failure. Used properly, non-invasive ventilation has been shown to
improve survival, reduce morbidity, decrease hospital length of stay, improve quality of life, and lower
healthcare costs. This presentation will cover the pathophysiology of hypoventilation as it progresses
from mild to advanced disease.

Overlap Syndrome: Obstructive Sleep Apnea and COPD

Teofilo Lee-Chiong, MD
Professor of Medicine, University of Colorado, National Jewish Health, Colorado, USA

ABSTRACT

Obstructive sleep apnea (OSA)-chronic obstructive pulmonary disease (COPD) overlap syndrome is
defined by the simultaneous presence of both disorders in the same individual. Each disorder has
unique presentations, but both share many common features. Managing patients with OSA-COPD
overlap syndrome can be challenging, and requires a thorough understanding of the mechanisms
responsible for sleep disturbances and respiratory derangements. This presentation will tackle some
of the main diagnostic and therapeutic conundrums of clinical management.

39 Phil J Chest Dis 2017

 Faculty abstracts: Sleep Medicine

Research collaboration across Asian countries

Yun Kwok Wing, MD
Professor, Department of Psychiatry, The Chinese University of Hong Kong, Hong Kong

ABSTRACT

Sleep problems and disorders, for example, sleep deprivation in school-aged children and
adolescents is an emerging epidemic across the world. Numerous studies consistently indicate that
the suggested amount of sleep is rarely followed by children and adolescents and poor sleep is
associated with pervasive consequences for their health, academic achievement and overall well-
being.

Previous studies suggested that Asian adolescents obtain nearly an hour less sleep than their
European and American counterparts. However, most studies varied in their methodologies such
sampling, measurement tools and study design. In addition, the similarities and differences in cross-
cultural/ethnic perspectives of sleep problems may assist to further the understanding of the etiology
of the disorders. An example is the difference in the facial morphology that may explain the paradox
of the epidemiology of OSA between Chinese and Caucasian (similar prevalence despite the
disparaging rate of obesity).

The establishment of the Asian Society of Sleep Medicine promotes a platform to foster and develop
research across Asian countries. It provides us a privileged opportunity to study sleep problems and
patterns across different age groups, cultures and regions. For example, as sleep deprivation is
closely related to a web of interactive factors including cultural, biological, school, environmental and
social aspects, a multi-country trans-Asian study will allow us to understand its complex interactions
that closely link to children and adolescents’ sleep and health.

We will re-examine the current scenario of sleep research across Asia, especially looking for
epidemiological aspects of sleep patterns and problems. We will then propose a feasible research
plan by establishing an Asian database (e.g., various sleep disorders like OSA) and examining the
potential cultural differences in sleep problems and patterns among school aged children and
adolescents and their parents.

Vol. 18 | Issue 01 | March 2017 40

 Faculty Abstracts: Sleep Medicine

Home Sleep Testing in Remote Areas in ASEAN region

Tripat Deep Singh, MD
Assistant Professor, College of Medicine, Pondicherry Institute of Medical Sciences, India

ABSTRACT

Prevalence of Obstructive Sleep Apnea (OSA) in general population is high and comparable to rest
of the world in ASEAN region. Prevalence of OSA is also high in different disease states. Treatment
of OSA improves quality of life and also lead to improvement in co-morbidities. OSA can be
diagnosed and treated by two methods- in-lab testing and CPAP titration or Home Sleep Testing
(HST) and Auto CPAP (APAP). There are very few Sleep labs and also shortage of trained
manpower, both Sleep Physicians and Sleep Technologist, in ASEAN region and Sleep labs are
mainly located in big cities. There is no re-imbursement for Sleep diagnostics or therapy and patients
pay for these services out of their pocket. There is a need for cheap, less technically demanding, less
time consuming and equally effective as PSG approach. HST-APAP approach is less costly, less
technically demanding and as effective as PSG-CPAP Titration approach. HST-APAP is a good
option to increase diagnosis of OSA and its treatment in remote areas of ASEAN region.

Sleep in the ICU

Tripat Deep Singh, MD
Assistant Professor, College of Medicine, Pondicherry Institute of Medical Sciences, India

ABSTRACT

Sleep and sedation are not same. Sleep in the ICU is highly fragmented and equally distributed
between day and night. Sleep in the ICU can be studied by polysomnography, bispectral index,
actigraphy or subjective assessment by questionnaires. In the ICU, sleep architecture is not the
same as in a healthy person, and two new stages has been proposed: atypical sleep and
pathological wakefulness. A lot of factors can disrupt sleep in the ICU, such as environmental factors,
pathophysiological factors, and disrupted circadian rhythm. There is no robust long-term ICU
outcomes with regards to sleep available. Non-pharmacological interventions like ear plug plus eye
mask has been shown to improve delirium and subjective sleep parameters in ICU patients. The
wise use of drugs in the ICU may help to improve sleep. There is conflicting evidence regarding role
of melatonin in ICU patients. Remelteon has been shown to improve delirium without effect on sleep
parameters.

41 Phil J Chest Dis 2017

 Faculty abstracts: Sleep Medicine

Late use of electronic media and its association with sleep,

depression, and suicidality among Korean adolescents
Seung Bong Hong, MD
Director, Epilepsy and Sleep Center, Samsung Medical Center, South Korea

ABSTRACT

Objective: We aimed to investigate the association of adolescents' last electronic media use time
with their sleep and mood disturbances, including depression and suicidality. We also examined
whether sleep disturbances and duration mediated the relationship between last media use time and
mood disturbances.

Methods: This cross-sectional, school-based, online survey was administered by the Sleep Center
at Samsung Medical Center and the Korea Centers for Disease Control and Prevention (KCDC) in
2011. A total of 26,395 participants (12,593 male and 13,802 female) were recruited from 150 middle
and high schools representative of nationwide adolescents from 15 administrative districts in Korea.
The sleep habits of participants on weekdays and weekends were evaluated using a questionnaire.
Sleep disturbances, depression, and suicidality were assessed using the Korean versions of the
Global Sleep Assessment Questionnaire, Epworth Sleepiness Scale, and Beck 19-item Scale for
Suicide Ideation. We also collected last media use time, from which we subtracted actual bedtime.

Results: Late electronic media use was significantly associated with increased mood disturbances
including depression and suicidality directly, but not indirectly via sleep duration or disturbances.

Conclusion: Our results suggest that adolescents might benefit from the restricted use of electronic
media after bedtime in terms of their mood and sleep. Moreover, education regarding media use at
night might be helpful in preventing youth suicide.

Vol. 18 | Issue 01 | March 2017 42

 Faculty Abstracts: Sleep Medicine

Adolescent sleep habits and their impact on school life

Joshua J. Gooley, MD
Vice President, Singapore Sleep Society, Singapore

ABSTRACT

Sleep is important for the mind and body. However, many adolescents curtail their sleep in exchange
for study time or the pursuit of leisure activities.

We examined the consequences of short sleep on performance and mood in adolescents attending
schools in Singapore. Based on a survey of sleep habits in more than 1,800 adolescents across 7
schools, we found that shorter nocturnal sleep duration on school nights was associated with poorer
self-rated health, higher body mass index, higher depression scores, and lower self-reported grades.

In a pair of quasi-laboratory studies performed at a boarding school, we also found that exposure to
short sleep (5 hours of time in bed per night) was associated with impaired vigilance, vocabulary
learning, and mood compared with exposure to an age-appropriate amount of sleep (9 hours of time
in bed per night). Together, these studies suggest that exposure to insufficient sleep may erode the
value of formal education, with negative consequences for student performance and well-being.

43 Phil J Chest Dis 2017

 Faculty abstracts: Sleep Medicine

Oral Appliances for Obstructive Sleep Apnea: An Update

Yu-Fang Liao, DDS, PhD
Director, Graduate Institute of Dental and Craniofacial Science, Chang Gung University,
Taoyuan, Taiwan

ABSTRACT

As the general public and our specialty better recognize the interactions between craniofacial
dental morphology and obstructive sleep apnea, orthodontists are expected to become proficient
in the diagnosis and management of obstructive sleep apnea. Although not as predictable and
effective as continuous positive airway pressure therapy, the gold standard treatment for
obstructive sleep apnea, oral appliances (OA) remain an important therapeutic consideration.

The most commonly used OA reduces upper airway collapse by advancing the mandible. There
is a strong evidence base demonstrating OA improve obstructive sleep apnea in the majority of
patients, including some with severe disease. Although short-term adverse effects are common,
OA are generally well tolerated. Long-term dental changes do occur, but these are subclinical
and do not preclude continued use.

This presentation will (1) introduce our interdisciplinary approach in treating obstructive sleep
apnea; and (2) provide our clinical guidelines for OA use, patient selection, design features, and
follow-up.

Vol. 18 | Issue 01 | March 2017 44

 Faculty Abstracts: Sleep Medicine

Beyond CPAP: Ventilation in Sleep Disordered Breathing

Mark Elliot, MD, FERS
Professor, University of Leeds, UK

ABSTRACT

There are a number of conditions for which continuous positive airway pressure (CPAP) would not
usually be considered as a mode of ventilatory support. These include patients with either slowly or
rapidly progressive neuromuscular disease, chest wall deformity and some patients with obstructive
lung disease. However in these patients, upper airway obstruction is more common and CPAP may
be an option initially. Detailed physiological testing and a sleep study will help in making this
decision. Other patients will initially start CPAP for obstructive sleep apnea but “fail” and for some
NIV is an option; what constitutes “failure” is a topic for discussion. Complex sleep apnoea refers to
the development of central sleep apnea de novo in patients with obstructive sleep apnea as a
consequence of CPAP therapy; the management options will be discussed. Finally the management
of central sleep apnea, particularly in patients with heart failure, will be discussed.

Obstructive Sleep Apnea and Stroke

Rimawati Tedjasukmana, MD
Head, Department of Neurology, Universitas Krida Wacana (Ukrida), Jakarta, Indonesia

ABSTRACT

Numerous studies have identified risk factors for stroke, including hypertension, atrial fibrillation,
diabetes, and smoking. OSA is associated with a 3.7 times increase incident of stroke. Emerging
data implicate obstructive sleep apnea (OSA) in the pathogenesis of risk factors associated with
ischemic stroke. These associations are believed to be mediated by adverse physiological responses
to recurrent periods of pharyngeal occlusion and consequent oxyhemoglobin desaturation-
resaturation. These responses result in free radical generation, release of proinflammatory and
prothrombotic mediators, and surges in sympathetic nervous system activity and blood pressure.

Several cross sectional and prospective studies have found strong associations between OSA and
stroke. The obstructive sleep apnea syndrome significantly increases the risk of stroke, and the
increase is independent of other risk factors. In addition several studies suggest that OSA in the post
stroke patient reduces motivation, decreases cognitive capacity, and may increase the risk of
recurrent stroke and death.

45 Phil J Chest Dis 2017

 Faculty abstracts: Sleep Medicine

Renal Disease in OSA

Ning-Hung Chen, MD
Director, Sleep Center, Chang Gung Memorial Hospital, Taiwan

Obstructive sleep apnea (OSA) syndrome is a prevalent disorder. Cardiovascular consequence such
as hypertension, ischemic heart or stroke, and neurocognitive deficit have mostly been addressed in
the past years. Endothelium injury due to intermittent hypoxia was the key mechanism of
cardiovascular and neurocognitive disorder. Albuminuria, indexed by UACR, is a sensitive indicator
for endothelium injury and has been shown to be a cardiovascular risk factor in diabetics,
hypertensives, and general population. Chronic kidney injury such as end-stage renal disease and
proteinuria were closely associated with OSA. Lowering albuminuria is associated with better health
outcomes and has become one of the targets in treating patients with chronic kidney disease with or
without hypertension or diabetes. Our group already demonstrated an increased UACR in OSA
syndrome patients without diabetes and hypertension. Treatment of OSA by CPAP could reverse the
proteinuria is also proved. A report of renal biopsies of OSA have shown glomerulomegaly and focal
segmental sclerosis which increased glomerular filtration and blood flow in previous report. In this
lecture, the prevalence and the mechanism of renal injury in patient of obstructive sleep apnea will
be introduced.

OSA Matters for Asians: Improving CPAP Acceptability

among your patients
Naricha Chirakalwasan, MD
Assistant Professor, Pulmonary and Critical Care Division, Department of Medicine, Faculty of
Medicine, Chulalongkorn University, Bangkok, Thailand

Continuous positive airway pressure (CPAP) is currently a goal standard treatment for obstructive
sleep apnea (OSA). However compliance remains the main problem for its success. Many
interventions designed to improve compliance have been proposed. Factors which are known to be
associated with good CPAP compliance include higher body mass index, higher Epworth sleepiness
scale score, history of witnessed apnea, reduction in daytime sleepiness with CPAP therapy, and
compliance during the first few weeks (2-4 weeks) (known to predict the long term compliance).
Factors which are known to be associated with poor CPAP compliance include the use of anti-
depressants and CPAP induced sleep disturbances. In order to improve CPAP compliance, the first
step is to educate the patients regarding the consequences of untreated OSA, how to properly use
CPAP, and the benefits of CPAP use. Auto adjusting positive airway pressure (APAP) may
marginally improve CPAP compliance. Bilevel positive airway pressure (BPAP) did not clearly show
the improvement in compliance. Heated humidification when utilized routinely also did not improve
compliance. However when it was utilized in the group with nasopharyngeal symptoms, significantly
increase in compliance was observed

Vol. 18 | Issue 01 | March 2017 46

 Faculty Abstracts: Sleep Medicine

Obstructive Sleep Apnea and Cardiovascular Disease

Albert L. Rafanan, MD
Head, Pulmonary Unit and Center for Sleep Disorders, Chong Hua Hospital

ABSTRACT

Obstructive sleep apnea (OSA) is increasingly recognized as an independent risk factor contributing
to cardiovascular morbidity and mortality. There is strong evidence supporting the association
between sleep apnea and hypertension, stroke, arrhythmias and coronary heart disease, as well as
overall cardiovascular mortality. Several physiological mechanisms have been suggested to link OSA
and vascular diseases including sympathetic activation, oxidative stress, vascular inflammation,
hypercoagulability, metabolic dysregulation and endothelial dysfunction. OSA adds to or aggravates
cardiovascular disease, and thus is increasingly recognized as a target for cardiovascular risk
reduction.

Continuous Positive Airway Pressure (CPAP) is the most effective treatment of OSA in reversing
hypoxemia and upper airway obstruction. The meta-analysis of Hu X et al (J Clin Hyperten 2015) on
randomized trials have shown that CPAP allows significant reductions in systemic arterial pressure,
and the effect is greater with higher adherence. Observational studies have shown significantly fewer
cardiovascular events in patients adherent to CPAP than in those who are not adherent. However, a
randomized trial by McEvoy et al (NEJM 2016) for the Sleep Apnea Cardiovascular Endpoints
(SAVE) trial, showed that CPAP did not prevent cardiovascular events in patients with moderate-to-
severe obstructive sleep apnea and established cardiovascular disease. These results need to be
interpreted in application to our clinical practice.

For symptomatic patients with OSA, CPAP should be offered. And CPAP should still be given to
patients with OSA and severe hypoxemia during sleep regardless of symptoms (as these patients
were excluded from the SAVE trial). However, providing CPAP in asymptomatic patients with OSA
and established cardiovascular disease cannot be recommended with the sole purpose of reducing
future cardiovascular events.

47 Phil J Chest Dis 2017

 Faculty abstracts: Sleep Medicine

Sudden Death in Sleep Among Asians

Maria Felicidad Soto, MD
Professor, Department of Neurology, College of Medicine, University of the East Ramon R.
Magsaysay, Philippines

ABSTRACT

Southeast Asian countries have always been proud that there is unity in spite of the diversity of their
cultures. Almost all of our peoples have the same outward appearance, and it is only when we speak
that we can distinguish which country we belong to.

There is another thing that seems to bind us together – and this is the frequency of sudden
unexplained nocturnal death syndrome or SUNDS among our peoples. In most of the ASEAN
countries, this syndrome has recurred repeatedly and has been the subject of speculation, fear and
dread for nearly the past 100 years. In these countries, the similarities stand out. The syndrome is
seen almost exclusively in young healthy males, not known to have any illnesses, who are heard to
struggle and moan in sleep, and inevitably die .

A lot has been learned about SUNDS in these regions, in terms of possible etiologies , mechanisms
and possible treatment. I would like to elaborate on what we know of SUNDS among Southeast
Asian people.

Solving the snore: From medical to surgical management

Michael Alexius Sarte, MD
Head, Center for Snoring and Sleep Disorders, The Medical City, Pasig City, Philippines

ABSTRACT

Snoring has always been and will always be a social problem. Unfortunately as it is the hallmark of
obstructive sleep apnea (OSA), that makes it a medical problem as well given the many
complications of OSA. Let us now review the myriad of solutions from the medical evidence to the
surgical procedures being offered to address snoring and what we can do to the multitude that
exhibit this most annoying manifestation.

Vol. 18 | Issue 01 | March 2017 48

 Faculty abstracts: Sleep Medicine

Preoperative Evaluation of OSA Patients

Agnes Remulla, MD
Head, Sleep Laboratory, Asian Hospital and Medical Center
Head, Section of Oropharyngology, Department of Otorhinolaryngology-Head and Neck Surgery,
University of the Philippines-Philippine General Hospital, Philippines

ABSTRACT

Patients with known or suspected obstructive sleep apnea (OSA) are known to have a higher risk for
anesthesia and surgical procedures. A team approach between the surgeon, sleep physician and
anesthesiologist should be performed in order to thoroughly map out strategies for pre-operative
preparation, selection of anesthesia technique, post-operative airway management and
anticipation/prevention of untoward events.

We discuss preoperative surgical practice and experiences among the attendees caring for patients
with OSA.

Movement Disorders in Sleep: Restless and Sleepless

Rosalina Espiritu-Picar, MD
Co-Director, Sleep Disorders Laboratory, Makati Medical Center, Makati City, Philippines

ABSTRACT

Motor movements during sleep are a common source of confusion not just for sleep medicine
practitioners but neurologists as well. This lecture will focus on restless legs syndrome and periodic
limb movements which are one of the most common movement related sleep disorders and a
common cause of poor sleep. Symptomatology, diagnosis and treatment of these conditions will be
highlighted.

REM sleep-related parasomnias, of which REM behavior disorder is the most described, will
likewise be discussed in terms of its symptomatology, diagnosis and management. Its linkage to
other degenerative neurologic disorders will also be discussed.

49 Phil J Chest Dis 2017

 Featured researches: Sleep Medicine

Sleep and Pregnancy

Ruth Divinagracia, MD
Clinical Associate Professor, College of Medicine, University of the Philippines-Philippine
General Hospital, Philippines

ABSTRACT

Pregnancy has been associated with increased sleep disturbances, even in women who never had
sleep problems. In a 1998 Women and Sleep Poll (National Sleep Foundation), 78% of women
report more disturbed sleep during pregnancy than at other times. The most common sleep problems
during this period include:
1. Insomnia;
2. Restless Leg Syndrome (RLS); and,
3. Obstructive Sleep Apnea Syndrome (OSAS).

Insomnia is not surprising since anxiety and stress about labor, balancing work/motherhood as well
as the hormonal changes associated with the pregnancy by themselves can cause it. The physical
discomforts of pregnancy (need to go to bathroom, back and joint pains, leg cramps, contractions)
have been cited by women in their 2nd and 3rd trimesters as main factors for sleep disturbance.

Restless Leg Syndrome (RLS) has been reported to occur in up to 30% of pregnant women and is
characterized by the urge to move the legs accompanied by disagreeable sensations. This leads to
disturbed sleep and daytime fatigue.

OSAS is daytime sleepiness associated with snoring, cessation of breathing and gasping and
choking sensations. OSAS is believed to be of higher prevalence during pregnancy brought about by
weight gain and the hormonal changes associated with pregnancy. The presence of OSAS has been
associated with increased risk of gestational hypertension and gestational diabetes. There have
been small studies that have shown increased risk for unplanned Caesarian deliveries as well as low
birthweight infants.

Pregnancy is a time of great joy and anticipation for most women but medical providers must be
cognizant of the fact that majority of expectant mothers have sleep problems that have to be
addressed to mitigate the risks for both mother and child.

Vol. 18 | Issue 01 | March 2017 50

 Faculty abstracts: Sleep Medicine

Chronobiology and Sleep Research and the Design of

Shift Work Routines
Gayline F. Manalang Jr., PTRP, MOH
Assistant Professor, College of Public Health, University of the Philippines Manila, Philippines

ABSTRACT

Contemporary society relies on 24/7 industries to meet their demand for products and services.
Economic contributions of the workforce following a night or shifting work routine are significant.
Safeguarding their productivity, well-being, and health is important, thus the effect of these work
routines has become a concern not just of workers but also their employers.

Differences in health and sleep outcomes between individuals who do shift work are found to result
from the interaction of characteristics of the shift or social routine (external time) and the individual’s
“body clock” (chronotype or one’s internal time). In order to effectively characterize shift work
outcomes, chronobiology research groups such as the German-Philippine collaboration PhilSHIFT
(http://philshift.upm.edu.ph) adapt approaches where the documenting external time-internal time
relationship is a core principle.

The above approach requires the development of chronotype tools for specific populations; a
chronotype database yielding reference values for sleep and key health indicators; and the pursuit of
a variety of chronobiology-oriented projects—field studies, laboratory experiments, as well as
modelling. Recent chronobiology and sleep projects have demonstrated the potential of using
products of such an approach to design work for productivity and sleep.

51 Phil J Chest Dis 2017

 Faculty abstracts: Sleep Medicine

Weight Management Strategies in Obstructive Sleep

Apnea
Gabriel Jasul, Jr., MD
Clinical Associate Professor, College of Medicine, University of the Philippines-Philippine
General Hospital, Philippines

ABSTRACT

Obesity and obstructive sleep apnea (OSA) are interrelated multidirectionally, involving complex
mechanisms that lead to adverse cardiovascular and metabolic outcomes. It is estimated from
reported studies that almost half of moderate to severe cases of OSA are attributed to excess
weight. Weight reduction is therefore clearly needed in a significant number of OSA cases. The
projected amount of weight loss to be of benefit with regards to OSA is at least 10% of baseline
weight. The amount of weight loss has been evaluated in relation to improvement in OSA
indices as well as quality of life.

Weight management in general is challenging. Many physicians are not well-trained in guiding
and treating obese patients. Health care facilities are also often not well-equipped to manage
obese patients. The treatment options for obesity are also not uniformly accessible. When the
complications of obesity, including OSA and cardiometabolic problems, are already present,
weight management even becomes more difficult. Practical steps in weight management
through lifestyle intervention (diet, physical activity), behavioral modification, drug therapy and
bariatric surgery will be highlighted vis-à-vis the limitations and challenges in clinical practice
specifically as they relate to obese patients already with OSA and with cardiovascular and
metabolic complications.

Vol. 18 | Issue 01 | March 2017 52

 Faculty abstracts: Sleep Medicine

Cognitive Behavioral Therapy for Insomnia (CBT-I)

Wynette Marie Solis, MA
Clinical Psychologist, Memory Center, University of Santo Tomas Hospital, Manila, Philippines

ABSTRACT

Cognitive Behavioral Therapy for Insomnia (CBT-I) aims to solve problems concerning dysfunctional
behaviors, cognitions, and emotions related to insomnia through goal-oriented and systematic
procedures. There is overwhelming evidence that CBT-I is as effective as sedative hypnotics, and is
more effective in the long-term treatment of insomnia. Unlike sleeping pills, CBT-I helps the client
overcome the underlying causes of his/her sleep problems. In a study by the American Academy of
Sleep Medicine, CBT-I was effective in treating up to 80% of people.

An effective initial screening process is needed in order to determine if the patient is a good
candidate for CBT-I, or if an alternative treatment would be more effective. Once the patient is
identified as a candidate for CBT-I, weekly one-hour therapy sessions, for a maximum of 8 sessions,
would ensue. CBT-I consists of psychoeducation, behavior therapy (sleep hygiene, stimulus control,
sleep restriction), cognitive therapy/cognitive restructuring, mindfulness-based therapy (relaxation
skills, distress tolerance skills, emotion regulation skills) as well as general psychotherapy. Re-
evaluation and relapse prevention is provided at the end of the therapy.

53 Phil J Chest Dis 2017

 Faculty abstracts: Sleep Medicine

Personalizing Treatments for Shift Work Disorder

Manuel Jorge II, MD
Chair, Department of Medicine, University of the Philippines- Philippine General Hospital,
Manila, Philippines

ABSTRACT

Shift work disorder (SWD) results from a misalignment of circadian rhythm. Its main manifestations
are insomnia during sleeping periods and excessive sleepiness during work periods. Treatment for
SWD are directed towards maintaining wakefulness and alertness during work period and promoting
sleep after work shift period.

Exposing the worker to bright light during work suppresses endogenous melatonin production
thereby decreasing the urge to sleep. Taking a nap shortly before work and during work decreases
fatigue and increases alertness. Caffeine, modafinil and armodafinil maintain wakefulness when
taken before work shift.

The cornerstone to promoting sleep is having good sleep hygiene practices. These include a cool,
dark and quiet sleeping bedroom. Wearing sunglasses on the way home from work blocks light and
promotes realignment. Melatonin, melatonin agonist and hypnotics are pharmacologic agents that
can be tried to promote sleep.

There is no single therapy for SWD. Each individual will need to try various combinations of
treatment strategies. But if nothing works, shifting to a daytime job is the best option.

Vol. 18 | Issue 01 | March 2017 54

 Poster presentation: Sleep Medicine

Poster presentation:
SLEEP MEDICINE
Clinical Characteristics of Obstructive Sleep Apnea Syndrome in
Indonesian Adults
Telly Kamelia, SpPD

Sleep, slipping away…

Leong Lai Kuan, MBBS

Prevalence of Restless Legs Syndrome and Sleep Related Disorders in

Filipino Hemodialysis Patients
Kristine Mae Vega-Alava, MD; Rodolfo Dizon, Jr, MD

Association of Excessive Daytime Somnolence and Metabolic Profile in

Newly Diagnosed Hypertensive OPD Patients seen in Ospital ng Makati
Marie Menette I. Agapito, MD; Rodolfo Dizon Jr, MD

Anthropometric Measurements as a Screening for Obstructive Sleep

Apnea among Employees of Philippine Heart Center
Mander L. Cambonga, MD; Aileen G. Banzon, MD; Ma. Encarnita B. Limpin, MD

Association of Sleep Quality with Glucose Control in Filipino Adults with

Type 2 Diabetes Mellitus
Abigail C. Zaraspe, MD; Virginia S. Delos Reyes, MD; Cecilia A. Jimeno, MD

55 Phil J Chest Dis 2017

 Poster presentation: Sleep Medicine

Clinical Characteristics of Obstructive Sleep Apnea

Syndrome in Indonesian Adults
Telly Kamelia, SpPD

ABSTRACT

BACKGROUND: Obstructive sleep apnea (OSA) is a recurrent episodes of upper airway collapse
either partial or complete during sleep. This causes the gas exchange and sleep disorders.
Prevalence and characteristics of obstructive sleep apnea syndrome in Indonesia remain unclear.
This study want to show the prevalence and characteristics of obstructive sleep apnea patients
based on polysomnography report in Jakarta, Indonesia.

METHODS: The study involved patients with suspected OSA investigated with polysomnography
(PSG) type III including continuous recordings of nasal airflow by thermistor, oximetry, body position
detection, and vibration sound detection at some sleep department in Jakarta, Indonesia. The sleep
report were used to assess characteristics of OSA based on Apnea-Hypopnea Index (AHI), AHI in
supine and non-supine position, average oxygen saturation, Oxygen Desaturation Index (ODI),
snoring time and number of snoring episodes. Results were analyzed using Pearson test,
Spearman test and Kolmogorov-Smirnov test.

RESULTS: Fifty-four subjects were included; 47 subjects were diagnose with OSA with AHI score
≥5. Most OSA subjects aged 68.1% are adults (41-65 years), 74.5% were men and 55% subjects
are obese (BMI ≥30 kg/m2). The PSG result showed that 31.5% had mild OSA; moderate OSA was
22.2%, and severe OSA was 33.3%. Based on sleep position, 71.8% of OSA are in supine position,
severe ODI (33.3%), median (minimum) average SaO2 was 94.5 (70.6), mean sleep duration was
434.3 ± 67.88 minutes with a mean snoring time of 26.18% ± 16.03% of total sleep duration. There
were significant differences between OSA severity and between BMI classified (p=0.006). BMI
significantly correlated with AHI (p=0.001; r=0.444), average oxygen saturation (p<0.001; r=-0.470),
ODI (p=0.002; r=0.405), and number of snoring episodes (p=0.044; r=0.276).

CONCLUSION: OSA is highly prevalent in adults (41-65 years of age), and increased with BMI.
There are correlations between BMI with AHI, average oxygen saturation, ODI, and number of
snoring episode.

Vol. 18 | Issue 01 | March 2017 56

 Poster presentation: Sleep Medicine

Sleep, slipping away…

Leong Lai Kuan, MBBS
University of Malaya, Kuala Lumpur, Malaysia

ABSTRACT

Introduction: Obstructive Sleep Apnea (OSA) and Obesity Hypoventilation Syndrome (OHS) often
co-exist, yet this overlap syndrome is often unrecognized, leading to significant morbidity and
mortality and delay in treatment. We report a case of a patient with an overlap syndrome who nearly
slipped into death in her sleep.

Case: A 63-year old obese lady (body mass index of 47.1 kg/m²) with diabetes mellitus and
hypertension presented with reduced effort tolerance for the past 1 year. At home, she dozed off
easily when watching television channel. One week prior to her admission to the hospital, she was
weaker than usual and was unable to do house chores. She slept more often than usual. One day
prior to admission, her son found it hard to wake her up for dinner. On awakening, she took some
food and slept again.

Thereafter, she was immediately brought to the hospital for unconsciousness. In the emergency
department, her Glasgow Coma Scale was 10/15. Her oxygen saturation was 80-90% on high flow
mask oxygen. She had severe type 2 respiratory failure and was put on bilevel positive airway
pressure (BiPAP) ventilation. She made a remarkable recovery on BiPAP ventilation.

Investigations: Her arterial blood gas showed type 2 respiratory failure on high flow mask with a pH
of 7.136, PCO2 of 106 mmHg, and HCO3 of 25.5 mmol/L. Chest x-ray showed no consolidation or
cardiomegaly. Her echocardiography showed a good left ventricular ejection fraction of 81% with
trace tricuspid regurgitation with a pulmonary artery systolic pressure of 29 mmHg. Her
polysomnography showed an apnea-hypopnea index of 78.6 and she had mainly hypopneic during
the diagnostic part of the polysomnography, with frequent desaturations, with the lowest saturation of
55%. The continuous positive airway pressure (CPAP) therapy up to 13 cmH2O during REM sleep
corrected almost all her respiratory events with a lowest saturation of 90%.

Conclusion: It is important to recognize and differentiate obstructive sleep apnea patients who are
eucapnic and those with OSA and OHS who are hypercapnic. Treatment options are different
between the two conditions. CPAP is used in OSA while BiPAP is used in overlap syndrome.

57 Phil J Chest Dis 2017

 Poster presentation: Sleep Medicine

Prevalence of Restless Legs Syndrome and Sleep-related

Disorders in Filipino Hemodialysis Patients
Kristine Mae Vega-Alava, MD; Rodolfo Dizon, Jr, MD
Department of Internal Medicine, Ospital ng Makati, Makati City, Philippines

ABSTRACT

Objective: This study aims to investigate the prevalence of Restless Legs Syndrome (RLS) and its
sleep related disorders in Filipino hemodialysis patients.

Methodology: We enrolled 71 eligible patients who answered questionnaires during a face-to-face

interview. The questionnaires used were International Restless Legs Syndrome Study Group
(IRLSSG) criteria for the diagnosis of RLS, Insomnia Severity Index (ISI), Epworth Sleepiness Scale
(ESS) and Pittsburgh Sleep Quality Index (PSQI). Other potential risk factors for RLS including
biochemical tests were also evaluated.

Results: Our study results showed that out of 71 hemodialysis patients, 34 (47.89%) presented with
RLS. Mean age of the patients was 56.97 years. It occurs most frequently in males (62%) and those
who are overweight (p=0.00), with lower glomerular filtration rate (p=0.011), and higher serum
potassium and phosphorus levels (p=0.00 and p=0.01 respectively). Hemodialysis patients with RLS
also have higher scores in ISI (p=0.00012) and ESS (p=0.0031) and PSQI (p=0.00026) than those
without RLS.

Conclusion: Our study suggests that RLS and its sleep related disorders are common among
hemodialysis patients and they should be properly recognized and treated to improve their quality of
life.

Vol. 18 | Issue 01 | March 2017 58

 Poster presentation: Sleep Medicine

Association of Excessive Daytime Somnolence and

Metabolic Profile in Newly Diagnosed Hypertensive OPD
Patients seen in Ospital ng Makati
Marie Menette I. Agapito, MD; Rodolfo Dizon Jr, MD
Department of Internal Medicine, Ospital ng Makati, Makati City, Philippines

ABSTRACT

Objective: To know the association of excessive daytime somnolence (EDS) and metabolic profile in
newly diagnosed hypertensive OPD patients

Methods: This was a prospective cross-sectional study that included 80 newly diagnosed
hypertensive patients seen at Ospital ng Makati OPD, aged over 19 years. A socio-demographic
questionnaire, and a validated Filipino version of Epworth Sleepiness Scale were used as data
collection tools.

Results: Patients with EDS had higher average fasting blood sugar (FBS) (6.05 mmol/L vs 5.1
mmol/L), HbA1c (6.65% vs 6%), low-density lipoprotein (LDL) (3.35 mmol/L vs 2.1 mmol/L),
triglycerides (TG) (1.87 mmol/L vs 1.56 mmol/L), and total cholesterol (5.9 mmol/L vs 5.02 mmol/L).
Patients with LDL levels >3 mmol/L or TG >1.8 mmol/L were 11 times as likely to have EDS vs those
with normal levels.

Conclusion: Patients with EDS had higher average FBS, HbA1c, LDL and cholesterol and can
therefore be an independent CV risk factor. Newly diagnosed hypertensives with LDL levels >3
mmol/L or TG >1.8 mmol/L were approximately 11 times as likely to have EDS vs normal.

59 Phil J Chest Dis 2017

 Poster presentation: Sleep Medicine

Anthropometric Measurements as a Screening for

Obstructive Sleep Apnea among Employees of Philippine
Heart Center
Mander L. Cambonga, MD; Aileen G. Banzon, MD; Ma. Encarnita B. Limpin, MD

ABSTRACT

Introduction: This study aims to determine the association of anthropometric measurements with
the risk for obstructive sleep apnea (OSA) through the use of Berlin Questionnaire among employees
of Philippine Heart Center.

Methodology: This is a cross sectional study conducted at the Philippine Heart Center, with
employees as the participants. Anthropometric measurements of 260 subjects were obtained and
assessed for risk of OSA through Berlin questionnaire.

Result: Subjects who were high risk for OSA based on the Berlin Questionnaire were significantly
more likely than those at low risk to have an increased weight, and body mass index (BMI); larger
neck circumference (NC), waist circumference (WC), hip circumference (HC) and thigh
circumference. Increased BMI, WC, and waist-to-hip ratio (WHR) were statistically significant risk
factors for OSA.

Conclusion: Increased BMI, WC and WHR, if associated with snoring, daytime somnolence, fatigue
and hypertension, makes a person high risk for OSA.

Vol. 18 | Issue 01 | March 2017 60

 Poster presentation: Sleep Medicine

Association Between Sleep Quality and Glucose Control in

Filipino Adults with Type 2 Diabetes Mellitus
Abigail C. Zaraspe, MD; Virginia S. Delos Reyes, MD; Cecilia A. Jimeno, MD

ABSTRACT

Objective: To determine the association between sleep quality and glucose control among type 2
diabetes mellitus (T2DM) Filipino adults.

Methods: This was a cross-sectional analytic study involving 241 T2DM Filipinos seen consecutively
at various outpatient clinics for 8 months. Sleep quality was measured using the Pittsburgh Sleep
Quality Index Questionnaire. HbA1c within one month was used to assess glucose control. Sleep
disordered breathing (SDB) and excessive daytime sleepiness (EDS) were screened using the
Berlin Questionnaire (BQ) and Epworth Sleepiness Scare (ESS) respectively.

Result: Poor sleep quality was noted in 55% of the population. Patients with poor glucose control
were more likely to have poor sleep quality (OR=5.5012; 95%CI 3.0881, 9.7997; p<0.001). HbA1c,
asthma/chronic obstructive pulmonary disease (COPD), and sleeping alone are predictors of poor
sleep quality based on PSQI scoring. Among the study population, 33% are high risk for SDB using
the BQ and 26% have EDS using ESS.

Conclusion: Poor sleep quality is directly correlated with poor glucose control. Factors that worsen
sleep quality among T2DM are elevated HbA1c, asthma/COPD and sleeping alone.

61 Phil J Chest Dis 2017

GENERAL RESEARCH PAPER
SUBMISSIONS FROM
PULMONARY MEDICINE
TRAINING INSTITUTIONS

Vol. 18 | Issue 01 | March 2017 62

 Asthma and COPD

Utility of DECAF score in Hospitalized Patients with COPD

in Acute Exacerbation
Dennis Mark N. Santos, MD; Guinevere Dy-Agra, MD
St. Luke’s Medical Center, Quezon City, Philippines

ABSTRACT

Background: Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) requiring

hospitalization, in-hospital mortality was 7.7%, as reported in the 2008 UK National COPD Audit.1 A
robust clinical prediction tool, developed from a large prospective cohort of unselected admissions,
could assist decisions regarding: location of care; early escalation of care; appropriateness for end-
of-life care; and suitability for early supported hospital discharge and therefore could help to reduce
morbidity and mortality and direct the most efficient use of resources.

Materials and Methods: This is a retrospective study that evaluated the predictive performance of
DECAF score in terms of in hospital stay and in hospital mortality of suspected patients admitted as
AECOPD at St. Luke’s Medical Center Quezon City, from March 2014 – March 2015. A
comprehensive chart review of included patients will be recovered from the Medical Records Section
of St. Luke’s Medical Center. Descriptive statistics was used to summarize the clinical characteristics
of the patients. Frequency and proportion was used for nominal variables, mean and standard
deviation were used as indicators of continuous variables.

Results: From March 2014 until March 2015 we had 408 patients who were admitted at St. Luke’s
Medical Center and diagnosed with COPD or COPD at risk, but only 67 patients were admitted due
acute exacerbation of COPD, and only 47(11.5%) patients who met the inclusion criteria. As shown
in Table 1, the baseline characteristics of 47 patients were, 38.2% were aged 73-82 years old,
majority were males [78.7%], 70.2% had normal BMI. Moreover, as noted in Table 2, 85.2% had
stayed in the hospital <15 days while 10.6% had expired, 87.3% were discharged. The assessment
of 47 patients revealed that 65.9% had high risk score, 27.7% had intermediate, and only 6.4% had
low risk. Using the intermediate risk score, in predicting overall accuracy it yielded 100% sensitivity,
20% specificity, likelihood ration of 1.25, and negative predictive value of 100%. Meanwhile, since
there is only 1 case of death with intermediate score and it occurred during in-hospital, the 30-day
mortality cannot be appropriately estimated. On the other hand, using the high risk score, it yielded
higher sensitivity of 100% in predicting in-hospital and 30-day mortality yet it generated very low
specificity of 10%. It also showed that the high risk score showed higher negative predictive values at
in-hospital (100%) and 30-days mortality (100%).

Conclusion: The DECAF Score is a simple yet effective predictor of mortality in patients hospitalized
with an exacerbation of COPD and has the potential to help clinicians more accurately predict
prognosis, and triage place and level of care to improve outcome in this common condition. It is
relatively a new prediction tool, and more prospective studies are needed to establish its clinical
utility.

63 Phil J Chest Dis 2017

 Asthma and COPD

Phenotyping of Adult Patients with Bronchial Asthma at the

Lung Center of the Philippines OPD Asthma Clinic: A 6-
month Pilot Study
Maria Jennifer A. Apurillo, MD; Paul Rilhelm M. Evangelista, MD; Glynna O. Cabrera, MD;
Vincent M. Balanag, MD
Department of Pulmonary, Sleep and Critical Care Medicine, Lung Center of the Philippines,
Quezon City, Philippines

ABSTRACT

Introduction: Bronchial asthma is a common heterogeneous disease with a complex

pathophysiology that carries a significant mortality rate and high morbidity. Current therapies based
on inhaled corticosteroids and long-acting beta-agonists remain effective; however, some patients do
not respond to these treatments even at high doses of corticosteroids. Our study aimed to investigate
the cellular phenotypes among asthma patients seen at the Out- patient Department (OPD) of the
Lung Center of the Philippines, which could account for differences in treatment response.

Methods: This was a cross-sectional study on 80 Filipino asthmatic patients. Peripheral blood and
sputum samples were collected, and demographic and clinical data such as gender, age, smoking
history, body mass index, co-morbidities, medications used and FEV1 were gathered. The patients’
cellular phenotypes were identified, with eosinophilic phenotype defined as >300 cells/mm3 per
blood sample or > or equal to 3% in sputum examination.

Results: The eosinophilic phenotype was predominant (57.5%) using peripheral blood among
asthmatic patients at the OPD. The sputum examination tested on a subset of these patients showed
that the paucigranulocytic and eosinophilic phenotypes were equally predominant at 46.7% each. No
demographic nor clinical characteristic was associated with the eosinophilic phenotype. Compliance
(p <0.01) and the dose of steroid use (p= 0.09) were statistically different between controlled and
uncontrolled asthmatic patients. There was no statistically significant association between the level of
asthma control and eosinophilic vs non-eosinophilc phenotypes.

CONCLUSION: Eosinophilic phenotype is the most predominant phenotype among asthmatic

patients at the Lung Center of the Philippines OPD Asthma Clinic using peripheral blood.
Eosinophilic and paucigranulocytic phenotypes are the most common phenotypes using sputum
analysis. There was no association between phenotypes and level of asthma control.

Vol. 18 | Issue 01 | March 2017 64

 Asthma and COPD

Association of Serum Uric Acid Levels and Outcomes of

Patients with Chronic Obstructive Pulmonary Disease: A
Prospective Cohort Study
John Ray T. Galamay, MD; Ma. Encarnita Limpin, MD; Fernando G. Ayuayo, MD
Division of Pulmonary and Critical Care Medicine, Philippine Heart Center, Quezon City,
Philippines

ABSTRACT

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is one of the leading causes of
morbidity and mortality with increasing prevalence worldwide. Changes in oxygen tension such as
hypoxia, has been found to modulate the release of purine metabolites such as uric acid. Serum uric
acid increases significantly during hypoxia. Elevated uric acid levels have been associated with the
presence of systemic inflammation and increased cardiovascular risk. Also, it could serve as a non-
invasive indicator for COPD severity.

METHODOLOGY: This is a prospective cohort analytic study among COPD in exacerbation patients
at Philippine Heart Center. Serum uric acid level determination was done as part of the routine blood
tests obtained during admission. Patients were followed-up until discharge and through a telephone
conversation 30 days after discharge to determine mortality. Serum uric acid level was then analysed
for correlation with mortality, length of hospitalization, intensive care unit (ICU) stay and noninvasive
ventilation (NIV).

RESULTS: A total of 159 patients were included in the study (57% male). Their mean age was 69
years old. Majority (91 %) were smoker, with a mean average smoking history of 25.57 9.03 pack-
year. One hundred forty-four patients (91%) had no previous pulmonary tuberculosis treatment.
Majority were under GOLD Classification C (55%). Patients with high serum uric acid levels had a
mean average hospital stay of 16.38 6.58 days (vs 14.48 7.24 days in those with low uric acid;
p=0.9535). They had a higher rate of 30-day mortality (10% vs 0%; p=0.005). Their ICU admission
rate was 19.0% (vs 11.59%; p=0.799). Moreover, patients with high serum uric acid levels were more
likely to required NIV (p<0.001).

CONCLUSION: Elevated serum uric acid levels on admission among patients with COPD in
exacerbation are associated with increased 30-day mortality and increased risk of NIV use.

65 Phil J Chest Dis 2017

 Asthma and COPD

Blood Eosinophilia as Predictor for Outcomes in Chronic

Obstructive Pulmonary Disease Exacerbations: A
Systematic Review And Meta-Analysis
Ralph Elvi M. Villalobos, MD; Aileen Wang, MD
Section of Pulmonary Medicine, University of the Philippines-Philippine General Hospital,
Manila, Philippines

ABSTRACT

INTRODUCTION: The eosinophilic phenotype of chronic obstructive pulmonary disease (COPD) has
been demonstrated to respond better to corticosteroids and associated with better outcomes. This
review aims to elucidate the correlation of blood eosinophilia and outcomes patients with COPD
exacerbations.

METHODS: Inclusion criteria include cohorts, case-control or trials that looked into blood
eosinophilia and outcomes in exacerbations. The primary study outcome was length of
hospitalization; other outcomes include readmission and mortality rate within 1 year, in-patient
mortality, and need for mechanical ventilation.

RESULTS: Six studies were included in the review. Patients with blood eosinophilia had significantly
shorter hospital stay compared to non-eosinophilic patients (mean difference 0.68 days [95% CI
1.09,0.27]). Eosinophilic patients had significantly less frequent readmissions (OR 0.69 [95% CI
0.55,0.87]) but there was no statistically significant difference in the 1-year mortality rate (OR 0.88
[95% CI 0.73, .06]). Analysis showed a trend toward lower in-patient mortality among eosinophilic
patients (OR 0.53 [95% CI 0.27,1.05]). Furthermore, COPD patients with eosinophilia had
significantly less need for mechanical ventilation during an exacerbation (OR 0.56 [95% CI
0.35,0.89]).

CONCLUSIONS: Our meta-analysis suggested that COPD patients with blood eosinophilia had
significantly shorter hospital stay, less frequent readmissions, and are less likely to require
mechanical ventilation compared to the non-eosinophilic phenotype but results are significantly
heterogeneous to draw concrete conclusions.

Vol. 18 | Issue 01 | March 2017 66

 Asthma and COPD

Efficacy and Safety of Long-Acting Beta-Agonists (LABA)

Plus Long-Acting Muscarinic Antagonists versus LABA
Plus Inhaled Corticosteroids in Chronic Obstructive
Pulmonary Disease: A Meta-Analysis
Ralph Elvi M. Villalobos, MD; Aileen Wang, MD
Section of Pulmonary Medicine, University of the Philippines-Philippine General Hospital,
Manila, Philippines

ABSTRACT

Background and Objectives: Current Global Initiative for Chronic Obstructive Lung Disease
(GOLD) guidelines recommend the use of long-acting beta agonists (LABA) plus inhaled
corticosteroids (ICS), or long-acting muscarinic antagonists (LAMA) for the treatment of patients with
moderate to severe COPD. The novel combination of LABA/LAMA has been approved for COPD
patients with severe symptoms; however, its role in reducing exacerbations is less clear.

Methods: We performed a meta-analysis of randomized controlled trials that compared efficacy and
safety of LABA+LAMA versus LABA+ICS in moderate to severe COPD patients. The primary
outcome is the rate of yearly COPD exacerbations. Other outcome measures include improvement in
trough FEV1, St. George Respiratory Questionnaire for COPD (SGRQ-C) scores, transition dyspnea
index (TDI) scores, rescue medication use and pneumonia risk. Analysis was performed in
accordance with the Quality of Reporting of Meta-Analyses (QUORUM) guidelines.

Results: Six randomized controlled trials, which were all assessed to be of good quality and low risk
of bias. It included 3,370 patients altogether. Over-all exacerbation rates were 21% lower in those
treated with LABA/LAMA versus LABA/ICS (RR 0.79, [95% CI 0.66-0.94]). This effect is more
pronounced in patients who had at least 1 exacerbation per year, showing 25% lower exacerbation
rates (RR 0.75 [0.60-0.95]) compared to those with no history of prior exacerbations (RR 0.85 [0.61-
1.14]). Patients given indacaterol/glycopyrronium also experienced lower exacerbation rates versus
LABA+ICS (RR 0.71 [0.57-0.59]), unlike those on umeclidinium/vilanterol (RR 1.16 [0.68-2.00]).
There were statistically significant improvements in FEV1 (mean difference 0.070 L [95% CI 0.07-
0.07 L]), SGRQ-C (mean difference -0.92 points [95% CI -0.95,-0.90]), and TDI scores (mean
difference 0.24 [95% CI 0.23-0.25]); as well as a decrease in use of rescue medications (mean
difference -0.20 puffs/day [95% CI -0.21, -0.20]) in patients given LABA/LAMA versus those on
LABA/ICS. Pneumonia risk was significantly lower in patients given LABA/LAMA vs LABA/ICS (RR
0.59 [95% CI 0.43-0.80]).

Conclusions: The combination of LABA+LAMA is safer and more effective in reducing

exacerbations and improving clinical outcomes compared with LABA+ICS in patients with moderate
to severe COPD.

67 Phil J Chest Dis 2017

 Asthma and COPD

Prevalence of Asthma-COPD Overlap Syndrome (ACOS)

Among Patients Presenting with Asthma of COPD in the
OPD of the UP-PGH Section of Pulmonary Medicine: A
Pilot Study
Mariella Macrina Araneta-Cuňada, MD; Ralph Elvi M. Villalobos, MD; Lenora C. Fernandez, MD
University of the Philippines – Philippine General Hospital, Manila, Philippines

ABSTRACT

Background: Asthma and chronic obstructive pulmonary disease (COPD) has significant overlap
and is known as Asthma-COPD Overlap Syndrome (ACOS). Its exact prevalence is still unknown.
ACOS patients have higher risk of exacerbation, and should thus be identified.

Methodology: This was a single-center cross-sectional study. Asthma and COPD patients at the
outpatient department were identified and included until the computed sample size of 54 COPD and
53 asthma patients was reached. Patients were then evaluated for ACOS by history and spirometry.
Clinical characteristics related to these conditions were also evaluated.

Results: The overall prevalence of ACOS was 22.45%. In asthma patients, 26.53% had ACOS while
the rate was 18.37% for COPD. Asthma patients had a mean age of 56.42 + 11.74 years; COPD
patients 66.63 + 9.53 years; and ACOS 65.32 + 8.58 years. Majority with asthma were females
(69.44%), while majority with COPD (92.5%) and ACOS (63.64%) were males. Of the asthma
patients, 5% had PTB. The rates were 40.91% for ACOS and 47.5% for COPD patients had PTB.
Only 13.9% with asthma smoked, while 97.5% of COPD and 62.2% of ACOS patients smoked. The
mean smoking history was 4.72 + 14.67 pack-years for asthma, 50.6 + 30.28 pack-years for COPD,
and 32.23 + 37.65 pack-years in ACOS.

Vol. 18 | Issue 01 | March 2017 68

 Asthma and COPD

Comparison of Glycopyrronium plus Indacaterol compared

to Inhaled Corticosteroids plus Long-Acting Beta-Agonists
in Patients with Chronic Obstructive Pulmonary Disease: A
Meta-Analysis
Jim Paulo Pantas, MD; Krislyn Panugayan, MD; Cristeta Perez, MD
Manila Doctors Hospital, Manila, Philippines

ABSTRACT

Overview: Chronic obstructive pulmonary disease (COPD) is a chronic lung disease that is of great
clinical importance because of its impact on people’s health. The GOLD guidelines have set the bar
for the clinical management of COPD. The guidelines have labeled inhaled corticosteroids (ICS) plus
long-acting beta-agonists (LABA) as the treatment of choice for moderate to severe COPD. However,
LABA plus long-acting muscarinic antagonists (LAMA) combinations are considered an alternative
therapy.

Objectives: The main objective of this study is to compare a LABA/LAMA combination (i.e.,
indacaterol/glycopyrronium) to ICS/LABA in terms of risk of exacerbation. Secondary outcomes
include risk of adverse events.

Methods: A thorough and extensive search was done using MEDLINE, clinicaltrials.gov and
Cochrane Library. Included studies should have been randomized controlled trials (RCT) that
included patients in moderate to severe COPD. Studies should have a minimum study period of 24
weeks. Participants should have been divided into a LABA/LAMA group (indacaterol/glycopyrronium)
and ICS + LABA. Pooled analysis and statistics was done using the Review Manager version 5.3.

Results: Three trials were included in this meta-analysis in which 4,625 participants were included.
The risk of exacerbations was less in the LABA/LAMA group (HR 0.74; 95% CI 0.61, 0.90).

Conclusion: LABA/LAMA combinations can be an effective and safe way to manage COPD
patients. These treatments have potential to be a first-line treatment option.

69 Phil J Chest Dis 2017

 Asthma and COPD

Knowledge and Use of Spirometry for the Diagnosis of

Chronic Obstructive Pulmonary Disease Among Senior
Medical Residents in Metro Manila
Erlyn D. Lopez, MD; Bernice Ong-Dela Cruz, MD
Section of Pulmonary Medicine, Chinese General Hospital and Medical Center, Manila,
Philippines

ABSTRACT

Background: Spirometry is an essential tool in the diagnosis of chronic obstructive pulmonary

disease (COPD). Therefore, in view of the clinical application of spirometry, this study aims to assess
the knowledge and use of spirometry among senior medical residents in different training institutions.

Methods: This was a questionnaire-based study conducted across 38 training hospitals in Metro
Manila.

Results: A total of 117 senior medical residents responded to the survey. Although majority of the
senior medical residents knew the importance of history and symptoms (>95%) and spirometry
(90%) to differentiate chronic obstructive pulmonary disease (COPD) from asthma, almost half (48%)
do not routinely use spirometry for the detection of COPD. The most common reasons for not
performing spirometry were additional patient expenses (60%), the test seemed unnecessary (34%),
and patient preference not to perform the test (29%). Only about 20% of senior medical residents are
very comfortable in interpreting spirometry results in contrast to more than 85% of them are very
comfortable in interpreting an electrocardiogram. Stated aims of COPD treatment included reduction
of exacerbations (97%), improvement of patient quality of life (95%), and the reduction of
hospitalization (90%). In respondents from institutions with pulmonary fellowship training programs,
38.33% stated that FEV1 is the bases of COPD diagnosis, versus 24.56% in institutions without
similar training programs (p=0.109).

Conclusion: The results showed that senior medical residents in training generally were lacking
adequate knowledge and use of spirometry in the detection of COPD. Hence, educational efforts
such as workshops and continuing medical education on spirometry are recommended as part of
their training programs.

Vol. 18 | Issue 01 | March 2017 70

 Asthma and COPD

Correlation of Fractional Exhaled Nitric Oxide Level with

Severity of Chronic Obstructive Pulmonary Disease
Johnson O. See, MD; Rommel Bayot, MD; Ma. Encarnita Blanco-Limpin, MD; Fernando G.
Ayuyao, MD
Division of Pulmonology Medicine, Philippine Heart Center, Quezon City, Philippines

ABSTRACT

Background: Fractional exhaled nitric oxide (FeNO) is being used as a marker of inflammation in
the disease activity of different lung diseases. Chronic obstructive pulmonary disease (COPD) is a
progressive airflow obstruction with neutrophilic inflammation. This study aimed to measure FeNO
levels in documented COPD patients to assess whether the FeNO level was related with the severity
of COPD.

Method: We measured the FeNO level of patients diagnosed with COPD thru spirometry and
correlated the FeNO level with the severity of the COPD as dictated by the lung function.

Results: We enrolled 35 COPD patients and categorized them based on the Combined GOLD
model of symptom/risk of evaluation of COPD (2011). Exhaled nitric oxide levels were significantly
higher in those in COPD GOLD D (38.5 + 7.7 parts per billion) as compared to those in COPD GOLD
A (23.4 + 1.14 parts per billion). However, the correlation between FeNO and lung function
assessment by % predicted FEV1 was weak and not statistically significant. (r= 0.21, p= 0.231).

Conclusion: FeNO shows potential as a marker for monitoring disease severity in COPD.

71 Phil J Chest Dis 2017

 Malignancy

Validity of the LENT Prognostic Score for Predicting

Survival in Malignant Pleural Effusion
Rylene A. Baquilod, MD
Section of Pulmonary and Pulmonary Critical Care Medicine, Chong Hua Hospital, Cebu City,
Philippines

ABSTRACT

Introduction and objectives: Malignant pleural effusion (MPE) is commonly a characteristic of

advanced malignancy, with reported median survival of 3 to 6 months among patients. It is
associated with debilitating symptoms contributing to a poor quality of life. Although options to
palliate symptoms are varied, treatment modalities themselves may cause morbidity and necessitate
an in-hospital stay – options that may not be acceptable to a patient at the end-stage of life. Thus,
identification of clinical factors that can predict survival among patients with MPE may guide the
palliative management of this group of patients. The LENT score is a risk stratification system to
predict survival in patients with MPE. It is calculated using readily available clinical data including
pleural fluid LDH, ECOG Performance score, neutrophil-to-lymphocyte ratio and tumor type. This
study aimed to determine the validity of the LENT Score as a predictor of survival in MPE.

Methods: The medical records of admitted adult patients with malignant pleural effusion were
retrospectively analyzed. Their baseline demographics and LENT parameters were collected and
their LENT scores calculated and reported. Survival based on retrospective analysis was then
correlated with the LENT scores.

Results: One hundred patients were included in the study. Calculation of their LENT scores showed
significant association with survival. Patients with high, moderate, and low-risk LENT scores had a
mean survival time of 1.76 months, 10 months, and 20 months, respectively. In particular, the LENT
score was more accurate at predicting patients with shorter projected survival.

Conclusion: The LENT score is a valid prognostic scoring system that can predict survival in
patients with MPE.

Vol. 18 | Issue 01 | March 2017 72

 Malignancy

LENT Prognostic Score in Malignant Pleural Effusion at

Veterans Memorial Medical Center
Mary Jane A. Cadiente MD; Tito C. Atienza MD
Veterans Memorial Medical Center, Quezon Cit, Philippines

ABSTRACT

BACKGROUND: Malignant pleural effusion represents an advanced malignant state and reduced
life expectancy following diagnosis. Invasive therapeutic options are performed to provide
symptomatic temporary relief but no intervention to date has been shown to improve survival. With
this, treatment strategies must be discriminative and prudent to reduce if not to avoid complications
that can cause significant morbidity adding more discomfort and inconvenience to the patient.
Therefore, the study aims to assess the use of LENT prognostic scoring system in predicting survival
time in patients with malignant pleural effusion to aid physicians in prognostication and help them in
making sound and optimal clinical management decisions.

METHODS: This is a retrospective-prospective observational cohort study of admitted adult patients

diagnosed with malignant pleural effusion who underwent diagnostic thoracentesis with or without
pleural biopsy. Components of the LENT prognostic scoring system were obtained and risk
stratification was done following the scoring system. All included patients were followed up for 6
months and survival outcome was recorded. Descriptive analysis was done using frequency
distribution for baseline characteristics, mean and median with 95% confidence interval (CI) for
survival time with comparison of the survival curves using the Kaplan Meier survival analysis and
Spearman r coefficient to correlate survival time and risk category.

RESULTS: Of the 98 patients included in the study, low risk LENT score occurred in 2.0% (2/98),
moderate risk LENT score in 54.0% (53/98) and high risk LENT score in 44.0% (43/98). The resulting
log rank test (Chi-squared) p value of 0.0001 indicates that risk level significantly affects the survival
time. Those who had low risk LENT score had longer median survival time of 180 days; 100% of
them survived up to 6 months while those who had moderate risk LENT score had a median survival
time of 128 days; 88.7%, 64.0% and 41.5% of them survived at 1, 3 and 6 months respectively and
those who had high risk LENT score had a shorter median survival time of only 37 days; 58.0%
survived at 1 month, 6.9% survived at 3 months and only 2.3% of them survived at 6 months. The
resulting Spearman r coefficient of -0.6327 signified that survival time and risk category is inversely
related to each other which indicates that as the risk level goes up, their survival time goes down and
becomes shorter. Among the LENT variables, ECOG PS (p=0.0001), serum NLR (p=0.0066) and
tumor type (p=0.0057) significantly affects survival time while pleural fluid LDH (p=0.8016) showed
no significant effect on survival time.

CONCLUSION: LENT prognostic scoring system can predict survival time among patients with
malignant pleural effusion of diverse tumor type, therefore, it can be used in the prognostication of
patients with malignant pleural effusion. However, further research with longer observation period is
recommended to accurately assess the survival time of those with low risk LENT score.

73 Phil J Chest Dis 2017

 Malignancy

Clinical Profiles and Survival of Female Patients

Diagnosed with Primary Lung Cancer Registered at the
Lung Cancer Registry of St. Luke’s Medical Center
Sheilla Mae C. Jalandra, MD; Windfield Tan, MD
Institute of Pulmonary Medicine, St. Luke’s Medical Center-Quezon City, Philippines

ABSTRACT

Introduction: Lung cancer is one of the most common malignancies in the world, and still the
leading cause of cancer death in both men and women.

Methods: This was a ddescriptive, cross-sectional study that determined the demographic pattern,
clinico-radiological presentation, smoking status, histologic type, performance status and stage at
presentation of lung cancer among female patients registered at St Luke’s Medical Center Lung
cancer registry. Records of female patients registered between July 1, 2012–December 31, 2014
were reviewed.

Results: A total of 52 female patients were registered. The mean age of patients was 63.2 ± 9.8
years. Forty-seven of the 52 never smoked. A family history of cancer was found in 27%. ECOG
performance status was 2 for 42% and 1 for 37% of women. Majority were at stage 4 cancer at the
time of diagnosis (83%). Adenocarcinoma was the most prevalent tumor histologic type 73%.
Patients with EGFR positive adenocarcinoma outnumbered those with an EGFR negative subtype.
Cough was most common in adenocarcinoma (84%). Radiologically, mass was the sole picture in
Undifferentiated Lung Cancer and adenosquamous lung CA, and was most common in the
adenocarcinoma (84%) and SCC (56%) types. A survival rate estimate of 50.27% (95% CI: 35.15%–
63.62%) was found at 1.95 years after the time of diagnosis.

Conclusion:
Adenocarcinoma of the lung is an increasingly more prevalent lung malignancy and our experience
shows that it predominantly affects women who have never smoked and are symptomatic on
presentation with advanced disease.

Vol. 18 | Issue 01 | March 2017 74

 Intensive care

The Association between Implementation of Bundles of

Care and Possible Ventilator Associated Pneumonia
Among Mechanically Ventilated Patients in the Intensive
Care Unit: A Quasi-Experimental Study
Anna Francesca Abarquez, MD-MBA; Patricia Ann Estrella, MD; Mary Claire Orden, MD-MBA;
Marissa Alejandria, MD; Evelyn Victoria Reside, MD
The Medical City, Pasig City, Philippines

ABSTRACT

Objectives and Methods: Ventilator associated pneumonia (VAP) is a serious medical condition
causing significant morbidity and mortality among mechanically ventilated patients. The “VAP
Bundles of Care” is a process improvement program designed to lessen the incidence of VAP. This
study primarily aims to determine the impact of implementation of “VAP Bundles of Care” program for
reducing episodes of possible VAP (pVAP) in The Medical City Adult Intensive Care Unit (TMC-ICU)
by comparing pVAP rates pre and post intervention period using a Quasi-experimental study design.
This study also aims to determine the association between the implementation of “Bundles of Care”
with secondary outcomes of ventilator days, length of ICU stay, length of hospital stay and mortality
among patients intubated adult patients at the TMC-ICU from January 2008-December 2015.

Results: A total of 235 patients were included in the study; 124 patients did not receive VAP Bundles
of Care while 111 did. Majority of patients who developed pVAP occurred prior to implementation of
the “Bundles of Care” (37 out of 47). Those with VAP bundle have lower odds of acquiring pVAP.
The length of hospital stay ranges from 3-72 days prior to implementation of the Bundles of Care and
2-91 days after its implementation while length of ICU stay ranges from 2-60 days prior to
implementation of the Bundles of Care and 1-72 days after its implementation. Finally, the number of
ventilator days ranges from 1-52 days prior to implementation of the Bundles of Care and 1-63 days
after its implementation. There is no significant difference between secondary outcomes between the
two groups. Moreover, mortality rates has increased from 11% (n=14) to 19% (n=21) after
implementation of the Bundles of Care program. Mortality in these patients may have been
influenced by other baseline characteristics and other complications that may have developed during
the patient’s admission; hence, continued implementation and improvement of delivery of the VAP
bundles of care is still recommended. To our knowledge this is the first study in the institution
assessing the impact of the VAP Bundles of Care in preventing VAP. This study may be used to
spring board future studies regarding VAP Bundles of Care in preventing pVAP.

75 Phil J Chest Dis 2017

 Intensive care

Neurocognitive Outcome of Patients with Delirium in the

Intensive Care Units at a Tertiary Government Hospital
Coleen Gulay, MD*; Gerard Saranza, MD*, Genevieve Tuble, MD*; Derick Erl
Sumalapao**; Albert Albay Jr., MD*; Veeda Michelle Anlacan, MD*; Lourdes
Ledesma, MD*

*Philippine General Hospital, Manila, Philippines

**Department of Biology, College of Science, De La Salle University

ABSTRACT

INTRODUCTION: Delirium among patients admitted in the intensive care units is associated with
impairment of cognitive function. This study aims to determine the presence of cognitive impairment
among patients who developed ICU delirium, as well as to identify the cognitive domains
compromised and preserved in this group of patients.

METHODS: This is a non-interventional, descriptive, longitudinal study which included patients with
ICU delirium. Montreal Cognitive Assessment Philippine Version (MoCA-P) was used to assess
cognitive function. Visual Reproduction (VR) and Logical Memory (LM) subtests of the WMS-IV and
the Symbol Search (SS) subtest of the WAIS-IV were also performed to further assess the cognitive
profile of the subjects.

RESULTS: Out of 39 patients diagnosed to have ICU delirium from November 2014 to February
2015, only 8 subjects were available for evaluation in this follow-up study due to high mortality rate.
Six out of the 8 patients (75%) developed cognitive impairment (MoCA-P score<20) within 18 months
after hospital discharge. Together with the VR and LM subtests of WMS-IV and the SS subtest of
WAIS-IV, item analysis showed that the cognitive domains affected are memory, executive function
and processing speed.

CONCLUSIONS: Critically ill patients who developed delirium during their ICU admission are at high
risk for development of long-term cognitive impairment. These findings underline the importance of
detection and treatment of ICU delirium as it leads to a high risk of mortality and poor cognitive
outcome among survivors.

Vol. 18 | Issue 01 | March 2017 76

 Intensive care

Non-invasive Ventilation versus Conventional Oxygen

Therapy in Immunocompromised Patients: A Meta-analysis
Ralph Elvi Villalobos, MD; Ulysses King, Gopez, MD; Karen Flores, MD; Norman Maghuyop, MD
University of the Philippines-Philippine General Hospital, Manila, Philippines

ABSTRACT

RATIONALE: Respiratory failure is common in immunocompromised patients. Intubation and

mechanical ventilation (MV) is the mainstay of treatment but is associated with increased risk of
pneumonia and other complications. Non-invasive ventilation (NIV) is an alternative to MV in a select
group of patients and aims to avoid the complications of MV. In these patients, we performed a meta-
analysis on the effect of NIV versus conventional oxygen therapy in reducing intubation rates and
other important clinical outcomes.

METHODS: We performed an extensive online and unpublished data search for relevant studies that
met the inclusion criteria. Randomized controlled trials that used NIV versus conventional oxygen
therapy in immunocompromised patients with respiratory failure were included in the review and
analysis. Eligibility and risk of bias assessments were performed independently by three authors.
The primary outcome of interest was intubation and mechanical ventilation rate. The secondary
outcomes were intensive-care unit (ICU) and all-cause mortality, ICU length of stay and duration of
mechanical ventilation.

RESULTS: Out of the 20 initially screened studies, four studies with a total of 553 patients met the
criteria for inclusion and were included in the analysis. Patients given NIV were 38% less likely to be
intubated vs. those given oxygen, RR 0.62 (95% CI 0.42, 0.93); however, this analysis result is
significantly heterogeneous. After sensitivity analysis, results showed 48% less likelihood of
intubation and mechanical ventilation in the group treated with NIV, RR 0.52 (95%CI 0.35, 0.77).
Patients on NIV had 1.08 days less stay in the ICU vs. oxygen group (95%CI -1.50, -0.65 days).
Three studies included ICU mortality in their outcomes and showed a statistically significant 23%
decrease in ICU mortality among patients given NIV, RR 0.67 (95% CI 0.45, 0.99), and this result is
homogenous I2=40%. There was no statistically significant decrease in all-cause mortality between
the two groups, RR 0.77 (95% CI 0.53, 1.11). After a sensitivity analysis performed specifically for
this outcome, results showed a 32% reduction in all-cause mortality in patients given NIV vs. oxygen
therapy; however was not statistically significant RR 0.68 (95% CI 0.53, 1.11) and was
heterogeneous (I2=50%). There is no difference in the duration of mechanical ventilation between
groups.

CONCLUSIONS: In immunocompromised patients with respiratory failure, NIV reduced intubation

rates, ICU mortality rates, and length of ICU stay, compared to standard oxygen therapy.

77 Phil J Chest Dis 2017

 Intensive care

A Preliminary Study on the Nutritional Intake and Clinical

Outcomes of Patients Admitted at the Medical Intensive
Care Unit
Aiza Chrysan C Blanco-Estabillo, MD; Albert B. Albay Jr., MD

ABSTRACT

Background: Malnutrition is a prevalent problem in the intensive care unit. Despite several studies
showing improvement in clinical outcomes with adequate and aptly timed delivery of nutritional
support there is still suboptimal delivery of proper nutrition. Factors that lead to inadequate nutrition
commonly includes frequent feeding interruptions, physician under prescription, gastrointestinal
complications and problems related to feeding access.

Objectives: The objective of the study was to compare the actual and recommended total caloric
intake of medical ICU patients and determine the relationship between the adequacy of intake and
clinical outcomes.

Methodology: Thirty-six patients admitted at the medical intensive care unit were enrolled in the
study. Charts were reviewed daily for prescribed caloric intake, interruptions of feeding and its
duration and reason. Actual caloric intake was recorded daily. The patients were followed up until
they were discharged from the ICU or expired. Paired t-test was used to compare actual caloric
intake and total caloric requirement. Binary regression, simple and multiple regressions were used
to determine relationship between adequacy of caloric intake, total duration of feeding interruptions
and clinical outcomes.

Results: Actual caloric intake in relation to recommended total caloric intake was inadequate in 23
patients (63.89%) included in the study (p-value = 0.003). The inadequate actual caloric intake in
comparison with the total caloric requirement in combination with longer duration of feeding
interruptions showed that there are increased rates of hospital acquired pneumonia (p-value =
0.012), prolonged duration of mechanical ventilation (p-value 0.001), longer ICU stay (p-value 0.003)
and higher mortality rates (p-value 0.001).

Conclusion: There is inadequate actual caloric intake as compared with the total caloric requirement
in patients admitted at the medical ICU. Inadequate caloric intake and prolonged duration of feeding
interruptions resulted to poorer clinical outcomes.

Vol. 18 | Issue 01 | March 2017 78

 Intensive care

Oxygen Saturation Index as a Surrogate of PaO2/FiO2

Ratio in Acute Respiratory Distress Syndrome
Caroline Bernadette O. King Kay, MD; Patrick Gerard L. Moral, MD
Section of Pulmonary and Critical Care, Department of Medicine, University of Santo Tomas
Hospital, Manila, Philippines

ABSTRACT

Background: Acute Respiratory Distress Syndrome (ARDS) is characterized by non-cardiogenic

pulmonary edema, lung inflammation, hypoxemia and decreased lung compliance. It is diagnosed by
using the Berlin criteria: 1) within one week of known clinical insult or new or worsening respiratory
symptoms, 2) chest radiograph or computed tomography scan finding of bilateral opacities not fully
explained by effusions, lobar/lung collapse, or nodules, 3) respiratory failure not fully explained by
cardiac failure or fluid overload, excluded by objective assessment, and 4) oxygenation dysfunction
classified as mild, moderate or severe based on PaO2/FiO2 Ratio. Recently, Oxygenation Index (OI),
another measure of oxygenation dysfunction, has been suggested as a more accurate means of
determining severity of respiratory failure compared to PaO2/FiO2 Ratio, due to incorporation of the
Mean Airway Pressure (MAP). However, both PaO2/FiO2 Ratio and OI require arterial blood gas
determination, which can be technically difficult, not readily available and expensive. Pulse oximetry
is an alternative, reliable, and inexpensive means of monitoring oxygenation dysfunction.

Objectives: Our objective was to determine the performance of Oxygen Saturation Index (OSI), as a
surrogate of PaO2/FiO2 Ratio, in the diagnosis of ARDS.

Methods: We reviewed the records of patients diagnosed with ARDS from January 2012 to
December 2015 at the University of Santo Tomas Hospital, Philippines. Simultaneous arterial blood
gas, pulse oximetry and ventilator settings were recorded during the first 1, 24, 48 and 72 hour of
mechanical ventilation. PaO2/FiO2 Ratio, OI and OSI were then calculated. Descriptive statistics and
two-way scatterplots were used to describe the correlation of PaO2/FiO2 Ratio, OI and OSI. A linear
modeling was used to derive predictive equation for PaO2/FiO2 Ratio using OSI, oxygen saturation
(SpO2), respiratory rate (f) and MAP.

Results: Eighty five arterial blood gas, SpO2 and MAP values from 27 patients (mean age = 57; 55%
males) were included. PaO2/FiO2 Ratio was inversely related to OI and OSI, with stronger linear
correlation with OI. OI and OSI were directly related. A predictive equation of PaO2/FiO2 Ratio was
derived with a R2 of 61.41%: PaO2/FiO2 Ratio = exp (3.33 + [0.03*xSpO2] – [9.92xOSI] – [0.02xf] +
[0.06xMAP]).

Conclusion: OSI may be a noninvasive surrogate measure of oxygen dysfunction in patients with
ARDS.

79 Phil J Chest Dis 2017

 Intensive care

Clinical Outcomes of Mechanically Ventilated Patients in

the Intensive Care Unit Referred to Clinical Nutrition
Services
Jenet B. Lim, MD; Joyce B. Bernardino, MD; Ma. Janeth Samson, MD
St. Luke’s Medical Center Quezon City, Philippines

ABSTRACT

INTRODUCTION: Nutritional assessment and intervention are vital in the management of critically ill
patients in the intensive care unit. This study presents a comparison of the clinical outcomes of
mechanically ventilated patients in the intensive care unit (ICU) who were referred or not referred to
clinical nutrition services.

METHODS: This was a retrospective cohort study conducted to compare mechanically ventilated
patients in the ICU referred and not referred to clinical nutrition services based on the length of ICU
stay, days on mechanical ventilator, serum parameters, APACHE II scores and mortality. Records of
ventilated patients admitted in the ICU from June 1, 2014 to May 31, 2015, aged more than 18 years
old, were reviewed, excluding those ventilated after cardiac arrest, dependent to mechanical
ventilation before admission, terminally ill and those who died less than 24 hours post-intubation.

RESULTS: A total of 84 patients were included, of whom 29 were referred to clinical nutrition
services. For both groups, there were no significant differences in the mean hemoglobin, albumin
and magnesium level, the length of ICU stay, and APACHE scores. The number of mechanical
ventilator days was longer for those with referral (median of 10 vs 6 days). The in-hospital mortality
rate of those with nutritional referral was lower compared to those not referred, at 17.2% versus
38.2%.

CONCLUSION: Patients referred to the clinical nutrition services have a longer duration of use of
mechanical ventilator but had lower mortality compared to those not referred. However, there was no
significant difference in weaning outcomes and length of ICU stay.

Vol. 18 | Issue 01 | March 2017 80

 Intensive care

Cohort Study on the Applicability of the Updated 2015 LCP

Algorithm on Preoperative Risk Assessment as a Predictor
of Postoperative Pulmonary Complications
Randy Joseph D.T. Castillo, MD; Glynna O. Cabrera, MD
Department of Pulmonary Medicine, Lung Center of the Philippines, Quezon City, Philippines

ABSTRACT

Purpose: Preoperative pulmonary evaluation is an essential prerequisite for lung resection because
it estimates the impact of surgery on the already compromised respiratory function. This study aimed
to assess the applicability of the updated Lung Cancer of the Philippines (LCP) 2015 algorithm on
preoperative risk assessment in predicting postoperative pulmonary complications (PPCs) among
lung resection patients.

Methods: This was a cohort observational study that included 78 patients for lung resection and
evaluated by the updated 2015 LCP algorithm. The patients were followed up until discharge to
observe for PPC development. The incidence of PPCs were determined in relation to the baseline
demographic variables, value of predictive factors and the risk assessment.

Results: The incidence of PPCs was 29.4% patients with prolonged air leak and nosocomial
pneumonia as the most common PPCs while the mortality rate was 1.3%. Male gender, smoking
history, smoking of at least 20 years, FEV1 % (predicted) and postoperative FEV1 (ppoFEV1) were
shown to predict PPC development. The applicability of updated algorithm in predicting PPC was
found to be significant for the non-neoplastic group.

Conclusion: The applicability of the updated 2015 LCP algorithm on preoperative risk is not only
limited to neoplastic patients but also for the non-neoplastic patients. The factors that predict
development of PPCs include male gender, smoking history, smoking of at least 20 years, FEV1%
(predicted) and ppoFEV1 value. The incidence of PPCs is the same as with other studies with
prolonged air leak and nosocomial pneumonia as the most common PPCs.

81 Phil J Chest Dis 2017

 Intensive care

Pre-operative Nutritional Assessment in Surgical Lung

Resection and Occurrence of Post-operative Pulmonary
Complication: A Prospective Cohort Study
Rely Ann Ronquillo, MD; Virginia Delos Reyes MD; Marianna Ramona Sioson, MD
Department of Pulmonary Medicine, Lung Center of the Philippines, Quezon City, Philippines

ABSTRACT

Purpose: Nutritional status is an independent factor that influences the outcome of surgery. The
objective of this study was to correlate pre-operative nutritional status and post-operative pulmonary
complications (PPC) among in-patients who underwent elective surgical lung resection.

Methods: This was a prospective cohort study on 27 Filipino in-patients who underwent elective
lung resection. Nutritional status was evaluated using Modified Subjective Global Assessment. Post-
operative pulmonary complications and length of hospital stay were then analyzed against their
nutritional status.

Results: The mean age of patients was 45.26 ± 16.83 years old. Most had moderate nutritional risk
(n=20), 6 were high risk and 1 was low risk. The incidence of PPC was 3 out of 27, with only 1
mortality. There was no sufficient evidence to associate nutritional status to pulmonary complications
(p>0.05). Patients at low risk stayed in the hospital for 18 days; those with moderate risk had a mean
length of stay of 18.55 ± 8.678 days; those with high risk stayed for 14.5 ± 5.01 days. There was no
statistically significant between-group difference of length of stay per nutritional group (p>0.05).

Conclusion: Nutritional risk status, whether low, moderate or high, was not conclusively proven to
be associated with PPC occurrence and increased in-hospital stay. There is a need to increase the
sample size in order to establish a pattern that will link poor nutritional status to pulmonary
complications and in-hospital stay.

Vol. 18 | Issue 01 | March 2017 82

 Intensive care

Adherence, Enablers and Barriers to the Implementation of

the Ventilator-Associated Pneumonia Bundle in the Intensive
Care Units at the Makati Medical Center
Cyrus Gerald P. Pasaporte, MD; Norman L. Maghuyop, MD
Section of Pulmonary Medicine, Makati Medical Center, Makati City, Philippines

ABSTRACT

Background: The ventilator-associated pneumonia (VAP) bundle has been implemented in Makati
Medical Center (MMC) since 2011. After it was implemented, we observed a significant decrease of the
incidence of VAP in all intensive care units (ICU), but was not eliminated. We sought to determine the
adherence rate, enablers, and barriers to the implementation of the VAP bundle in the ICUs at MMC.

Methods: This prospective cross-sectional study was conducted at the ICUs of MMC from June 2016 to
December 2016. Nurses with intubated patients were monitored on how they performed the VAP
bundle. The chart was checked for compliance of medical ICU officers to the VAP bundle. A self-
reported survey was administered to measure adherence to interventions, guideline quality and
contextual factors of the VAP bundle.

Results: A total of 45 nurses participated in the survey; in general, all had positive attitudes and
reported adhering to the VAP bundle guidelines. However, 39% of respondents have poor knowledge
with the initial ventilator mode in settings for Spontaneous Breathing Trials. A fourth of respondents had
low knowledge on the policies and guidelines behind the VAP bundles. Medical ICU officers were able
to practice VAP care bundle by assessing readiness to extubate (97.70%) and complete VAP bundle
protocol order (88.89%). Universal precaution of hand hygiene was not regularly performed by staff
nurses (60% compliance).

Conclusion: Nurses generally had favourable attitudes towards the VAP bundle, but improvement is
needed in terms of knowledge and practice. Therefore, interventions geared for increasing adherence
to the VAP bundle should focus on training to increase knowledge, and administrative policies that
would support each component of the VAP bundle practice.

83 Phil J Chest Dis 2017

 Tuberculosis

Yield Pattern of Three Sputum Smears in the Case

Detection of Pulmonary Tuberculosis in a Tertiary Hospital
(2012-2014)
Lowell N. Bascara II, MD; Gwendolyn D. Pepito, MD; John Clifford E. Aranas, MD

ABSTRACT

Background: Sputum smear microscopy remains the cornerstone of case detection; however, its
utility is limited by poor sensitivity. In 2007, the World Health Organization (WHO) reduced the
minimum number of sputum smear specimens to be examined from 3 to 2 owing to a low
incremental yield in the 3rd sputum smear specimen. However, differing yield patterns of sputum
smears across studies in different countries have been noted, with significant diagnostic yield in the
third sputum smear and higher positivity rates utilizing 3 sputum smear specimens in high
prevalence areas. The utility of a third sputum smear cannot be underestimated in a high burden of
disease setting and increasing risk population such as the Philippines.

Methods: This study is a hospital-based retrospective cross-sectional chart review design from
2012 to 2014, including 893 presumptive pulmonary tuberculosis patients, aged > 18 years and with
no prior history of pulmonary tuberculosis subjected to a 3-sputum smear microscopy. The pattern
of positive smears, incremental yield of each sputum smear and the positivity rate of 2-smear
combinations were analyzed.

Results: The study shows that the first 2 sputum smears can detect majority of cases (N=185), with
the third smear adding only a minimal diagnostic yield (N=2). However, it is noted that the positivity
rate increases in the succeeding sputum smear specimens with a comparable positivity rate in the
second (20.4%) and third (20%) smears. Among 2-smear positive combinations, a significantly
higher rate of smear positivity (2.8 %) and a higher incremental increase of positivity rate (40%) is
noted with the second and third specimens over the other combinations.

Conclusion: A 3-sputum smear specimen in the case detection of pulmonary tuberculosis has non-
negligible diagnostic yield in the succeeding specimens and a significantly higher rate of smear
positivity is observed with 3 specimens over those with less.

Vol. 18 | Issue 01 | March 2017 84

 Tuberculosis

Adherence to the National Tuberculosis Control Program

Guidelines 2013 and Outcome of Treatment on People
Living With HIV Co-Infected with Tuberculosis Enrolled in
the Philippine General Hospital Treatment Hub (SAGIP)
Rhea Joy P. Tabujara, MD; Ellan Lyll B. Sallada, MD; Jubert P. Benedicto, MD
Philippine General Hospital, Manila, Philippines

ABSTRACT

Background: Since diagnosing of tuberculosis (TB) among people living with human
immunodeficiency virus infection (PLHIV) could be difficult, there is a delay in detection of TB and
subsequent treatment. Hence, HIV-related TB deaths are significant public health problem in high HIV-
prevalent settings.

Methodology: This was an observational study that accessed medical records of adult patients with
HIV co-infected with TB enrolled at the SAGIP Unit from January 2014 to December 2014 seen by
physicians in Philippine General Hospital were reviewed.

Results: One hundred seventy-eight HIV patients were diagnosed with TB based on the National TB
Control Program (NTCP) Guidelines 2013. It was noted that all cases of HIV/pulmonary TB (PTB), the
infectious diseases fellows adhered to the guidelines set by the NTCP in requesting CD4 count upon
diagnosis. In majority of the cases of HIV/PTB clinically and bacteriologically diagnosed, the physician
requested for a chest radiograph in 99% and 98%, respectively. All HIV/PTB that were bacteriologically
diagnosed underwent direct sputum smear microscopy (DSSM) while only 96% of cases of HIV/PTB
clinically diagnosed were requested by DSSM. Majority of the cases for HIV/PTB had TB culture
performed. The rate of use of MTB/Rif examination was low.

85 Phil J Chest Dis 2017

 Tuberculosis

Assessment of the Utilization of Gene Xpert MTB/RIF in

the Philippine Tuberculosis Society, Inc.
Rianne L. de la Cruz, MD; Michelle B. Recana; Jubert P. Benedicto, MD

ABSTRACT

Background: The Xpert MTB/RIF assay offers an automated, real-time molecular diagnostic
system that simultaneously detects TB and rifampicin resistance with minimal hands-on time with
results being available in less than two hours. In the Philippine Tuberculosis Society, Inc. (PTSI),
the Gene Xpert MTB/RiF apparatus is used for all TB re-treatment cases and individuals with
symptomatic HIV infection.

Purpose: To assess the current state of utilization of MTB/ RIF (Gene Xpert) machine in PTSI

Findings: The PTSI received numerous (n=4,050) referrals from at least 7 different treatment
centers; however, policies in the management of referrals from the private sector are lacking.
Therefore, these referrals were enrolled in a treatment centre prior to testing. Only one of the three
medical technologists in PTSI has undergone Gene Xpert training.

Conclusion: This study shows that the use of Gene Xpert MTB/RIF is not being maximized by
treatment centers. Operating procedures need to be implemented to fully optimize the use of the
Gene Xpert MTB/RIF module—including a guideline in dealing with referrals from the private sector.

Vol. 18 | Issue 01 | March 2017 86

 Tuberculosis

Validity study of Gene Xpert MTB/Rif Assay in the Diagnosis

of Tuberculous Pleural Effusion among Adult Patients at the
Lung Center of the Philippines
Ronel G. Sario, MD; Joven Roque V. Gonong, MD
Lung Center of the Philippines, Quezon City, Philippines

ABSTRACT

Introduction: Tuberculous pleural effusion can be difficult to diagnose and existing tests to confirm the
disease are limited in accuracy, time to diagnosis and requires costly invasive procedures. The
objective of this study was to determine the accuracy of Gene Xpert MTB/Rif Assays in the diagnosis of
tuberculous pleural effusion among adult patients at the Lung Center of the Philippines.

Methodology: This was a cross sectional analytical study among 60 patients with unilateral pleural
effusion seen at the Lung Center of the Philippines from October 2014 to September 2016. Either
thoracentesis, closed tube thoracostomy or VATS with pleural biopsy was done. The specimens were
sent for histology, MTB culture, and Gene Xpert. Results were collected for data analyses.

Results: Of the 60 study participants, 26 (43.3%) had definite tuberculous pleural effusion. The
diagnostic accuracy of this test was compared to MTB Culture, Histology and Composite Reference
Standard. Gene Xpert in relation to MTB culture showed sensitivity and specificity of 100% and 94.34%
respectively, in relation to histopathology, the sensitivity was 14.29% and the specificity was 82.05%
and in relation to the composite reference standard, the sensitivity was 30.77% and the specificity was
94.12%.

Conclusion: The Gene Xpert MTB/RIF assay has poor sensitivity, thus, it is not a good routine
diagnostic tool for the diagnosis of tuberculous pleural effusion even in high burden settings such as
our country. On the other hand, with its high specificity, it can forestall further invasive procedures in
some patients with tuberculous pleural effusion.

87 Phil J Chest Dis 2017

 Tuberculosis

Performance of TB Diagnostic Committee in Certifying

Disease Activity of Smear Negative Category II Cases in
District IV of Manila
Caroline Bernadette O. King Kay, MD; Julie Christie G. Visperas, MD; Jose Hesron D. Morfe, MD
Section of Pulmonary and Critical Care, Department of Medicine, University of Santo Tomas
Hospital, Manila, Philippines

ABSTRACT

Introduction: Tuberculosis (TB) is a major global health problem. The initial work-up of choice is
direct sputum smear microscopy (DSSM). Yet, smear negative TB accounts for 50% of cases in the
Philippines. The TB Diagnostic Committee (TBDC) functions is to review presumptive TB cases who
are smear-negative on DSSM, with chest radiograph findings suggestive of TB, and give
recommendations for treatment.

Objectives: To determine the performance of the TBDC in certifying disease activity of smear
negative Category II cases in District IV of Manila from January 2013 to June 2014, using the MTB
culture or Xpert MTB/RIF as the standard. Secondly, to establish association between symptoms
and chest radiograph findings which members of the USTH TBDC relate with TB disease activity
and which eventually tested positive for MTB culture or Xpert MTB/RIF.

Methodology: Patients suspected of having active pulmonary TB based on symptoms and chest
radiograph findings, with negative sputum AFB smear results, in District IV of Manila, referred to the
TBDC for possible Category II treatment from January 2013 to June 2014 were listed. TB culture or
Xpert MTB/RIF results of the presumptive TB cases recommended for Category II treatment were
obtained. The frequency of symptoms and chest radiograph findings among patients were listed
and cross-tabulated with sputum MTB culture or Xpert MTB/RIF results.

Results: The TBDC assessed a total of 257/952 (27%) smear negative patients to have active TB,
for possible Category II treatment during the study period. Out of 143 (55.64%) patients who
followed up and submitted sputum specimens for MTB culture or Xpert MTB/RIF testing, only
22/116 (19%) tested positive for Xpert MTB/RIF, and 7/27 (26%) tested positive for MTB culture, for
a total of 29 (20.28%) bacteriologically confirmed smear negative cases. Symptoms highly
correlated with TB activity are cough and sputum production. Chest radiograph finding of ill defined
infiltrates had moderate correlation to disease activity..

Conclusion: There is limited data to conclude the correlation of TBDC decision with TB disease
activity. A prospective study is recommended. However, in the absence of laboratory tests or
ancillaries and expert opinion, presence of cough, sputum production, together with ill-defined
infiltrates on chest radiographs can help primary physicians in deciding disease activity in smear
negative TB.

Vol. 18 | Issue 01 | March 2017 88

 Tuberculosis

Turnaround Time for Smear Negative Category I Cases to

Initiation of Treatment in District IV of Manila
Radha Marie M. Sillano, MD; Caroline Bernadette O. King Kay, MD; Jose Hesron D. Morfe, MD
Section of Pulmonary and Critical Care Medicine, University of Santo Tomas Hospital, Manila,
Philippines

ABSTRACT

Background: The diagnosis of tuberculosis (TB) requires bacteriologic confirmation through direct
sputum smear microscopy, allowing early access to treatment. Thus, smear negative cases become a
diagnostic dilemma. Certification of disease activity from TB Diagnostic Committee (TBDC) is needed to
curb unnecessary treatment. Turnaround time starts from collection of first sputum sample to initiation
of treatment and should be within five working days based on local guidelines.

Objectives: To determine the mean turnaround time for new smear-negative pulmonary TB (PTB)
cases in District IV of Manila referred to the University of Santo Tomas Hospital TBDC from January to
December 2014.

Methods: A retrospective descriptive study was done to determine the number of days it took for new
smear negative PTB cases to initiate treatment. Demographic data was noted. The intervals between
submission of sputum, TBDC certification and the first dose of anti-TB medication were obtained.

Results: There were 153 patients in the study. The mean total turnaround time was 37.78 + 24.62
days, with a mean of 14.30 + 18.58 days from sputum collection to follow-up at the health care facility;
12.74 + 10.15 days thereafter to TBDC referral, and another 10.69 + 15.18 days to initiation of
treatment.

Conclusion: There was significant delay in initiation of treatment among smear negative PTB cases,
mostly observed for follow-up visits after sputum collection and interval time to TBDC referral. This
reflects a poorly functioning default tracing mechanism among Directly Observed Treatment Strategy
facilities even at the diagnostic phase, which has negative implications for infection prevention and
control.

89 Phil J Chest Dis 2017

 Tuberculosis

Risk Factors for Development of Secondary Spontaneous

Pneumothorax in Patients with Pulmonary Tuberculosis
Admitted to the Lung Center of the Philippines: A 10-year
Experience
Reya S. Domingo MD; Guia Elena Imelda Ladrera, MD
Lung Center of the Philippines, Quezon City, Philippines

ABSTRACT

Purpose: Tuberculosis (TB) remains one of the world’s deadliest communicable diseases and
remains an important cause of secondary spontaneous pneumothorax (SSP) especially in the
developing world. Although a rare but well-recognized complication, spontaneous pneumothorax
complicating pulmonary TB (PTB) is scantily reported in the literature. For this reason, our study
aimed identifying frequency of presentation and variables that will predispose PTB patients in
developing secondary spontaneous pneumothorax.

Methods: This was a retrospective cohort study analyzing data corresponding to the medical
records of all patients with SSP and TB admitted and treated in our hospital between January 1,
2004 to December 31, 2013. The following data were collected: demographic (age, gender, body
mass index [BMI], social service classification), history of smoking, co-morbid illness (chronic
obstructive pulmonary disease, bronchial asthma, pneumonia, diabetes and bronchiectasis),
radiographic presentation (atelectasis, cavitation, bronchiectasis, consolidation, destroyed lung,
effusion and pleural thickening), and treatment course of anti-TB medications.

Results: The mean age was 44±16 years old. The average BMI was 19.26 ± 3.94 kg/m2 while
average smoking history was 13.92 ± 19.73 pack-years The study population was predominantly
male (68.9%). Majority had a normal BMI (52.2%); 31.7% were underweight and 16.1% were
overweight. Out of the 508 patients in this study, 14.4% developed SSP. Incidence of SSP were
significantly associated with middle-aged patients, males, underweight and who were under the
“Service” classification. Pneumonia as a co-morbid illness and chest x-ray findings of reticular
infiltrates were significantly related to the development of SSP in this study.

Conclusion: The incidence of SSP was 14.4%. There were higher incidences of SSP among
patients in the middle-aged group, males, underweight, and patients availing of service
classification upon admission.

Vol. 18 | Issue 01 | March 2017 90

 Tuberculosis

Outcomes of Multi Drug Resistant Tuberculosis Contacts

who received Category I Treatment for Clinically Diagnosed
Pulmonary Tuberculosis under DOTS
Pamela Joy V. Dionisio, MD; Joven Roque V. Gonong MD
Department of Pulmonary Medicine, Lung Center of the Philippines, Quezon City, Philippines

ABSTRACT

Introduction: MDRTB is a highly infectious disease and containing its spread requires close contact
investigation and treatment of contacts with TB disease. The objective of this study was to determine
the outcome of Multi Drug Resistant Tuberculosis (MDRTB) Contacts who were recommended
Category I Treatment for Clinically Diagnosed Pulmonary Tuberculosis under DOTS.

Methods: This is a cross-sectional study involving MDRTB close contacts diagnosed to have clinically
diagnosed TB. Subjects were followed up through phone call and were asked as to outcome of
treatment with Category I anti-Tuberculosis medication. Subjects were then asked to come for follow up
at the Lung Center OPD wherein a repeat chest x-ray and sputum acid-fast bacilli smear were done to
validate if treatment was successful or not. Demographic profiles were obtained and correlated with the
outcome of treatment.

Results: Forty-one MDRTB contacts were included in the study. However, only 31 were contacted.
Fourteen refused to participate. Demographic data were obtained. Among the subjects, 6 were lost to
follow-up during treatment and 11 completed treatment. On their follow-up, 58.8% had no TB relapse;
hence treatment was considered successful. Younger age (18-40 years old) showed association with
successful outcome among all the other factors evaluated (p=0.0397).

Conclusion: Treatment with Category I drugs for Clinically Diagnosed PTB among MDRTB contacts
resulted in a successful outcome in majority of subjects. Among the factors evaluated, only younger
age group showed association with a successful treatment outcome.

91 Phil J Chest Dis 2017

 Tuberculosis

Prevalence of Tuberculosis Infection in Cancer Patients at

Veterans Memorial Medical Center
Maryanne Cristy T Dadulla, MD; Teresita Aquino, MD
Veterans Memorial Medical Center, Quezon City, Philippines

ABSTRACT

Cancer patients have depressed adaptive cellular immunity which predisposes them to infections
associated with cell-mediated immunity deficiencies like Mycobacterium tuberculosis. Cancer therapy
also adds to adaptive cellular immunity dysfunction it further increase the risk for development or
reactivation of TB. There is paucity of data in the Philippines describing the burden of TB in cancer
patients hence this study.

This study retrospectively reviewed charts of cancer patients histologically diagnosed from 2011 to
2013 and followed up for development or TB reactivation prior, during and after cancer specific
therapies. The overall computed period prevalence of TB infection in cancer patients in Veterans
Memorial Medical Center was 2.3% or 6 cases per person-years. Tuberculosis infection developed in
67% (12) of case patients prior to cancer specific therapies, 5% (1) during the duration of cancer
specific therapy and 28% (5) after cancer specific therapy completion. Cancer therapy posed 15
times odds for tuberculosis infection (OR 15; 95% CI 3.0968, 77.7371; p=0.0009). Among the
different cancer types, lung cancer patients (12.5%) were more associated with tuberculosis
infection. Lung cancer had 6 times odds of TB infection than other cancer type (OR 5.9; 95% CI:
1.2484-28.4083; p=0.0252). Six percent developed in hematologic and bone malignancy (6%), 2.8%
in head and neck malignancies, 2.5% in breast cancer patients (2.5%), 2% in patients with
gastrointestinal malignancy and 1.3% in genitourinary malignancy patients.

Association of cancer with chronic illness like COPD posed 9 times odds for TB infection (OR 9.1;
95% CI 2.6122-31.7018; p=0.0005). Cancer patients with pulmonary manifestations had 5 times
odds for TB infection compared to asymptomatics (OR 4.9231; 95% CI 1.5234-15.9100; p=0.0077).
History of previous TB infection and treatment had 6 times odds for TB infection in cancer patients
than those without previous anti-TB treatment (OR 5.8000; 95% CI 2.0040, 16.6577; p<0.0012).
Lung cancer was commonly associated with tuberculosis infection (OR 5.9554; 95% CI 1.2484,
28.4083; p=0.0252). In this study, no deaths were noted among cancer patients with associated TB
infection.

It is thereby prudent that proper assessment for concurrent TB infection be undertaken during cancer
diagnosis, prior to initiation, during and after cancer specific therapies. However, because of the
limitations of the study, it is recommended that a prospective and multicenter study be done to fully
assess the prevalence and characteristics of cancer patients prone to develop tuberculosis in the
Philippine setting.

Vol. 18 | Issue 01 | March 2017 92

Clinical Profile and Outcome of Patients Presenting with
Hemoptysis Admitted in a Tertiary Hospital
Jan Sydiongco-Fernando, MD; Ralph Elvi Villalobos, MD; Jubert Benedicto, MD
Philippine General Hospital, Manila, Philippines

ABSTRACT

Background: There is a paucity of epidemiologic data on patients presenting with hemoptysis in the
Philippines. This study primarily aims to determine the causes of hemoptysis, diagnostic tests used,
treatment administered and outcome of patients who present with hemoptysis.

Methods: A retrospective chart review was performed on patients with hemoptysis admitted to
Philippine General Hospital (PGH) from January 2011 to December 2015. Demographic data, initial
clinical symptoms and signs, diagnostic tests after initial chest x-ray, treatment and outcomes were
collected for analysis.

Results: Twenty-six patient charts from January 2011 to December 2015 were reviewed. Only 69.2%
of patients initially presented with hemoptysis. Diagnostic tests done after the initial chest x-ray were
Chest CT scan (12%), bronchoscopy (15%), both chest computed tomography (CT) scan and
bronchoscopy (4%). The causes of hemoptysis were bronchiectasis (50%), aspergilloma (19%),
tuberculosis (12%), pneumonia (12%), recurrent papillary thyroid carcinoma (4%) and severe
thrombocytopenia (4%). Twenty-four (92%) patients were given conservative medical therapy and two
(8%) patients underwent surgery. Control of bleeding was achieved in all of the patients.

Conclusion: The most common causes of admission for hemoptysis in PGH are benign treatable
diseases. Conservative medical therapy can stop bleeding in about 90% of patients with either non-
massive or massive hemoptysis. Further diagnostic tests after chest x-ray should still be done.
Bronchial artery embolization should be considered in cases of persistent hemoptysis. Surgical
intervention should be done in appropriate cases as an elective procedure.

93 Phil J Chest Dis 2017

Validity of Pleural Fluid Cholesterol in Differentiating
Exudative from Transudative Pleural Effusions
Cynthia M. Buhain, MD; Sergio S. Andres, Jr., MD
Department of Pulmonary Medicine, Lung Center of the Philippines, Quezon City, Philippines

ABSTRACT

Introduction: Pleural effusion is one of the most common diagnoses in pulmonary medicine.
Distinguishing between exudative and transudative effusions is the first step in its management.
Light’s criteria have long been the method used for such. This study aims to compare Light’s criteria
with pleural fluid cholesterol and its ratio with serum cholesterol in separating exudative from
transudative pleural effusions and to possibly introduce an easier, more cost-effective method than
Light’s criteria.

Methods: A cross sectional, analytical study design was used. Sixty-three patients with pleural
effusion were included in the study. After pleural effusion drainage, pleural fluid and blood were
submitted to the laboratory for protein, lactate dehydrogenase (LDH), and cholesterol. The pleural
effusion is labeled exudative according to Light’s criteria, pleural fluid cholesterol > 45 mg/dL (1.2
mmol/L), or pleural fluid cholesterol/serum (P/S) cholesterol ratio ≥ 0.4.

Results: Based on diagnosis, most patients had pulmonary tuberculosis (44.4%), followed by
bronchogenic carcinoma (27%). The resulting sensitivity indicates a 96.49% probability that the
pleural fluid cholesterol and P/S cholesterol ratio result is exudative when the Light’s criteria result is
exudative. The resulting specificity (probability that the pleural fluid cholesterol results to transudate
when the Light’s criteria is transudate) is 100%. The high values indicate that pleural fluid cholesterol
and P/S cholesterol ratio can predict the result of Light’s criteria. Light’s criteria, pleural fluid
cholesterol, and P/S cholesterol ratio all misclassified a small percentage of exudative pleural
effusions as transudates; the difference in accuracy of the parameters was not statistically significant.

Conclusion: After recognizing the limitation of a population with purely exudative pleural effusions,
pleural fluid cholesterol levels and its ratio with serum cholesterol can significantly aid the diagnosis
of pleural exudates since it can accurately predict the results of Light’s criteria.

Vol. 18 | Issue 01 | March 2017 94

 Effectiveness of Mechanical Cough Assist (Insufflator-
Exsufflator) among Hospitalized Patients: An Open-Label
Randomized Control Study
Joyce T. Manalo, MD; Virginia Delos Reyes, MD; Glynna Ong-Cabrera, MD
Department of Pulmonary Medicine, Lung Center of the Philippines, Quezon City, Philippines

ABSTRACT

Introduction: Cough reflex is very important to propel secretions. Airway clearance may be impaired
in several patients. Interventions for enhancing airway clearance are already available however
limited studies are available in determining its benefit and endpoints. Chest Physiotherapy (CPT) is
already established as a standard of care for selected pulmonary conditions. However, CPT may not
be feasible at all times. With these, mechanical cough assist machine may be an option and studies
are yet to develop among other subset of patients, especially those with pulmonary conditions.

Method: This was a randomized open-label study that included adults admitted either of pneumonia
or bronchiectasis in infectious exacerbation, with a Peak Cough Flow (PCF) rate of <270L/min.
Patients who were intubated or had COPD in exacerbation, history of bullous emphysema,
susceptibility to pneumothorax or pneumo-mediastinum, barotrauma, facial fractures, gastric
distention, hypotension, increased intracranial pressure and hemoptysis were excluded. Patients
were enrolled and randomly allocated to CPT or CPT plus mechanical insufflation-exufflation (MI-E).
PCF rate were measured and compared.

Results: Patients given with CPT plus MI-E rated the machine in terms of helping in expectoration,
convenient and easy to use, well tolerated and satisfaction as effective. The peak cough flow rate
and sputum volume in CPT plus MI-E is significantly higher than the CPT. No sufficient evidence to
say that the difference on the length of hospital stay, intubation and mortality between treatments
were significant.

Conclusion: A good cough reflex is important in maintaining the integrity of the airway. In general
the machine was rated as effective in terms of helping in expectoration (increased sputum volume
production and improvement in the PCF rate), convenience, tolerance and satisfaction. The peak
cough flow rate and sputum volume improved more with the CPT plus MI-E. There was not sufficient
evidence to say that there was a statistical difference in terms of length of hospital stay, intubation
and mortality rate between the two groups.

95 Phil J Chest Dis 2017

Diagnostic Accuracy of Berlin, Sleep Apnea Clinical Score,
and St. Luke’s Medical Center-Obstructive Sleep Apnea
(OSA) Clinical Score Questionnaires for OSA Screening
Among Filipinos: A 4-Year Retrospective Study
Babyleen E. Macaraig, MD; Mercy Antoinette S. Gappi, MD
Institute of Pulmonary Medicine, St. Luke’s Medical Center-Quezon City, Philippines

ABSTRACT

Introduction: Obstructive sleep apnea (OSA) is a chronic condition that is less recognized. There
are ethnic differences in prevalence of OSA and its severity. South Asians had significantly increased
prevalence of OSA. Although considered as a gold standard, the polysomnogram process is time
consuming, labor intensive, and can be costly. Using prediction rule is the easiest and least costly
approach. Hence, a simple but accurate screening tool to identify patients with high risk for OSA
should be established for Filipinos.

Methods: Records of all Filipino patients, 18 years old or above, referred to the Comprehensive
Sleep Disorders Center of SLMC-QC for overnight polysomnography from January 2011 to June
2015 were reviewed. Subjects were excluded if they were known OSA patients, had incomplete
questionnaires and unable to tolerate sleep study. Screening tools namely Berlin, Sleep Apnea
Clinical Score (SACS), and St. Luke’s Medical Center-Obstructive Sleep Apnea Clinical Score
Questionnaires (SLMC-OSACS) were scored identifying patients for OSA. Results were compared to
overnight polysomnogram.

Results: SLMC–OSACS score showed higher sensitivity (87%) and overall accuracy (84%) in
predicting OSA. It showed higher overall accuracy (63%) and sensitivity (77%) in predicting mild
OSA. It also has higher overall accuracy (66%) and sensitivity (80%) in predicting moderate OSA. In
predicting severe OSA, it also has higher overall accuracy (86%) and sensitivity (90%) while
specificity showed almost similar estimates in all of the three screening tools.

Conclusion: SLMC–OSACS showed higher sensitivity and higher overall accuracy in predicting
OSA at different risk levels. Therefore, SLMC-OSACS is recommended as a screening tool for OSA
for Filipinos.

Vol. 18 | Issue 01 | March 2017 96

 Endobronchial Ultrasound-Guided Transbronchial Needle
Aspiration in the Philippines: A Preliminary Retrospective
Cohort Study on Diagnostic Performance
Fatima Antonia F. Ponte, MD; Christine L. Chavez, MD; Regina Elena M. Bisnar, MD; Maria
Katrina R. Rivera, MD
Section of Pulmonary Medicine, The Medical City, Pasig City, Philippines

ABSTRACT

Background and Aims: Endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA)

is a bronchoscopic technique utilized for staging lung cancer and evaluating mediastinal
lymphadenopathy. EBUS-TBNA was introduced in the Philippines during a seminar in 2013 and has
been in regular use at our institution since 2014. The objective of this study was to evaluate the
diagnostic yield and complications of the procedure, as well as the factors affecting both.

Methods: A retrospective chart and histopathologic review was done on 26 consecutive adult
patients who underwent EBUS-TBNA at The Medical City between January 2015 and December
2015. Procedural and patient-related factors were analyzed for association with diagnostic yield.

Results: The overall diagnostic yield of EBUS-TBNA was 85% (22/26); of these, 82% (18/22) were
malignant and 18% (4/22) were benign disease secondary to tuberculosis. Subcarinal lymph node
location and three or more aspirations per procedure showed a tendency to improve diagnostic yield.
No major complications were associated with the procedure.

Conclusion: This preliminary experience in the Philippines showed that EBUS-TBNA is a promising
tool for the evaluation of mediastinal lymphadenopathy and lesions, with high diagnostic yield and
safety profile. Future, larger-scale studies are needed to determine the ways of significantly
improving diagnostic performance.

97 Phil J Chest Dis 2017

 OUTSIDE BACK COVER

The Philippine Journal of Chest Diseases

An official publication of:
Philippine College of Chest Physicians
84-A Malakas St., Pinyahan, Quezon City, Philippines
Email: secretariat@philchest.org
Phone: (+632) 924 9204
 Volume 18 Number 4
October-December 2017

Primary
• •PCCP ciliary
Position dyskinesia
Statement on E- Cigarettes
Good syndrome
• •MDMA-induced pneumothorax
• Three-sputum Smear for TB
• Gene Xpert in TB pleural effusion
• OSA screening: SLMC-OSACS
• 2015 LCP Algorithm on Pre-operative
Risk Assessment
 PHILIPPINE JOURNAL OF CHEST DISEASES
AN OFFICIAL PUBLICATION OF THE
PHILIPPINE COLLEGE OF CHEST PHYSICIANS

Editor-in-Chief
Evelyn Victoria E. Reside, MD, FPCCP

Managing Editor
Camilo C. Roa, Jr., MD, FPCCP

Reviewers
Ria Edwina M. Gripaldo, MD, FACP Genesis Samonte, MD, MSc, PHSAE
Joy Althea Pabellon, MD, PHSAE Jennifer Ann M. Wi, MD, FPCCP

Copy Editor
Blesilda O. Adlaon

Editorial Assistant
Ivan Noel G. Olegario, MD, MDC

PHILIPPINE COLLEGE OF CHEST PHYSICIANS OFFICERS 2017-2018

Charles Y. Yu, MD, FPCCP

President

Lenora C. Fernandez, MD, FPCCP

Vice President

Malbar G. Ferrer, MD, FPCCP

Secretary

Ivan N. Villespin, MD, FPCCP

Treasurer

Gregorio P. Ocampo, MD, FPCCP

Imelda M. Mateo, MD, FPCCP
Eileen G. Aniceto, MD, FPCCP
Ma. Janeth T. Samson, MD, FPCCP
Jubert P. Benedicto, MD, FPCCP
Board Members

Vincent M. Balanag Jr., MD, FPCCP

Immediate Past President

The opinions and data expressed in the Philippine Journal of Chest Diseases (PJCD) are those of the individual authors. They are not
attributable to the editors or editorial board of the PJCD and should not be regarded as the official stand of/or endorsement by the
Philippine College of Chest Physicians. References may be made in the articles regarding drug usage, which may not be included in the
current prescribing information. The reader is, thus, urged to check the full prescribing information of drugs. No part of the PJCD may be
reproduced without the written permission of the publisher.

Address all communication and manuscripts for publication to the following: The Editor, Philippine Journal of Chest Diseases, 84-A Malakas
St., Pinyahan, Quezon City. Email: secretariat@philchest.org. Phone: (+632) 924 9204.
 INSTRUCTIONS TO AUTHORS
The Philippine Journal of Chest Diseases
publishes scientific papers in the field of
pulmonary medicine. These papers may be in the
form of collective and current reviews (state of the
art, meta-analyses), original investigations, case
reports, editorials or letters to the editor. All
manuscripts must be submitted electronically to
secretariat@philchest.org. Manuscripts should be
single spaced and left-justified, including
references. Use 10-point type, approximately 1-
inch margins, and format for 8 ½ x 11 paper. The
editorial staff requires files that can be opened and
manipulated in Word 2004-2009, PowerPoint or
Excel.
Accepted manuscripts become the property of the
Philippine College of Chest Physicians and are
published with the understanding that they are not
for publication elsewhere without approval.
These manuscripts are subject to editorial
modification.
Generally, write using the first person, active
voice; for example, “We analyzed data,” not
“Data were analyzed.” The Abstract
and acknowledgments or disclaimers are the
exceptions to this guideline, and should be written
in the third person, active voice; “The authors
analyzed,” “The authors wish to thank.”
Supply a title page as the first page of the
manuscript with the following information:
1. The manuscript’s full title which should
provide sufficient information regarding the
contents of the manuscript.
2. All authors should provide their complete
names, professional titles, and institutional
affiliations. Include an author byline that lists
all authors’ full names and academic degrees
above a Masters; for example, “Juana Cruz,
MD, PhD, and Juan Ramos, MD”. Also
include sentence-style bios for each author
than list position(s) or title(s) and institutional
affiliation(s); for example, “Dr. Cruz is
assistant professor, Section of Pulmonary
Medicine, Department of Internal Medicine,
State University College of Medicine”.
3. Contact information (address and email
address, plus telephone and/or fax) for the
corresponding author.
4. Disclosure of funding received for this work
from any organization or company.
5. State if the paper has been presented in any
convention and whether any awards have
been conferred on the paper.
Abstract. The abstract should not be longer than
250 words. It should contain a summary of what
was done in the study, including objectives, study
design, important results and conclusions. Only
findings restricted to the study should be
mentioned in the abstract. For research reports
only, abstracts must be in the structured form of
four paragraphs, with headings Purpose,
Methods, Results, and Conclusions; and must
include the year of the study. The authors should
also provide three key words under which the
article can be indexed.
Headings
For all manuscripts. Use main headings and
short subheadings as needed. Do not create a
heading at the very top of the manuscript (e.g.,
“Introduction”), since layout constraints make
such headings unworkable. Text should be set in
Times New Roman font, 10 point in size, and
single-spaced. The main heading of the online-
only text should be in 12 point and boldface;
subheadings should be in 10-point and boldface.
If subheadings are used, two or more such
headings must be used, as in outline style.
For research reports. Structure the body of the
manuscript using the headings Introduction,
Methods, Results, and Conclusions. At least a full
paragraph of text must precede the Introduction
heading, for layout reasons.
For articles. Create headings that are substantive
and interesting and that will give readers a sense
of the article’s organization. Make headings as
short as is feasible. At least a full paragraph of
text must precede the initial heading, for layout
reasons.
Text. Formal scientific or technical style shall be
followed in writing the manuscripts. All
abbreviations should be spelled out when used
for the first time. For standard terminology,
such as chronic obstructive pulmonary disease
 INSTRUCTIONS TO AUTHORS
(COPD) or forced vital capacity (FVC), only
standard abbreviations should be used. Information
or data that is best described in tables should be
presented as such. Tables which duplicate
information provided in the text shall be removed.
Generic names of drugs shall be used except in
instances where trade names are vital, such as in
clinical trials.
Tables and Figures. Only tables cited in the text
should be included. All tables should be called out
in the text and shall be numbered in ascending
order depending on the sequence they were
referred to in the text. A different order for tables
and figures is to be used. Symbols are * † ‡ § ¶.
A single table or figure with the appropriate labels
should be printed on a single page. The text and
data in online tables should be Arial font, 10 point
in size, and single-spaced. The table title should be
set in Arial font 12 point, and bold. Headings
within tables should be set in 10 point bold.
Explanatory notes or legends should be written
at bottom of the table or figure. Table titles should
make the table sufficiently understandable
independent of the manuscript. Typically, include
type of data, number and type of respondents, place
of study, year of study. Titles should be placed
directly above the table, not in a data cell. Columns
should be clearly labeled, including unit of
measure.
Footnotes: If information is needed to make the
table understandable that won’t easily fit into the
table title or data cells, create one or more
footnotes. Table footnotes should be set in 8 point
and single-spaced. Place footnotes at the bottom of
the table, not in a data cell. All abbreviations
should also be explained.
Figures. Only figures (or pictures) cited in the text
should be included. All figures should be called out
in the text and shall be numbered in ascending
order depending on the sequence they were
referred to in the text. A different order for tables
and figures is to be used.
Figures are acceptable as Excel, PowerPoint
or Word 2004-2009 files. All files supplied must be
“live” figures that can be opened and formatted.
PDFs and JPGs are not accepted. Figures should
be two-dimensional; black-and-white or
grayscale; and without gridlines or background
shading. X and Y axes, if present, must be
labeled.
Figure legends should make the figure
sufficiently understandable independent of the
manuscript. Legends should be placed on the last
page in the manuscript. All figures should be
separated from the text file, yet bundled into a
common file, if possible, with individual figures
separated by page breaks.
The editorial staff reserves the right to determine
whether the graphical instruments are appropriate
for the information being imparted and modify or
request modification/s for inappropriate
illustrations. The editorial staff reserves the right
to generate illustrations compatible with the
professional standards of the journal.
References. Authors are responsible for the
accuracy and completeness of their references and
for correct text citations. All references should be
identified at the appropriate parts of the text using
Arabic numerals enclosed in parentheses. All
references should then be typed double-spaced at
the end of the manuscript and numbered
according to the order they were cited in the text.
Journal references should include the names of all
the authors and inclusive page numbers.
Abbreviations of names of journals should
conform to those used in the Index Medicus.
For world wide web citations, follow the
following format: <author’s name> <title of
document> <<URL>> <date of document>
(accessed <date accessed>). You may break
URLS across lines, but if possible, arrange for
breaks to occur only at punctuation separators
(but not on hyphens, and don’t ever add hyphens).
Samples of the style to be followed in the listing
references are enumerated below:
JOURNAL ARTICLE: Tanchuco JQ, Young J.
Normal standards for spirometric tests in Filipino
children. Chest Dis J 1989. 16:93-100.
 INSTRUCTIONS TO AUTHORS
BOOK: Kelley MA, Fishman AP. Exercise
Testing. In: Pulmonary Diseases. 2 edition.
Fishman AP, (ed.). McGraw-Hill Book Co.; 1989.
pp.2525-2532.
WORLD WIDE WEB: Horton M, Adams R.
Standard for interchange of USENET messages
Request for comment s 1036, Network Working
Group. <ftp://ftp.demon.co.uk/pub/doc/rfc/rfc1036.
txt> Dec.1987 (Accessed 19 June 1995)
Personal communications, unpublished data or
manuscripts in preparation should not be used as
numbered reference. Instead, these may be cited in
parentheses or as a footnote on the page where they
are mentioned. Authors assume responsibility for
verifying the accuracy of their cited reference.
Advertisements. All requests for rates should be
add-ressed to: The Business Manager, Philippine
Journal of Chest Diseases, PCCP Secretariat, 84-A
Malakas St., Brgy. Pinyahan, Diliman, Quezon
City (Telephone No. 924-9204 and Fax No. 924-
0144). The journal also accepts announcements
from institutions or professional
invitations to forthcoming symposia or convention
for publication at minimal cost depending on
available space.
Reprints. Requests for additional reprints of
individual articles should be addressed to: The
Editor-In-Chief, Philippine Journal of Chest
Diseases, PCCP Secretariat, 84-A Malakas St.,
Brgy. Pinyahan, Diliman, Quezon City (Telephone
No. 924-9204 and Fax No. 924-0144). Author/s of
each manuscript are entitled to 25 copies of the
article. These shall be sent to the major author.
Requests for reprints should be addressed to the
senior author. Reprints of entire issues may be
provided at cost, depending on availability of
copies.
Subscriptions. All requests for subscriptions should
be addressed to: The Business Manager, Philippine
Journal of Chest Diseases, PCCP Secretariat, 84-A
Malakas St., Brgy. Pinyahan, Diliman, Quezon City
(Telephone No. 9249204 and Fax No. 924-0144. E-
mail address secretariat@philchest.org. One issue
(P120.00). Back issues (depending on availability
P120.00).
 OCTOBER-DECEMBER 2017 VOLUME 18 NUMBER 4

1 EDITORIAL

3 A Case Report on Primary Ciliary Dyskinesia in a 16-Year-Old Male With

Bronchiectasis, Normal Situs, and Sperm Immotility
Raiza A. Visita, MD; Miriam Y. Lalas, MD, Virgina S. delos Reyes, MD, FPCCP;
Dina V. Diaz, MD, FPCCP

14 Good Syndrome: A Case Report

Janiza J. Villalon, MD; Erlyn D. Lopez, MD, FPCCP; Ligaya C. Dy, MD, FPCCP

18 Yield Pattern of Three-sputum Smears in the Case Detection of Pulmonary

Tuberculosis in a Tertiary Hospital
Lowell N. Bascara II, MD; Gwendolyn D. Pepito, MD; John Clifford E. Aranas, MD

24 Validity Study of Gene Xpert MTB/RIF Assay in the Diagnosis of Tuberculous

Pleural Effusion among Adult Patients at the Lung Center of the Philippines
Ronel G. Sario, MD; Joven Roque V. Gonong, MD, FPCCP

30 Diagnostic Accuracy of Berlin, Flemons Sleep Apnea Clinical Score and St.
Luke’s Medical Center–Obstructive Sleep Apnea Clinical Score Questionnaires
for Screening Obstructive Sleep Apnea in Filipino Patients
Babyleen E. Macaraig, MD, FPCP; Mercy Antoinette S. Gappi, MD, FPCP, FPCCP

40 Cohort Study on the Applicability of the Updated 2015 Lung Center of the
Philippines Algorithm on Pre-operative Risk Assessment as a Predictor of Post-
operative Pulmonary Complications
Randy Joseph D.T. Castillo, MD; Glynna O. Cabrera, MD

53 Image Gallery: Primary Ciliary Dyskinesia

EDITORIAL
Remember not to forget
Evelyn Victoria E. Reside, MD, FPCCP
Editor-in-Chief
“Remember how we forgot?”
- Shane L. Koyczan, “Remembrance Year”
There is a understandable premium
clinicians place on diagnostic tests and tools
which are not only simple, but speedy as well.
Health care has become increasingly more
expensive, and in many instances when urgent
care is required, time is of the essence, especially
since every day spent waiting for a test result
means additional cost to care.
However, our articles in this issue describe
situations wherein diagnostic testing, although
considerably costly, is worth both the expense
and the wait. The case reports on Primary Ciliary
Dyskinesia (PCD) and Good Syndrome
demonstrate the value of complete diagnostic
testing, despite the attendant costs, since it
clinches the diagnosis for rare and less common
conditions, especially because these patients may
present with signs and symptoms which may be
often associated with more endemic illness.
The 16-year-old patient with PCD
presented with hemoptysis, and already
underwent two treatment courses for pulmonary
tuberculosis, and was only considered for the
diagnosis upon review of his childhood history.
The 50 year-old patient with Good Syndrome
was also frequently diagnosed with pulmonary
infections, and it was only after a more extensive
review of her medical background allowed her
1 Philipp J Chest Dis 2017
medical team to consider the syndrome. Both of
these patients were able to clinch their rare
diagnoses through complete albeit expensive
diagnostic testing. However, none of these
investigative testing would have been pursued if
the attending physicians did not recognize the
possibility of the less common diagnoses.
Furthermore, if costly testing such as CT scans,
bronchoscopy, and immunological work-up were
not done, then these patients would have ended up
misdiagnosed.
On the other hand, the other articles in this
issue remind us that there are simple and less
costly ways of evaluating patients. Despite the fact
that sputum AFB testing is slowly being replaced
by the Gene Xpert MTB/Rif Assay as the go-to
initial test to diagnose pulmonary tuberculosis, it
still remains valuable when cost of work-up is
restrictive. Likewise, this article from Bascara et
al reminds us that a third sputum AFB smear can
still be helpful, in the same way that Sario and
Gonong have demonstrated that the testing
characteristics of Gene Xpert MTB/Rif Assay do
not necessarily outperform histopathology and
culture in diagnosing tuberculous pleural effusion.
Moreover, the use of checklists and
questionnaires in augmenting medical history
taking has proven to be helpful tools in evaluating
patients either in-hospital or in an outpatient
setting. In addition, these tools aid clinicians
ensure that all significant patient medical data are
captured, especially in urgent and critical care
situations where quick decision-making is
required despite limited patient history-taking.
Eventually, questionnaires and checklists also
allow for more focused diagnostic testing,
such as sleep testing for patients screened for
likely obstructive sleep apnea (OSA), which
become even more valuable since the
screening tool recommended by Macaraig and
Gappi is homegrown and tailored for
Filipinos.
In the same way, algorithms such as the
one presented by Castillo and Cabrera is a
tool similar to a checklist in that it directs the
clinician to the next diagnostic and/or
therapeutic step/s. Being a pre-operative
algorithm, the Lung Center of the Philippines
(LCP) Risk Assessment tool was initially
designed to evaluate patients with lung
cancer, but this study demonstrates that it
easily evaluates for non-neoplastic cases as
well.
Essentially, this issue reminds us that
some diagnostic tests such as sputum AFB
testing, histopathology and culture remain
relevant despite the fact that there are more
updated and sophisticated tests available
nowadays. Also, remembering less common
medical conditions comes in handy in the
approach to patients with potentially rare
syndromes or illnesses. It is definitely difficult
to imagine how many patients have been – and
continue to be – misdiagnosed with pulmonary
tuberculosis for such manifestations as cough,
hemoptysis and bronchiectasis.
Checklists and questionnaires as
diagnostic screening tools, as well as
algorithms as means to direct therapeutic
approaches, help clinicians remember
necessary aspects in medical history taking,
and steps in moving patient care forward.
Nevertheless, local versions of these tools
come few and far between and so to develop
those tailor-fit for Filipinos will prove to be
extremely valuable contributions to patient
care.
In the end, let this PJCD issue help us
remember not to forget the basic essentials in
the diagnosis of TB, which continue to play
significant roles especially among the cost-
conscious, or not to forget the less common
diagnostic possibilities which can mimic more
endemic medical conditions.
Indeed, let it not be said that, in the
diagnostic and therapeutic approach to our
patients’ illness, we did not remember certain
key aspects that can direct (or redirect) patient
care. Let us, therefore, always make a
conscious effort to remember not to forget.
Vol. 18
Vol.
| Issue
18 | Issue
04 | December
02 | June 2017 2
Primary ciliary dyskinesia

CASE REPORT

A Case Report on Primary Ciliary Dyskinesia in a 16-Year-Old

Male With Bronchiectasis, Normal Situs, and Sperm Immotility
Raiza A. Visita, MD; Miriam Y. Lalas, MD, Virgina S. delos Reyes, MD, FPCCP; Dina V. Diaz,
MD, FPCCP
Department of Pulmonary Medicine, Lung Center of the Philippines, Quezon Avenue, Quezon
City, Metro Manila, Philippines.

Corresponding author
E-mail: raizavisita@yahoo.com.

ABSTRACT
Primary ciliary dyskinesia (PCD) is a rare genetic disorder of the motile cilia. The common
manifestations are recurrent infection of the upper and lower respiratory tract due to impaired mucociliary
clearance, leading to development of bronchiectasis with predilection to the middle and bilateral lower
lobe, situs abnormalities in 50% of cases, and infertility due to poor motility of spermatozoa flagella in
males and poor ciliary movement of the epithelial lining of the oviduct in females.
This paper reports a case of a 16-year-old male who came in with recurrent non-massive
hemoptysis, secondary to bronchiectasis via chest CT scan. He presents with perennial rhinosinusitis and
a history of neonatal pneumonia. Patient was worked up for congenital causes of bronchiectasis.
Fiberoptic bronchoscopy revealed normal bronchial tree with suppurations and no obstruction, low
fractional exhaled nitric oxide (FeNO) level (using chemiluminescence analyzer), and low sperm count
with predominant non-motile population. The semen sample was sent for transmission electron
microscopy (TEM) analysis, which revealed various ultrastructural defects such as missing central
microtubules, microtubular disorganization and missing inner and outer dynein arms. These structural
abnormalities in the spermatozoa flagella were associated with PCD.
Keywords: primary ciliary dyskinesia, bronchiectasis, FeNO, TEM, sperm immotility

INTRODUCTION
Bronchiectasis is the irreversible dilatation
of the bronchial airway, developed from
inflammation secondary to infection. Reid
classified the types of bronchiectasis as
cylindrical, cystic and varicose. It can be localized
or diffuse in presentation and can be congenital or
acquired. The more common of the two is the
acquired type, which occurs after repeated bouts of
airway infections, including post-tuberculous (TB)
infection. Among the congenital causes, the most
commonly reported are cystic fibrosis and primary
ciliary dyskinesia (PCD).
Bronchiectasis is best assessed with the help
of high-resolution computed tomography (HRCT),
and its location in the bronchial tree can lead to the
identification of its etiology. Bronchiectasis in the
upper lobes is associated with post-TB infection
and cystic fibrosis, while middle lobe and lower
lobe predominance are associated with PCD.
PCD is a rare autosomal recessive genetic
disorder of the motile cilia found in the all-ciliated
epithelial lining and the spermatozoa flagellum
with a 9+2 microtubular structure arrangement in
the axoneme.1 However, there are rare reports of
an autosomal-dominant and X-linked
transmission.2 PCD is the general diagnostic
nomenclature for all congenital ciliary disorders,
including Kartagener syndrome (bronchiectasis,
situs inversus, sinusitis), which occur in 70% of

3 Philipp J Chest Dis 2017


patients with PCD.3 PCD in general occurs in 1 of
every 10,000 to 40,000 live births and is often
misdiagnosed due to misinterpretation of signs and
symptoms, such as the absence of laterality defects,
and also because its diagnosis requires highly
specialized diagnostics tools, such as high-speed
video microscopy analysis for the evaluation of
ciliary beat pattern and frequency and transmission
electron microscopy (TEM) for the identification of
ultrastructural defects on cross-sectional view of the
ciliary structure.
CASE REPORT
A 16-year-old male student from the
province of Pampanga came to our institution due
to recurrent hemoptysis.
Three years prior to admission, he had
experienced massive hemoptysis with severe
anemia and had been admitted at a local hospital.
He required transfusion of three units of packed red
blood cells and was worked up for pulmonary TB
(PTB). Acid-fast bacilli (AFB) smears were both
negative, but patient was treated as PTB clinically
diagnosed and was started with category I TB
treatment under direct observational treatment
strategy (DOTS), which he completed in six
months. There was no recurrence of hemoptysis
until 14 months prior, with four episodes at one cup
per episode. Patient was then referred to a tertiary
hospital for further work-up and management.
Upon transfer, a chest radiograph was done (Figure
1). Patient underwent fiberoptic bronchoscopy, and
bleeding was identified at the superior segment of
the left lower lobe. A Fogarty blockade was done.
Bronchial aspirate during the procedure was also
sent for cultures and came back negative for all,
including TB. Cell block cytology found
degenerated squames in a mixed inflammatory
background.
A chest computed tomography (Figure 2)
was done for work-up. It showed diffuse left lower
lobe (LLL) volume loss, bronchiectatic
changes/cavity formations within the atelectatic
LLL, a compensatory hyperaeration of both upper
Visita et al
Figure 1. Chest radiograph, posteroanterior and left
lateral views showing heterogenous opacities in both
lungs with obscuration of the left hemidiaphragm and
both sulci, suggesting pneumonia on top of TB with
possible pleural effusion more on the left.
and right lower lung, and an atelectatic right
middle lobe (RML) with tubulocystic
bronchiectasis. Diffuse centrilobular nodules with
tree-in-bud pattern were demonstrated in both
lungs, predominantly in the right lower lobe.
Patient was referred to pediatric service for co-
management. Patient was then worked up for PTB
relapse. TB Gene Xpert showed negative results,
but patient was treated as PTB relapse and started
on Category II anti-TB treatment under DOTS,
which he completed in eight months as outpatient.
Prior to discharge, patient had no recurrence of
hemoptysis, and the Fogarty catheter was
removed. Plans for possible left lower lobectomy
was discussed with the relatives after two to three
months of anti-TB treatment. Patient was asked to
follow up.
Six months prior to admission, patient
followed up as outpatient. A repeat scan was done,
which showed significant clearing of the LLL
opacities, but with chronic contraction of the LLL
and RML. Severe tubulocystic bronchiectasis are
unchanged (Figure 3).
Patient was referred to pulmonary service
for further work-up. Impression at this time was
post-infectious bronchiectasis vs congenital causes
of bronchiectasis, and patient was admitted. Upon
Vol. 18 | Issue 04 | December 2017 4
 Primary ciliary dyskinesia
Figure 2. Chest computed tomography 3 years prior to admission showing right-middle and left-
lower-lobe bronchiectasis
further investigation of history, the patient was
found to have had neonatal pneumonia that required
his admission to the neonatal unit and a month-long
stay in the hospital. He also had perennial
rhinosinusitis without any identified triggers,
productive cough with yellowish and whitish
sputum but no hearing loss noted. Diabetes mellitus
type II was identified from the maternal
grandmother (family history came only from the
maternal side due to the patient’s estrangement
from his father). Patient never smoked nor drank
alcoholic beverages. There were no pertinent
environmental exposures.
Upon admission, patient was ambulatory,
well nourished and had a BMI of 23.43 kg/m2. His
5 Philipp J Chest Dis 2017
vital signs where within normal range, and he had
peripheral capillary oxygen saturation (SpO2) of
98% on room air. No clubbing or cyanosis was
noted. Pertinent chest findings were crackles and
end-inspiratory wheeze on the right middle lung
field. The rest of the physical examination results
were unremarkable.
A pulmonary function test was done to
determine ventilatory impairment. It showed very
severe obstructive ventilatory defect with severe
air trapping and no significant bronchodilator
response, as well as moderate reduction in
diffusing capacity of the lungs for carbon
monoxide (DLCO). A lung perfusion scan was
also done to determine the extent of the disease

and to rule out vascular abnormalities and
anomalous blood supply, such as pulmonary
sequestration, as possible causes of the
bronchiectasis; it showed that the differential
contribution to total perfusion in the left and
right lung were 23.9% and 76.1%, respectively,
but there were no signs of any pulmonary
sequestrations.
The patient underwent fiber optic
bronchoscopy to evaluate for presence of
obstructive lesions, congenital deformities such
as tracheal dilatation, and any signs of granulo-
Figure 3. Comparative chest CT scan 14 months prior (left) and 6 months prior (right) to admission
Visita et al
matous lesions, like in sarcoidosis, as possible
causes of the bronchiectasis. On images at the
level of the carina up to the bilateral lower lobes,
there were purulent secretions but no tracheal
dilations, nor any granulomatous lesions or
obstructive lesions identified, except for a nodular
lesion on the RB8, which revealed chronic
inflammation and submucosal gland hyperplasia
on histopathology (Figure 4). Bronchial washing
and bronchial lavage were done, and specimens
were sent for analysis, which showed
predominance of neutrophils (73%) but no growth
the same as in non-pregnant asthmatics based on
the stepwise approach to asthma control.10 Inmost
w omen, asthma reverts back to the pre-pregnancy
level of severity within 3 months after delivery. All
asthma medications should be continued during
pregnancy and lactation.7
Patients’ education is mandatory to optimize
the outcomes of therapy in asthmatic patients.
However, in the case of pregnant women, strict
and repeated reassurance on the significance and
safety of a regular therapy for controlling airway
inflammation is definitely essential to ensure
adequate compliance.
CASE 2: TUBERCULOSIS (TB) IN
PREGNANCY
A.B. is a 25-year-old woman, G2P1 (1001),
on her 29th week of pregnancy, with regular
prenatal check-ups at a local health center. She
was treated for 6 months for smear-positive TB in
2008, after which there was documentation of
sputum smear conversion was documented.
Vol. 18 | Issue 04 | December 2017 6
Primary ciliary dyskinesia
Figure 4. Fiberoptic bronchoscopy images: (A) level of
the carina showing purulent secretions; (B) view from
the bronchus intermedius; (C) view from LC2; and (D)
nodular lesion on the orifice of RB8
on either culture study and also negative for acid-
fast bacilli (AFB). Summarizing all pertinent
findings and diagnostic tests results, we were
highly considering at this point the diagnosis of
PCD. Hence, additional tests were done.
Two-dimensional echocardiography was
done to evaluate for presence of cardiac defect,
and an ultrasound of the abdomen was done to
identify any laterality defects; both tests revealed
normal results. Then we proceeded with other
diagnostics to confirm diagnosis of PCD. In lieu
of the nasal nitric oxide test, we did a FeNO test
using a chemiluminescence analyzer. It gave a
low result of 4 parts per billion. The semen
specimen was then sent for TEM analysis due to
the high percentage of immotile population. This
revealed 8+2 pattern with missing inner and
dynein arms and missing central microtubular
pairs (Figure 5), all of which are associated with
PCD.
Patient and relatives were informed of the
diagnosis and were advised to do regular follow-
7 Philipp J Chest Dis 2017
up with periodic chest imaging, lung function
monitoring and sputum surveillance via culture.
Airway clearance therapy for bronchiectasis and
monitoring for extrapulmonary manifestations
were emphasized. Further genetic testing and
genogram on the relatives were also discussed.
DISCUSSION
PCD, a rare autosomal recessive genetic
disorder of the motile cilia, encompasses all
congenital ciliary disorders. A limited number of
patients are identified with PCD because there are
no specific manifestations pertaining to it, so
studies regarding its epidemiology are few and
usually involve both children and adult
populations.
The cilia
The cilia, the main structure of concern in
PCD, are hairlike attachments (approximately 200
per cell) found along epithelial surfaces such as
the respiratory tract.1 There are two types of cilia
in a normal individual: motile and non-motile.
Motile cilia with a wavelike pattern and a 9+2
microtubule structural arrangement are found in
the ependymal lining of the brain ventricles,
epithelial lining of the upper and lower respiratory
tract, eustachian tube in the middle ear and
oviducts, and have the same structural
arrangement as the spermatozoa flagella. Motile
cilia with the rotational motion and 9+0
arrangement are seen in the primary monocilia
that established the left-right asymmetry during
embryogenesis, where the placement of the apex
of the heart, stomach and spleen are at the left side
while the liver is predominantly at the right side.
Non-motile cilia are mostly sensory in nature and
are found in the eyes, ears, nose, bile duct and
kidney tubules.4
The structure of the cilium is composed of
the axoneme, or the body attached to the base,
found on the epithelial lining. This axoneme is
composed of different microtubular structures that

are important for producing the ciliary beat or
movement. These microtubular structures are in a
9+2 arrangement best seen on cross-sectional
view, composed of nine microtubular doublets
arranged in the periphery of the axoneme and two
central microtubular pairs. Attached to one of the
microtubular pairs on the periphery are the dynein
arms (outer and inner). These arms generate the
ciliary beat at a frequency of 6 to 12 Hz by
allowing the microtubules to slide against one
another using adenosine triphosphate (ATP).
While the cilia move, the axoneme structure is
maintained by the radial spokes that connect the
microtubular doublets on the periphery to the
central microtubular pair, as well as the nexin
links that connect each microtubular doublet to
one another, seen in the diagram below. These
structures provide the force and movement of the
cilia. They move in a wavelike pattern that
propels the surrounding fluid against the beating
cilia or move the entire cell, like in the
spermatozoa. The cilia move the cerebrospinal
fluid within the brain ventricles, facilitate
mucociliary clearance of the upper and lower
respiratory tract, provide the undulating
movement of the spermatozoa flagella and
transport the ovum through the oviduct.
PCD genetics
In PCD, there are more than 30 genetic
mutations currently identified.5 These mutations
lead to the disrupted encoding of the proteins, for
the assembly of the structural components of the
axoneme of the cilium. Hence in PCD, all cilia
may be affected. These genetic mutations occur in
closed communities inherited from the carrier
parent via autosomal recessive transmission. But
reports of autosomal-dominant transmission and
X-linked transmission occur on rare occasions.
These genetic mutations are heterogenous; that
shows variable phenotypical features. Therefore,
there are no specific manifestations
pathognomonic of PCD, but these genetic mutati-
Visita et al
ons that lead to the ultrastructural defects seen on
the TEM of any ciliated structures cause
immotility or inefficient function of the cilia.
Pathophysiology
Patients commonly present with
otosinopulmonary diseases. The most common
manifestations are chronic productive cough;
otitis media; development of bronchiectasis due to
poor mucociliary clearance causing repeated
infections; microbial colonization followed by
continuous inflammation and eventual destruction
of the bronchial structures,6 which leads to
progressive airway obrstrction7; history of
neonatal pneumonia due to poor clearance of
amniotic fluid from the lungs upon birth;
perennial sinusitis; and situs abnormalities in 50%
of the patients, due to the poor leftward rotational
movement of the primary monocilia during
embryogenesis. Situs abnormalities like
dextrocardia occur in Kartagener syndrome,
which is 70% of all PCD-diagnosed patients.
Other ciliary structures are also affected in PCD;
therefore, PCD can present as hydrocephalus, due
to stagnant flow of CSF, and infertility, due to
poor motility of the spermatozoa flagellum and
high incidence of ectopic pregnancies. Congenital
cardiac defect is noted in 5% of cases; hence, the
use of 2D echocardiogram.
Diagnosis of PCD is a tedious process, so
Figure 5. TEM results of the spermatozoa flagella:
(A) 8+2 pattern with both inner dynein arms
missing and (B) missing central microtubular pairs
Vol. 18 | Issue 04 | December 2017 8
Primary ciliary dyskinesia
good clinical history is important to identify
clinical manifestations from the patient highly
suspicious of PCD, like our patient, a young
person who presented with massive hemoptysis at
14 years of age, with bronchiectasis on the right
middle and lower lobes. In the Philippines,
hemoptysis is one the common manifestations of
PTB, so our patient was treated as PTB clinically
diagnosed twice (negative AFB smear, TB Gene
Xpert). But despite adequate treatment under
DOTS, there was a note of progression of the
bronchiectasis. The consideration of bronchi-
ectasis as the main problem in this particular case
led to the series of work-ups to rule out other
etiologies of bronchiectasis aside from the post-
TB infection most likely associated with our
patient.
Differential diagnoses for PCD
Post-infectious bronchiectasis—TB, in
particular—was ruled out because despite the
reading of upper-lobe PTB findings on chest CT
scan, the bronchiectasis was noted on the middle
lobe and lower lobes8 least likely to be affected by
TB infection. Therefore, congenital causes of
bronchiectasis were considered, due to the age of
our patient. The most common identified cause of
bronchiectasis in children is cystic fibrosis. This
was an unlikely diagnosis for our patient because
cystic fibrosis is associated more with the
Caucasian population and is rare in the Asian
race. Also, the affected lobes of bronchiectasis
were in the upper lobes, in contrast to what was
seen in our patient. Other causes, such as
pulmonary sequestration, were ruled out through
the results of the lung perfusion scan. Idiopathic
or inflammatory causes such as sarcoidosis were
ruled out due to the absence of granulomatous
lesions from bronchoscopy. Autoimmune causes
such as systemic lupus erythematous (SLE) were
ruled out due to the patient’s gender, age, and
absence of systemic manifestations such as
cutaneous lesions, photosensitivity and arthritis.
9 Philipp J Chest Dis 2017
Inhalational causes were ruled out because
our patient had no significant exposures to
biomass fumes, inert gases and metals. This left
PCD as the probable cause of the bronchiectasis,
especially considering the history of neonatal
pneumonia, perennial rhinosinusitis, and low
sperm count with predominance of immotile
population.
Diagnosis of PCD
In 2016, the European Respiratory Society
(ERS) published a guideline on the diagnosis of
PCD.9 The main goal was to provide evidence-
based recommendations on diagnostic tools for
PCD. It focused on clinical presentation, use of
nasal nitric oxide, evaluation of ciliary beat
pattern and frequency using high-speed video
microscopy analysis, identification of
ultrastructural defects under TEM, genetic testing
and use of immunofluorescence.
Patients with more than one of the
following manifestations should undergo further
testing for PCD: persistent wet cough, situs
anomalies, congenital cardiac arrest, persistent
rhinitis, chronic middle-ear disease with or
without hearing loss, and history of term infants
with neonatal upper and lower respiratory
symptoms or neonatal intensive care admittance
Our patient had normal situs but had
productive cough, a history of neonatal
pneumonia and admission to the neonatal unit,
and perennial rhinosinusitis.
The ERS, also recommended the use of the
PCD Rule (PICADAR) diagnostic tool. The
PICADAR was developed by Behan at al to help
general practitioners identify which among their
patients presenting with chronic productive cough
have PCD.10 This tool has seven significant
predictors that lead to a maximum score of 14.
Patients with scores ≥10 have >90% probability
of having a PCD-positive diagnosis, while a score
≥5 suggests an 11.1% probability. We applied this
to our patient and came up with a score of 7.

We compared this to the probability
predictive curve from the derivation group in
the study and found a 44.1% probability of a
PCD-positive diagnosis. The PICADAR was
developed from the data of a large heterogenous
group, so it has only a weak recommendation.
These findings prompted us to proceed with
nitric oxide determination.
Nasal nitric oxide (nNO) has been proven
to be a good screening tool for PCD. The ERS
also recommended it to be part of the diagnostic
work-up of patients for PCD. NO is produced
from the interaction of the substrate L-arginine
with inducible NO isoenzyme within the
epithelial cells. It is an important signaling
molecule present in the respiratory tract and
other systems. It causes bronchodilation and
vasodilatation in the respiratory tract in
particular. Noone et al compared nNO levels of
patients with confirmed PCD from those of the
parents of PCD patients, normal controls and
patients with cystic fibrosis. They found that
patients with PCD had significantly lower
levels of nNO than the normal controls and the
patients with cystic fibrosis. They also noted
that the nNO of the parents of the PCD patients
who carried the genetic mutation also had
significantly lower levels of nNO compared to
the normal controls.11 The reasons behind low
nNO levels in PCD patients was explored by
Walker et al, who proposed four hypotheses: (1)
there is an increased breakdown of NO within
the epithelial cells, trapped in the mucus layer
or being used up by the denitrifying bacteria
present in the mucus layer; (2) there is reduced
biosynthesis of NO and its metabolites due to
decreased expression of inducible nitric oxide
synthase (iNOS) or low substrate levels of L-
arginine; (3) there is a normal biosynthesis of
NO trapped within the paranasal sinuses; and
(4) there is hypoplasia and agenesis of the
paranasal sinuses, so there is reduced
production and storage capacity for NO.12
However, in lieu of nNO, we used FeNO deter-
Visita et al
mination in our patient because it was the one
available. Exhaled nitric oxide level
determination has been standardized by the
American Thoracic Society (ATS) for clinical
use. The ATS uses ranges of FeNO in children
(normal >20 and <35 ppb) and adults (normal
>25 and <50 ppb) populations. A low FeNO
implies a non-eosinophilic or no airway
inflammation, including PCD, cystic fibrosis,
and rhinosinusitis, while a high FeNO implies
an uncontrolled or deteriorating eosinophilic
airway inflammation seen in atopic asthma and
eosinophilic bronchitis.6 Our patient had a
FeNO of 4 ppb, which supported PCD as our
diagnosis.
The ERS recommended the use of high-
speed video microscopy analysis (HSVA) to
evaluate ciliary pattern and frequency, but this
tool is only available in highly specialized
centers. It can show the wavelike pattern seen
in normal cilia and in the case of PCD.13 It can
show different patterns such as dyskinetic,
asynchronous movement, immotile or circular
movement. But there are patients with PCD
who still present with normal ciliary beating
and frequency but are nonetheless proven to
have genetic mutation and ultrastructural
defects on electron microscopy. Therefore, a
normal HSVA cannot totally exclude PCD
diagnosis. This specific test was not available in
our institution, so we proceeded with another
diagnostic tool.
TEM can clearly show the ultrastructural
abnormalities within the axoneme of the cilium.
It was previously considered the gold standard
for PCD diagnosis. However, normal TEM
findings among patients with clinical
presentations suspicious for PCD cannot rule
out PCD, because 30% of patient with
identified genetic mutations can present with
normal TEM. The most commonly identified
ultrastructural defect is the absence of defect of
the outer dynein arm, seen in 50% to 55% of
cases, while the combined defect of both dynein
Vol. 18 | Issue 04 | December 2017 10
 Primary ciliary dyskinesia
arms occurs in 10% to 15%.1 Other
ultrastructural defects associated with PCD are
missing central microtubule pair, like the one
presented in our patient; the absence or defect
of the inner dynein arm; or a combination of
defects of any components of the axoneme,
such as inner dynein arm absence and
microtubular disorganization or defect, which
can present as different pattern arrangements,
such as 8+2 (also seen in our patient) or 9+0.
We were able to send out the semen specimen
of our patient to another tertiary hospital for the
sperm flagella TEM analysis, which revealed an
8+2 pattern with both dynein arms missing and
missing central microtubule pairs on other
flagella.
The ERS has not made any
recommendation yet for the role of genetic
testing and immunofluorescence in the
diagnosis of PCD, because of the limited
number of literature to answer the inclusion-
criteria questions. However, these tests can be
done to identify which particular genetic
mutation is involved.8 Also to be able to
provide genetic counselling to relatives, to be
able to identify whom among them have the
same disorder, to be able to initiate monitoring
strategies regarding pulmonary and
extrapulmonary diseases.
A diagnostic algorithm (Appendix)
adapted from Lobo et al1 enabled us to diagnose
our patient as PCD.
Management and monitoring
Once a diagnosis of PCD is made, the
goals of each physician must focus on the
identification and management of
extrapulmonary manifestations that are not
associated with other causes of bronchiectasis,
otitis media, rhinosinusitis, cardiac defect and
infertility. The recommended are standard
therapy that must be given for acute episodes of
otitis media and rhinosinusoidal diseases: sche-
11 Philipp J Chest Dis 2017
duled audiology assessment to identify hearing
loss among the patients and surgical interventions
such as polypectomy for sinus drainage to prevent
recurrent sinusitis. Infertility is one of the major
concerns in patients with PCD. It must be part of
the work-up among these patients, and assisted
fertilization techniques may be given.
The most common pathology in PCD is
bronchiectasis. However, at present, there are no
randomized controlled trials regarding the
management of PCD patients. It is empirically
based on the management of bronchiectasis and
involves airway clearance therapy, antibiotic use,
oral anti-inflammatory agents, and surgical
intervention if warranted. Airway clearance
therapy is composed of different pulmonary
rehabilitation exercises, which are highly
recommended to improve quality of life and lung
capacity, and mechanical cough assist, such as
insufflator/exsufflator cough assist or lung flute.
Antibiotics target the most common pathogens
identified with bronchiectasis. In children, these
are Haemophilus influenza, Staphylococcus aureus
and Streptococcus pneumoniae, while in adults
there is the predominance of Pseudomonas
aeruginosa, other Gram-negative bacteria and
non-TB mycobacteria. Use of inhaled antibiotics
such as gentamicin has been proven to prevent
exacerbation and improve lung function. Oral anti-
inflammatories such as macrolide have proven
benefits, but the patient must be worked up first
for the presence of non-TB mycobacteria to
prevent the development of resistance. Surgical
interventions are not generally recommended, but
if there is presence of localized severe
bronchiectasis, lobectomy may be offered.2
Important also in the management of these
patients is the regular follow-up or monitoring of
the patients’ status, especially with regard to their
lung function and the extent of lung disease. It is
recommended for severe cases that a spirometry
test be done at least twice a year, sputum
surveillance at least every 3 months and periodic

imaging using HRCT to monitor the extent of the
lung disease.2
In summary, we have reported the case of
a 16-year-old male initially presenting with
bronchiectasis with predominance on the right
middle and bilateral lower lobes and chronic
productive cough. By the location of
bronchiectasis and the smear and culture negative
for TB, we were able to rule out post-TB
infection bronchiectasis and lead our diagnostic
work-up to the congenital causes of
bronchiectasis, given the age of the patient. Other
congenital causes of bronchiectasis were ruled
out, the most common of which within the age
group of our patient was cystic fibrosis, due to
cystic fibrosis’ low incidence among Asians and
the location of bronchiectasis. The history of
neonatal pneumonia and perennial rhinosinusitis
led our diagnostic work-ups to the diagnosis of
PCD. Despite no laterality defects identified, the
very low FeNO level and various ultrastructural
defects identified on the TEM of spermatozoa
flagella confirmed the diagnosis of PCD.
It is important for physicians to consider
PCD in patients presenting with unusual location
of bronchiectasis, like in our case, to identify the
clinical manifestations associated with PCD and
to be aware of the different diagnostic tools
available to support the diagnosis of PCD. It is
also important to be able to identify and manage
pulmonary and extrapulmonary diseases among
these patients—these diseases include otitis
media, rhinosinusitis, infertility and other
ciliopathies that are not associated with other
causes of bronchiectasis. Further studies on the
genetics and management of patients with PCD
are still in process.
Visita et al
REFERENCES
1. Lobo LJ, Zariwala MA, Noone PG. Primary
ciliary dyskinesia. QJM. 2014;107(9):691-699.
2. Kuehni CE, Frischer T, Strippoli MP, et al.
Factors influencing age at diagnosis of primary
ciliary dyskinesia in European children. Eur
Respir J. 2010;36(6):1248-1258.
3. Berdon WE, McManus C, Afzelius B. More
on Kartagener's syndrome and the
contributions of Afzelius and A.K. Siewert.
Pediatr Radiol. 2004;34(7):585-586.
4. Faus-Pérez A, Sanchis-Calvo A, Codoñer-
Franch P. Ciliopathies: an update. Pediatr Res
Int J. 2015;2015:1-23.
5. Kurkowiak M, Ziętkiewicz E, Witt M. Recent
advances in primary ciliary dyskinesia
genetics. J Med Genet. 2015;52(1):1-9.
6. Barbato A, Frischer T, Kuehni CE, et al.
Primary ciliary dyskinesia: a consensus
statement on diagnostic and treatment
approaches in children. Eur Respir J. 2009
Dec;34(6):1264-1276.
7. Kennedy MP, Noone PG, Leigh MW, et al.
High-resolution CT of patients with primary
ciliary dyskinesia. AJR Am J Roentgenol.
2007;188(5):1232-1238.
8. Lucas JS, Barbato A, Collins SA, et al.
European Respiratory Society guidelines for
the diagnosis of primary ciliary dyskinesia.
Eur Respir J. 2017;49(1). pii: 1601090.
9. Behan L, Dimitrov BD, Kuehni CE, et al.
PICADAR: a diagnostic predictive tool for
primary ciliary dyskinesia. Eur Respir J.
2016;47(4):1103-1112.
10. Noone PG1, Leigh MW, Sannuti A, et al.
Primary ciliary dyskinesia: diagnostic and
phenotypic features. Am J Respir Crit Care
Med. 2004;169(4):459-467.
Vol. 18 | Issue 04 | December 2017 12
 Primary ciliary dyskinesia

11. Walker WT1, Jackson CL, Lackie PM, et al.

Nitric oxide in primary ciliary dyskinesia. Eur
Respir J. 2012;40(4):1024-1032.
12. Dweik RA, Boggs PB, Erzurum SC, et al. An
official ats clinical practice guideline:
interpretation of exhaled nitric oxide levels
(FeNO) for clinical applications. Am J Respir
Crit Care Med. 2011;184(5): 602-615.
13. Amirav I, Mussaffi H, Roth Y, et al. A reach-
out system for video microscopy analysis of
ciliary motions aiding PCD diagnosis. BMC
Res Notes. 2015;8:71.

Appendix

Diagnostic algorithm for Primary Ciliary Dyskinesia

Adapted from Lobo LJ, Zariwala MA, Noone PG. Primary ciliary
dyskinesia. QJM. 2014;107(9):691-699.

13 Philipp J Chest Dis 2017

 Villalon et al

CASE REPORT

Good Syndrome: A Case Report

Janiza J. Villalon, MD; Erlyn D. Lopez, MD, FPCCP; Ligaya C. Dy, MD, FPCCP
Chinese General Hospital and Medical Center

ABSTRACT
Good syndrome, a rare cause of combined B-cell and T-cell immunodeficiency, occurs in 7% to
13% of patients with adult-onset hypogammaglobulinemia and in 6% to 11% of patients with
thymoma. We report the case of a 50-year-old Filipino female who presented with chronic
productive cough and had an extensive history of recurrent pneumonia and an incidental finding of
oral candidiasis.

THE CASE ted. Review of systems only revealed a decrease

SD, a 50-year-old female, single,
Filipino, from Caloocan City, came in with the
chief complaint of cough. Seven months prior
to admission, she had experienced productive
cough with occasional whitish phlegm but no
associated fever, weight loss or dyspnea. She
was admitted at a provincial hospital, managed
as a case of community-acquired pneumonia,
given unrecalled intravenous antibiotics for a
week and then was discharged improved with
oral antibiotics. However, the recurrence of
productive cough prompted the patient to
medically consult again with two other private
physicians, who gave her unrecalled antibiotics.
Three months prior to admission, due to
productive cough, the patient went to Taiwan
for general medical consult and work-up. Chest
radiography showed infiltrates within the right
lung. Chest CT scan suggested multiple
intrathoracic masses. The esophagoduo-
denoscopy report indicated the presence of
esophagitis and oral candidiasis. The patient
was given fluconazole 100 mg/tab once a day
for 14 days.
A week prior to admission, despite taking
herbal supplements and antitussives, the patient
experienced persistent and increasingly severe
productive cough. This prompted her to seek
consult at our institution and was, hence, admit
in patient’s appetite. Past medical history
revealed that a medical consult in 1985 had
diagnosed her with an anterior chest mass on
chest radiograph. The said mass was surgically
removed. Histopathologic report revealed
thymoma. There was no follow-up thereafter. In
1992, a medical consult due to persistent cough
revealed via chest X-ray a recurrence of the
anterior chest mass. Repeat surgical removal of
the mass was done, and histopathologic report
showed thymoma. Oncologic evaluation was
advised, but the patient was lost to follow-up.
Between May 2012 and September 2014,
the patient medically consulted several times due
to on-and-off cough, treated with various
unrecalled antibiotics. A succeeding chest CT
scan revealed heterogeneously enhancing, well-
defined mediastinal and pleural lesions in the
right lower lung, with chest wall nodules and
minimal pleural effusion in the right and fibrosis
in the right upper lobe. No axillary lymph nodes
were enlarged. There was an incidental finding of
hepatic cysts. The patient was referred to an
oncologist, and she underwent four cycles of neo-
adjuvant chemotherapy. Surgical debulking was
subsequently done because there was no change
in the size of the mass. Histopathologic results
showed thymoma, WHO type AB, with three
unremarkable lymph nodes but no capsular inva-

Vol. 18 | Issue 04 | December 2017 14

 Good syndrome
sion. Follow-up plain chest CT scan revealed the
disappearance of the anterior-right infrahilar-
enhancing soft tissue density. The tumor did not
recur. Pleural-based nodules in the right lung did
not change. There was no evidence of enlarged
lymph nodes or pleural or pericardial effusion.
The patient had received no previous blood
transfusions, no anti-Koch’s treatment, and had no
known comorbidities. She claimed to be allergic to
nystatin. Family history was unremarkable. She
worked as an accountant and was a non-smoker,
single, with no history of sexual contact. Recent
travel history was in Taiwan in November 2015
for medical consultation.
Course on admission
Patient came in ambulatory, conscious,
coherent, oriented to time and place and person
and not in cardiorespiratory distress. Blood
pressure was 110/80 mm Hg; cardiac rate, 81 bpm;
respiratory rate, 20 cpm; temperature, 36.5° C;
weight, 37.3 kg; oxygen saturation, 97% at room
air. Significant physical examination noted whitish
oral plaques in the posterior area of the tongue.
Patient had no palpable cervical
lymphadenopathies. She had symmetrical chest
expansion and no retractions. The surgical incision
scar over the right subchondral area and right
anterior axillary line and anterior thorax was
noted, with a palpable 4-by-4-cm firm and
movable non-tender mass at the right mid-axillary
line. There were crackles on the right lower lung
field. Neurologic exam results were unremarkable.
Upon admission, the patient’s chest
radiography showed an elevated right
hemidiaphragm with ill-defined infiltrates in the
right lung, defined as pneumonia but Koch’s
infection in the right upper lobe could not be ruled
out. A deformity was noted in her right seventh
posterior rib with the presence of a sternotomy,
surgical staple wires and a port catheter. Complete
blood count suggested mild anemia (hemoglobin
100 g/L), thrombocytopenia (platelet 102,000/µL),
and the presence of bands (15%) (white blood
15 Philipp J Chest Dis 2017
cells of 6.1x109 cells/mm3; segmenters of 61x109
cells/mm3; lymphocytes of 20 x109 cells/mm3;
monocytes of 4x109 cells/mm3). Empiric treatment for
community-acquired pneumonia was started with
piperacillin-tazobactam 4.5-g IV every 8 hours and
azithromycin 500-mg tablet once a day. Chest CT scan
showed interstitial pneumonia in the superior segment
of the left lower lobe and a cavitary nodule in the
superior segment of the right lower lobe;
emphysematous lungs; fibrosis in the right apex and in
both lower lobes; bronchiectatic changes in the right
lower lobe; no enlarged mediastinal lymph nodes and
no pleural effusion. Sputum culture growth was
Candida spp; Mycobacterium tuberculosis (MTB)
culture was negative.
Esophagogastroduodenoscopy showed whitish
plaques on the tongue, in the oral cavity and in the
esophagus, consistent with oral candidiasis.
Fluconazole was started at 100-mg tablet twice a day.
Enzyme-linked immunosorbent assay (ELISA) for
HIV was non-reactive.
The primary immunodeficiency panel showed
low results: lymphocytes, 430 (13.7%); monocytes,
289 (9.2%); granulocytes, 2,421 (77.1%); total
leukocytes, 3,140 (100%).
Confirmatory flow cytometry with T-cell
markers revealed low counts of both B and T
lymphocytes: CD3 pan T-lymphocytes, 389; CD4 T
helper cells, 114; CD8 T suppressor, 290; CD4:CD8 T
helper/T suppressor, 0.39; CD16+56 natural killer
(NK) cells, 34; CD20 pan B-cells (B1), 5; CD19 B-
cells:pre-B cells, 10; serum IgG, 64.9; serum IgA,
27.4; serum IgM, 15.2; total serum IgE <5.00;
complement C3, 138. Direct and indirect Coombs tests
came back negative.
IVIG therapy was initiated thereafter. This
improved the patient’s clinical symptoms, and she was
subsequently discharged. Follow-up chest CT scan
plain, done one week after discharge, showed interval
regression of the interstitial infiltrates in the superior
segment of the left lower lobe, with interval decrease
in the size of the previously noted cavitary lesion in the
superior segment of the right lower lobe.
One month after discharge, there was complete

resolution of the patient’s cough, and repeat plain
chest CT scan further showed interval clearing of
the interstitial densities in the superior segment of
the left lower lobe. Patient was maintained on
IVIG therapy.
DISCUSSION
The triad of thymoma, hypogamma-
globulinemia and a concomitant immuno-
deficiency state (clinically apparent as recurrent
pulmonary infection)is classically defined as Good
syndrome. This disorder was first characterized in
1955 by Robert Alan Good, a pioneer in the field
of immunodeficiency diseases, who recognized
the crucial role played by the thymus in the
development of the immune system.1
Good syndrome is a rare cause of combined
B-cell and T-cell immunodeficiency. It occurs in
7% to 13% of patients with adult-onset
hypogammaglobulinemia and in 6% to 11% of
patients with thymoma.2 Good syndrome usually
manifests in the fourth or fifth decade of life,
without preference for either sex. The
immunodeficiency may precede or follow the
diagnosis of thymoma. Although the cause and
pathogenesis of this disorder are unknown, its
main characteristics are hypogammaglobulinemia,
a low B-cell count or the absence of B cells, CD4+
T-cell lymphopenia and reduced serum levels of
IgG, IgA and IgM.3 Because their cell-mediated
immunity is compromised, individuals with Good
syndrome are susceptible to bacterial and
opportunistic infection, which are part of the
disease’s clinical characteristics. Systemic fungal
infection is not a common feature of Good
syndrome. However, mucocutaneous candidiasis
has been diagnosed in 24% of cases.3
The diagnosis of Good syndrome should be
considered in patients presenting with recurrent
airway infections and an anterior mediastinal
mass.4 Immunological workup, including T-cell
subsets, B cells and quantitative immunoglobulins,
should be considered part of the routine diagnostic
evaluation in patients with a thymoma and
recurrent infections.5
Villalon et al
Treatment of Good syndrome involves
resection of the thymoma, IVIG replacement to
maintain adequate immunoglobulin values, and
antibiotic treatment if necessary.6 Therapy with
IVIG can reduce the risk of infection, excessive
antibiotic administration, hospitalization and the
development of pulmonary damage. In contrast to
other paraneoplastic disorders associated with
thymoma (ie, pure red cell aplasia or myasthenia
gravis), Good syndrome is not influenced by
thymectomy. It is also important to note that Good
syndrome may progress even after thymectomy
and corticosteroid treatment.
Mortality among Good syndrome patients is
usually due to infection, autoimmune disease, or
hematological complications. So far, Good
syndrome has only been studied retrospectively in
case reports and small retrospective case series.
Therefore, the course of the disease is not well
understood. A recent study showed a Kaplan-
Meier survival analysis indicating 5-year survival
for approximately 82% and 10-year survival for
68%, with a median survival of 14 years.7 Thus,
early recognition and treatment with antibiotics or
immunoglobulin replacement can change the
natural course of this rare condition and have been
proven effective in keeping patients symptom-free.
REFERENCES
1. Good RA, Varco RL. A clinical and
experimental study of agammaglobulinemia. J
Lancet. 1955;75(6):245-271.
2. Tsoukas C. The natural history and long-term
management of Good’s syndrome. Clin
Immunol. 2006;119:Suppl.:S137-S138.
3. Kelleher P, Misbah SA. What is Good’s
syndrome? Immunological abnormalities in
patients with thymoma. J Clin Pathol.
2003;56(1):12-16.
4. Tarr PE, Lucey DR; Infectious Complications
of Immunodeficiency with Thymoma (ICIT)
Investigators. Good's syndrome: the
association of thymoma with
immunodeficiency. Clin Infect Dis.
2001;33(4):585-586.
Vol. 18 | Issue 04 | December 2017 16
 Good syndrome

5. Tachdjian R, Keller JJ, Pfeffer M. A bad case

of Good's syndrome. Infect Dis Ther.
2014;3(2):333-337.
6. Popovic M, Glisic B, Mitrovic D, et al.
Intravenous immunoglobulins in the therapy of
severe bacterial infections,
immunodeficiencies, and autoimmune
diseases. Transplant Proc. 2001;33(3):2376-
2377.
7. Hermaszewski RA, Webster AD. Primary
hypogammaglobulinemia: a survey of clinical
manifestations and complications. Q J Med.
1993;86(1):31-42.

17 Philipp J Chest Dis 2017

 Bascara et al

RETROSPECTIVE STUDY

Yield Pattern of Three-sputum Smears in the Case

Detection of Pulmonary Tuberculosis in a Tertiary Hospital
Lowell N. Bascara II, MD; Gwendolyn D. Pepito, MD; John Clifford E. Aranas, MD
Perpetual Succor Hospital, Manila

ABSTRACT
Background: Sputum smear microscopy remains the cornerstone of pulmonary tuberculosis (PTB)
case detection. However, its utility is limited by poor sensitivity. In 2007, the World Health
Organization (WHO) reduced the minimum number of sputum smear specimens needed to be
examined for PTB diagnosis, from three to two, owing to the low incremental yield in the third
sputum smear specimen. However, differing yield patterns of sputum smears across studies in
different countries have been noted, with significant diagnostic yield in the third sputum smear and
higher positivity rates when utilizing three-sputum smear specimens in high-prevalence areas. The
utility of a third sputum smear cannot be underestimated in a high-burden-of-disease setting and an
increasing-risk population such as found in the Philippines.

Methodology: This was a hospital-based retrospective, cross-sectional chart review study

conducted from 2012 to 2014. It included 893 presumptive PTB patients aged ≥18 years, with no
prior history of PTB, who were subjected to three-sputum smear microscopy examinations. The
pattern of positive smears, the incremental yield of each sputum smear, and the positivity rate of
two-smear combinations were analyzed.

Results: Of the 893 three-sputum-smear combinations analyzed, 20.8% had at least a single
positive smear. The first smear was positive in 17.6%; 20.4% in the second smear and 20.0% in the
third smear. Majority of cases were detected in the first smear; 3.1% more patients were diagnosed
with the second smear and the incremental yield from the third smear was minimal (0.2%).
However, of those that had only two positive smears, two-sputum positivity was highest in those
with positive second and third smear (2.8%).

Conclusion: A three-sputum smear specimen in the case detection of PTB has a non-negligible
diagnostic yield. Furthermore, a significantly higher rate of two-smear positivity is observed for PTB
suspects from whom three specimens were collected, compared to those with fewer.

INTRODUCTION principles of PTB control, leading to reduction in

The prevalence of pulmonary tuberculosis
(PTB) in the Philippines is 500 cases per 100,000
members of the population.1 It is generally
estimated that up to 20 contacts may be infected
by each acid-fast bacilli (AFB)–positive case
before the index case is diagnosed.2 The current
data still equate to a high burden of disease in our
setting. Early diagnosis and timely treatment are
illness, death and spread of PTB.3
Sputum smear microscopy remains the
cornerstone of case detection in high-burden,
resource-poor settings, owing to its relatively low
complexity, low cost and high specificity.3 Poor
sensitivity, however, remains a significant
problem. Consequently, the optimization of
smear microscopy techniques to improve sensiti-

Vol. 18 | Issue 04 | December 2017 18

 Yield Pattern of Three-sputum Smears for TB
vity and the development of new diagnostic tools
are still areas of active investigation.3 The
examination of three-sputum specimens for PTB
diagnosis became routine following studies that
showed three specimens collected over two days
identified the highest number of patients while
requiring the least number of visits.3 Over time,
there have been arguments as to the number of
sputum specimens that needed to be collected,
assessing the specimens’ benefit and adequacy for
diagnosis and aiming to reduce expenses in the
diagnosis of PTB.
In 2007, the World Health Organization
(WHO) revised the minimum number of sputum
smear specimens that needed to be examined for
PTB diagnosis, reducing it from three to two in
settings where a well-functioning external quality
assurance (EQA) scheme exists. This revision was
due to a low incremental yield—between 2% and
5%—in the third sputum smear specimen, based
on the meta-analysis by Mase et al, done on 37
eligible studies.3 However, the authors’
conclusions had limitations to their
generalizability. Furthermore, studies in different
countries have noted differing yield patterns of
sputum smears. There are findings (notably in
high-burden-of-disease areas) of significant
diagnostic yield in the third sputum smear and an
increasing smear positivity rate in the succeeding
sputum smear specimens.4-7 In addition, as
stipulated in the seventh edition of the Canadian
Tuberculosis Standards, at least three-sputum
smears should still be collected because the yield
of the third sputum specimen may be significant,
as high as 5% to 10%.8 Therefore, the utility of a
third sputum smear cannot be underestimated in a
high-burden-of-disease setting and in increasing-
risk populations (e.g., multi-drug–resistant
tuberculosis– and human immunodeficiency virus–
infected individuals) such as those found in the
Philippines.
This study aimed to determine the yield
pattern of three-sputum smear specimens in the
case detection of PTB in a tertiary hospital from
19 Philipp J Chest Dis 2017
2012 to 201, including the three-sputum smear
positivity and incremental-yield patterns in our
locale, and to correlate these with the current
Department of Health (DOH) recommendation.
This will assist clinicians in improving the case
detection process.
METHODOLOGY
This was a retrospective, cross-sectional
chart review study conducted at a tertiary hospital
that included patients with presumptive PTB
enrolled at the private-public mix directly
observed treatment short course (DOTS) of the
hospital, aged 18 years or above, with no prior
history of PTB and who underwent three-sputum
smear microscopy examinations. Only patients
from 2012 to 2014 were included. Those who did
not meet all criteria were excluded.
We retrieved the individual sputum smear
microscopy results of all included patients, and
encoded in MS Excel 2013 spreadsheets. The
positive yield rates of three specimens for each
patient were computed and plotted using the
time-series graph. Change rates and cumulative
true positive were estimated. To test whether the
rates were significant, z-test of difference in
proportions was used. IBM SPSS version 21 was
used as statistical software.
RESULTS
Out of 1,048 patients, 893 patients met the
inclusion criteria while 155 were excluded (77
submitted only two-sputum smear specimens and
78 had a previous history of PTB). Of the 893
three-sputum-smear combinations analyzed, 187
(20.8%) had at least a single positive smear
(Table 1). The first smear was positive in 17.6%;
20.4% in the second smear and 20.0% in the third
smear. Of those that had only two positive
smears, two-sputum positivity was highest in
those with positive second and third smear.
Finally, the two-sputum combination that gave
the highest overall positivity rate was the
combination of positive second and third smears.
 Bascara et al

Table 1. Pattern of Sputum Smear Positivity in Three-sputum Smear Specimens

Pattern of Smear Positivity Positive (N=893) % p-value

Any smear positive 187 20.8 <0.001

First 157 17.6 0.048
Second 182 20.4 <0.001
Third 179 20.0 <0.001

All 3 smears positive 149 16.7 <0.001

Only 2 smears positive 32 3.6 <0.001

Positive-positive-negative 4 0.4 <0.001
Positive-negative-positive 3 0.3 <0.001
Negative-positive-positive 25 2.8 <0.001

Patients diagnosed using a two-sputum smear-

positive combination
Positive smear 1 and 2 (positive-positive-any) 153 17.1%
Positive smear 1 and 3 (positive-any-positive) 152 17.0%
Positive smear 2 and 3 (any-positive-positive) 174 19.5%

Table 2. Incremental Yield of Positive Smears from Three-sputum Collections

Incremental Yield Pattern Smear Positive (N=893) Incremental yield (%)
Positive identified on first smear
157 17.6%
(positive first smear)

Positive identified on second smear

28 3.1%
(negative first smear, positive second smear)

Positive identified on third smear

2 0.2%
(positive third smear only)

Table 2 shows the incremental yield of
positive smears from three-sputum collections
(i.e., the additional number of smear-positive
patients diagnosed with the additional smear).
While majority of cases were detected in the first
smear (18%), 3% more patients were diagnosed
with the second smear and the incremental yield
from the third smear was minimal (0.22%).
DISCUSSION
The DOH, in its 2014 update on the manual
of procedures (MOP) for case detection and
handling of PTB, advocated the use of two sputum
smear specimens instead of the routine three.
This was adapted from the WHO
recommendation, which was largely based on a
systematic review of 37 studies (18 prospective,
19 retrospective), which demonstrated that an
average of 85.8% of cases are detected with the
first specimen, an incremental yield of 11.9%
with the second specimen and an insignificant
incremental yield of 3.1% with the third
specimen.3,9 However, the same meta-analysis
highlighted limitations such as the heterogeneity
in study design, population and methodology,
which potentially introduce significant variability

Vol. 18 | Issue 04 | December 2017 20

 Yield Pattern of Three-sputum Smears for TB
in findings and thus affect their generalizability.3
The meta-analysis recognized the issue on
accuracy of results, stemming from the absence of
blinding in most studies and the absence of
assessment of positive sputum smear specificity.3
The recommendation was that before national TB
programs consider changing the examination
procedure to only two sputum smear specimens, a
functional EQA program and an internationally
standardized approach should be established, both
to strengthen the country-specific evidence base
and to allow comparisons to be made among
studies.3 Publication bias may have caused
important and relevant data to be missed, because
older studies and some non-English publications
were excluded from the review.3 In addition, the
Centre for Reviews and Dissemination (CRD),
upon reviewing the meta-analysis, noted that there
were no data provided on the differences in results
across studies, so it was not certain whether
average values reflected the findings of all studies.
The quality of the included studies also appeared
poor, which weakened the evidence base.10 With
the study appearing to have limited evidence from
generally poor-quality and heterogeneous studies,
a more cautious conclusion should be
considered.10
Differing yield patterns of sputum smears
have been observed across studies in different
countries, and there are findings (notably in high-
burden-of-disease areas) of a significant diagnostic
yield increase with the third sputum smear.
Descriptive studies by Saleem et al and Van Deun
et al noted incremental yields from 7.9% to 9.8%
in the third sputum smear.7,11 Similar studies
conducted in Nairobi and Zambia showed
contributions of 8% and 7.9%, respectively, from
the third sputum smear.12,13 A re-analysis of data
from a study involving 42 laboratories in four
high-burden countries showed the incremental
yield of the third smear reaching 7.4%.14 A
retrospective study by Kisa et al noted that the
detection of Mycobacterium tuberculosis was
directly proportional to the number of specimens
collected and that obtaining at least three speci-
21 Philipp J Chest Dis 2017
mens increased smear positivity and consequent
sensitivity.5 Furthermore, studies have
documented a higher yield involving the third
sputum smear with two-smear positive
combinations in a three-sputum collection.
Hamid et al noted a 6.8% yield from the first and
third samples and an 8.2% yield from the second
and third samples, compared to only 1.4% from
the first and second samples among two smear
positive cases.15 Similarly, Saleem et al identified
around 1.9% yield from the first and third
samples and a 2.2% yield from the second and
third samples, compared to 1.8% detection from
the first and second samples among two smear
positive cases.7
The study shows that the first two sputum
smear examinations of a three-sputum smear
specimen can detect majority of cases, with the
third smear adding only a minimal incremental
yield. This is consistent with the meta-analysis
findings of Mase et al and other studies.3,15
However, it is noted that the smear positivity rate
increases in the succeeding sputum smear
specimens, and this study found a comparable
positivity rate of the second (20.4%) and third
(20%) smears. This data is consistent with the
findings of Kisa et al and the existing national
guidelines for tuberculosis control, which
recommend a three-sputum smear specimen for
the evaluation of PTB suspects.5,7 In addition, a
review of sputum smears noted a significant
difference of 7% smear positivity for PTB
suspects from whom three specimens were
collected, compared to those with fewer collected
specimens.7 This implies the non-negligible
utility of the third sputum smear specimen.
Using two smear positive combinations,
we noted a significantly higher rate of smear
positivity (2.8%) with the second and third
specimens compared to other two smear positive
combinations. This is consistent with the findings
of Saleem et al and Hamid et al, wherein smear
positivity was higher with the second and third
specimens (2.2% and 8.2%) than the first and
second (1.8% and 1.4%) and the first and third

(1.9% and 3.8%) combinations.7,15 In a similar
analysis by Hamid et al, the yield was higher with
the first and third smears (6.8%), compared to the
first and second (4.4%) and the second and third
smears (2.4%)15; nevertheless, these findings
support the bearing of the third sputum smear
specimen. These data suggest that the third smear
contributes to a higher positivity rate.
Although recent findings show high rates of
detection with the first and second sputum smears,
the general limitation is the overall variable
sensitivity of sputum smear microscopy in PTB
case finding. Variations in results could be related
to the probability that the detection of AFB is
directly related to the concentration of bacilli in the
sputum.7 In this study, smear positivity was
notably varied among some of the sputum
specimens submitted by the same PTB suspect. In
two cases where only the third sputum smear was
positive, the bacilli load was surprisingly high
(3+). Furthermore, the studies used as basis for
related literature (especially those done in high-
burden areas) had an established expanded EQA
program that ensured smear quality, thereby
eliminating erroneous results.7,15 Conversely, the
Philippines has yet to establish a fully functional
expanded EQA program nationwide. In our
locality with a high burden of disease and
emerging multi-drug–resistant tuberculosis, it
would be wise to reconsider the minimal yet
additive diagnostic information of the third sputum
smear rather than miss an opportunity to treat a
possible infectious PTB case.
CONCLUSION AND RECOMMENDATIONS
A three-sputum smear specimen in the case
detection of PTB shows a non-negligible
diagnostic yield in the succeeding specimens.
Furthermore, a significantly higher rate of two-
smear positivity is observed for PTB suspects from
whom three specimens were collected, compared
to those with fewer. In a setting where the
establishment of an expanded EQA program
nationwide is still an ongoing process, the utility of
a third sputum smear cannot be underestimated in
Bascara et al
a high-burden-of-disease setting and an increasing-
risk population (e.g., multi-drug–resistant TB
patients and people living with human
immunodeficiency virus) such as in the
Philippines.
This study was conducted in a local hospital
with a limited number of samples. A wider scale of
sputum specimens for evaluation is recommended
to increase the sample size. Although inter-reader
variability was addressed by employing DOTS-
accredited medical technologists, the analysis of
specimens by an EQA program will ensure
acceptability and reproducibility of results. In
addition, the retrospective methodology of the
study precluded the availability of a number of
patient data and specimen results. A prospective
study will address these inadequacies.
REFERENCES
1. World Health Organization. Global
tuberculosis control 2009: epidemiology,
strategy, financing.
2. Kasper DL, Braunwald E, Fauci AS, et al.
Harrison’s Principles of Internal Medicine.
19th ed. NY: McGraw-Hill Education; 2016.
3. Mase SR, Ramsay A, Ng V, et al. Yield of
serial sputum specimen examinations in the
diagnosis of pulmonary tuberculosis: a
systematic review. Int J Tuberc Lung Dis.
2007;11(5):485-495.
4. Rao S. Sputum smear microscopy in DOTS:
Are three samples necessary? An analysis and
its implications in tuberculosis control. Lung
India. 2009;26(1):3-4.
5. Kisa O, Albay A, Baylan O, Doganci L. The
value of submitting multiple sputum
specimens for accurate diagnosis of pulmonary
tuberculosis. J Microbiol. 2002;40(4):301-304.
6. Rehman S, Iqbal R, Munir MK, et al.
Incremental yield of submitting three-sputum
specimens for the diagnosis of pulmonary
tuberculosis. Pak J Med Res. 2013;52(2):35-
38.
7. Saleem S, Shabbir I, Iqbal R, Khan SU. Value
of three-sputum smears microscopy in diag-
Vol. 18 | Issue 04 | December 2017 22
 Yield Pattern of Three-sputum Smears for TB

nosis of pulmonary tuberculosis. Pak J Med

Res. 2007;46(4):1-5.
8. Public Health Agency of Canada. Canadian
Tuberculosis Standards. 7th ed. CA: Her
Majesty the Queen in Right of Canada; 2014.
9. World Health Organization. Revision of the
case definition for sputum smear positive
pulmonary TB. Geneva, Switzerland: WHO;
2010.
10. The University of York Centre for Reviews
and Dissemination. 2014
11. Van Deun A, Salim AH, Cooreman E, et al.
Optimal tuberculosis case detection by direct
sputum smear microscopy: how much better is
more? Int J Tuberc Lung Dis. 2002;6(3):222-
230.
12. van Cleeff MR, Kivihya-Ndugga L, Githui W,
et al. A comprehensive study of the efficiency
of the routine pulmonary tuberculosis
diagnostic process in Nairobi. Int J Tuberc
Lung Dis. 2003;7(2):186-189.
13. Walker D, McNerney R, Mwembo MK, et al.
An incremental cost-effectiveness analysis of
the first, second and third sputum examination
in the diagnosis of pulmonary tuberculosis. Int
J Tuberc Lung Dis. 2000;4(3):246-251.
14. Rieder HL, Chiang CY, Rusen ID. A method
to determine the utility of the third diagnostic
and the second follow-up sputum smear
examination to diagnose tuberculosis cases and
failures. Int J Tuberc Lung Dis. 2005;9(4):384-
391.
15. Hamid S, Hussain SA, Imtiyaz A. Screening
tuberculosis suspects: how many sputum
specimens are adequate? Ann Trop Med
Public Health. 2012;5(4):317-320.

23 Philipp J Chest Dis 2017

 Sario and Gonong

RETROSPECTIVE STUDY

Validity Study of Gene Xpert MTB/RIF Assay in the Diagnosis

of Tuberculous Pleural Effusion among Adult Patients at the
Lung Center of the Philippines
Ronel G. Sario, MD; Joven Roque V. Gonong, MD
Lung Center of the Philippines, Quezon City

ABSTRACT

Introduction: Tuberculous pleural effusion (TPE) can be difficult to diagnose. Existing tests to
confirm the disease are limited in accuracy and time to diagnosis, and also require costly invasive
procedures. The objective of this study is to determine the accuracy of Gene Xpert MTB/RIF assays
in the diagnosis of TPE among adult patients at the Lung Center of the Philippines (LCP).

Methodology: This was a cross-sectional analytical study done among 60 patients with unilateral
pleural effusion seen at LCP from October 2014 to September 2016. Thoracentesis, closed tube
thoracostomy or video-assisted thoracoscopic surgery (VATS) with pleural biopsy was done. The
specimens were sent for histology and Mycobacterium tuberculosis (MTB) culture, and Gene Xpert
results were collected for data analysis.

Results: Of 60 participants, 26 (43.3%) had definite TPE. The diagnostic accuracy of this test was
compared to MTB culture, histology and composite reference standard. Gene Xpert in relation to
MTB culture showed sensitivity and specificity of 100% and 94.34%, respectively. In relation to
histopathology, its sensitivity was 14.29% and its specificity was 82.05%. In relation to the
composite reference standard, sensitivity was 30.77% and specificity was 94.12%.

Conclusion: The Gene Xpert MTB/RIF assay has poor sensitivity; therefore, it is not a good routine
diagnostic tool for the diagnosis of TPE even in high-burden settings such as our country. On the
other hand, with its high specificity, it can forestall further invasive procedures in some patients with
TPE.

Keywords: tuberculous pleural effusion, Gene Xpert MTB/RIF assay

INTRODUCTION pleural effusions in the absence of demonstrable

Tuberculosis (TB) is predominantly a
respiratory disease, affecting the lungs in about
80% of cases. About 30% of TB cases involve an
extrapulmonary site, occurring with or without
concomitant lung involvement. TB can affect
virtually any organ, although peripheral lymph
nodes and pleural space are the most common
extrapulmonary sites.1 In many areas of the
world, TB remains the most common cause of
pulmonary disease.2
Tuberculous pleural effusion (TPE) is
thought to result from the rupture of a subpleural
caseous focus in the lung, into the pleural space;2
its diagnosis can be difficult because of the low
positivity of the various diagnostic tests, since
TPE usually contains a low number of
Mycobacterium bacilli, and the diagnostic
sensitivity of pleural fluid cultures is relatively

Vol. 18 | Issue 04 | December 2017 24

 Validity of Gene Xpert MTB/RIF in diagnosing TB pleural effusion
low, at 30% to 50%. Conventional diagnostic tests
for TPE include microscopic examination of the
pleural fluid for acid-fast bacilli (AFB);
mycobacterial culture of pleural fluid, sputum or
pleural tissue; and histopathological examination
of pleural tissue. These tests have recognized
limitations for clinical use when used alone, but in
combination, they have been recognized as the best
reference standard for evaluation of the accuracy
of novel tests.
As mentioned, existing diagnostic
modalities to confirm the diagnosis of this specific
extrapulmonary tuberculosis (EPTB) are limited in
accuracy and time to diagnosis, and they often
require invasive procedures that are too costly for
most of the patients in our setting.
Gene Xpert MTB/RIF assays have high
accuracy and do not only have a high sensitivity
and specificity in smear-positive pulmonary
tuberculosis (PTB) (98% and 98%, respectively)
but are also considered a reasonable diagnostic tool
in smear-negative PTB (sensitivity and specificity
at 67% and 99%, respectively).3 This test has been
proven to improve the diagnosis of PTB with
accuracy and results that are released in less than
two hours. However, the varying levels of
accuracy of this test in the diagnosis of EPTB—
specifically, TPE—has been reported from small
pilot studies abroad. However, a South African
study by Friedrich et al demonstrated a sensitivity
of 25% and specificity of 100% on 20 samples of
confirmed pleural TB patients.4 Currently, no
studies on this topic had been done in the
Philippines. Therefore, involving subjects from our
local setting was needed, to improve our local
practice as pulmonologists in diagnosing TPE.
This paper aims to determine the accuracy
of Gene Xpert MTB/RIF assays in the diagnosis of
TPE among adult patients at the Lung Center of
the Philippines (LCP).
METHODOLOGY
This cross-sectional analytic study included
male or female patients ≥18 years old; with chest
radiography finding consistent with unilateral
25 Philipp J Chest Dis 2017
pleural effusion; who underwent thoracentesis
with pleural biopsy, closed tube thoracostomy
with pleural biopsy or VATS with pleural
biopsy; and who were seen at LCP from
October 2014 to September 2016. Excluded
were patients who were diagnosed with
malignancy, had recurrent pleural effusion, were
previously treated with anti-TB regimen or had
parenchymal lesions consistent with PTB.
Either thoracentesis with pleural biopsy,
closed tube thoracostomy with pleural biopsy or
VATS biopsy was done. The biopsy specimens
were sent for histology, part of the pleural fluid
was sent for MTB culture and sensitivity, and
10 mL of pleural fluid was collected and
submitted for Gene Xpert testing. Results were
collected for data analysis.
Patient participation was voluntary. The
process and methods were explained to each
patient by the investigators. Written informed
consent was taken from all the patients. Aspects
of the research were fully explained, and the
participants were given enough time to ask
questions. Questions from the participants were
answered until the participants were fully
satisfied. Confidentiality was assured. No
monetary compensation was given. The
participants were given copies of the informed
consent with contact numbers of the principal
investigator.
The demographic characteristics,
presenting signs and symptoms, and procedures
done on patients who were diagnosed with TPE
and those who were not, based on the composite
reference standard, were compared using chi-
square test for dichotomous variables, while
Student’s t-test and the Wilcoxon rank sum test
were used for continuous normally distributed
and non-normally distributed variables,
respectively.
Sensitivity, specificity, positive predictive
value, negative predictive value and likelihood
ratios for Gene Xpert were calculated using
MTB culture, histology and the composite
reference standard.4
 Sario and Gonong

RESULTS who were positive for TPE were younger (37. 2

Of the 60 participants, 26 (43.3%) had
definite TPE based on the positive composite
reference standard which includes sputum AFB,
MTB culture and histopathology. Mean age was
37.2 years. Majority were males (84.6%). The
most common clinical manifestation was cough
(80.8%), followed by dyspnea (61.5%), fever
(46.2%), chest/back pain (42.3%), weight loss
(30.8%), sputum production (26.9%), hemoptysis
and others (e.g., loss of appetite, dizziness)
(11.5%) and tiredness (3.8%). These
manifestations were mostly presented at more
than two weeks’ duration.
There was a significant difference on the
mean age of patients (p=0.030) and the duration
of presenting signs and symptoms (p=0.011)
between the two groups. It was noted that those
years) than those who were negative (47.8 years),
and the duration of presenting signs and
symptoms was mostly longer than two weeks in
the former (96.2%) as compared to the latter
(70.6%). Eleven (42.3%) patients who were
positive for TPE underwent VATS with pleural
biopsy, while 8 (30.6%) underwent thoracentesis
with pleural biopsy (PB) and 7 (26.9%) had
closed tube thoracostomy (CTT) with PB.
To determine the accuracy of Gene Xpert
MTB/RIF assay for diagnosing TPE, the results
of this test was compared to MTB culture,
histology and composite reference standard.
Gene Xpert was performed on 60 patients
and TPE was detected on 10: seven were true
positives and three were false positives. The rest
were true negatives (Table 2).

Table 1. Included Patients with or without TPE based on the Composite Reference Standard

Demographic Positive (%) Negative (%)

p-value
Characteristic n=26 n=34
Age, years (mean) 37.2±15.48 47.8±21.50 0.03*
Sex 0.942
Male 22 (84.6) 29 (85.3)
Female 4 (15.4) 5 (14.7)

Signs and symptoms

Cough 21 (80.8) 23 (67.6) 0.255
Sputum production 7 (26.9) 16 (47.1) 0.112
Hemoptysis 3 (11.5) 1 (2.9) 0.186
Fever 12 (46.2) 8 (23.5) 0.065
Weight loss 8 (30.8) 8 (23.5) 0.530
Tiredness 1 (3.8) 6 (17.6) 0.099
Chest/back pain 11 (42.3) 11 (32.4) 0.428
Dyspnea 16 (61.5) 20 (58.8) 0.832
Others 3 (11.5) 3 (8.8) 0.365
Duration 0.011*
<2 weeks 1 (3.8) 10 (29.4)
>2 weeks 25 (96.2) 24 (70.6)
Procedure
Thoracentesis/PB 8 (30.6) 21 (61.8) 0.017*
CTT/PB 7 (26.9) 10 (29.4) 0.834
VATS/PB 11 (42.3) 3 (8.8) 0.002*
TPE, tuberculous pleural effusion; CTT, closed tube thoracostomy; PB, pleural biopsy; VATS, video-assisted
thoracoscopic surgery.
*Significant.

Vol. 18 | Issue 04 | December 2017 26

 Validity of Gene Xpert MTB/RIF in diagnosing TB pleural effusion

To determine the accuracy of Gene Xpert Gene Xpert detected TPE on 10 of 60

MTB/RIF assay for diagnosing TPE, the results of
this test was compared to MTB culture, histology
and composite reference standard.
Gene Xpert was performed on 60 patients
and TPE was detected on 10 subjects: seven were
true positives and three were false positives. The
rest were true negatives, with no false negatives
(Table 2).
The sensitivity (95% CI) and specificity
were 100% and 94.34%, respectively. The positive
predictive value was 70%, and the negative
predictive value was 100% (Table 3).
patients: three were true positives and seven were
false positives. Eighteen were false negatives and
32 were true negatives (Table 4).
Sensitivity and specificity were 14.29% and
82.05%, respectively. The positive predictive value
was 30%, and the negative predictive value was
64% (Table 5).
Compared to the composite reference
standard, which includes sputum AFB smear,
MTB culture and histopathology, Gene Xpert
detected TPE on 10 of 60 patients: eight were true
positives and two were false positives. Eighteen

Table 2. Performance Outcome for Gene Xpert Table 4. Comparison of Gene Xpert Result with
MTB/RIF Assay in Relation to MTB Culture Histopathology

MTB Culture Histopathology Histopathology

MTB Culture (+)
(–) (+) (–)

Gene Xpert Gene Xpert

7 3 3 7
(+) (+)

Gene Xpert Gene Xpert

0 50 18 32
(–) (–)
MTB, Mycobacterium tuberculosis; RIF, rifampicin.

Table 3. Validity/Accuracy of Gene Xpert in Table 5. Validity/Accuracy of Gene Xpert in

Diagnosing TPE in Relation to MTB Culture Predicting TPE in Relation to Histopathology

Diagnostic Point Diagnostic Point

95% CI 95% CI
Parameter Estimate Parameter Estimate

Sensitivity 100.00 59.04–100.00 Sensitivity 14.29 3.05–36.34

Specificity 94.34 84.34–98.82 Specificity 82.05 66.47–92.46

Positive predictive Positive predictive

70.00 34.75–93.33 30.00 6.67–65.25
value negative value

Negative predictive Negative predictive

100.00 92.89–100.00 64.00 49.19–77.08
value value

Positive likelihood Positive likelihood

17.67 5.89–53.03 0.80 0.23–2.76
ratio ratio

Negative likelihood Negative likelihood

0.00 – 1.04 0.83–1.31
ratio ratio

TPE, tuberculous pleural effusion; MTB, Mycobacterium TPE, tuberculous pleural effusion; CI, confidence interval.
tuberculosis; CI, confidence interval.

27
19 Philipp J Chest Dis 2017
 Sario and Gonong

were false negatives and 32 were true negatives Table 4. Comparison of Gene Xpert Result with CRS
(Table 6).
CRS (+) CRS (–)
Sensitivity and specificity were 30.77% and
94.12%, respectively. The positive predictive value Gene Xpert
8 2
was 80%, and the negative predictive value was (+)
64% (Table 7). Gene Xpert
18 32
(–)
DISCUSSION CRS, composite reference standard, which includes sputum
The Gene Xpert MTB/RIF assay has proven smear, culture and histopathology.
to be a promising breakthrough in the diagnosis of
PTB and was even included in the recently
Table 7. Validity/Accuracy of Gene Xpert in
updated clinical practice guidelines for the Predicting TPE in Relation to CRS
diagnosis, treatment, prevention and control of TB
as one of the modalities for bacteriologically Diagnostic Point
95% CI
Parameter Estimate
confirming PTB among patients who were sputum-
smear negative. However, limited data have been Sensitivity 14.29 3.05–36.34
published about the performance of Gene Xpert on Specificity 82.05 66.47–92.46
pleural fluid in high burden settings such as the 30.00 6.67–65.25
Positive predictive
Philippines.
value
In a systematic review, Sehgal et al
64.00 49.19–77.08
investigated the role of Xpert MTB/RIF in the Negative predictive
diagnosis of TPE and found the pooled value
sensitivities and specificities of Xpert MTB/RIF to 0.80 0.23–2.76
Positive likelihood
be 51.4% and 98.6%, respectively, with culture ratio
used as a reference standard.3 By contrast our study
1.04 0.83–1.31
found higher sensitivity but relatively the same Negative likelihood
ratio
specificity, i.e., 100% and 94.34% respectively.
These findings are contradictory to a South Africa TPE, tuberculous pleural effusion; CRS, composite reference
study that stated the reason for the high sensitivity standard, which includes sputum smear, culture and
histopathology; CI, confidence interval.
found in previous studies was due to the low
burden of disease in the settings where the studies
were done, as well as the fact that these only In response to the recommendation of one
reported a handful of patients with TPE.5 We meta-analysis done in India to use histopathology
attribute these findings to the standard technique as a reference standard3: the sensitivity and
used and the better experience of handlers in specificity of Xpert MTB/RIF in this study were
processing the specimen for Gene Xpert study at 14.29% and 82.05%, respectively—lower than the
our center. previously mentioned results. Nevertheless, Xpert
Furthermore, as shown in Table 2, the MTB/RIF assay demonstrated low sensitivity but
diagnostic accuracy of Gene Xpert is comparable high specificity as a diagnostic tool.
to MTB culture. Thus, Gene Xpert is a better The pooled sensitivities and specificities of
option than culture, considering its ability to detect Xpert MTB/RIF were 22.7% and 99.8%,
MTB in pleural effusion and provide information respectively, with composite reference standard
about rifampicin susceptibility within 2 hours. (CRS) used as the benchmark in a meta-analysis

Vol. 18 | Issue 04 | December 2017 28

 Validity of Gene Xpert MTB/RIF in diagnosing TB pleural effusion
by Sehgal et al.3 In comparison, this study showed
a sensitivity of 30.77% and a specificity of
94.12%. Gene Xpert MTB/RIF assay consistently
showed low sensitivity but excellent specificity in
the diagnosis of TPE.
In clinical practice, the ideal initial test used
in the diagnosis of TPE is the pleural fluid
adenosine deaminase level. However, due to the
limited accessibility of this test, clinicians still rely
on the clinical signs and symptoms; conventional
diagnostic tests such as microscopic examination
of the pleural fluid for AFB; mycobacterial culture
of pleural fluid, sputum or pleural tissue; and
histopathological examination of pleural tissue.
Although the Gene Xpert MTB/RIF assay is
currently being utilized in many TB-endemic
countries,6 this study has demonstrated that its
sensitivity is largely suboptimal for extra-
pulmonary specimen.7,8 Therefore, it is not
practical to use Gene Xpert as an initial diagnostic
tool for TPE, considering its cost. Affordability,
availability and cost-effectiveness remain
important considerations in resource-poor TB-
endemic countries. However, due to its high
specificity, this test can be utilized for further
investigation in patients with undiagnosed pleural
effusion.
One limitation of this study was that is was
conducted only among Service patients of LCP.
The investigators recommend the continuation of
this study on a bigger sample size, to further
strengthen the data. It is also recommended that
future studies evaluate the potential impact of
response to treatment of TPE patients who were
given an anti-TB regimen.
CONCLUSION
The Gene Xpert MTB/RIF assay has poor
sensitivity, so it is not a good routine diagnostic
tool for the diagnosis of TPE, even in high-burden
settings such as our country. On the other hand,
with its high specificity, it can forestall further
invasive procedures in some patients with TPE.
29 Philipp J Chest Dis 2017
REFERENCES
1. Doucette K, Cooper R. Tuberculosis. In:
Grippi M, eds. Fishman’s Pulmonary Diseases
and Disorders. 5th ed. USA: McGraw-Hill
Education; 2015; chapter 131.
2. Light RW. Tuberculous pleural effusions. In:
Light RW, ed. Pleural Diseases. 5th ed.
Baltimore: Lippincott, Williams and Wilkins;
2007:211-224.
3. Sehgal IS, Dhooria S, Aggarwal AN, et al.
Diagnostic performance of Xpert MTB/RIF in
tuberculous pleural effusion: systematic review
and meta-analysis. J Clin Microbiol.
2016;54(4):1133-1136.
4. Friedrich SO, von Groote-Bidlingmaier F,
Diacon AH. Xpert MTB/RIF assay for
diagnosis of pleural tuberculosis. J Clin
Microbiol. 2011;49(12):4341-4342.
5. Meldau R, Peter J, Theron G, et al.
Comparison of same day diagnostic tools
including Gene Xpert and unstimulated IFN-γ
for the evaluation of pleural tuberculosis:
a
prospective cohort study. BMC Pulm Med.
2014 Apr 8;14:58.
6. Theron G, Zijenah L, Chanda D, et al.
Feasibility, accuracy, and clinical effect of
point-of-care Xpert MTB/RIF testing for
tuberculosis in primary-care settings in Africa:
a multicentre, randomised, controlled trial.
Lancet. 2014;383(9915):424-435.
7. Dheda K, van Zyl-Smit RN, Sechi LA, et al,
Utility of quantitative T-cell responses versus
unstimulated interferon-γ for the diagnosis of
pleural tuberculosis. Eur Respir J.
2009;34(5):1118-1126.
8. Maartens G, Bateman ED. Tuberculous pleural
effusions: increased culture yield with bedside
inoculation of pleural fluid and poor diagnostic
value of adenosine deaminase. Thorax.
1991;46(2):96-99.
 Macaraig and Gappi

RETROSPECTIVE STUDY

Diagnostic Accuracy of Berlin, Flemons Sleep Apnea Clinical

Score and St. Luke’s Medical Center–Obstructive Sleep Apnea
Clinical Score Questionnaires for Screening Obstructive Sleep
Apnea in Filipino Patients
Babyleen E. Macaraig, MD, FPCP; Mercy Antoinette S. Gappi, MD, FPCP, FPCCP
Institute of Pulmonary Medicine, St. Luke’s Medical Center, Quezon City

ABSTRACT

Introduction: Although considered the gold standard for diagnosing obstructive sleep apnea
(OSA), the polysomnogram (PSG) is time consuming, labor intensive and can be costly. Hence, a
simple but accurate screening tool to identify patients with high risk for OSA should be established
for Filipinos.

Methods: Records of all adult Filipino patients referred to the Comprehensive Sleep Disorders
Center of St. Luke’s Medical Center (SLMC)–Quezon City for overnight PSG from January 2011 to
June 2015 were reviewed. Subjects were excluded if they were known OSA patients, had
incompletely filled questionnaires, or were unable to tolerate a sleep study. OSA was screened
using the Berlin sleep score, the Flemons sleep apnea clinical score and the SLMC–obstructive
sleep apnea clinical score (OSACS). Results were compared to their overnight PSG results.

Results: SLMC-OSACS showed higher sensitivity (87%) and overall accuracy (84%) in predicting
OSA. It showed higher overall accuracy (63%) and sensitivity (77%) in predicting mild OSA (63%
and 77%, respectively) and moderate OSA (66% and 80%). In predicting severe OSA, it also had
higher overall accuracy (86%) and sensitivity (90%), while specificity showed almost similar
estimates in all of the three screening tools.

Conclusion: SLMC-OSACS showed higher sensitivity and higher overall accuracy in predicting
OSA at different risk levels. Therefore, SLMC-OSACS is recommended as a screening tool for OSA
for Filipinos.

INTRODUCTION neural activity.2 Its effect on nocturnal sleep

Obstructive sleep apnea (OSA) is a chronic
condition characterized by frequent episodes of
upper airway collapse during sleep. It consists of
decreased airflow due to repetitive complete or
partial obstruction of the upper airway, associated
with progressive respiratory efforts` to overcome
the obstruction.1,2 These obstructive respiratory
events are typically associated with cortical
microarousals and oxygen desaturation, leading
to sleep fragmentation and increased sympathetic
quality and the ensuing daytime fatigue and
sleepiness is widely acknowledged.
OSA syndrome is first suspected on
clinical grounds based on a typical history.
Patients complain of non-restoring sleep, daytime
fatigue and sleepiness, sometimes even sleep
attacks. Classic signs and symptoms that indicate
a patient may be at risk for OSA include obesity,
snoring, witnessed apnea during sleep, apparent
arousals during sleep, wake-time somnolence and

Vol. 18 | Issue 04 | December 2017 30

 Accuracy of OSA screening tools including SLMC-OSACS
fatigue despite apparently adequate sleep.3
Apnea is defined as the complete cessation
of airflow for at least 10 seconds. Hypopnea is
defined as a reduction in airflow, followed by an
arousal from sleep or a decrease in oxyhemoglobin
saturation. Commonly used definitions of
hypopnea require a 25% or 50% reduction in
oronasal airflow associated with either a reduction
in oxyhemoglobin saturation or an arousal from
sleep.1
The apnea-hypopnea index (AHI) is often
used to quantify the severity of OSA. The AHI is a
measure of the number of apneas and hypopneas
per hour of sleep. By consensus, mild sleep apnea
is an AHI of 5 to 15 events per hour, moderate
OSA is 15 to 30 events per hour, and severe OSA
is >30 events per hour.4
The prevalence rates of OSA have been
estimated in the range of 2% to 10% worldwide,
and the risk factors for OSA include advanced age,
male sex, obesity, family history, craniofacial
abnormalities, smoking, alcohol consumption,
neck circumference, sedative use, health illiteracy
and Indian or Chinese ethnicity.5,6
There is accumulating evidence that OSA is
being considered as an independent risk factor for
hypertension, glucose intolerance/diabetes
mellitus, cardiovascular diseases and stroke,
leading to increased cardiometabolic morbidity
and mortality.6
OSA is present in 2% of women and 4% of
men living in Western communities.5 It affects an
estimated 20% of all Americans.3 South Asians
have a significantly higher prevalence of OSA
compared to white Europeans (85% vs. 66%,
p=0.017).7
The American Thoracic Society and the
American Academy of Sleep Medicine
recommend supervised polysomnography (PSG)
in the sleep laboratory for two nights for the
diagnosis of OSA and the initiation of continuous
positive airway pressure (CPAP).8
Although considered a gold standard in
OSA diagnosis, the PSG is not without its
limitations. PSG requires an overnight stay in a
31 Philipp J Chest Dis 2017
sleep laboratory staffed with qualified personnel
that can collect and interpret complex physiologic
data. The process is time consuming, labor
intensive, and can be costly.1
Early detection of OSA will mean
prevention of its various serious consequences.
Therefore, a simple but accurate screening tool
should be established for Filipinos to stratify
patients based on their clinical symptoms, physical
examinations, and risk factors, and to identify both
patients at high risk and in urgent need of PSG and
further treatment, and also patients at low risk and
who may not need PSG.
The primary objective of this study is to
compare the diagnostic accuracies of OSA
screening tools—namely, Berlin, Flemons sleep
apnea clinical score (SACS) and the SLMC–
obstructive sleep apnea clinical score (OSACS)
questionnaires—among Filipino patients.
METHODS
This descriptive cross-sectional study
compared the predictive probabilities for OSA of
different sleep questionnaires, namely, Berlin
questionnaire, Flemons SACS and the SLMC-
OSACS utilized in the Comprehensive Sleep
Disorders Center of SLMC–Quezon City. The
study was done from January 2011 to June 2015.
Results were compared with the gold standard,
PSG.
This study retrieved and reviewed 719
cases. Anthropometric measures including body
weight, height, body mass index (BMI) and neck
circumference were documented for all patients.
The study included adults (≥18 years old) of
Filipino nationality. Patients were excluded if they
were <18 years old, had known OSA, did not
complete their questionnaires, could not tolerate a
sleep study or were not Filipinos.
The Berlin questionnaire has 11 questions
grouped in three categories. The first category
comprises five questions concerning snoring,
witnessed apneas and the frequency of such
events. The second comprises four questions
addressing daytime sleepiness, with a sub-question

Figure 1. Patient Selection Process
FLEMONS SACS, Flemons sleep apnea clinical score; OSA, obstructive sleep apnea; SLMC-OSACS, St. Luke’s Medical Center–
Obstructive Sleep Apnea Clinical Score.
about drowsy driving. The third comprises two
questions concerning history of high blood
pressure (>140/90 mmHg) and BMI >30 kg/m2.
Categories 1 and 2 are considered positive if there
are two positive responses in each category, while
category 3 is considered positive if there is a self-
report of high blood pressure or BMI >30 kg/m2.
Macaraig and Gappi
Study patients are scored as high risk if
scores are positive for two or more of the three
categories.9
The Flemons SACS predictors of sleep
apnea include neck circumference, hypertension,
habitual snoring and bed partner reports of
nocturnal gasping/choking respirations. Probabi-
Vol. 18 | Issue 04 | December 2017 32
 Accuracy of OSA screening tools including SLMC-OSACS
lity of sleep apnea is considered high if SACS is
≥15.9
The SLMC-OSACS comprises three
independent variables: snoring affecting others,
BMI and bothersome daytime sleepiness
(Appendix). A validation study in 2003 for the
best cut-off value for the clinical score found that
a cut-off value ≥8 showed 84% sensitivity, 92%
specificity, 8% false positive rate and LR of 14.
A lower cut-off value of ≥5 revealed 100%
sensitivity, 92% specificity, 8% false positive rate
and LR of 12.5.10
Diagnostic PSG was performed using
SomnoStar z4 or the Viasys Nicolet One
machine, including pulse oximeter to check for
desaturation; electroencephalogram (EEG) leads
(eight on the head, two on the eyes, two on the
chin); electrocardiogram (ECG) leads (two on the
chest, one on each leg); transducer; thermistor on
the nose to note for apnea/hypopnea; and
respiratory bands on the chest and stomach.
During actual PSG, the following data were
obtained: respiratory effort by thoraco-abdominal
excursion, respiratory inductive plethysmography
and oronasal airflow pressure, oxygen saturation
and sleep architectural data. The actual sleep
study lasted for seven to eight hours.
The minimum computed sample size of
120 was based on the findings of published
literatures wherein the Berlin, SACS, and OSA
questionnaires yielded accuracies (sensitivity and
specificity) of 80% and above, assuming that the
tools would yield a clinically acceptable accuracy
of 80%, with precisions +/-7.2% estimated at
confidence index (CI) 95%. The sample size of
120 was considered sufficient to validate the
diagnostic accuracies of the three tools.
Patients’ profiles were described using
mean values, standard deviations, frequencies,
and percentages. These data were encoded in MS
Excel 2013. In comparing profiles with mean
values as indicators and grouped by OSA status,
one-way ANOVA was used; for testing
associations among categorical data, we used the
chi-squared test of independence with appropriate
33 Philipp J Chest Dis 2017
matrices and the 2x2 Fisher’s exact test. The
accuracies of the three tools were estimated in
terms of sensitivity, specificity, positive likelihood
ratio (LR+), negative likelihood ratio (LR–),
positive predictive value (PPV), negative
predictive value (NPV) and overall accuracy. Any
associated p-values less than 0.05 alpha were
considered significant. IBM SPSS v.21 and NCSS
PASS 2000 were used as statistical software.
RESULTS
A total of 719 patients were included in the
study (Figure 1). The overall mean age was 45
years, and 72% were males. Older age was
associated with increasing severity of OSA.
Among those without OSA, mean age was 39
years; among those with severe OSA, mean age
was 46 years (p<0.001). Most of the patients with
normal results (62%) were females; most of the
males were in the affected group (p<0.001). Fifty
percent of patients with no OSA had ideal BMI.
Among those with severe OSA, 38% were obese
and 12% were severely obese (p<0.001). Those
with larger neck circumferences had moderate to
severe OSA, compared with those with normal size
(p<0.001). Patients with high risk of OSA were
73% using the Berlin tool, 45.3% using Flemons
SACS, and 86% by SLMC-OSACS (Table 1).
In predicting OSA, SLMC-OSACS score
showed higher sensitivity (87%) than Berlin (74%)
and Flemons (52%). In terms of specificity,
Flemons showed the highest estimate (73%).
Flemons also yielded the highest LR+ (1.92),
followed by SLMC-OSACS (1.30). All tools
yielded high PPV. In terms of overall accuracy,
SLMC-OSACS ranked first (84%), followed by
Berlin (71%) (Table 2).
SLMC-OSACS had the highest overall
accuracy (63%) in predicting mild OSA. It was
followed by the Berlin tool (56%). Sensitivity was
also highest in SLMC-OSACS (77%), while
specificity was equal between Flemons and Berlin.
In predicting moderate OSA, SLMC-OSACS had
the highest accuracy (66%) and sensitivity (80%),
while Flemons and Berlin had similar specificity
 Macaraig and Gappi

Table 7. Radiologic Severity According to Ventilatory Impairment

With OSA
P-value P-value
Moderate Normal vs Normal vs
Mild (%) Severe (%) Normal (%)
(%) OSA levels All OSA
n=91 n=486 n=42
n=100
45.81 ± 44.54 ± 46.13 ± 38.81 ±
Age (years)* <0.001 <0.001
11.52 12.98 11.35 12.78
Sex (n, %)

Females 41 (45.1) 35 (35) 99 (20.4) 26 (61.9) <0.001 <0.001

Males 50 (54.9) 65 (65) 387 (79.6) 16 (38.1)

BMI (kg/m2)* 27.57 ± 5.38 29.28 ± 6.08 31.19 ± 6.59 26.34 ± 5.22

Ideal (n, %) 35 (38.5) 27 (27) 80 (16.5) 21 (50.0)

Underweight (n, %) 1 (1.1) 1 (1) 2 (0.4) 1 (2.4)

<0.001 <0.001
Overweight (n, %) 30 (33.0) 41 (41) 164 (33.7) 9 (21.4)

Morbidly obese (n, %) 21 (23.1) 25 (25) 183 (37.7) 9 (21.4)

Severely obese (n, %) 4 (4.4) 6 (6) 57 (11.7) 2 (4.8)

Neck circumference,
38.73 ± 4.13 40.27 ± 3.81 42.04 ± 7.56 38.25 ± 6.13 <0.001 0.008
cm*

Berlin score* 1.85 ± 0.88 1.83 ± 0.79 2.03 ± 0.76 1.83 ± 0.85 <0.001 0.295

Low risk 31 (34.1) 31 (31) 117 (24.1) 13 (31.0) 0.026 0.341

High risk 60 (65.9) 69 (69) 369 (75.9) 29 (69.0)

17.29 ± 24.54 ±
Flemons SACS* 12.84 ± 9.08 9.62 ± 8.53 <0.001 <0.001
18.53 20.63

Low risk 54 (59.3) 57 (57) 183 (37.7) 27 (64.3) <0.001 0.003

High risk 28 (30.8) 38 (38) 250 (51.4) 10 (23.8)

SLMC-OSACS* 6.12 ± 2.25 6.26 ± 2.33 7.08 ± 1.97 5.76 ± 2.53 <0.001 0.002

Low risk 21 (23.1) 20 (20) 48 (9.9) 14 (33.3) <0.001 <0.001

High risk 70 (76.9) 80 (80) 438 (90.1) 28 (66.7)

BMI, body mass index; OSA, obstructive sleep apnea; OSACS, obstructive sleep apnea clinical score; SACS, sleep apnea clinical
score; SLMC, St. Luke’s Medical Center.
*Mean ± standard deviation.

Vol. 18 | Issue 04 | December 2017 34

 Accuracy of OSA screening tools including SLMC-OSACS

indices. In predicting severe OSA, SLMC-OSACS
yielded the highest overall accuracy (86%),
followed by Berlin (72%). SLMC-OSACS
generated the highest sensitivity (90%), followed
by Berlin (76%). Specificity was similar in all
three tools (Table 3).
DISCUSSION
This study compared three sleep questionnaires—
Berlin, Flemons SACS and SLMC-OSACS—for
their predictive probabilities for OSA. The
questionnaires were tested within the same
population, and scores were evaluated against the
results of PSG as the gold standard for OSA
diagnosis. The cut-off values used in this study
were those previously published.4,9,12
The Berlin questionnaire is a validated
instrument used to identify individuals at risk for
OSA in primary and some non-primary care
settings.10 The Berlin has shown 95% sensitivity in
predicting moderate-to-severe OSA (95.48%) and
severe OSA (97.3%) but has demonstrated a very
low specificity for OSA patients (25%),
moderate-to-severe OSA patients (7.41%) and
severe OSA patients (10.71%).9
Flemons SACS is a relatively simple
model that can generate a sleep apnea score the
sensitivity and specificity of which, at various
levels, have been calculated and summarized as
LRs. SACS <5 had LR of 0.25 (95% CI: 0.15 to
0.42) and a corresponding post-test probability of
17%, while a score >15 had LR of 5.17 (95% CI:
2.54 to 10.51) and a post-test probability of 81%.
These LRs can simply and accurately determine
the probability of a patient having sleep apnea.4
SLMC-OSACS is a devised prediction rule
for the Filipino Asian population that was
reported by Cua et al in 2000. The model
provided a sensitivity of 71%, a specificity of
77% and a PPV of 83% in predicting a priori
probability of having OSA, with a score ≥8 as the
best cuff-off. In 2003, a validation study by Cua

Table 2: Diagnostic Accuracies of Berlin, Flemons SACS, and SLMC-OSACS Questionnaires in Predicting
OSA in General*

Accuracy SLMC-OSACS Flemons SACS Berlin

Sensitivity, % 87 52 74

Specificity, % 33 73 31

LR+ 1.30 1.92 1.07

LR– 0.40 0.66 0.85

PPV, % 96 97 94

NPV, % 13 8 7

Overall accuracy, % 84 53 71

LR, likelihood ratio; NPV, negative predictive value; OSA, obstructive sleep apnea; OSACS, obstructive sleep
apnea clinical score; PPV, positive predictive value; SACS, sleep apnea clinical score; SLMC, St. Luke’s Medical
Center.
*Predicting OSA using low-high risk scores.

35 Philipp J Chest Dis 2017

 Macaraig and Gappi

Table 3: Diagnostic Accuracies of Berlin, FSACS, and SLMC-OSACS Questionnaires in Predicting the
Severity of OSA
Predicting Mild OSA Predicting Moderate OSA Predicting Severe OSA
Accuracy SLMC- SLMC- SLMC-
FSACS Berlin FSACS Berlin FSACS Berlin
OSACS OSACS OSACS

Sensitivity, % 77 41 56 80 40 58 90 69 76

Specificity, % 33 55 55 33 73 73 33 31 31

LR+ 1.15 0.906 1.242 1.2 1.480 2.136 1.35 0.999 1.100

LR– 0.69 1.077 0.800 0.6 0.822 0.579 0.3 1.002 0.778

PPV, % 71 68 93 74 79 96 94 70 93

NPV,% 40 28 10 41 32 13 23 30 10

Overall
63 45 56 66 49 59 86 58 72
accuracy, %

FSACS, Flemons sleep apnea clinical score; LR, likelihood ratio; NPV, negative predictive value; OSA, obstructive sleep apnea;
OSACS, obstructive sleep apnea clinical score; PPV, positive predictive value; SLMC, St. Luke’s Medical Center.

et al revealed the clinical score ≥8 as the best
cut-off value, with an overall accuracy of 89%,
sensitivity of 84%, specificity of 92%, false rate
of 8%, and LR of 14. This validation study
revealed a lower cut-off value ≥5 with
sensitivity of 100%, specificity of 92%, false
positive rate 8%, and LR of 12.5.10 A study on
the prevalence and association of OSA risk in
Filipino patients with diabetes has been
conducted using SLMC-OSACS. Twenty-one
percent had high OSA risk, with 14% having
estimated true OSA prevalence.11
In our study, Flemons demonstrated
higher specificity (73%), while SLMC-OSACS
showed higher sensitivity (87%). In overall
performance, Flemons demonstrated higher
likelihood that a patient would have OSA,
implying that patients who attained the risk cut-
off score in Flemons were 1.92 times more
likely to have OSA.
In terms of having higher overall
accuracy for OSA by demonstrating higher
rates of true positive plus true negative among
the total population assessed, SLMC-OSACS
showed a higher estimate (84%).
As a whole, in predicting mild, moderate
and severe OSA, SLMC-OSACS yielded
consistently higher sensitivity estimates, followed
by Berlin. This trend was also noted in the
overall accuracies for both SLMC-OSACS and
Berlin tools. Meanwhile, SLMC-OSACS showed
consistently lower specificity than the other tools.
Lastly, LR+ was higher in mild and severe OSA
by SLMC-OSACS, and the trend of higher
estimates was followed by Berlin.
OSA is considered to be a long-standing
illness, and with its associated complications, it
can bring economic burden to society. Referrals
to sleep physicians or experts for further
investigations and diagnostic evaluations may
prevent adverse health outcomes. Hence,
screening tools that may be used—especially in
areas with limited resources—in order to identify
patients who may need further work-up for OSA
must be mandated. In addition, screening tools
may also be used in formulating health care

Vol. 18 | Issue 04 | December 2017 36

 Accuracy of OSA screening tools including SLMC-OSACS
diagnostic work-up and treatment.
An ideal diagnostic test for a general
population should have a relatively high specificity
to minimize false positives, but it should have
sufficient sensitivity. Conversely, an ideal
diagnostic test for a population with a high pre-test
probability of disease should have higher
sensitivity while maintaining high specificity.2
Given that SLMC-OSACS demonstrated
higher sensitivity and overall accuracy in
predicting OSA, physicians can identify patients
who are at high risk for OSA and who need urgent
evaluation and treatment.
In the general population, moderately severe
OSA is present in 11.4% of men and 4.7% of
women.12 In a related study, using an AHI cut-off
point of ≥5 events, 204 patients (87%) were found
to have OSA. Using an AHI cut-off point of ≥15
events, 177 (76%) had moderate-to-severe OSA,
while using an AHI cut-off point of ≥30 events
showed 148 (63%) to have severe OSA.9 Evidence
suggests that a large proportion of individuals with
OSA remain undiagnosed.
The presence and severity of OSA must be
determined before initiating treatment. In the
published guidelines by the Adult Obstructive
Sleep Apnea Task Force of the American
Academy of Sleep Medicine, treatment options
should be discussed with patients who have AHI
≥5 plus symptoms of OSA, as well as those with
AHI ≥15 that is moderate OSA.13 Since SLMC-
OSACS yielded consistently higher sensitivity
estimates for mild, moderate and severe OSA and
higher LR+ in mild and severe OSA, it can be used
to predict patients most likely to be treated. Since
PSG is expensive and not readily available, there is
a need to improve access to diagnostic and
effective treatment strategies for patients with
OSA. Of particular interest is the utility of portable
monitoring and empiric auto-CPAP treatment for
patients who have a high pre-test clinical
probability for at least moderate or severe OSA
and who do not have co-existing cardiopulmonary
conditions complicating OSA.2 Home unattended
37 Philipp J Chest Dis 2017
PSG is a viable option for evaluating patients
with moderate-to-high clinical suspicion for
sleep-disordered breathing. Nevertheless,
patients with failed or equivocal home studies
and those with negative studies but persistent
symptoms should undergo standard PSG.6
In addition, there are ethnic differences in
prevalence and severity of OSA. In one study,
despite the overall lower average BMI in the
Asian population compared to Western societies,
the prevalence of OSA syndrome in Asians was
found to be similar that of Caucasian population.
This could be attributed to differences in
craniofacial features between Asian and
Caucasian patients, such as an inferiorly
positioned hyoid bone, enlarged soft palate and
reduced upper airway width at the soft palate.1,2
Therefore, any screening tool utilized should first
be validated in the population where the tool will
be used.
In this study, the target population was
patients presenting to the sleep clinic with sleep
disorders as evaluated clinically by referring
physicians. This might present a potential bias in
the evaluation of the strengths of the different
questionnaires in identifying patients at risk for
OSA, because OSA is highly prevalent in
patients with a history of sleep disorders. It is
therefore recommended that screening tools be
used in general population in a clinical setting, to
identify high-risk patients.
CONCLUSION
With the increasing burden of OSA
complications, screening tools are important for
identifying patients who may need further work-
up. Screening tools must be simple and easy to
use, and the variables applied must be from
similar ethnic populations. SLMC-OSACS
showed higher sensitivity, higher overall
accuracy for OSA and higher sensitivity for
predicting mild, moderate, and severe OSA.
Therefore, SLMC-OSACS is the recommended
screening tool for OSA among Filipinos.
 Macaraig and Gappi

REFERENCES 11. Sison C, Lantion-Ang F, Jorge M. Prevalence

1. Punjabi NM. The epidemiology of adult and associations of obstructive sleep apnea in
obstructive sleep apnea. Proc Am Thorac Soc. Filipino patients with diabetes mellitus. Phil J
2008:5(2):136-143. Intern Med. 2008;46:195-204.
2. Lee W, Nagubadi S, Kryger MH, Mokhlesi B. 12. Chung F. Screening for obstructive sleep
Epidemiology of obstructive sleep apnea: a apnea syndrome in preoperative patients.
population-based perspective. Expert Rev Open Anes J. 2011;5(1-M2):7-11.
Respir Med. 2008;2(3):349-364. 13. Epstein LJ, Kristo D, Strollo PJ, et al.
3. Boese ML, Ransom RK, Roadfuss RJ, et al. Clinical guideline for the evaluation,
Utility of the Berlin questionnaire to screen for management and long4term care of
obstructive sleep apnea among patients obstructive sleep apnea in adults. J Clin Sleep
receiving intravenous sedation for Med. 2009;5(3):2634.
colonoscopy. AANA J. 2014;82(1):38-45.
4. Sundar E, Chang J, Smetana GW.
Perioperative screening for and management
of patients with obstructive sleep apnea. J Clin
Outcomes Manag. 2011;18(9):399-411.
5. Mirrakhimov AE, Sooronbaev T, Mirrakhimov
EM. Prevalence of obstructive sleep apnea in
Asian adults: a systematic review of the
literature. BMC Pulm Med. 2013;13:10.
6. Lam J, Sharma SK, Lam B. Obstructive sleep
apnoea: definitions, epidemiology & natural
history. Indian J Med Res. 2010:131:165-170.
7. Leong WB, Arora T, Jenkinson D, et al. The
prevalence and severity of obstructive sleep
apnea in severe obesity: the impact of
ethnicity. J Clin Sleep Med. 2013;9(9):853-
858.
8. Mulgrew AT, Fox N, Ayas NT, Ryan CF.
Diagnosis and initial management of
obstructive sleep apnea without
polysomnography: a randomized validation
study. Ann Intern Med. 2007;146:157-166.
9. El-Sayed IH. Comparison of four sleep
questionnaires for screening obstructive sleep
apnea. Egypt J Chest Dis Tuberc.
2012;61(4):433-441.
10. Cua IHY, Codamos LJ, Gappi MAS.
Validation of the St. Luke’s Medical Center
obstructive sleep apnea clinical scoring
system. Phil J Intern Med. 2003;41:175-178.

Vol. 18 | Issue 04 | December 2017 38

 Accuracy of OSA screening tools including SLMC-OSACS

Appendix
St. Luke’s Medical Center–Obstructive Sleep Apnea
Clinical Score (SLMC-OSACS) Questionnaire

Body mass index (BMI)

Are you bothered by sleepiness during the day? YES NO

Does snoring disturb

A bed partner or a roommate? YES NO

Someone in the adjacent room? YES NO

SLMC-OSACS for Filipinos

Bothersome Snoring
BMI (kg/m2) None Daytime Affecting Both
Sleepiness Others Only
19 1 4 5 7
21 1 4 5 8
23 2 4 5 8
25 2 4 6 8
27 2 4 6 8
29 2 5 6 8
31 2 5 6 9
33 3 5 6 9
35 3 5 6 9
37 3 5 7 9
39 3 6 7 9
41 3 6 7 9
43 3 6 7 10
45 4 6 7 10
47 4 6 8 10
49 4 6 8 10
Note:
Probability of sleep apnea is low for SLMC-OSACS <5.
Probability of sleep apnea is high for SLMC-OSACS ≥5.
Adapted from Chung F. Open Anesth J. 2011;5(Suppl 1-M2):7-11.

39 Philipp J Chest Dis 2017

 Castillo and Cabrera

COHORT STUDY

Cohort Study on the Applicability of the Updated 2015 Lung

Center of the Philippines Algorithm on Pre-operative Risk
Assessment as a Predictor of Post-operative Pulmonary
Complications
Randy Joseph D.T. Castillo, MD; Glynna O. Cabrera, MD
Department of Pulmonary Medicine, Lung Center of the Philippines, Quezon City
ABSTRACT
Introduction: Pre-operative pulmonary evaluation is an essential prerequisite for lung resection
because it estimates the impact of surgery on the already-compromised respiratory function. This
study aims to assess the applicability of the updated Lung Center of the Philippines (LCP) 2015
algorithm on pre-operative risk assessment for predicting post-operative pulmonary complications
(PPCs) among lung resection patients.

Methods: This cohort observational study included 78 patients for lung resection, evaluated by the
updated 2015 LCP algorithm. The patients were followed up until discharge to observe for PPC
development. PPC incidence was determined in relation to baseline demographic variables, value
of predictive factors and the risk assessment.

Results: PPC incidence was 29% of patients. Prolonged air leak and nosocomial pneumonia were
the most common PPCs. Mortality rate was 1.3%. Male gender, smoking history, smoking ≥20
years, FEV1 % predicted and predicted post-operative (ppo) FEV1 were shown to predict PPC
development. The applicability of the updated algorithm in predicting PPC was found to be
significant for the non-neoplastic group.

Conclusion: The updated 2015 LCP algorithm on pre-operative risk is applicable not only to
neoplastic patients but also for non-neoplastic patients. The factors that predict PPC development
include male gender, smoking history, smoking ≥20 years, FEV1% predicted and ppo FEV1 value.
PPC incidence rate is the same as in other studies, with prolonged air leak and nosocomial
pneumonia as the most common PPCs.

Keywords: pre-operative risk assessment, post-operative pulmonary complications

INTRODUCTION
Pre-operative pulmonary evaluation is a
prerequisite to every lung resection procedure
because it estimates the possible impact of
surgery on the already-compromised respiratory
function. It encompasses risk assessment, to
identify patients at increased risk of pulmonary
complications, and risk reduction, to institute
corrective and preventive measures that will
minimize the risk of respiratory morbidity and
mortality. It also facilitates the adequate
counselling of patients on treatment options and
identifies possible steps to reduce long-term
pulmonary disability (eg, pre-operative cardio-
pulmonary rehabilitation).

Vol. 18 | Issue 04 | December 2017 40

 2015 LCP Algorithm on Pre-operative Risk Assessment
Lung resection provides a great likelihood
of cure for patients with localized lung disease,
but the procedure is associated with a risk of
mortality, decreased post-operative lung function
and other complications.1 It is generally accepted
that post-operative lung function will decrease
such that forced expiratory volume in 1 second
(FEV1) is reduced by 9%–17% post lobectomy
and 34%–36% post pneumonectomy, while
forced vital capacity (FVC) is reduced by 7%–
11% post lobectomy and 36%–40% post
pneumonectomy.2 Serial studies have shown
decline on lung function for several months
following resection, but this may be recovered to
a smaller extent within six months.3
The quest for the ideal pre-operative test
for predicting patients at higher pre-operative risk
began with spirometry in 1955.4 Since then,
varied scientific evidence has been presented for
setting the most appropriate diagnostic tests for
adequate evaluation and stratification. These tests
include simple arterial blood gas determination,
pre-operative pulmonary function
tests/spirometry measuring FEV1, diffusing
capacity of the lung for carbon monoxide
(DLCO), lung perfusion scan and
cardiopulmonary exercise testing (CPET). The
predictive factors for pulmonary morbidity and
mortality used in these guidelines include FEV1,
DLCO, predicted post-operative (ppo) FEV1, ppo
DLCO, and the maximum amount of oxygen an
individual can use (VO2max). These predictive
factors were then integrated and recommended as
part of pre-operative evaluation algorithm.
The pre-operative algorithms for risk
assessment available at present are from the
American College of Chest Physicians,5 the
British Thoracic Society6 and the European
Respiratory Society/European Society of
Thoracic Surgery.7 The differentiating factor
among these algorithms is the specific
recommended stepwise order of the diagnostic
tests to arrive at a specific risk stratification.
These algorithms are also primarily used to risk
assess patients with early-stage lung cancer. In
41 Philipp J Chest Dis 2017
our setting, the algorithms are used not only for
lung cancer patients but also for patients with
non-neoplastic conditions requiring lung
resection, such as bronchiectasis, bulla and
aspergilloma.
This study aims to assess the applicability
of the updated Lung Center of the Philippines
(LCP) 2015 algorithm on pre-operative risk
assessment8 in predicting PPCs among patients
undergoing lung resection at the LCP. In this
updated algorithm, CPET was escalated as the
next diagnostic test if FEV1 or DLCO is <80%
predicted values. In comparison, the 2010 LCP
algorithm, which was patterned from the
American College of Chest Physicians
Guidelines,5 sets lung perfusion scan as the next
diagnostic test if FEV1 and DLCO are <80%.
This study also aims to correlate the baseline
demographic, clinical variables and predictive
factors with the occurrence of PPCs.
The revision of the LCP algorithm on pre-
operative risk assessment could be more cost-
effective with the availability of CPET in our
center (compared to lung perfusion scan) and as
supported and validated by other evidence-based
studies.2,9,10
METHODS
This is a cohort observational study
conducted on adult patients ≥18 years old who
were scheduled for lung resection from January
2016 to October 2016. Included were those who
underwent the prescribed diagnostic tests for
adequate risk stratification based on the latest
2015 LCP algorithm on pre-operative risk
assessment (Appendix). Excluded were patients
with incomplete diagnostic tests for adequate pre-
operative evaluation using the LCP algorithm and
those assessed to have high risk for cardiac
complications by Goldman’s score.
Baseline data were recorded, including
age, sex, ward of admission, presence of co-
morbidities, smoking history, underlying disease
(neoplastic or non-neoplastic), surgical approach
(thoracotomy or video-assisted thoracoscopic

surgery), type of resection (pneumonectomy,
lobectomy or lesser resection), cardiac risk
assessment by Goldman’s score, smoking
cessation (≥8 weeks before surgery) and post-
operative use of incentive spirometry until
discharge. The values of the predictive factors
obtained from the diagnostic tests indicated in the
algorithm (partial pressure of carbon dioxide
[pCO2], partial pressure of oxygen [pO2], FEV1,
FEV1 % predicted, ppo FEV1, DLCO %
predicted, ppo DLCO and VO2max) were
recorded. Lengths of post-operative hospital stay
were determined.
The patients were followed up until
discharge to observe for post-operative
pulmonary complications (PPCs). PPC incidence
rate was determined in relation to the baseline
data, value of predictive factors, pulmonary risk
assessment and length of post-operative stay.
Sample size for this study was computed to
≥76 using Fleiss with continuity correction and
assuming 5% level of significance and a default
statistical power of 80%.
Categorical variables were presented using
frequency counts and percentages, while
continuous variables were summarized using
measures of central tendency. The statistical
differences in the proportions of patients grouped
per specified risk variable and the associations of
risk factors to post-operative complications and
clinical outputs to neoplastic disease were
calculated using Pearson’s chi-squared test or
Fisher’s exact test. Independent-samples t-test
was used to determine difference and correlation
between length of post-operative stay of patients
and predictive values to incidence of
complications. IBM SPSS version 20.0 was used
to output the statistical tables. Significance level
was set at 5%, indicating statistical difference and
association. Binary logistic regression was
employed to determine the joint association of
variables that were deemed significant in the
univariate assessment. Significance level was set
at 10% for multivariate regression analysis.
We conducted this study in compliance
Castillo and Cabrera
with the ethical principles set in the Declaration
of Helsinki. The Institutional Ethics Review
Board of LCP reviewed and approved the study
protocol and subsequent amendments prior to
initiation. The investigator obtained a written and
signed informed consent from each study
participant prior to data collection.
RESULTS
A total of 119 patients were admitted for
lung resection during the study period. Forty-one
were excluded: 4 did not undergo spirometry due
to hemoptysis, 36 had inadequate diagnostics
precluding pre-operative evaluation using the
2015 LCP algorithm (11 with no baseline
spirometry, 6 without DLCO component in
spirometry, 15 did not undergo CPET, and 4 did
not undergo lung perfusion scan) and 1 was
assessed as high risk for cardiac complications.
Seventy-eight satisfied the inclusion criteria and
were assessed using the 2015 LCP algorithm on
pre-operative risk assessment. Among them, 49
had FEV1 % predicted and DLCO % predicted
≥80%, so they were labeled outright as low risk.
The 29 with FEV1 % predicted and DLCO %
predicted <80% underwent CPET: 10 had VO2max
>20 ml/kg/min and were categorized as low risk,
while 19 underwent lung perfusion scan, were
found to have ppo FEV1 and ppo DLCO ≥40%,
and were categorized as moderate risk.
The mean age of participants was 55 years.
Most were <65 years old. Out of the 23 patients
who developed PPCs, 74% were male. Gender
was a significant factor associated with the
development of complications (χ2=4.064,
p=0.04). Male patients were found to have
approximately two times higher chance of getting
complications (RR: 2.1). Forty-nine percent had
non-neoplastic diseases, mostly post-tuberculous
bronchiectasis, aspergilloma and bulla. Sixty-one
percent of complication incidences came from the
non-neoplastic group, but the diagnosis was not a
significant factor in predicting complications
(p=0.216). Seventy-four percent of those with
PPC had a prior history of smoking. Previous
Vol. 18 | Issue 04 | December 2017 42
 2015 LCP Algorithm on Pre-operative Risk Assessment

Table 1. Baseline Characteristics of Patients

Without PPCs
With PPCs (n=23) Total (n=78) P-value
Baseline Characteristics (n=55)

n % n % n %
<65 years old 17 73.9 40 72.7 57 73.1 NS
Age group ≥65 years old 6 26.1 15 27.3 21 26.9
Mean ± SD 53.22±13.9 55.8±13.7 55.04±13.73
Male 17 73.9 27 49.1 44 56.4 0.04
Sex
Female 6 26.1 28 50.9 34 43.6
Service 11 47.8 16 29.1 27 34.6 0.126
Ward
Pay 12 52.2 39 70.9 51 65.4
Neoplastic 9 39.1 31 56.4 40 51.3 0.216
Diagnosis
Non-neoplastic 14 60.9 24 43.6 38 48.7
Smoking Smoker 17 73.9 19 34.5 36 46.2 0.002
status Non-smoker 6 26.1 36 65.5 42 53.8
<20 pack years 12 43 78.2 55 70.5 0.03
Smoking 52.2
≥20 pack years 11 12 21.8 23 29.5
pack years 47.8
Mean±SD 16.13±14.35 7.75±13.58 10.22±14.25

Breast cancer 0 0 1 1.8 1 1.3 NS

Bronchial asthma 2 8.7 1 1.8 3 3.8 0.206
COPD 3 13 5 9.1 8 10.3 0.687
Co-
Hypertension 6 26.1 15 27.3 21 26.9 NS
morbidities
Goiter 0 0 1 1.8 1 1.3 NS
Diabetes mellitus 5 21.7 12 21.8 17 21.8 NS
None 11 47.8 27 49.1 38 48.7 NS

Surgical VATS 15 65.2 31 56.4 46 59 0.558

approach Uniportal VATS 4 17.4 16 29.1 20 25.6
Thoracotomy 4 17.4 8 14.5 12 15.4

Type of Lobectomy 22 95. 50 90.9 72 92.3

0.347
resection
Pneumonectomy 1 4.3 1 1.8 2 2.6
Lesser resections 0 0 4 7.3 4 5.1

Cardiac risk Low 20 87 50 90.9 70 89.7 0.687

assessment Moderate 3 13 5 9.1 8 10.3

Smoking Yes 21 91 52 95 73 94 0.594

Cessation No 2 9 3 5 5 6
Post-op Yes 19 83 48 87 67 86
incentive 0.589
spirometry
No 4 17 7 13 11 14
use

COPD = chronic obstructive pulmonary disease; PPC = post-operative pulmonary complications; SD = standard
deviation; VATS = video-assisted thoracoscopic surgery.

43 Philipp J Chest Dis 2017


smokers were three times more likely to get
complications (RR: 3.35). Mean duration of
smoking was 16 years in those with complication,
8 years in those without. Patients with ≥20 pack-
year smoking history had two times higher
likelyhood of getting complications (RR: 2.18).
With a certainty level of 95%, smoking history and
having ≥20 pack years significantly contributed to
complications (p=0.002 and p=0.03, respectively)
(Table 1).
Most participants had no known co-
morbidities, were admitted at the pay ward,
underwent VATS/lobectomy, had low-risk cardiac
assessment, stopped smoking ≥8 weeks prior to
surgery and used post-operative incentive
spirometry until discharge. However, none of the
abovementioned baseline data were statistically
significant with respect to occurrence of PPCs.
Most of the patients who developed PPCs
had significantly lower mean FEV1 % predicted
(68.53% vs 86.16%). Mean pO2 was higher among
those who developed complications (91.04 mm Hg
vs 90.74 mm Hg), but more than half (57%) of
those who developed complications had pO2 <90
mm Hg. FEV1 % predicted was the only predictive
value statistically associated with occurrence of
complication (p<0.001) (Table 2).
A comparison of means showed that the
observed mean FEV1 % and ppo FEV1 were
statistically significant to the development of PPCs
(p=0.001 and p<0.001, respectively) (Table 3).
Binary logistic regression showed that
significant variables in the univariate analysis,
when combined, resulted in having smoking
history and FEV1 as significant predictors of PPC
at 90% confidence level (Table 4).
Summarizing the PPC incidence per risk
assessment using the 2015 LCP algorithm, a total
of 59 patients were categorized as low risk (29,
neoplastic; 30, non-neoplastic) while 19 were
categorized as moderate risk (11, neoplastic; 8,
non-neoplastic).
Chi-squared test showed significant
association between the combination of type of
Castillo and Cabrera
disease and risk assessment and incidence of
complications (p=0.036). The applicability of the
algorithm in predicting PPC was statistically
significant to the non-neoplastic group (p=0.09)
(Table 5).
Using the 2015 LCP algorithm, PPC
incidence was found to be at 29% (23/78
patients), the most common PPC being
prolonged air leak (10%), followed by
nosocomial pneumonia (8%) with noted Gram-
negative isolated strains: three with Klebsiella
pneumoniae, one with Pseudomonas aeruginosa,
one with Enterobacter cloacae and one with
Acinetobacter baumannii. There was no statistic-
ally significant difference between neoplastic and
non-neoplastic disease when grouped according
to the incidence of each PPC (Table 6).
Patients with complications had greater
median post-operative stay (9 vs 6 days). The
difference was statistically proven at 95%
confidence level (H=3.66, p=0.003) (Table 7).
DISCUSSION
There are many pre-operative risk
assessment algorithms and guidelines available
for reference. All aim to systematically facilitate
and adequately evaluate perioperative and long-
term risks of pulmonary disability. These
algorithms mostly differ on the order of
diagnostic tests to request prior to risk
stratification. The 2015 LCP algorithm for pre-
operative risk assessment was patterned from the
2009 ERS/ESTS guideline,7 but the cut-off
values for the predictive factors such as ppo
FEV1, ppo DLCO and VO2max were adapted from
Bolliger et al.9 Based on this study, the
applicability of the updated 2015 LCP algorithm
in predicting PPCs is not only for patients with
lung cancer but also for patients with a diagnosis
of bronchiectasis, aspergilloma or bulla (p=0.09).
In contrast, in the latest guidelines available
globally, the target clinical group for pre-
operative evaluation is specifically designed for
lung cancer patients.
Vol. 18 | Issue 04 | December 2017 44
 2015 LCP Algorithm on Pre-operative Risk Assessment

Table 2. Predictive Diagnostic Test Factors of the Patients

With Without
Total
Predictive Diagnostic Test Complications Complications
P-value
Factors
n % n % n %

>45 mm Hg 4 17 3 5 7 9
0.093
pCO2 ≤45 mm Hg 19 83 52 95 71 91

Mean±SD 37.71±5.74 37.29±4.68 37.41±4.82

≥90 mm Hg 10 43.5 26 47.3 36 46.2

0.807
pO2 <90 mm Hg 13 56.5 29 52.7 42 53.8

Mean±SD 91.04 ±13.04 90.74±10.81 90.83±11.43

≥80% 9 39.1 46 83.6 55 70.5

FEV1 <0.001
% predicted <80% 14 60.9 9 16.4 23 29.5

Mean±SD 68.53±21.35 86.16 ±12.89 80.97 ±17.67

≥1.5 L 18 78.3 49 89.1 67 85.9

0.285
FEV1 <1.5 L 5 21.7 6 10.9 11 14.1

Mean±SD 1.89±0.45 2.09±0.49 2.03±0.48

≥40% 21 91.3 54 98.2 75 96.2

0.206
ppo FEV1 <40% 2 8.7 1 1.8 3 3.8

Mean±SD 67.30±17.73 81.10±13.44 77.03±16.02

≥80% 11 47.8 37 67.3 48 61.5

DLCO 0.13
% predicted <80% 12 52.2 18 32.7 30 38.5

Mean±SD 80.78±13.32 82.70±10.42 82.13±11.31

≥40% 23 100.0 54 98.2 77 98.7

0.99
ppo DLCO <40% 0 0.0 1 1.8 1 1.3

Mean±SD 73.02±12.57 76.32±13.21 75.35±13.03

>20 ml/kg/min 6 20.6 5 17.3 11 37.9

0.99
VO2max ≤20 ml/kg/min 8 27.6 10 34.5 18 62.1

Mean±SD 19.6±3.57 20.43±6.28 20.15±5.18

FEV1=forced expiratory volume in 1 second; DLCO=diffusing capacity of the lung for carbon monoxide; pCO 2=partial pressure of
carbon dioxide; ppo=predicted post-operative; pO2=partial pressure of oxygen; SD=standard deviation; VO2max=the maximum
amount of oxygen an individual can use.

45 Philipp J Chest Dis 2017

 Castillo and Cabrera

Table 3. Means of Analyzed Predictive Diagnostic Factors

Without
Predictive Values With Complications P-value
Complications
pCO2 37.71±5.74 37.29±4.68 0.727
pO2 91.04 ±13.04 90.74±10.81 0.916
FEV1 1.89±0.45 2.09±0.49 0.091
FEV1 % predicted 68.53±21.35 86.16 ±12.89 0.001
ppo FEV1 67.30±17.73 81.10±13.44 <0.001
DLCO % predicted 80.78±13.32 82.70±10.42 0.499
ppo DLCO values 73.02±12.57 76.32±13.21 0.311
VO2Max 19.6±3.57 20.43±6.28 0.547

FEV1=forced expiratory volume in 1 second; DLCO=diffusing capacity of the lung for carbon monoxide; pCO 2=partial pressure of
carbon dioxide; ppo=predicted post-operative; pO2=partial pressure of oxygen; SD=standard deviation; VO2max=maximal oxygen
consumption.

Table 4. Binary Logistic Regression of Significant Variables

Predictors B SE Wald df P-value Odds Ratio

Gender –1.031 0.759 1.848 1 0.174 0.356

Smoking –1.514 0.837 3.27 1 0.071 0.22

Smoking pack years –0.018 0.81 0.001 1 0.982 0.982

FEV1 0.071 0.021 11.074 1 0.001 1.074

Constant –3.226 1.909 2.854 1 0.091 0.04

df=degrees of freedom; FEV1=forced expiratory volume in 1 second.

Table 5. Post-operative pulmonary complication Incidence per Risk Assessment Among Neoplastic and Non-
Neoplastic Patients
With Without
Total P-value* P-value†
Complications Complications
Risk
Disease n % n % n %
Assessment
Low 8 88.89 21 67.74 29 72.50 0.211
Neoplastic
Moderate 1 11.11 10 32.26 11 27.50 0.036
0.090 (<0.05)
Non- Low 9 64.29 21 87.50 30 78.95
(<0.10)
Neoplastic
Moderate 5 35.71 3 12.50 8 21.05

*P-values for main effect of risk assessment on incidence of complications per disease group (neoplastic or non-neoplastic)
†P-value for combined effect of disease group and risk assessment on incidence of complications.

Vol. 18 | Issue 04 | December 2017 46

 2015 LCP Algorithm on Pre-operative Risk Assessment

Table 6. Incidence of Specific PPCs

Neoplastic Non-Neoplastic Total

PPC P-value
n % n % n %
Prolonged air leak 5 6.4 3 3.8 8 10.2 0.179
Nosocomial pneumonia 1 1.3 5 6.4 6 7.7 0.34
Hemothorax 1 1.3 3 3.8 4 5.1 1
Prolonged mechanical ventilator 0 0 2 2.6 2 2.6 0.234
Acute respiratory failure 1 1.3 1 1.3 2 2.6 1
Atelectasis 1 1.3 1 1.3 2 2.6 1
Bronchospasm 2 2.6 0 0 2 2.6 0.142
Death 0 0 1 1.3 1 1.3 1

PPC=post-operative pulmonary complication.

Table 7. Length of Post-operative Stay

Minimum Maximum
Std. Stat
Stay Stay Median Mean P-value
Deviation Value*
(days) (days)

With
5 15 9 8.65 2.95
Complications

Without 3.66 0.003

2 13 6 6.4 2.02
Complications

Total 2 15 7 7.06 2.53

*Mann-Whitney Test

In both neoplastic and non-neoplastic
groups, 70%–72% of those classified as low risk
came out without complication (21/29 and 21/30
cases, respectively). In this study, sensitivity is the
ability to identify patients (assessed as low risk)
who will not experience complication; it was 88%
for the non-neoplastic group and 68% for
neoplastic. However, when it comes to classifying
cases as moderate risk, the algorithm had better
accuracy in predicting PPCs in the non-neoplastic
group (63%) than in the neoplastic group (9%).
Specificity was shown to be low for both groups
(36% for non-neoplastic, 11% for neoplastic).
Overall PPC incidence in our study was
29%, with the most common being prolonged air
leak (10%), followed by nosocomial pneumonia
(8%). Mortality rate was 1.3%. These findings
are similar to that of other studies. In a three-year
local retrospective study by Catacutan et al, PPC
rate in 53 patients was 32%, with the most
common PPCs being nosocomial pneumonia
(11%) and prolonged air leak (9%), while
mortality rate was 4%.11 In another four-year
local retrospective study by Mapanao et al,12 PPC

47 Philipp J Chest Dis 2017


incidence was 43%, with nosocomial pneumonia
(13%) and prolonged air leak (12%) as the most
common and a mortality rate of 2%. A local
prospective study by Aloc-Samaniego et al13 found
PPCs in 12% of 55 patients, with the most
common PPC being prolonged air leak (17%),
followed by hemothorax and pneumonia (both
3%), but with zero mortality. Globally, the overall
incidence of PPC is approximately 30%; however,
estimations may vary from 7% to 49%. Prolonged
air leak (4%–26%), nosocomial pneumonia (15%–
22%) and acute respiratory failure (2.4%–17%)
have been found to be the most common causes of
PPC.3 In general, prolonged air leak carries a low
mortality rate but great morbidity because it is
associated with prolonged hospitalization, and
pleural air leaks may further deteriorate pulmonary
gas exchange by increasing the amount of wasted
ventilation and work of breathing.14 As for
nosocomial pneumonia, many factors may
influence this, including patient population,
isolation procedures and antibiotic use; but the
most common bacterial isolates are gram-negative
organisms,3 as in our case.
In our study, we have one mortality
recorded: a 39-year-old with no known co-
morbidities. He underwent right lung
pneumonectomy due to recurrent non-massive
hemoptysis secondary to post-tuberculous
bronchiectasis. The patient’s predictive factors
were FEV1 % predicted of 45%, ppo FEV1 of 45%,
DLCO % predicted of 73%, ppo DLCO of 76%
and VO2max of 15.8 ml/kg/min, so he was risk
stratified as moderate risk. The patient also
suffered from other PPCs, including hemothorax
and prolonged mechanical ventilation use prior to
demise. We found that the morbidity of post-
operative complications in pneumonectomy was
significantly higher than in lobectomy (p=0.01).14
Lobectomy and pneumonectomy are consistently
described with mortality rates of 2%–4% and 6%–
8%, respectively.14 FEV1 % and DLCO <60% are
also predictors of increased morbidity and
mortality.3
Castillo and Cabrera
Among the baseline demographic/clinical
factors in this study, the major predictors of PPC
were male gender and smoking history. Most of
the patients that developed PPCs were male
(74%), and male patients had approximately 2
times higher chance of getting complications
(RR: 2.1). This is consistent with the study of
Kearny et al,15 in which 2/3 of those with
complications were male, and the local study of
Mapanao et al,12 in which 77% of those with
PPCs were males (p=0.04). It could be noted that
84% of the smokers in our study were males.
Male gender developing PPCs with smoking
history could be interrelated, because smoking is
a proven risk factor for the development of post-
operative complications. In this study, 74% of
those with PPCs had a prior history of smoking.
Previous smokers had 3 times higher likelihood
of getting complications (RR: 3.35). Similarly,
Smetana et al16 found a relative risk of 1.4- to
4.3-fold in smokers for occurrence of
complications. Mean smoking duration among
those with complication was 16 years; among
those who did not develop complication, it was 8
years. With a certainty level of 95%, smoking
history and having ≥20 pack years significantly
contribute to complications (p=0.002 and p=0.03,
respectively). Age is not considered contributory
to PPCs, and age alone is not a contraindication
to surgery.5 The mean age in this study was 53
years, and most patients were <65 years old.
Factors such as tumor stage, patient life
expectancy, performance status and co-
morbidities should be taken into account in the
surgical decision-making process.3 Our study
found that advanced age (>65 years) was not
related with occurrence of PPCs, as stated by
Lim et al,6 who reported that elderly patients,
while being aware of their lower health status
pre-operatively (had poorer ECOG performance
status and ASA scores compared with the
younger subjects), had no significant differences
in their quality of life at three months after
surgery.6 As to the factors that could be employ-
Vol. 18 | Issue 04 | December 2017 48
 2015 LCP Algorithm on Pre-operative Risk Assessment
ed to decrease the occurrence of PPC, our study
included smoking cessation and the use of
incentive spirometry. The beneficial effects of
smoking cessation include improvement in ciliary
and small-airway function and a decrease in
sputum production, which occur gradually over
several weeks. The risk of PPC is said to be
highest in patients who were smoking within the
last two months and patients who had quit
smoking for more than six months.17 The
correlation of timing of smoking cessation prior
to surgery, in general, has only a minimal impact
on PPC. In one study,7 the patients enrolling in a
smoking cessation program 6–8 weeks prior to
elective surgery had decreased morbidity and a
reduced need for post-operative ventilatory
support. However, in another study,15 patients
still smoking at the time of surgery did not have
significantly more complications than those who
stopped smoking. Post-operative incentive
spirometry use is said to decrease the risk of
PPCs, because the lung expansion maneuver
controls the adverse effects of surgery on lung
and chest wall mechanics that cause atelectasis
and retained secretions. However, a systematic
review by Overend et al and a randomized
controlled trial by Gosselink et al, both found no
benefit of incentive spirometry.18 Literature
supports the use of CPAP therapy to decrease
PPC.7 In our study, both smoking cessation and
post-operative use of incentive spirometry were
not proven to be determinants for minimizing
development of PPC. This might be attributed to
the general consensus based on the
abovementioned studies, but another loophole for
this non-significance was the small sample
representation (only 6% of our patients did not
stop smoking prior to surgery, and only 14% did
not use spirometry).
Among the predictive diagnostic factors in
our study, only FEV1 % and ppo FEV1 were
found to statistically significant and related to the
development of PPC. Pulmonary function tests—
in particular, FEV1 and ppo FEV1—have
traditionally represented the key test in functional
49 Philipp J Chest Dis 2017
workup of surgical candidates.19 Berry et al
in 2007 reported that FEV1 was an independent
predictor of respiratory complications: patients
with pre-operative FEV1 <30% had an incidence
of respiratory morbidity as high as 43%, while
those with FEV1 >60% had a morbidity rate of
12%.7 In our study, the mean FEV % predicted of
the patients with PPCs was significantly lower
(68.53±21.35%) than those without
(86.16%±12.89) (p<0.001). Mean ppo FEV1 was
lower among patients with PPC than those
without (67.30±17.73% vs 81.10±13.44%).
Kearney et al15 found that ppo FEV1 was the best
predictor of complications after controlling for
the effect of other risk factors in a multivariate
analysis. Although ppo FEV1 is fairly accurate in
predicting the definitive residual value of FEV1
three to six months after surgery, it substantially
overestimates the actual FEV1 observed in the
initial post-operative days, when most
complications occur.6 Therefore, ppo FEV1
should not to be used alone to assess candidates
for lung resection, as it tends to underestimate the
functional loss in the early post-operative phase
and does not appear to be a reliable predictor of
complications.7
Other predictive factors that were found to
be statistically non-significant in our study but
generally showed a correlation in development of
PPCs include pCO2 (37.71 mm Hg vs 37.29 mm
Hg), DLCO % predicted (80.78% vs 82.70%),
ppo DLCO (73.02 vs 76.32) and VO2max (19.5
ml/kg/min vs 20.56 ml/kg/min). With regard to
pCO2 and pO2, most studies have showed that
hypercapnea and hypoxemia are not directly
related to the development of PPCs. Kearney et al
reported that in 30 patients with pCO2 >45 mm
Hg and desaturation to pO2 <90 mm Hg, they did
not find an increased occurrence of PPCs.15 As
for DLCO, it is recommended to systematically
measure it in all lung resection candidates
regardless of their pre-operative FEV1 level,
because ≥40% of them can have abnormal DLCO
despite a normal FEV1, and ppo DLCO has been
shown to be a valid predictor of major morbidity

even in patients without airflow limitation.19 The
strong correlation between diffusing capacity and
PPCs is probably due to the contribution of a
reduced pulmonary capillary bed and alveolar
capillary membrane to pulmonary compli-
cations.20 The last predictive diagnostic factor is
VO2max, which is a value derived from CPET.
The patients who developed PPCs in our study
had a lower VO2max than non-complicated
patients (19.5±3.56 ml/kg/min vs 20.56±6.34
ml/kg/min). Most of the studies published so far
agree 10–15 ml/kg/min indicates an increased
risk for PPC and perioperative death compared
with higher values of VO2max.5 On the other hand,
VO2max >20ml/kg/min has been reported to be
safe for any kind of resection, including
pneumonectomy. In one study by Brunelli et al,
which included 200 participants with major
anatomic lung resections and complete CPET,
patients with VO2max >20 ml/kg/min had no
mortality and only 7% morbidity rate compared
to those with VO2max <12, whose mortality rate
was 13%.5
This study involved only 78 patients,
because most patients were excluded due to the
diagnostic tests in the algorithm not being
followed by most attending physicians. With the
conclusion that the updated algorithm is
predictive of PPCs specifically to non-neoplastic
patients, we recommend that this algorithm be
applied for all patients undergoing lung resection.
This, in effect, will help increase the sample size
for future studies, to strengthen the association of
other clinical variables found to be non-
significant in this study.
Other recommendations include a longer
follow-up period not limited to the day of
discharge, studying the correlation of pulmonary
rehabilitation with the development of post-
operative complications, and the possible effect
of anesthesia and post-operative analgesia in PPC
occurrence.
Castillo and Cabrera
CONCLUSION
The updated 2015 LCP algorithm on pre-
operative risk assessment in predicting PPCs is
not only applicable to patients with lung cancer
but also for those with non-neoplastic diseases.
Moreover, this algorithm is more predictive in
determining among the non-neoplastic group who
with low risk will not develop complication and
who in the moderate-risk group will develop
complication. The factors that predict
development of PPCs include male gender,
smoking history, smoking ≥20 years, FEV1 %
predicted and ppo FEV1 value. PPC incidence is
29%, almost the same as with other studies, with
prolonged air leak and nosocomial pneumonia as
the most common PPCs. There is also a longer
hospital stay for patients developing PPCs.
REFERENCES
1. Mazzone P. Preoperative evaluation of the
lung resection candidate. Cleve Clin J Med.
2012;79(e-suppl):eS17-eS22.
2. Mazzone PJ, Arroliga AC. Lung cancer:
preoperative pulmonary evaluation of the lung
resection candidate. Am J Med. 2005;118(6):578-
583.
3. Beckles M, Spiro G, Colice G, et al. The
physiologic evaluation of patients with lung
cancer being considered for resectional surgery.
Chest. 2003;123(1 Suppl):105S-114S.
4. Puente-Maestú L, Villar F, González-
Casurrán G, et al. Early and long-term validation
of an algorithm assessing fitness for surgery in
patients with postoperative FEV₁ and diffusing
capacity of the lung for carbon monoxide < 40%.
Chest. 2011;139(6):1430-1438.
5. Brunelli A, Kim AW, Berger KI, et al.
Physiologic evaluation of the patient with lung
cancer being considered for resectional surgery:
Diagnosis and management of lung cancer, 3rd
ed: American College of Chest Physicians
evidence-based clinical practice guidelines.
Chest. 2013;143(5 Suppl):e166S-e190S.
Vol. 18 | Issue 04 | December 2017 50
 2015 LCP Algorithm on Pre-operative Risk Assessment

6. Lim E, Baldwin D, Beckles M, et al. 16. Smetana GW. Preoperative pulmonary

Guidelines on the radical management of evaluation. N Engl J Med.
patients with lung cancer. Thorax. 1999;340(12):937-944.
2010;65(Suppl 3):iii1-iii27. 17. Fernandes EO, Teixeira C, Silva LC.
7. Brunelli A, Charloux C, Bolliger CT, et al. Thoracic surgery: risk factors for
ERS/ESTS clinical guidelines on fitness for postoperative complications of lung
radical therapy in lung cancer patients (surgery resection. Rev Assoc Med Bras. 2011;57
and chemo-radiotherapy). Eur Respir J. 2009 (3):292-298.
Jul;34(1):17-41. 18. Bapoje SR, Whitaker JF, Schulz T, et al.
8. Algorithm for physiologic evaluation for lung Preoperative evaluation of the patient with
resection candidates (2015 update). Lung pulmonary disease. Chest. 2007;132(5):
Center of the Philippines Clinical Protocols. 1637-1645.
2015. 19. Agostini P, Cieslik H, Rathinam S, et al.
9. Bolliger CT, Perruchoud AP. Functional Postoperative pulmonary complications
evaluation of the lung resection candidate. Eur following thoracic surgery: are there any
Respir J. 1998;11(1):198-212. modifiable risk factors? Thorax. 2010;65
10. Benzo R, Kelley GA, Recchi L, et al. (9):815-818.
Complications of lung resection and exercise 20. Wang JS. Relationship of carbon monoxide
capacity: a meta-analysis. Respir Med. 2007; pulmonary diffusing capacity to post-
101(8):1790-1797. 
 operative cardiopulmonary complications in
11. Catacutan M, Mendoza J, Francisco N. patients undergoing pneumonectomy.
Pulmonary complications following lung Kaohsiung J Med Sci. 2003;19(9):437-446.
resection: Lung Center of the Philippines
experience. Sci Proc. 2012;7(1):50-55.
12. Mapanao D, Delos Reyes V, Balanag V. The
rate of postoperative complications following
lung resection surgery among patients
evaluated preoperatively using the LCP
protocol. 2006.
13. Aloc-Samaniego I, Galvez B. Prospective
evaluation of an algorithm on preoperative
pulmonary risk assessment of lung resection
candidates at Lung Center of the Philippines.
2012.
14. Fujiu K, Kanno R, Suzuki H, et al.
Preoperative pulmonary function as a predictor
of respiratory complications and mortality in
patients undergoing lung cancer resection.
Fukushima J Med Sci. 2003;49(2):117-127.
15. Kearney DJ, Lee TH, Reilly JJ, et al.
assessment of operative risk in patients
undergoing lung resection importance of
predicted pulmonary function. Chest.
1994;105(3):753-759.

51 Philipp J Chest Dis 2017

 Castillo and Cabrera

APPENDIX

Formulae for Calculating Predicted Post-operative Values for FEV1 and DLCO

A. Anatomic Method

ppo FEV1 (post lobectomy) = pre-operative FEV1 x (1–a/b)

reference FEV1

ppo DLCO (post lobectomy) = pre-operative DLCO x (1–a/b)

reference DLCO

a=number of functional or unobstructed segments to be resected

b=total number of functional or unobstructed segments.

B. Perfusion Method

ppo FEV1 (post pneumonectomy) = pre-operative FEV1 x (1 – fraction of total perfusion

of lung to be resected)

ppo DLCO (post pneumonectomy) = pre-operative DLCO x (1 – fraction of total perfusion

of lung to be resected)

The total number of segments is 19 (10 right, 9 left). Distribution of segments:

• Right upper lobe=3
• Middle lobe=2
• Right lower lobe=5
• Left upper lobe=5 (3 upper division, 2 lingula)
• Left lower lobe=4

The ppo FEV1 is expressed as percentage of predicted to calculate % ppo FEV1.

The ppo DLCO and % ppo DLCO can be calculated using the same formula.
The percentage of ppo (% ppo) values of FEV1 and DLCO are routinely used instead of
absolute values.

Vol. 18 | Issue 04 | December 2017 52

 IMAGE GALLERY

Primary Ciliary Dyskinesia

Sagittal reformatted CT image showing "tree in CT scan of the lower chest in primary ciliary
bud" appearance of impacted distal small airways dyskinesia showing mild bronchial wall thickening
in Kartagener Syndrome. and bronchiectasis.

Axial CT image showing dextrocardia and situs Sagittal reformatted CT image showing cylindrical
inversus in a patient with Kartagener syndrome. bronchiectasis in Kartagener syndrome.

All four images courtesy of John S. To, MD (Own work) [Public domain], via Wikimedia Commons.

53 Philipp J Chest Dis 2017

 NOTES

____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________

Vol. 18 | Issue 04 | December 2017 54

 NOTES

____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________

55 Philipp J Chest Dis 2017

 OUTSIDE BACK COVER

The Philippine Journal of Chest Diseases

An official publication of:
Philippine College of Chest Physicians
84-A Malakas St., Pinyahan, Quezon City, Philippines
Email: secretariat@philchest.org
Phone: (+632) 924 9204
 Legal Prescription Philippine Journal of Internal Medicine

Res Ipsa Loquitor Doctrine

Atty. Rodel V. Capule M.D.*

The meaning of res ipsa loquitor is known to everyone
in the medical community. “Literally, res ipsa loquitur
means the thing speaks for itself. It is the rule that the
fact of the occurrence of an injury, taken with the
surrounding circumstances, may permit an inference
or raise a presumption of negligence ....” 1 “Under this
doctrine, the happening of an injury permits an inference
of negligence.” 2 “It is allowed because there is no other
way, under usual and ordinary conditions, by which the
patient can obtain redress for injury suffered by him.” 3
Furthermore, “when the doctrine of res ipsa loquitur is
availed by the plaintiff, the need for expert medical
testimony is dispensed with because the injury itself
provides the proof of negligence. 4
Res ipsa loquitur doctrine becomes applicable
only when the following elements are present: (1) the
occurrence of an injury; (2) the thing which caused the
injury was under the control and management of the
[physician]; (3) the occurrence was such that in the
ordinary course of things, would not have happened if
those who had control or management used proper care;
and (4) the absence of explanation by the [physician]. 5
But the Supreme Court has put caution on its
applicability saying that “the doctrine is not a rule of
substantive law, but merely a mode of proof or a mere
procedural convenience. The doctrine, when applicable
to the facts and circumstances of a given case, is not
meant to and does not dispense with the requirement of
proof of culpable negligence against the party charged.
It merely determines and regulates what shall be prima
facie evidence thereof, and helps the plaintiff in proving
a breach of the duty. The doctrine can be invoked when
and only when, under the circumstances involved, direct
evidence is absent and not readily available.” 6
In other cases, the Supreme Court clearly stated the
other limits of its applicability. For example, “[i]t does not
automatically apply to all cases of medical negligence as
to mechanically shift the burden of proof to the defendant
to show that he is not guilty of the ascribed negligence.” 7
“It is generally restricted to situations in malpractice cases
where a layman is able to say, as a matter of common
knowledge and observation, that the consequences of
professional care were not as such as would ordinarily have
followed if due care had been exercised.” 8 The doctrine is
also not available if the only argument by the complainant
is that “the desired result of an operation or treatment
was not accomplished.” 9 Specifically the doctrine is not
applicable just because injury occurs to a patient while
under anesthesia, or to any and all anesthesia cases. 10
In the case of Reyes v. Sisters of Mercy Hospital 11 the
Supreme Court held that the doctrine has no application
in a suit against a physician or a surgeon which involves
the merits of a diagnosis or of a scientific treatment. Even
the occurrence of a rare unfavorable result of treatment
or rare complication of surgery, standing alone, does not
invite the application of res ipsa loquitor. 12
Physicians can take comfort from the fact that
“generally, the doctrine of res ipsa loquitur is not
applicable in malpractice cases, and only in unusual
circumstances may a physician or surgeon be found guilty
of a failure to exercise the requisite degree of care in
the absence of expert medical testimony tending to so
prove.” 13
R eferences
1. 1. Dr. Jaime T. Cruz v. Felicisimo V. Agas, Jr., G.R. No. 204095,
June 15, 2015
2. Sps. Alfredo Bontilao and Sherlina Bontilao v. Dr. Carlos Gerona,
G.R. No. 176675, September 15, 2010
3. R amos v. Court of Appeals, G.R. No. 124354, December 29, 1999
4. R osit v. Davao Doctors Hospital, G.R. No. 210445, December 07,
2015
5. D r. Jaime T. Cruz v. Felicisimo V. Agas, Jr., G.R. No. 204095, June
15, 2015
6. D r. Fernando P. Solidum v. People of the Philippines, G.R. No.
192123, March 10, 2014
7. R amos v. Court of Appeals, supra.
8. Id.
9. Id.
10. Id.
11. G .R. No. 130547, October 3, 2000
12. H asemeier v. Smith, 361 S.W.2d 697 (1962)
13. Id.

*Dr. R.V. Capule is an attorney specializing in medical malpractice,
physical injuries and food torts. He is a law professor of Legal Medicine at
Arellano University School of Law and a consultant in Legal Medicine at
Adventist Medical Center Manila and Makati Medical Center.
 Philippine Journal of Internal Medicine
Accuracy of Blood Glucose Measurements Using Capillary and
Arterial Line of Extracorporeal Circuit of Hemodialysis Among
Diabetic Patients Undergoing Outpatient Hemodialysis at The
Medical City
Genevieve F. Sia, M.D.*; Christy S. Yao, M.D.*
Abstract
Introduction: Accurate and reliable glucose level
measurements are essential for ensuring safe and effective
glycemic control among diabetic patients undergoing
hemodialysis (HD). Capillary blood glucose (CBG) monitoring
is the standard of care of glycemic control assessment in
patients with diabetes on maintenance HD. In the Philippines,
glucose monitoring during HD involves either standard finger
stick (CBG) or blood sample from the arterial line (AL) of
extracorporeal circuit of HD machine. However, anecdotal
observations noted over the years have shown discrepancies
in the glucose values from the two sites. This study aimed to
determine the accuracy of blood glucose measurements
of capillary and AL of extracorporeal circuit of HD machine
using point-of-care (POC) glucose meter in comparison to
central laboratory venous plasma among diabetic patients
undergoing outpatient HD in a private tertiary hospital in
the Philippines. Determining the most accurate and reliable
method of glucose level measurement is vital in helping
patients attain glycemic control. To date, there is limited
published data regarding the accuracy of blood glucose
values obtained through CBG and AL of extracorporeal
circuit of HD machine while patients are undergoing dialysis.
Methods: This is a prospective, cross-sectional, analytical
study involving thirty patients. Forty blood samples from
30 patients obtained through CBG, AL and the peripheral
venous plasma of the opposite arm were simultaneously
analyzed. Specifically, StatStrip was utilized as the POC
Introduction
The number of end stage renal disease (ESRD) patients
is growing rapidly in developed and developing countries.
The increase in incidence of ESRD has been linked to chronic
noncommunicable diseases especially diabetes mellitus
(DM) and hypertension. Current projections indicate that
by 2030, the global population of ESRD patients on dialysis
may exceed two million.1
*Section of Endocrinology, Diabetes and Metabolism, Department of Internal
Medicine, The Medical City
Corresponding author: Genevieve F. Sia, M.D., The Medical City,
Manila, Philippines
Email:gensia22@yahoo.com
The PHILIPPINE JOURNAL OF INTERNAL MEDICINE is a peer reviewed journal and a copyrighted publication of the Philippine College of Physicians
Original Article
glucose meter. Accuracy of AL of extracorporeal circuit
and CBG were determined and assessed in accordance
with International Organization for Standardization (ISO)
15197:2013 minimum accuracy criteria for glucose meters.
Regression analysis was used to determine whether AL and
CBG significantly predict peripheral venous blood glucose
levels.
Results: Analysis showed that there is a statistically significant
difference in the glucose values obtained from AL and
CBG (p-values 0.005 and <0.0001) when compared to
venous plasma glucose. However, this may not pose clinical
significance in routine practice. It is noteworthy that both
AL (concordance rate (CR)=100%) and CBG (CR=96.5%)
satisfied the revised ISO 15197:2013 accuracy criteria for
glucose value greater than or equal to 100mg/dL.
Conclusion: Both CBG and AL blood glucose measurement
significantly predict venous plasma blood glucose level.
POC blood glucose value from both AL of extracorporeal
circuit during HD and CBG satisfied the accuracy criteria set
by ISO 15197: 2013 for glucose value greater than or equal
to 100mg/dL. Thus, confirming the glucose level by CBG
monitoring is not necessary in patients with arterial glucose
value of greater than or equal to 100 mg/dL during HD.
Keywords: accuracy, arterial line, capillary blood glucose,
hemodialysis, point of care glucose meter
In the Philippines, DM is noted to be the most common
cause of ESRD leading to dialysis since 2001. The incidence
of ESRD secondary to DM comprised 38% of all dialysis cases
conducted between 2001 to 2005.2 Glycemic control is a key
predictor of survival among ESRD patients and is therefore
a vital consideration in managing these patients.3 Frequent
episodes of hyperglycemia and/or hypoglycaemia during
dialysis is associated with long term morbidity and shortened
survival. 4,5
The accuracy of blood glucose measurements is
therefore critical in treatment decisions directed towards
glycemic control. Erroneously low or high glucose values
obtained using point-of-care (POC) glucose meter during
dialysis may lead to inappropriate correction resulting in
Volume 55 Number 4 Oct.-Dec., 2017 1
 Sia GF, et al.
hyperglycemia or hypoglycemia.6 Thus, inaccurate glucose
monitoring may negatively impact clinical outcomes.7
Different strategies are employed in monitoring blood
glucose during hemodialysis (HD). These include blood
sample obtained from the standard capillary blood glucose
(CBG) or finger stick procedure, 8,9 from the arterial line
(AL) of extracorporeal circuit of HD machine. 4,10,11 and
continuous glucose monitoring system (CGMS).12,13 However,
CBG monitoring is the standard of care of glycemic control
assessment in patients with diabetes on maintenance HD.14
Most HD facilities in the Philippines use the standard
CBG monitoring during HD. In The Medical City (TMC),
where this study was conducted, sample obtained from
AL of extracorporeal circuit is used to minimize discomfort
caused by finger pricking. Review of charts in the research
setting showed a difference of 35mg/dL (1.95 mmol/L) in
blood glucose values from two sites. Based on anecdotal
observations, when blood glucose value from the AL is low,
rechecking with the CBG is done and the value of the latter
is considered as the basis of clinical decisions.
Review of literature revealed that there is no published
data comparing blood glucose values obtained from
AL of extracorporeal circuit versus CBG during HD. Thus,
this study was conducted to test the accuracy of blood
glucose obtained from two different sites in diabetic patients
undergoing HD using POC glucose meter vis-à-vis peripheral
venous blood glucose.
General objective
To determine the accuracy of blood glucose
measurements of capillary and AL of extracorporeal
circuit of HD machine using POC glucose meter vis-à-vis
central laboratory venous plasma among diabetic patients
undergoing outpatient HD.
Specific objectives
1. To compare the blood glucose levels from AL of
extracorporeal circuit of HD machine and CBG using
POC glucose meter compared with central laboratory
peripheral venous plasma.
2. To determine whether blood glucose measurements
of AL of extracorporeal circuit of HD machine and
CBG using POC glucose meter can predict the central
laboratory peripheral venous plasma.
3. To determine the concordance of the AL and CBG
measurement using Statstrip glucose meter with the
revised ISO 15197:2013 accuracy criteria.
Methods
This is a prospective cross-sectional, analytical study
conducted at TMC hemodialysis unit in December 2016.
2 Volume 55 Number 4 Oct.-Dec., 2017
Accuracy of Blood Glucose Measurements using Capillary and Arterial Line
Patients who were at least 18-years-old with type 1 or type
2 DM, undergoing outpatient HD in TMC. Only patients who
freely signified their consent were included in this study. A
sample size of 30 was computed at 95% level of confidence
and 0.98 reliability coefficient based on the study of Ogawa
et al. 9 The present study was able to collect 30 patients with
40 blood samples.
( zα ) 2 pq
n=
e2
Where:
n = is the number of subjects needed
p = estimated reliability coefficient = 0.98
q = 1 – p = 1 – 0.98 = 0.02
Zα = 95% confidence level = 1.96
The study was approved by the hospital’s Institutional
Review Board Ethics Committee. All patients gave informed
consents to participate. Patient baseline characteristics
including age, sex, duration of diabetes, antidiabetic
therapy, and duration of HD were determined through
interview and patient records review.
The standard protocol in determining the POC glucose
level in the AL of the extracorporeal circuit of HD was
measured at the second hour by a well-trained HD nursing
staff. An additional determination was done for patients who
manifested signs and symptoms of hypoglycemia 15 such as
sweating, hunger, shaking, heart pounding, nervousness
or anxiety, feeling of warmth, weakness, confusion,
drowsiness, dizziness, speech difficulty, and blurring of vision.
Simultaneously, CBG from the opposite arm was collected by
the same nursing staff and the five milliliter plasma venous
blood sample from the peripheral vein was extracted
by a skilled medical technologist and sent to the clinical
laboratory for analysis.
A total of 40 sets of blood samples from 30 patients
were collected for analysis. There were 10 patients who had
two sets of glucose measurement because they manifested
with hunger symptoms during HD. The blood samples from
AL and CBG were analyzed using the same POC glucose
meter StatStrip (Nova Biomedical UK) that was calibrated
every 24 hours according to manufacturer’s instructions.
The POC glucose meter utilized a modified glucose
oxidase enzyme method and multilayer-gold, multielectrode,
four-well test strip. It provides excellent correlation versus
plasma hexokinase reference methods throughout a
range of 10 to 600mg/dL (0.5 to 33.3 mmol/L) 16 and has
good clinical reliability when used in dialysis setting. 17
This glucose meter eliminates haematocrit interferences,
electrochemical interferences such as acetaminophen, uric
acid and ascorbic acid; and interferences from maltose
 Accuracy of Blood Glucose Measurements using Capillary and Arterial Line
Table I. Demographic characteristics of subjects
Frequency
(n=30)
Age (in years)
Mean ± SD 65.43 ± 14.94
Sex
Male 13
Female 17
Duration of hemodialysis (years) 2.56 ± 2.37
Duration of diabetes (years) 17.57 ± 8.29
Antidiabetic therapy
Insulin 9 30.0
Insulin+oral hypoglycemic agent 4 13.3
Oral hypoglycemic agent only 5 16.7
None 12
and galactose, icodextrin and oxygen, thus reducing the
likelihood of erroneous results arising from interference
factors that influence current conventional glucose meters.17
This POC blood glucose meter has passed the standards set
by the ISO 1519718 and the Clinical and Laboratory Standards
Institute (CLSI) POCT 12-A3 accuracy guidelines.20
The peripheral venous samples, on the other hand,
were analyzed in the clinical laboratory using the Abbott
Architect i2000SR which delivers high quality immunoassays
using chemiluminescence detection technology.
Data were encoded and analyzed in SPSS version 10
for windows. Descriptive statistics were generated for all
variables. Frequencies and percentages were determined
for nominal data. Mean and standard deviation (SD) were
generated. Analysis of the different variables was done using
the following test statistics:
Paired T-test – used to compare two groups with
numerical data that are dependent.
Regression analysis – used to determine predictor/s of
an outcome variable.
In accordance to the most recent ISO 15197:2013
criteria for glucose meter accuracy,18 the acceptable level
of accuracy is set at ≥ 95% of POC values within ± 15% of
the reference method for glucose values greater than or
equal to 100 mg/dL and within ± 15mg/dL of the reference
method for POC glucose values less than 100mg/dL. The
reading was expressed in proportion of values falling within
various intervals following the ISO recommended format.
Results
A total of 30 patients were included in the study,10
of whom manifested symptoms of hypoglycaemia during
data collection thus requiring two sets of blood glucose
determinations. As shown in Table I, the participants’ age
ranged from 36 to 88 years with a mean age of 65.43 years.
Sia GF, et al.
Table II. Blood glucose levels (mg/dL) by arterial line of the
dialysis machine, capillary and peripheral vein blood samples
Percentage
n Mean ± SD
Arterial line (AL) 40 119.85 ± 27.99
---
Capillary 40 117.38 ± 27.67
43.3 Venous †
40 123.95 ± 28.49
56.7 †Reference standard
--- Table III. Predicting central laboratory venous plasma using
--- capillary blood glucose measurement among diabetic patients
undergoing outpatient hemodialysis
Beta coefficient p-value*
Constant 7.848 0.214
40.0
Arterial line (AL) 0.969 <0.0001
* p>0.05- Not significant; p≤0.05-Significant
Dependent Variable: Venous
More than half (56.67%) of the participants were females.
Forty percent were not on maintenance antidiabetic therapy
at the time of data collection. The average duration of DM
is 17.57 years and an average duration of HD of 2.56 years.
Table II shows the mean values of glucose levels on AL
and CBG using POC glucose meter, and venous plasma as
reference standard using clinical laboratory instrument. There
is a significant difference in the glucose level measurements
from blood samples obtained from AL and CBG when
compared to venous plasma glucose with p-values 0.005
and <0.0001 respectively. However, this difference may not
be clinically significant in routine practice.
Table III shows the regression analysis results when AL
blood glucose measurement was used in predicting venous
plasma blood glucose level. The results showed that AL blood
measurement significantly predicts (p<0.0001) venous plasma
blood glucose level and a regression equation below was
derived to compute venous plasma blood glucose levels
using AL:
y = 7.848 + 0.969 (x)
where y is the venous plasma blood glucose level
computed given x, the AL blood glucose level.
Table IV shows the regression analysis results when CBG
measurement was used in predicting venous plasma blood
glucose level. The results showed that CBG measurement
significantly predicts (p<0.0001) venous plasma blood
glucose level and a regression equation below was derived
to compute venous plasma blood glucose levels using
capillary blood glucose level:
y = 7.438 + 0.993 (x)
where y is the venous plasma blood glucose level
computed given x, the CBG level.
The most recent ISO 15197:2013 criteria for glucose
meter accuracy sets ≥ 95% of POC values within ±15% of the
Volume 55 Number 4 Oct.-Dec., 2017 3
 Sia GF, et al.
Table IV. Predicting central laboratory venous plasma using
arterial line blood glucose measurement among diabetic patients
undergoing outpatient hemodialysis
Beta coefficient
Constant 7.438
Capillary 0.993
*p>0.05- Not significant; p≤0.05-Significant from AL predicts significantly the peripheral venous plasma
Dependent Variable: Venous
Table V. Evaluation of the accuracy of blood glucose level
concordance to ISO 15197:2013 criteria
Glucose Glucose
Method <100mg/dL ≥100mg/dL
Within±15mg/dL Within 15%
Arterial Line (AL) 70.0% (7/10) 100% (30/30)
Capillary 81.8% (9/11) 96.5% (28/29)
reference method for glucose values greater than or equal
to 100 mg/dL and within ± 15mg/dL of the reference method
for glucose values less than 100mg/dL as the acceptable
level of accuracy. 18 With this criteria as reference, both AL
and CBG satisfied the accuracy criteria for glucose value
greater than or equal to 100mg/dL, but neither satisfied the
accuracy criteria for glucose values less than 100mg/dL as
shown in Table V.
Discussion
Accurate and reliable glucose level measurements are
essential for ensuring safe and effective glycemic control
among diabetic patients undergoing HD. Accuracy criteria
for POC glucose meters set by the ISO 15197 ensures that
blood glucose monitors used for patients are reliable on a
day to day basis. 18
Ogawa et al. found that 100% of predialysis capillary
glucose sample and 99.3% of post dialysis samples met the
ISO 15197:2003 criteria when the glucose levels were more
than 75mg/dL. Out of 148 subjects, only three patients were
documented to have glucose levels of less than 75mg/dL
which satisfy 100% of the accuracy criteria. 9 The recent ISO
15197:2013 criteria sets glucose level of 100mg/dL instead
of 75mg/dL as cut off. Out of 40 blood samples in our study,
we only documented 11 blood glucose levels of less than
100mg/dL. However, unlike Ogawa's study, our results did
not satisfy the accuracy criteria if blood glucose level is less
than 100 mg/dL.
In this study, it was found that in accordance with
ISO 15197:2013 accuracy criteria, both the AL from
extracorporeal circuit of HD machine and CBG were able to
meet the accuracy criteria when glucose values are greater
than 100 mg/dL but not for glucose values less than 100 mg/
dL.
4 Volume 55 Number 4 Oct.-Dec., 2017
Accuracy of Blood Glucose Measurements using Capillary and Arterial Line
The common practice in our institution in determining
blood glucose level during HD is through the arterial line.
Burmeister et al reported that glucose levels measured
in blood samples from AL of extracorporeal circuit of HD
p-value*
did not differ from those obtained simultaneously from the
0.172 peripheral vein of the arm opposite to the vascular access. 4
<0.0001 This finding was similar in this study in which blood samples
glucose level.
Limitations
Overall
Thirty is the mimimum sample size requirement however
concordance
increasing the sample size of those glucose values less than
100mg/dL will increase the statistical power of the study.
92.5% Most patients did not manifest hypoglycemic signs and
92.5% symptoms because majority of them had no maintenance
antidiabetic medications. Furthermore, the presence of
hypoglycaemia unawareness, which is commonly found in
patients with longstanding diabetes might have contributed.
Conclusion
Both blood samples obtained from AL and CBG are
in concordance with venous blood glucose as seen in
Table V. Moreover, the results of the study showed that
both AL and CBG predict central laboratory venous blood
glucose level significantly. With the recent ISO 15197: 2013
accuracy criteria, both AL and CBG satisfied the criteria
for glucose value greater than or equal to 100mg/dL but
not for glucose value less than 100mg/dL. CBG monitoring
is not necessary in patients with arterial glucose value of
greater than or equal to 100 mg/dL during HD.
Recommendation
In view of the results of this study, a similar study involving
a larger sample size of blood glucose level less than 100mg/
dL is recommended.
Acknowledgment
The authors would like to thank The Medical City Section
of Endocrinology, Section of Nephrology, Hemodialysis unit
staffs, Laboratory staffs, Institutional Review Board-Ethics
Review Committee, Mr. Luthew Bryan Tan, Mr. Jundelle
Jalique, Mrs. Grace Rosales, Ms. Carielle Joy Rio, Dr.
Raymond Lee, Dr. Dennis Dumaplin and Mr. Lukasz Karol
Majewski for helping and supporting this study.
References
1. Szczech LA and Lazar IL; Projecting the United States ESRD
Population: Issues Regarding Treatment of Patients with
 Accuracy of Blood Glucose Measurements using Capillary and Arterial Line Sia GF, et al.

ESRD.  Kidney International, Supplement, Vol. 66, No. 90, 2004. Guideline. 3rd edition 2013.
2. Philippine Renal Disease Registry. http://www.redcop-nkti.org/
Prdr.htm (accessed Aug 12, 2016).
3. Morioka T, Emoto M, Tabata T, Shoji T, Tahara H, Kishimoto
H, Ishimura E, Nishizawa Y; Glycemic Control is a Predictor of
Survival for Diabetic Patients on Hemodialysis. Diabetes Care,
24 (5):909-13, May 2001.
4. Burmeister JE, Campos JF, Miltersteiner DR; Effect of Different
Levels of Glucose in the Dialysate on the Risk of Hypoglycaemia
during Hemodialysis in Diabetic Patients. J. Bras. Nefrol. Vol.
34, No.4, 2012.
5. A b e M a n d K a l a n t a r- Z a d e h K ; H e m o d i a l y s i s - i n d u c e d
Hypoglycaemia and Glycemic Disarrays. Nature Reviews
Nephrology May 2015.
6. Rebel A, Rice MA, Fahy BG; The Accuracy of Point-of-care
Glucose Measurements. Journal of Diabetes Science and
Technology 1; 6(2):396-411, March 2012.
7. Brazg RL, Klaff LJ, Parkin CG; Performance Variability of Seven
commonly used Self-monitoring of Blood Glucose Systems:
Clinical Considerations for Patients and Providers. Journal of
Diabetes Science and Technology 1;7(1):144-52, January 2013.
8. McKee-Waddle R, Jacksonwhite S, Shapiro SE, Hall M, Barbir
DD, Hanfelt J; Blood Glucose Levels of Patients with Diabetes in
the Immediate Post-acute Hemodialysis Period: An Exploratory
Study. Nephrology Nursing Journal. Vol.41, No.5, Sept-Oct 2014.
9. Ogawa T, Murakawa M, Matsuda A, Kanozawa K, Kato H,
Hasegawa H, Mitarai T; Endogenous Factors Modified by
Hemodialysis may Interfere with the Accuracy of Blood Glucose-
measuring Device. Hemodialysis International 2011.
10. St. George Hospital, Renal Department. Guidelines for Taking
Blood Sugar Level during Hemodialysis. 2013.
11. Abe M, Kaizu K, Matsumoto K; Evaluation of the Hemodialysis-
induced Changes in Plasma Glucose and Insulin Concentrations
in Diabetic Patients: Comparison between the Hemodialysis and
Non-hemodialysis Days. Therapeutic Apheresis and Dialysis Vol.
11, No.4, 2007.
12. Yue-ping J, Xiao-fei S, Guo-ping Y, Xiao-hua X, Ji-zhuang L,
Jian-jun C, Yue Z, Jie L, Bing J, Zheng L, Kok-Onn L, Lei Y,
Jian-hua M; Blood Glucose Fluctuations in Hemodialysis Patients
with End Stage Diabetic Nephropathy. Journal of Diabetes and its
Complications 29. 395-399, 2015.
13. Kazempour-Ardebili S, Lecamwasam V, Dassanyake T, Frankel
A, Tam F, Dornhorst A, Frost G, Turner J; Assessing Glycemic
Control in Maintenance Hemodialysis Patients with Type 2
Diabetes. Diabetes Care, Vol. 32, No. 7, July 2009.
14. Frankel A, and Kazempour-Ardebili S; Management of Adults
with Diabetes on the Hemodialysis Unit. Joint British Diabetes
Societies for Inpatient Care April 2016.
15. Towler DA, Havlin CE, Craft S, Cryer P; Mechanism of Awareness
of Hypoglycaemia. Perception of Neurogenic (Predominantly
Cholinergic) rather than Neuroglycopenic Symptoms. Diabetes.
Vol. 42, December 1993.
16. Kost GJ, Tran NK, Louie RF, Gentile NL, Abad VJ; Assessing
the Performance of Handheld Glucose Testing for Critical Care.
Diabetes Technology and Therapeutics. Vol. 10, No. 6, 2008.
17. Bewley B, O’Rahilly S, Tassell R, DuBois J, Donald E; Evaluation
of the Analytical Specificity and Clinical Application of a New
Generation Hospital-based Glucose Meter in a Dialysis Setting.
Point of Care, Vol. 8, No. 2, 2009.
18. International Organization for Standardization. In Vitro
Diagnostic Test System Requirements for Blood Glucose
Monitoring for Self-testing in Managing Diabetes Mellitus. ISO
15197:2013.
19. ISO Standards for Blood Glucose Meters.www.diabetes.co.uk
(accessed Aug. 2016).
20. Clinical Laboratory Standards Institute. Point of Care Blood
Glucose Testing in Acute and Chronic Care Facilities: Approved

Volume 55 Number 4 Oct.-Dec., 2017 5

 Philippine Journal of Internal Medicine
The Effect of a Single-Session Diabetes Education on the
Knowledge, and Attitudes of Patients with Type 2 Diabetes
Mellitus Seen at Out-patient Clinics in Chinese General Hospital:
A Prospective Cohort Study
Michelle U. Cornel, M.D.*; Lora May T. Tin Hay, M.D.*
Abstract
Introduction: With the increasing prevalence of diabetes
mellitus (DM) in the Philippines, Diabetes Self-Management
Education (DSME) remains to play a vital role in diabetes
care. It is important in optimizing metabolic control,
preventing and managing complications, and maximizing
quality of life in a cost-effective manner. This study aimed
to determine the effect of diabetes education on the
knowledge and attitudes of type 2 DM patients. It also aimed
to determine the topics that needed more emphasis during
education.
Methods: A prospective study, which included 75 patients: 38
patients in the education group and 37 patients in the non-
education group, was conducted. A single session diabetes
education was given to the patients in the education group.
Baseline and follow-up knowledge and attitude scores by
using the modified, validated, Filipino versions of American
Association of Clinical Endocrinologists (AACE) Knowledge
Evaluation Form and Diabetes Attitude Scale–3 (DAS–3),
respectively, were compared between the education and
Introduction
According to World Health Organization (WHO) in 2014,
the global prevalence of type 2 diabetes mellitus (DM) was
estimated to be 8.5% among adults.1 In the Philippines last
2016, the prevalence of diabetes reached 5.8% .2 WHO also
predicted that in 2030 diabetes will be the seventh leading
cause of death worldwide.2
Diabetes Self-Management Education (DSME) and
Diabetes Self-Management Support (DSMS) are vital
elements of diabetes care. These help people with diabetes
mellitus initiate effective self-management when they are
first diagnosed. DSME and DSMS guide patients in optimizing
metabolic control, preventing and managing complications,
and maximizing quality of life in a cost-effective manner. The
American Diabetes Association (ADA) recommends that
patients with diabetes should engage in DSME to enhance
their knowledge, skills and ability, which are necessary for
*Section of Endocrinology, Diabetes and Metabolism, Chinese General
Hospital and Medical Center
Corresponding author: Michelle U. Cornel, M.D., Chinese General
Hospital and Medical Center, Manila, Philippines
Email:michellecornel@yahoo.com
The PHILIPPINE JOURNAL OF INTERNAL MEDICINE is a peer reviewed journal and a copyrighted publication of the Philippine College of Physicians
Original Article
non-education groups. The changes in weight and body
mass index (BMI) for both groups were also compared.
Results: Results showed that on follow-up, there was a
significant increase in the mean percentage scores for
knowledge in the education group. There was no significant
increase in mean frequency of correct answers for questions
on precautions prior to exercise, monitoring, nutrition
and medication adjustment during ill days. Questions on
psychosocial impact, and value of tight glucose control
showed significant improvement in the education group,
while one question on seriousness of diabetes did not
improve significantly.
Conclusion: Diabetes education generally improved the
knowledge and attitudes of patients towards their disease.
Keywords: diabetes education, knowledge, attitude, type
2 diabetes mellitus
diabetes self-care.3 In a number of studies, DSME is associated
with improved diabetes knowledge, self-care behavior,
clinical outcomes, such as lower A1C and self-reported
weight.3
In 2014, Ku, et al. in the Philippines, investigated the
effects of implementing a context-adapted DSME and
DSMS projects on knowledge, attitudes, self-management
practices, adiposity/obesity and glycemia among diabetic
patients for one year.4 They utilized the Diabetes Knowledge
Test, Diabetes Knowledge Questionnaire and the Diabetes
Attitude Scale–3 (DAS-3) of the University of Michigan
Diabetes and Training.
Recently in our institution, the Diabetes and Endocrine
Center (DEC) was established to render comprehensive
individualized education for diabetic patients. This would
help them understand their disease, and reinforce their
initiative to maintain a healthy lifestyle and eventually live
a life with minimal complications.
The main objective of this study was to determine
the effect of diabetes education on the knowledge and
attitude of patients with type 2 DM by using the modified,
Volume 55 Number 4 Oct.-Dec., 2017 1
 Cornel MU, et al. The Effect of a Single-Session Diabetes Education

pre-validated Filipino translated questionnaires, namely,
American Association of Clinical Endocrinologists (AACE)
Knowledge Evaluation Form5, and the DAS-3 6, respectively.
This study also aimed to compare the frequency of patients
who answered correctly for each knowledge question,
median scores and the range of scores for each attitude
question between education group and non-education
group at baseline and on follow-up. This was also designed
to determine the change in the weight, and body mass index
(BMI) of the patients between education and non-education
group from baseline until follow-up.
for special training, seriousness of DM, value of tight control,
psychosocial impact, and patient autonomy (Appendix C
and D). Initial testing of the final knowledge and attitude
questionnaire was done among 10 patients to observe the
time needed to complete the questionnaire and to check
their understanding on the questions given. A lower score
indicated that the patients strongly agreed on the given
issues implying a strong impact on their attitude but the
reverse scoring was applied to one question on value of
tight control (A5).
Diabetes education

Methods Full module diabetes education offered by the DEC

at the Chinese General Hospital (CGH) is a single session
Study design and subjects
counseling which lasts for approximately 90 to 120 minutes.
A one-on-one session is offered to private patients, while a
This is a prospective cohort study. Patients who were
group session is rendered to charity patients. Patients were
more than 18 years old, diagnosed with type 2 DM based
presented with flip charts for each module. It included the
on the ADA criteria, and seen at outpatient clinics were
following modules: diabetes overview; nutrition and exercise;
included in the study. Pregnant, or hospitalized patients and
glucose monitoring and insulin administration; and foot
those who had previous diabetes education counseling were
care. At the end of the module, educational kits were given
excluded. Subjects were recruited by convenience sampling
to patients, which included leaflets on diabetes, dietary
from June to August 2016.
counseling and their personalized meal plan.

Questionnaires
Data collection

A three-part questionnaire was given to patients upon

Convenience sampling was done by the researcher
enrollment and on follow-up. It was composed of the
during clinic hours. Patients who were seen at the OPD Clinics
Patient information sheet or follow-up form, Knowledge
(private and charity) but not referred to DEC were included
Questionnaire, and Attitude Questionnaire (DAS-3).
in the non-education group. On the other hand, patients who
were seen at DEC for full module diabetes education were
Patient information sheet included the following:
included in the education group. Referral to DEC was made
patient’s name, age, sex, address, contact number, duration
based on the physician’s discretion. Informed consent was
of diabetes, medications (diet, oral medication, insulin, or
secured. Information and other parameters were recorded
both), attending physician, educational attainment, and
including height, weight, and BMI.
compliance with medications. This was filled up by the
patient upon enrollment in the study. Height, weight and
Patients were then requested to answer the questionnaire
BMI were recorded.
with the assistance of the investigator if necessary.
Afterwards, the education group proceeded to the full
The Knowledge Questionnaire was adapted from the
module diabetes education. For the non-education group,
previously translated and validated Filipino version of AACE
they were reminded to follow-up with their physician on their
Knowledge Evaluation Form by Verastigue-Custodio.5 This
assigned date. On follow-up, patients were instructed to
included topics on diabetes overview, nutrition, exercise,
answer the same questionnaire. Due to some unavoidable
monitoring and medications. Content validity was performed
circumstances of the subjects, their follow-up period differed
by four diabetes educators (two nurses and two dietitians)
from three to six months from the enrollment date. Enrollment
who independently selected 15 out of the 67 questions which
in the study was not disclosed to the attending physicians to
they deemed to be most relevant and applicable to the
avoid deliberate reiteration of the answers to the questions,
present local setting. (Appendix A and B).
which may lead to recall bias.

The Filipino version of the DAS-3 that was previously

Recruitment of subjects was done between June to
formulated by Yao et al. in 20046 was used in this study.
August 2016 for the baseline period and from September to
After a review of the 33-item questionnaire, content
December 2016 for the follow-up of patients.
validity was performed by selecting 10 questions. Five
subcategories, with two questions for each subcategory
were included. Subcategories included the following: need

2 Volume 55 Number 4 Oct.-Dec., 2017

 The Effect of a Single-Session Diabetes Education
Outcome
Primary outcome was the change in the mean
percentage scores and frequency of correct answers per
item on the knowledge questionnaire and median and range
of scores on the attitude questionnaire from baseline and
on follow-up (three to six months). Secondary outcomes
included comparison in the change in weight, and BMI from
baseline and on follow-up.
Ethics approval
The research protocol was approved by the Research
and Ethics Review Board of the CGH. Informed consent,
written both in Filipino and English, was explained by the
investigator to the patients.
Statistical analysis
A minimum sample size of 68, or 34 per group, was
required for this study. This value gives 80% power, a margin
of 20% to detect an effect size of 0.282 and 0.05 α-level of
significance. The value used for this sample size computation
was based on a study by Tuomilehto J.7 Descriptive statistics
was used to summarize the clinical characteristics of the
patients. Frequency and proportion were used for nominal
variables, median and range for ordinal variables, and mean
and standard deviation (SD) for interval/ratio variables.
Independent Sample T-test, Mann-Whitney U and Fisher’s
Exact/Chi-square test were used to determine the difference
of mean, median and frequency between the education
and non-education patient groups. Paired sample t-test,
Wilcoxon signed rank test and Mcnemar’s test were used to
determine the difference of mean, median and frequency
between baseline and follow up. Comparison among the
different intervals from baseline until follow-up was made
between the education and non-education groups by using
oneway ANOVA and Kruskal wallis test. Subgroup analysis
was made among female and male groups as well as the
private and charity clinics by using Mann-whitney U test and
independent sample T–test.
All valid data was included in the analysis. Missing
variables were neither replaced nor estimated. Null
hypotheses were rejected at 0.05 α-level of significance.
STATA 12.0 was used for data analysis.
Results
There were 44 patients initially enrolled in each group.
In the education group, five patients were lost to follow-up
and one died. While in the non-education group, there were
seven patients who were lost to follow-up. At the end of the
study, there were 38 patients in the education group, and 37
Cornel MU, et al.
patients in the non-education group. At baseline, as shown in
Table I, there were no differences in the age, marital status,
educational attainment, anthropometrics, medications
and duration of diabetes between the education and non-
education groups. Differences were found in sex composition
and clinic attended, where the education group had a
higher percentage of females (82% vs. 59%) and charity-
attending members (39% vs. 11%) as compared to the non-
education group.
Since the subjects had different follow-up periods,
namely three, four, five and six months, we compared the
characteristics of the patients among the different intervals
as shown in Table II. There was no significant difference in
their characteristics among patients with different follow-up
intervals except for age, gender, marital status and type of
clinic attended. For those who had their follow-up at four
months, there was significant proportion of older age group
in the non-education group and also a greater proportion of
married patients in the education group. There was greater
proportion of females in the education group who had their
follow-up at five months. Among those who had their follow-
up at six months, there was greater proportion of private
patients in the non-education group.
At baseline, both education and non-education groups
were similar in their knowledge scores (Table III). On follow-up,
the education group, but not the non-education group, had
significant improvements in scores for knowledge (baseline,
67% ± 17%; follow-up, 87% ± 12%; p<0.001).
Proportion of correct answers in the knowledge
questionnaire increased significantly upon follow-up among
education group for all items except five: two pertaining to
exercise (K4 and K5), one on monitoring (K7), and medication
adjustment during illness (K10), and one about nutrition (K14)
(Table IV). On the other hand, significant improvements in
scores were demonstrated for only two questions in the
non-education group: one on general knowledge (K2) and
another on nutrition (K12). When frequency was compared
between two groups on follow-up, there was significantly
higher frequency in the education group except for
one question pertaining to also to exercise (K5), and on
medication adjustment (K10) and four questions (K12-K15)
on nutrition.
Furthermore, when the scores were compared among
patients with different follow-up intervals, namely three,
four, five and six months, there was no significant difference
observed as shown in Table V.
For the attitude scores, both education and non-
education patients were similar in their attitudes towards
diabetes at baseline (Table VI). Although there was
a decrease in median scores and range of scores in
the education group from baseline to follow-up for all
Volume 55 Number 4 Oct.-Dec., 2017 3
 Cornel MU, et al. The Effect of a Single-Session Diabetes Education

subcategories, which implied that after education more

patients had agreed that these issues had an impact on their
Discussion

attitude towards diabetes, this did not show any statistical
In this study, the baseline characteristics did not differ
significance. In the non-education group, the median
significantly except that in the education group there were
and range remained relatively the same. On follow-up,
greater proportion of females (81% vs 59% in non-education
there was a significantly lower score for the categories on
group) and charity patients (39% vs 10% in the non-education
need for special training and patient autonomy (p<0.001
group). The disproportion of females in the education group
and p=0.005, respectively) in the education group when
may be due to the fact that they are housewives and it was
compared with the non-education group. Since a reverse
more feasible for them to attend the teaching modules. There
scoring was assigned to one of the questions on seriousness
was also greater prevalence of diabetes among women
of DM, this was not included for the subcategory analysis
compared with men, 6.1% vs 5.5% respectively. 2 Another
but was analyzed separately.
possible reason for the increased proportion of women may
be due to the increasing awareness that diabetic women
Three out of ten attitude items significantly improved in
were at higher risk of developing cardiovascular disease
the education group (Table VII). These involved decrease
as well as risk of mortality from coronary heart disease and
in scores of: items A4 on the seriousness of diabetes and
stroke. 8 While the higher proportion of charity patients in
A9 on the psychosocial impact of diabetes. Their scores for
the education group may be attributed to the lower costs
item A5 on value of tight glucose control also became more
of diabetes education offered for these patients. Also, since
desirable (p=0.036). No comparable changes were seen
most of the charity patients were unemployed, it was more
with the non-education group.
feasible for them to attend the diabetes education.

Also, when the change in scores were compared

Among the different follow-up intervals, the significant
among the groups at different follow-up periods, it showed
differences in the age, gender, marital status and type of
no significant difference except for the question on the
clinic attended may be due to personal factors such as
seriousness of diabetes in patients who had their follow-up
the subjects’ availability and their socioeconomic status in
at three months versus patients who had their follow-up at
complying with the follow-up.
four months, as shown in Table VIII.

For the knowledge questionnaire, the education

Since there was greater proportion of female and
group had significantly increased scores on follow-up
charity patients in the education group, subgroup analysis
(86%) compared to the baseline scores (67%). While in the
was done to determine whether these factors may act as
non-education group, the mean percentage of scores at
effect modifiers or confounders. It showed that there was
baseline (63%) decreased on follow-up (55%). When scores
consistent increase in knowledge scores for all subgroup
on follow-up were compared between the two groups,
analysis as presented in Tables IX and X. For the attitude
there were significantly higher scores in the education group
scores, there was significant improvement in scores for the
(86%) than in the non-education group (55%). Several studies
need for special training, psychosocial impact of diabetes
showed that diabetes education strategies, in general, had
and patient autonomy among the private patients and male
positive effects on the patients’ knowledge.9
patients (Tables XI and XII). Among charity patients, there
was also significant improvement in the scores for value of
Upon analyzing the effect of diabetes education for
tight glucose control, whilst among female patients, there
each question on diabetes knowledge, we found that there
was noted improvement in the scores for the need for special
was significantly increased frequency of correct answers on
training, and patient autonomy.
all questions for definition of diabetes, and some questions
on need for monitoring, medications and nutrition. While
We had insufficient evidence to demonstrate significant
there was an increase in frequency of correct answers on
changes in the weight and BMI of patients who underwent
all questions for exercise precaution and some questions
education, but among non-education patients, there was
on monitoring, adjustment of medication during sick days,
a significant increase in average weight from baseline until
and nutrition, this was not significant. In a study by Pereira
follow-up, as shown in Table XIII (68.26 ± 14.71 and 69.05 ±
in 2012, it showed that diabetes education increased
14.94, respectively).
the knowledge of the patients in all the topics including
general questions, physical activity, diet, foot care, clinical
On follow-up, only wo percent in the education group
parameters, hypoglycemia, chronic complications, and
and four percent in the non-education group had other
family support. 10 Our study showed that more emphasis
source of diabetes education, which included television
and clarifications should be given for the topics on exercise
and radio but this was non-significant between the groups
precautions, monitoring, medications and nutrition during
(Table XIV).
the diabetes education.

4 Volume 55 Number 4 Oct.-Dec., 2017

 The Effect of a Single-Session Diabetes Education
When the different follow-up periods were compared
between the education and non-education groups, there
was no significant difference, which implies that different
intervals did not influence the outcomes on the knowledge
scores.
For this study, the increase in scores cannot be correlated
with any change in their behavior. Also, it is important to
understand that although the patient’s knowledge is the
basis to maintain diabetes self-management, increase in
knowledge may not always necessarily mean a change in
behavior.
We also observed the effect on the attitude since
both knowledge and attitude would affect the behavior
of the patients towards their disease. When analyzed per
subcategory, diabetes education had a positive effect on
their attitude as reflected by the decrease in the median of
scores and range, although these differences from baseline
to follow-up were not significant (Table VI). However,
on follow-up, there were greater number of patients in
the education group compared with the non-education
that strongly agreed on the need for special training and
patient autonomy. While for the seriousness of diabetes
and psychosocial impact on follow-up, most of the patients
only somewhat agreed that these attitudes had an impact
towards their disease.
When the answers for each of the attitude questionnaire
on follow-up were analyzed, there were significantly more
number of patients who strongly agreed on all questions
pertaining to the need for special training, psychosocial
impact, patient autonomy, and value of tight control.
Question comparing the seriousness of type 1 and type
2 DM had no significant difference at baseline and on
follow-up for both groups. This may be due to the lack of
knowledge and misconceptions regarding type 1 diabetes.
While for the question on the seriousness of DM, there was
significant difference on baseline and on follow-up for the
education group. Their perception on the seriousness of DM
may be affected by several factors. In a study by Yao, et al.,
educational attainment and family history were identified as
factors that have effects on attitude of patients especially
pertaining to value of tight glucose control and seriousness
of diabetes, respectively.6 The seriousness of DM may also
have different impact on the patients. In a study by Daly,
they showed that participants who indicated that type 2
DM is a very serious disease were more likely to have higher
HbA1c11. This is in contrast with the study of Nuaimi12, which
showed that there was no significant association between
the patient’s attitude and glycemic control. Hence, this issue
must be addressed based on the patient’s perception of
their disease and their corresponding behavior.
When the attitude scores were compared at different
follow-up periods, there was no significant difference except
Cornel MU, et al.
for the question on the seriousness of diabetes, with the
education having more impact at four months than at three
months. This observation may be due to other several factors
such as personal experiences and family history as discussed
previously.
Subgroup analysis was done for the knowledge and
attitude scores among the female and male groups and
private and charity patients. There was a consistent increase
in the knowledge scores, which may imply that the type
of session given did not influence the outcome. However,
the attitude scores varied among the different groups. In
a study by Shakibasadeh in 2011, five main barriers that
influence diabetes self-care were enumerated, namely
physical, psychological, education, social and care system
barriers. They also enumerated motivators such as perceived
responsibility for family, religious beliefs and the view of
significant others. 13 These results suggested that gender
and type of clinic may be confounders to the outcomes
in attitude scores but there was insufficient evidence to
conclude this observation.
The change in the weight and BMI were compared
between the education and non-education groups
to determine if the education had an effect on these
parameters since the importance of weight loss was also
part of the module. This study showed that in the education
group, the weight and BMI slightly decreased but they were
not significant. The weight in the non-education group
increased but BMI remained relatively the same. However,
other factors such as exercise, diet, medications and other
comorbidities may affect these parameters and should also
be taken into consideration during further analysis.
This study compared the effect of diabetes education
on the knowledge and attitude from baseline and on follow-
up in both the education and non-education groups. It
also utilized the previously validated Filipino version of the
questionnaires best suited for our Filipino patients. Topics on
knowledge and attitude that should be given more emphasis
during education were identified. Comparison of outcomes
between the groups at different follow-up periods was done
which showed different intervals did not affect the outcome.
Subgroup analysis showed that gender and type of clinic
attended did not influence outcomes on knowledge scores.
In this study, selection of subjects was not randomized.
Also, ideally follow-up should be done after three months,
but due to unavoidable circumstances, patients were able
to follow-up at different periods, ranging from three to six
months.
Recommendations
Comparing the outcomes at short and long-term
intervals may be conducted. Follow-up study can be done at
Volume 55 Number 4 Oct.-Dec., 2017 5
 Cornel MU, et al. The Effect of a Single-Session Diabetes Education

long term intervals such as at one year to determine which org/doi/full/10.1056/NEJM200105033441801#t=article

information has been retained. If results showed significantly 8. Gucciardi E, Chan VW, Manuel L, Sidani S. A systematic
literature review of diabetes self-management education features to
decreasing scores, then a refresher course may be offered
improve diabetes education in women of Black African/Caribbean
to the patients. Also, comparison of the outcomes between and Hispanic/ Latin American ethnicity, Patient Education and
the group session and the one-on-one session may be Counseling; 2013 Aug 31;92(2): 235–245. Available from: http://
considered. Other metabolic parameters, such as fasting www.pec-journal.com/article/S0738-3991(13)00116-X/fulltext
blood sugar, blood pressure, HbA1c, lipid profile may be 9. Otero LM, Zanetti ML, Ogrizia MD. Knowledge of diabetic patients
about their diseases before and after implementing a diabetes
included as outcomes to establish the effect of education
education program, Revista latino-americana de enfermagem 2008
on glucose control. The effect of education on the behavior April; 16(2):231-237. Available from: http://www.scielo.br/scielo.
or practices of diabetic patients may also be assessed. php?script=sci_arttext&pid=S0104-11692008000200010
10. Pereira D, Costa N, Sousa A, Jardim P, Zanini CR. The effect
of educational intervention on the disease knowledge of diabetes
Conclusion mellitus patients, Rev. latino-Am. Enfermagem 2012 June;20(3).
Available from: http://www.scielo.br/scielo.php?script=sci_artte
Diabetes education still plays a vital role in the self- xt&pid=S0104-11692012000300008
11. Daly JM, Hartz AJ, Xu Y, Levy BT, James PA, Merchant ML,
management of patients with type 2 DM. Among Filipino
Garrett RE. An assessment of attitudes, behaviors, and outcomes
patients, diabetes education improved their knowledge of patients with type 2 diabetes, JABFM 2009 May1; 22(3): 280-
and attitude towards their disease. Certain topics such 90. Available from: http://www.jabfm.org/content/22/3/280.full.
as precautions during exercise, monitoring, medication 12. Nuaimi A, Yousif E, Al Chetachi WF. Attitudes and self-care
adjustment during ill days and nutrition should be given more behavior of patients with type 2 diabetes attending the Emergency
Department at Hamad General Hospital, Qatar Medical Journal,
emphasis during education. Also, their attitudes towards
2011; 20(1):1-8. Available from: http://www.qscience.com/doi/
seriousness of diabetes differ which may be attributable to pdf/10.5339/qmj.2011.1.6
other factors such as educational attainment. Further study 13. Shakibasadeh E. Larijani B. Shojaeezadeh D. Rashidian A.
on the effect of diabetes education on the behavior and Forouzanfar MH. Bartholomew LK. Patients’ Perspectives on
glucose control would be valuable. Factos that Influence Diabetes Self-Care. Iran Journal of Public
Health, December 2011: 40(4): 146-158. Available from: https://
www.ncbi.nlm.nih.gov/pmc/articles/PMC3481743/
References
1. WHO. Diabetes Fact Sheet [Internet]. Geneva: World Health
Organization. 2017. Available from: http://www.who.int/
mediacentre/factsheets/fs312/en/
2. World Health Organization [Internet] Diabetes Country Profiles
- 2016 [cited 2016] Available from: http://www.who.int/diabetes/
country-profiles/phl_en.pdf?ua=1
3. Cefalu WT, Bakris G, Blonde L. et al. American Diabetes
Association – Standards of Medical Care in Diabetes - 2017,
Diabetes Care. 2017:40(Suppl 1): S4-5. American Diabetes
Association. Promoting health and reducing disparities in
populations. Diabetes Care. 2017; 40 (Suppl 1): S6-10.
Available from: http://care.diabetesjournals.org/content/diacare/
suppl/2016/12/15/40.Supplement_1.DC1/DC_40_S1_final.pdf
4. Ku GM, Kegels G. Effects of the First Line Diabetes Care
(FiLDCare) self-management education and support project on
knowledge, attitudes, perceptions, self-management practices
and glycaemic control: a quasi-experimental study conducted in
the Northern Philippines. BMJ open. 2014 Aug 1;:4, (8):e005317.
Available from: http://bmjopen.bmj.com/content/4/8/e005317.
5. Trajano-Acampado L, Isip-Tan IT, Jimeno CA, Verastigue-
Custodio MC. A survey of diabetes knowledge among type
2 diabetes at UP-PGH using the Filipino version of American
Association of Clinical Endocrinology (AACE) knowledge
evaluation form. Philippine Journal of Internal Medicine 2006;
44 (5):;225-230.
6. Yao CS, Jimeno C, Trajano-Acampado L. A survey of Diabetes-
related attitudes among Patients at the UP-PGH out-patient
department using the Filipino version of Diabetes Attitude Scale
3 (DAS-3), Philippine Journal of Internal Medicine 2004;42:261-
274.
7. Tuomilehto J, Lindström J, Eriksson J, Valle T. et al. Prevention of
type 2 diabetes mellitus by changes in lifestyle among subjects with
impaired glucose tolerance. The New England Journal of Medicine
2001 May 3;344(18):1343-50. Available from: http://www.nejm.

6 Volume 55 Number 4 Oct.-Dec., 2017

The Effect of a Single-Session Diabetes Education Cornel MU, et al.

Tables
Table I. Baseline characteristics of type 2 diabetic patients (n=75)

Education Patients Non-Education Patients

(n=38) (n=37) p-value
Mean ± SD; Frequency (%)
Age (years) 53.79 ± 10.11 58.35 ± 10.86
18–30 1 (2.63) 1 (2.7) 0.064‡
31–60 27 (71.05) 18 (48.65) 0.087§
Older than 60 10 (26.32) 18 (48.65)
Sex
Male 7 (18.42) 15 (40.54) 0.035¶
Female 31 (81.58) 22 (59.46)
Marital status
Single 1 (2.63) 3 (8.11) 0.501§
Married 32 (84.21) 28 (75.68)
Separated or widowed 5 (13.16) 6 (16.22)
Educational attainment
Elementary 3 (7.89) 5 (13.51)
High school 9 (23.68) 10 (27.03) 0.740§
College 22 (57.89) 20 (54.05)
None 4 (10.53) 2 (5.41)
Weight (kg) 66.5 ± 16.09 68.26 ± 14.71 0.623‡
Height (cm) 155.84 ± 9.48 158.2 ± 9.76 0.291‡
BMI (kg/m ) 2
27.98 ± 5.92 27.26 ± 3.75
Normal 6 (15.79) 3 (8.11) 0.536‡
Overweight 6 (15.79) 10 (27.03) 0.338§
Obese 26 (68.42) 24 (64.86)
Waist circumference (cm) 95.34 ± 10.64 95.77 ± 12.87 0.891‡
Hip circumference (cm) 100.62 ± 11.12 101.89 ± 10.37 0.610‡
Waist-hip ratio 0.96 (0.81–1.1) 0.94 (0.76–1.2) 0.147†
Therapeutic regimen
Diet only 0 0
Oral antihyperglycemic agents 21 (55.26) 27 (72.97) 0.269§
Insulin 5 (13.16) 3 (8.11)
Both 12 (31.58) 7 (18.92)
Duration of diabetes
< 1 year 7 (18.42) 2 (5.41) 0.153§
> 1 year 31 (82.58) 35 (94.59)
Type of clinic attended
Private 23 (60.53) 33 (89.19) 0.004¶
Charity 15 (39.47) 4 (10.81)
Statistical methods: †Mann-Whitney U test; ‡independent sample T test; §Fisher’s exact test; ¶chi square test.

Table II. Comparison of the baseline characteristics between the education and non-education groups at different follow-up periods (n=75)
Education Patients Non-education Patients
(n=38) (n=37) p-value
Mean ± SD; Frequency (%); Median (Range)
Age (years)
At 3 months follow-up (n = 10) 53.63 ± 11.33 51.5 ± 0.71 .897‡
At 4 months follow-up (n = 14) 49.11 ± 4.65 61.8 ± 8.67 0.004‡
At 5 months follow-up (n = 19) 55.5 ± 8.82 59.22 ± 9.87 0.397‡
At 6 months follow-up (n = 32) 56.91 ± 12.91 57.81 ± 12.25 0.848‡

Volume 55 Number 4 Oct.-Dec., 2017 7

Cornel MU, et al. The Effect of a Single-Session Diabetes Education

Table II. Comparison of the baseline characteristics between the education and non-education groups at different follow-up periods (n=75)
Education Patients Non-education Patients
(n=38) (n=37) p-value
Mean ± SD; Frequency (%); Median (Range)
Sex
At 3 months follow-up [n=8] [n=2] .133§
Male 2 (25) 2 (100)
Female 6 (75) 0
At 4 months follow-up [n=9] [n=5] .258§
Male 3 (33.3) 0
Female 6 (66.7) 5 (100)
At 5 months follow-up [n=10] [n=9] .033§
Male 0 4 (44.4)
Female 10 (100) 5 (55.6)
At 6 months follow-up [n=11] [n=21] .248§
Male 2 (18.2) 9 (42.9)
Female 9 (81.8) 12 (57.1)
Marital status
At 3 months follow-up [n=8] [n=2] 1.000§
Single 0 0
Married 7 (87.5) 2 (100)
Separated or widowed 1 (12.5) 0
At 4 months follow-up [n=9] [n=5] .027§
Single 0 2 (40)
Married 9 (100) 2 (40)
Separated or widowed 0 1 (20)
At 5 months follow-up [n=10] [n=9] .334§
Single 1 (10) 0
Married 7 (70) 9 (100)
Separated or widowed 2 (20) 0
At 6 months follow-up [n=11] [n=21] 1.000§
Single 0 1 (4.8)
Married 9 (81.8) 15 (71.4)
Separated or widowed 2 (18.2) 5 (23.8)
Educational attainment
At 3 months follow-up [n=8] [n=2] .289§
Elementary 0 0
High school 2 (25) 2 (100)
College 4 (50) 0
None 2 (25) 0
At 4 months follow-up [n=9] [n=5] 1.000§
Elementary 0 0
High school 2 (22.2) 2 (40)
College 6 (66.7) 3 (60)
None 1 (11.1) 0
At 5 months follow-up [n=10] [n=9] .902§
Elementary 2 (20) 2 (22.2)
High school 1 (10) 2 (22.2)
College 6 (60) 4 (44.4)
None 1 (10) 1 (11.1)
At 6 months follow-up [n=11] [n=21] .711§
Elementary 1 (9.09) 3 (14.3)
High school 4 (36.4) 4 (19.0)
College 6 (54.6) 13 (61.9)
None 0 1 (4.8)
BMI (kg/m2)
At 3 months follow-up 30.25 ± 7.04 28.35 ± 2.05 .726‡
At 4 months follow-up 28.92 ± 6.5 26.94 ± 3.59 .545‡
At 5 months follow-up 27.76 ± 6.0 28.57 ± 4.82 .752‡
At 6 months follow-up 25.75 ± 4.26 26.68 ± 3.46 .510‡
Waist circumference (cm)
At 3 months follow-up 96.88 ± 8.22 111.0 ± 12.73 .080‡
At 4 months follow-up 99.56 ± 13.21 102.8 ± 14.65 .679‡
At 5 months follow-up 94.1 ±± 11.30 94.56 ± 13.36 .937‡
At 6 months follow-up 92.09 ± 9.29 93.17 ± 11.51 .791‡

8 Volume 55 Number 4 Oct.-Dec., 2017

The Effect of a Single-Session Diabetes Education Cornel MU, et al.

Table II. Comparison of the baseline characteristics between the education and non-education groups at different follow-up periods (n=75)
Education Patients Non-education Patients
(n=38) (n=37) p-value
Mean ± SD; Frequency (%); Median (Range)
Hip circumference (cm)
At 3 months follow-up 101.56 ± 8.3 113 ± 4.24 .105‡
At 4 months follow-up 103.11 ± 13.36 102.4 ± 12.6 .924‡
At 5 months follow-up 99.5 ± 13.78 101 ± 13.20 .812‡
At 6 months follow-up 98.91 ± 9.22 101.10 ± 8.82 .517‡
Waist-hip ratio
At 3 months follow-up 0.96 ± 0.03 0.98 ± 0.07 .445‡
At 4 months follow-up 0.97 ± 0.06 1.002 ± 0.12 .549‡
At 5 months follow-up 0.95 ± 0.08 0.94 ± 0.05 .626‡
At 6 months follow-up 0.93 ± 0.07 0.92 ± 0.06 .552‡
Therapeutic regimen
At 3 months follow-up [n=8] [n=2] .600§
Oral antihyperglycemic agents 4 (50) 2 (100)
Insulin 3 (37.5) 0
Both 1 (12.5) 0
At 4 months follow-up [n=9] [n=5] .670§
Oral antihyperglycemic agents 6 (66.7) 5 (100)
Insulin 1 (11.1) 0
Both 2 (22.2) 0
At 5 months follow-up [n=10] [n=9] 1.000§
Oral antihyperglycemic agents 4 (40) 4 (44.4)
Insulin 1 (10) 1 (11.1)
Both 5 (50) 4 (44.4)
At 6 months follow-up [n=11] [n=21] .353§
Oral antihyperglycemic agents 7 (63.6) 16 (76.2)
Insulin 0 2 (9.5)
Both 4 (36.4) 3 (14.3)

Duration of diabetes
At 3 months follow-up [n=8] [n=2] 1.000§
< 1 year 1 (12.5) 0
> 1 year 7 (87.5) 2 (100)
At 4 months follow-up [n=9] [n=5] .221§
< 1 year 4 (44.4) 0
> 1 year 5 (55.6) 5 (100)
At 5 months follow-up [n=10] [n=9] 1.000§
< 1 year 1 (10) 1 (11.1)
> 1 year 9 (90) 8 (88.9)
At 6 months follow-up [n=11] [n=21] 1.000§
< 1 year 1 (9.1) 1 (4.8)
> 1 year 10 (90.9) 20 (95.2)
Type of clinic attended
At 3 months follow-up [n=8] [n=2] 1.000§
Private 5 (62.5) 1 (50)
Charity 3 (37.5) 1 (50)
At 4 months follow-up [n=9] [n=5] 1.000§
Private 6 (66.7) 4 (80)
Charity 3 (33.3) 1 (20)
At 5 months follow-up [n=10] [n=9] .303§
Private 6 (60) 8 (88.9)
Charity 4 (40) 1 (11.1)
At 6 months follow-up [n=11] [n=21] .011§
Private 6 (54.6) 20 (95.2)
Charity 5 (45.4) 1 (4.8)
Statistical methods: ‡independent sample T test; §Fisher’s exact test;

Volume 55 Number 4 Oct.-Dec., 2017 9

Cornel MU, et al. The Effect of a Single-Session Diabetes Education

Table III. Comparison of mean percentage scores in knowledge of patients in the education and non-education groups (n=75).

Education Patients Non-Education Patients (n=37)

(n=38) p-value
Mean ± SD
Knowledge score* (%)
Baseline 67.02 ± 16.98 63.6 ± 18.5 0.408§
Follow-up 86.67 ± 12.01 55.68 ± 18.07 <0.001§
P-value (baseline < follow up) <0.001‡ 0.973‡
Statistical tests used: §Independent sample T-test; ‡Paired sample T-test
* covers 15 items in all

Table IV. Itemized comparison of correct answers for the knowledge questionnaire between the education and non-education groups (n=75)
Education Patients Non-Education
(n=38) Patients (n=37) p-value
Frequency (%)
What is Diabetes
K1 - In type 2 diabetes, the body cannot use insulin well.
Baseline 23 (60.53) 20 (54.05) <0.001‡
Follow-up 35 (92.11) 11 (29.73) 0.044‡
P value 0.003 0.0495
K2 - Insulin helps the body turn sugar into energy.
Baseline 17 (44.74) 9 (24.32) 0.063‡
Follow-up 28 (73.68) 14 (37.84) 0.002‡
P value 0.005 0.166
K3 - Weakness, sweating, and shakiness are symptoms of hypoglycemia.
Baseline 20 (52.63) 18 (48.65) 0.730‡
Follow-up 33 (86.84) 11 (29.73) <0.001‡
P value 0.0003 0.090
Exercise
K4 - Patients who need insulin should inject it into the thigh muscle before
running.
0.077‡
Baseline 28 (73.68) 20 (54.05)
0.035‡
Follow-up 31 (81.58) 22 (59.46)
P value 0.366 0.617
K5 - If blood glucose is more than 300 mg/dL, insulin should be adjusted or
exercise should be delayed.
0.414‡
Baseline 27 (71.05) 23 (62.16)
0.300‡
Follow-up 25 (65.79) 20 (54.05)
P value 0.617 0.467
Blood glucose monitoring
K6 - Self-monitoring of blood glucose is (...)*
Baseline 17 (44.74) 19 (51.35) 0.566‡
Follow-up 30 (78.95) 10 (27.03) <0.001‡
P value† 0.003 0.039
K7- Monitoring should be done more often (...)**
Baseline 22 (57.89) 22 (59.46) 0.891‡
Follow-up 29 (76.32) 12 (32.43) <0.001‡
P value† 0.090 0.033
Medications
K8 - The preferred site for an insulin injection is the abdomen.
Baseline 28 (73.68) 19 (51.35) 0.046‡
Follow-up 37 (97.37) 20 (54.05) <0.001‡
P value† 0.003 0.763
K9 - Insulin should not always be injected in the same site.
Baseline 26 (68.42) 28 (75.68) 0.484‡
Follow-up 36 (94.74) 22 (59.46) <0.001‡
P value† 0.008 0.058

10 Volume 55 Number 4 Oct.-Dec., 2017

The Effect of a Single-Session Diabetes Education Cornel MU, et al.

Table IV. Itemized comparison of correct answers for the knowledge questionnaire between the education and non-education groups (n=75)
Education Patients Non-Education
(n=38) Patients (n=37) p-value
Frequency (%)
K10 - During illness, you should not stop taking your medications.
Baseline 33 (86.84) 35 (94.59) 0.430§
Follow-up 34 (89.47) 28 (75.68) 0.115‡
P value† 0.739 0.035
Nutrition
K11 - In overweight patients with diabetes, losing weight may (...)***
Baseline 20 (52.63) 17 (45.95) 0.563‡
Follow-up 30 (78.95) 10 (27.03) <0.001‡
P value† 0.008 0.071
K12 - Cheddar cheese is high in fat.
Baseline 31 (81.58) 30 (81.08)
0.956‡
Follow-up 38 (100) 34 (91.89)
0.115§
P value† 0.008 0.103
K13 - Cholesterol is the fatty substance in food linked to heart disease.
Baseline 34 (89.47) 33 (89.19) 1.000§
Follow-up 38 (100) 34 (91.89) 0.115§
P value† 0.046 0.655
K14 - To decrease dietary fat and cholesterol, broiled chicken without skin
is the best choice.
0.736§
Baseline 32 (84.21) 33 (89.19)
0.711§
Follow-up 35 (92.11) 33 (89.19)
P value† 0.317 1.000
K15 - Soluble fiber may help lower blood glucose.
Baseline 24 (63.16) 27 (72.97) 0.362‡
Follow-up 35 (92.11) 28 (75.68) 0.052‡
P value† 0.002 0.763
Statistical methods: †McNemar’s test; ‡Chi square test; §Fisher’s exact test.
All were correct statements: *essential for intensive therapy, the key to determining the right amount of medication, and useful even if diabetes is controlled with diet and
exercise; **on sick days, when traveling, and when meal or exercise plans change; ***help the body use insulin better, lower blood glucose, and decrease the risk of heart
disease.

Table V. Comparison of knowledge scores between the education and non-education group at different follow-up intervals (n=75)

3 months follow-up 4 months follow-up 5 months follow-up 6 months follow-up

(n=10) (n=14) (n=19) (n=32) p-value
Mean ± SD; Median (Range)
Knowledge score* (%)
Education
Pre-test 78.3 ± 15.8 57.8 ± 17.0 70.7 ± 13.8 63.03 ± 16.7 0.056§
Post-test 85 ± 16.6 84.45 ± 11.1 86.7 ± 11.8 89.7 ± 10.1 0.777§
Non-Education
Pre-test 83.3 ± 4.7 52 ± 20.2 57.04 ± 17.4 67.3 ± 17.5 0.096§
Post-test 66.67 ± 18.6 45.3 ±11.1 60.7 ± 17.5 54.9 ± 18.2 0.386§
Statistical methods: §Oneway ANOVA; †Kruskal wallis test
*Covers 15 items in all

Table VI. Comparison of the median scores and range of scores of attitude between the education and non-education groups at baseline and
on follow-up (n=75).
Education Patients Non-education
(n=38) (n=37) p-value
Median (Range)
Attitude Category
Need for special training
Baseline 1.5 (1 to 4) 2 (1 to 3) 0.412‡
Follow-up 1 (1 to 2) 2 (1 to 3) <0.001‡
P-value 0.169† 0.481†

Volume 55 Number 4 Oct.-Dec., 2017 11

Cornel MU, et al. The Effect of a Single-Session Diabetes Education

Table VI. Comparison of the median scores and range of scores of attitude between the education and non-education groups at baseline and
on follow-up (n=75).
Education Patients Non-education
(n=38) (n=37) p-value
Median (Range)
Seriousness of DM
Baseline 2.5 (1 to 5) 3 (1 to 4) 0.167‡
Follow-up 2 (1 to 4) 3 (1 to 4) 0.271‡
P-value 0.076† 0.327†
Psychosocial impact of DM
Baseline 2 (1 to 4) 2 (1 to 4) 0.299‡
Follow-up 2 (1 to 3) 2 (1 to 4) 0.086‡
P-value 0.678† 0.815†
Patient autonomy
Baseline 1 (1 to 3) 2 (1 to 3) 0.127‡
Follow-up 1 (1 to 2) 2 (1 to 3) 0.005‡
P-value 1.000† 0.238†
Statistical methods: ‡Mann-Whitney U test; †Wilcoxon Signed rank test

Table VII. Itemized comparison of answers for the attitude questionnaire between the education and non-education groups (n=75)
Education Patients Non-Education
(n=38) Patients (n=37) p-value
Median (Range)
Need for special training
A1 - Health care professionals who treat people with diabetes should be trained to
communicate well with their patients.
0.226*
Baseline 1 (1–4) 1 (1–3)
0.003*
Follow-up 1 (1–2) 2 (1–3)
P value† 0.481 0.648
A2 - Health care professionals should be taught how daily diabetes care affects
patients’ lives.
0.257*
Baseline 1 (1–4) 2 (1–4)
<0.001*
Follow-up 1 (1–2) 2 (1–4)
P value† 0.210 0.664
Seriousness of Type 2 diabetes
A3 - Type 2 is as serious as Type 1 diabetes.
Baseline 2 (1–5) 3 (1–5) 0.037*
Follow-up 2 (1–4) 2 (1–5) 0.205*
P value† 0.424 0.122
A4 - Type 2 diabetes is a very serious disease.
Baseline 2 (1–5) 2 (1–4) 0.955*
Follow-up 2 (1–4) 2 (1–4) 0.114*
P value† 0.019 1.000
Value of tight glucose control
A5 - There is not much use in trying to have good blood sugar control because the
complications of diabetes will happen anyway.
0.726*
Baseline 4 (1–5) 3 (1–5)
0.001*
Follow-up 4 (1–5) 3 (1–5)
P value† 0.036 0.690
A8 - Almost everyone with diabetes should do whatever it takes to keep their blood
sugar close to normal.
0.096*
Baseline 1 (1–4) 2 (1–5)
0.001*
Follow-up 1 (1–2) 2 (1–3)
P value† 0.481 0.503
Psychosocial impact of diabetes
A6 - Diabetes affects almost every part of a diabetic person’s life.
Baseline 1 (1–4) 2 (1–4) 0.073*
Follow-up 2 (1–4) 2 (1–4) 0.027*
P value† 0.832 0.481

12 Volume 55 Number 4 Oct.-Dec., 2017

The Effect of a Single-Session Diabetes Education Cornel MU, et al.

Table VII. Itemized comparison of answers for the attitude questionnaire between the education and non-education groups (n=75)
Education Patients Non-Education
(n=38) Patients (n=37) p-value
Median (Range)
A9 - Having diabetes changes a person’s outlook on life.
Baseline 2 (1–4) 2 (1–5) 0.248*
Follow-up 1 (1–4) 2 (1–5) 0.022*
P value† 0.043 0.167
Patient autonomy
A7 - The important decisions regarding daily diabetes care should be made by the
person with diabetes.
0.150*
Baseline 1 (1–3) 2 (1–5)
0.013*
Follow-up 1 (1–2) 2 (1–3)
P value† 1.000 0.332
A10. - To do a good job, diabetes educators should learn a lot about being teacher.
Baseline
0.073*
Follow-up 1 (1–2) 2 (1–5)
0.001*
P value† 1 (1–2) 2 (1–3)
0.180 0.815
Statistical methods: *Mann-Whitney U test; †Wilcoxon Signed rank test.
Scoring for attitude subscales (except item A5 with reverse scoring): 1, strongly disagree; 2, disagree; 3, neutral; 4, agree; 5, strongly agree.

Table VIII. Comparison of scores in attitude between the education and non-education groups at different follow-up intervals (n=75)
3 months follow-up 4 months follow-up 5 months follow-up 6 months follow-up
(n=10) (n=14) (n=19) (n=32) p-value
Mean ± SD; Median (Range)
Attitude score** (average per subscale)
Need for special training (A1–2)
Education
Pre-test 1.25 (1–3) 1.5 (1-3.5) 1.5 (1-2) 1 (1-2) 0.665†
Post-test 1.25 (1-2) 1 (1-2) 1 (1-2) 1 (1-2) 0.245†
Non-Education
Pre-test 1.25 (1-1.5) 2 (1.5-2) 1 (1-2) 2 (1-3) 0.144†
Post-test 1.25 (1-1.5) 1.5 (1-2) 2 (1-2.5) 2 (1-2.5) 0.329†
Seriousness of Type 2 diabetes (A3–4)
Education
Pre-test 2.5 (2-4) 2 (1-3.5) 2 (1.5-5) 2.5 (1-4) 0.787†
Post-test 3 (2-4) 1 (1-2.5) 1.25 (1-4) 2 (1-4) 0.030†
Non-Education
Pre-test 2 (1-3) 3 (1-3) 2 (1-3.5) 3 (1-4) 0.247†
Post-test 1.5 (1-2) 3 (2-3.5) 3 (2-4) 2.5 (1-4) 0.097†
Value of tight glucose control (A5, 8)
Education
Pre-test 2.75 (2-3) 2 (1-3) 2.5 (1-3) 2 (1-3) 0.120†
Post-test 2.5 (1.5-3) 2.5 (1-3) 3 (2.5-3.5) 2.5 (2-3) 0.367†
Non-Education
Pre-test 2 (1.5-2.5) 2 (1.5-3) 2.5 (1-3) 3 (1.5-5) 0.211†
Post-test 2 3 (1-3) 3 (1.5-3) 2.5 (1.5-3) 0.408†
Psychosocial impact of diabetes (A6, 9)
Education
Pre-test 2 (1-3) 2 (1-2.5) 2 (1-3.5) 1.5 (1-2.5) 0.350†
Post-test 2 (1-3) 1.5 (1-2.5) 1.5 (1-2.5) 1.5 (1-3) 0.224†
Non-Education
Pre-test 1.25 (1-1.5) 2 (2-3) 2 (1-3.5) 2 (1-3) 0.123†
Post-test 1.75 (1.5-2) 2 (1-3) 2 (1-3) 2 (1-3.5) 0.668†
Patient autonomy (A7, 10)
Education
Pre-test 1.5 (1-2) 1.5 (1-2) 1 (1-2.5) 1 (1-2) 0.395†
Post-test 1.25 (1-2) 1 (1-2) 1 (1-1.5) 1 (1-2) 0.409†
Non-Education
Pre-test 1.5 (1-2) 2 (1-2) 2 (1-3) 2 (1-3) 0.994†
Post-test 1.75 (1.5-2) 1 (1-2.5) 1.5 (1-2) 2 (1-2.5) 0.662†

Volume 55 Number 4 Oct.-Dec., 2017 13

Cornel MU, et al. The Effect of a Single-Session Diabetes Education

Table VIII. Comparison of scores in attitude between the education and non-education groups at different follow-up intervals (n=75)
3 months follow-up 4 months follow-up 5 months follow-up 6 months follow-up
(n=10) (n=14) (n=19) (n=32) p-value
Mean ± SD; Median (Range)
Statistical methods: §Oneway ANOVA; †Kruskal wallis test
**Covers 10 items. Scoring for attitude subscales (except for item A5 with reverse scoring): 1, strongly disagree; 2, disagree; 3, neutral; 4, agree; 5, strongly agree.

Table IX. Comparison of knowledge scores between the private and charity patients (n=75)

PRIVATE CHARITY
Education Non-Education Education Non-Education
Patients (n=23) Patients (n=33) P-value Patients (n=15) Patients (n=4) p-value
Mean ± SD; Median (Range) Mean ± SD; Median (Range)
Knowledge score* (%)
Pre-test 67.54 ± 18.2 65.05 ± 17.88 0.614§ 66.22 ± 15.42 51.67 ± 22.03 0.142§
Post-test 88.41 ± 12.59 55.56 ± 19.12 <0.0001§ 84.0 ± 10.92 56.67 ± 3.85 0.0002§
Statistical methods ‡ Mann-Whitney U test; §independent sample T test
*Covers 15 items in all.

Table X. Comparison of knowledge scores between male and female patients (n=75)

MALE FEMALE
Education Non-Education Education Non-Education
Patients (n=7) Patients (n=15) P-value Patients (n=31) Patients (n=22) p-value
Mean ± SD; Median (Range) Mean ± SD; Median (Range)
Knowledge score* (%)
Pre-test 66.7 ± 16.3 69.33 ± 14.8 0.708§ 67.1 ± 17.4 59.7 ± 20.0 0.157§
Post-test 89.5 ± 19.6 52.0 ± 15.4 <0.0001§ 86.0 ± 9.9 58.2 ± 19.6 <0.0001§
Statistical methods: ‡ Mann-Whitney U test; §independent sample T test
*Covers 15 items in all.

Table XI. Comparison of attitude scores between the private and charity patients (n=75)
PRIVATE CHARITY
Education Non-Education Education Non-Education
Patients (n=23) Patients (n=33) P-value Patients (n=15) Patients (n=4) p-value
Mean ± SD; Median (Range) Mean ± SD; Median (Range)
Attitude score** (average per subscale)
Need for special training (A1–2)
Pre-test 1 (1-3.5) 2 (1-2.5) 0.108‡ 1.5 (1-3) 1.25 (1-3) 0.958‡
Post-test 1 (1-2) 1.5 (1-2) 0.001‡ 1 (1-2) 2 (1-2.5) 0.074‡
Seriousness of Type 2 diabetes (A3–4)
Pre-test 2 (1-5) 3 (1-4) 0.072‡ 2.5 (1-4) 2 (1-3.5) 0.611‡
Post-test 2 (1-4) 2.5 (1-4) 0.152‡ 2.5 (1-4) 3 (1-3) 0.331‡
Value of tight glucose control (A5, 8)
Pre-test 2.5 (1-3) 2.5 (1-5) 0.438‡ 2.5 (1-3) 1.75 (1.5-2.5) 0.353‡
Post-test 2.5 (2-3) 2.5 (2-3) 0.264‡ 2.5 (1-3.5) 1.5 (1-2) 0.014‡
Psychosocial impact of diabetes (A6, 9)
Pre-test 1.5 (1-3.5) 2 (1-3) 0.077‡ 2 (1-3) 2.25 (1-3.5) 0.508‡
Post-test 1.5 (1-3) 2 (1-3.5) 0.014‡ 1.5 (1-3) 1.5 (1-3) 0.754‡
Patient autonomy (A7, 10)
Pre-test 1 (1-.5) 2 (1-3) 0.212‡ 1 (1-2) 1.25 (1-3) 0.486‡
Post-test 1 (1-2) 2 (1-2.5) 0.001‡ 1 (1-2) 1 (1-1.5) 0.394‡
Statistical methods: ‡ Mann-Whitney U test; §independent sample T test
*Covers 15 items in all.
**Covers 10 items. Scoring for attitude subscales (except for item A5 with reverse scoring): 1, strongly disagree; 2, disagree; 3, neutral; 4, agree; 5, strongly agree.

14 Volume 55 Number 4 Oct.-Dec., 2017

 The Effect of a Single-Session Diabetes Education Cornel MU, et al.

Table XII. Comparison of attitude scores between male and female diabetic patients (n=56)

MALE FEMALE
Education Non-Education Education Non-Education
Patients (n=7) Patients (n=33) p-value Patients(n=31) Patients (n=22) p-value
Mean ± SD; Median (Range) Mean ± SD; Median (Range)
Attitude score** (average per subscale)
Need for special training (A1–2)
Pre-test 1 (1-2) 1 (1-2.5) 0.830‡ 1.5 (1-3.5) 2 (1-3) 0.022‡
Post-test 1 (1-1.5) 2 (1-2) 0.003‡ 1 (1-2) 2 (1-2.5) 0.005‡
Seriousness of Type 2 diabetes (A3–4)
Pre-test 2 (1-3) 2.5 (1-3.5) 0.188‡ 2.5 (1-5) 3 (1-4) 0.162‡
Post-test 1 (1-3.5) 2 (1-4) 0.116‡ 2 (1-4) 2.5 (1-4) 0.217‡
Value of tight glucose control (A5, 8)
Pre-test 2 (1-3) 2.5 (1-3.5) 0.587‡ 2.5 (1-3) 2.5 (1.5-5) 0.508‡
Post-test 2.5 (2-3) 2 (2-3) 0.069‡ 2.5 (1-3.5) 2.5 (1-3) 0.433‡
Psychosocial impact of diabetes (A6, 9)
Pre-test 1.5 (1-2) 1.5 (1-3) 0.575‡ 2 (1-3.5) 2 (1-3.5) 0.028‡
Post-test 1.5 (1-2) 2 (1-.35) 0.016‡ 1.5 (1-3) 2 (1-3) 0.089‡
Patient autonomy (A7, 10)
Pre-test 1 (1-2) 1 (1-2) 0.903‡ 1 (1-2.5) 2 (1-3) 0.013‡
Post-test 1 (1-2) 2 (1-2.5) 0.022‡ 1 (1-2) 1.5 (1-2.5) 0.037‡
Statistical methods ‡ Mann-Whitney U test; §independent sample T test
**Covers 10 items. Scoring for attitude subscales (except for item A5 with reverse scoring): 1, strongly disagree; 2, disagree; 3, neutral; 4, agree; 5, strongly agree.

APPENDICES
Appendix A. Knowledge Questionnaire: Modified, Validated AACE Knowledge Evaluation Form (Filipino Version)

1. Sa Type 2 diabetes, ang katawan ng tao ay: b. kung nagbibyahe

a. Hindi nakakagamit ng insulin ng mabuti c. kung nagbago ng plano sa pagkain at ehersisyo
b. walang anumang insulin na ginagawa d. sa lahat ng nakasaad sa itaas
c. nire-reject ang insulin
d. winawasak ang insulin 8. Ang pinakamainam na bahagi ng katawan para sa iniksyon ng
insulin ay ang:
2. Tinutulungan ng insulin ang katawan ng tao upang: a. Tiyan
a. gawing enerhiya ang asukal b. Balakang
b. alisin ang asukal c. Pigi
c. panatilihin ang asukal sa dugo d. lahat ng nakasaad sa itaas
d. gumawa ng red blood cell
9. Ang insulin ay dapat na iniiniksyon sa iisang lugar lamang:
3. Alin sa mga sumusunod ang sintomas ng hypoglycemia? a. Tama
a. Panghihina b. Mali
b. Pagpapawis 10. Habang may sakit, dapat itigil ang paggamit ng gamot.
c. Panginginig a. Tama
d. lahat ng nakasaad sa itaas b. Mali

4. Ang mga pasyenteng kailangan ng insulin ay dapat na iniksyonan 11. Sa mga pasyente ng diabetes na sobra sa timbang, ang magpa-
sa hita bago sila tumakbo. payat ay:
a. Tama a. makatutulong upang gumanang mabuti ang insulin sa
b. Mali katawan
b. makakapagpababa ng blood glucose
5. Kung ang blood glucose ay higit sa 300 mg/dL, kailangang i-adjust c. makakabawas sa peligro na sakit sa puso
ang insulin o iliban ang pag-eehersisyo d. nagbubunga ng lahat ng nakasaad sa itaas
a. Tama
b. Mali 12. Alin sa mga sumusunod na pagkain ang mataas sa taba?
a. Mansanas
6. Ang pansariling pagmonitor ng blood glucose ay: b. Letsugas
a. napakahalaga para sa masidhing/ intensibong panggaga- c. kesong cheddar
mot. d. oatmeal
b. susi upang malaman ang tamang dami ng gamot
c. magagamit kahit na ang diabetes ay nakokontrol ng dyeta 13. Ang mga pagkaing mayaman sa taba na nauugnay sa sakit sa
o ehersisyo puso ay:
d. lahat ng nakasaad sa itaas a. mga karbohaydreyt
b. protina
7. Ang pagmomonitor ay dapat gawin nang mas madalas: c. kolesterol
a. sa mga araw na may sakit d. fiber/hibla

Volume 55 Number 4 Oct.-Dec., 2017 15

 Cornel MU, et al. The Effect of a Single-Session Diabetes Education

14. Upang mabawasan ang mga taba at kolesterol, aling pagkain 15. Alin sa mga sumusunod ang nakakatulong makapagpababa ng
ang pinakamainam piliin? blood glucose?
a. Bistik a. taba/fat
b. pritong itlog b. protina
c. inihaw na manok na walang balat c. soluble fiber
d. tinapay na may palamang keso at ham d. lahat ng nakasaad sa itaas
Appendix B Knowledge Questionnaire: Modified, Validated AACE Knowledge Evaluation Form (English Version)

Encircle the correct answer:

1. In type 2 diabetes, the body : 9. Insulin should always be injected in the same site.
a. Cannot use insulin well a. true
b. Makes no insulin at all b. false
c. Reject insulin
d. Destroys insulin 10. During illness, you should stop taking your medications.
a. true
2. Insulin helps the body b. false
a. turn sugar into energy
b. get rid of sugar 11. In overweight patients with diabetes, losing weight may
c. store sugar in the blood a. help the body use insulin better
d. make red blood cells b. lower blood glucose
c. decrease the risk of heart disease
3. Which of the following is a symptom of hypoglycemia? d. do all of the above
a. weakness
b. sweating 12. Which of the following foods is high in fat?
c. shakiness a. apples
d. all of the above b. lettuce
c. cheddar cheese
4. Patients who need insulin should inject it into the thigh muscle d. oatmeal
before running.
a. true 13. The fatty substance in food linked to heart disease is
b. false a. carbohydrates
b. protein
5. If blood glucose is more than 300 mg/dL, insulin should be ad- c. cholesterol
justed or exercise should be delayed. d. fiber
a. true
b. false 14. To decrease dietary fat and cholesterol, which food is the best
choice?
6. Self-monitoring of blood glucose is a. steak
a. essential for intensive therapy b. fried eggs
b. the key to determining the right amount of medication c. broiled chicken without skin
c. useful even if diabetes is controlled with diet and exercise d. ham and cheese sandwich
d. all of the above
15. Which of the following may help lower blood glucose?
7. Monitoring should be done more often a. fat
a. on sick days b. protein
b. when traveling c. soluble fiber
c. when meal or exercise plans change d. all of the above
d. at all of the above times

8. The preferred site for an insulin injection is

a. the abdomen
b. the hips
c. the buttocks
d. all of the above

Appendix C: Attitude Questionnaire: Modified, Validated Translated Diabetes Attitude Scale 3 (DAS–3) (Filipino Version)

Piliin lamang sa pamamagitan ng pagbiolog ang mga kasagutang sa tingin ninyo ay pinakamalapit sa inyong pananaw tungkol sa bawat
pangungusap. Wala pong tama o malig kasagutan. Mahalagang sagutin ang lahat ng katanungan
Lubos na Walang Hindi
Sumasang- Lubos na hindi
Sa pangkalahatan, ako ay naniniwala na: sumasang- kinikilin- sumasang-
ayon sumasang-ayon
ayon gan ayon
1…ang mga doktor, nurses at dietitian ay kailangan maturuan ng
wastong/tamang pamamaraan ng pakikipagusap sa pasyente
2…kailangang maturuan ang mga doktor, nurses at dietitian kung
paano nakakaapekto sa buhay ng isang may diabetes ang pang-
araw-araw na pangangalaga sa sarili

16 Volume 55 Number 4 Oct.-Dec., 2017

 The Effect of a Single-Session Diabetes Education Cornel MU, et al.

Lubos na Walang Hindi

Sumasang- Lubos na hindi
Sa pangkalahatan, ako ay naniniwala na: sumasang- kinikilin- sumasang-
ayon sumasang-ayon
ayon gan ayon
3... magkasinglubha ang type 1 diabetes at type 2 diabetes
4…isang napakalubhang sakit ang type 2 Diabetes
5…wala ring silbi kung pagsikapan ang mabuting pagkontrol ng
asukal sa dugo (blood sugar) dahil mangyayari din haman ang
mga komplikasyong dulot ng diabetes
6…nakakaapekto ang diabetes sa halos lahat ng bahagi ng buhay
ng isang pasyente
7…kailangang pagpasiyahan ng may diabetes ang mahahalagang
desisyon ukol sa pangaraw-araw na pangangalaga sa sarili
8...kailangang gawin ng isang may diabetes ang lahat upang
mapanatiling normal ang kanyang asukal sa dugo (blood sugar)
9…nakakapagpabago ng pananaw ng buhay ng isang tao ang
pagkakaroon ng diabetes
10…kailangang matutunan ng isang may diabetes ang lahat ng
nauukol sa saki upang lubos na mapangalagaan ang kanyang sarili

Appendix D: Attitude Questionnaire: Modified, Validated Translated Diabetes Attitude Scale 3 (DAS–3) (English Version)

Below are some statements about diabetes. Each numbered statement finishes the sentence “In general, l believe that._.” You may believe that
a statement is true for one person but not for another person or may be true one time but not be true another time. Mark the answer that you
believe is true most of the time or is true for most people. Place a check mark in the box below the word or phrase that is closest to your opinion
about each statement. It is important that you answer every statement. Note: The term “health care professionals” in this survey refers to doctors,
nurses, and dietitians.
In general, I believe that: 1 2 3 4 5
1. …health care professionals who treat people with diabetes should be trained to communicate
well with their patients.
2. … health care professionals should be taught how daily diabetes care affects patients’ lives.
3. Type 2 is as serious as Type 1 diabetes.
4. Type 2 diabetes is a very serious disease.
5. there is not much use in trying to have good blood sugar control because the complications of
diabetes will happen anyway.
6. diabetes affects almost every part of a diabetic person’s life.
7. the important decisions regarding daily diabetes care should be made by the person with diabetes.
8. almost everyone with diabetes should do whatever it takes to keep their blood sugar close to normal.
9. having diabetes changes a person’s outlook on life.
10. to do a good job, diabetes educators should learn a lot about being teachers

Scale Name Scale Equation Special Instruction

Need for Special Training 1,2
Seriousness of DM 3,4
Value of Tight Control 5,8 Reverse scores for Q5
Psychosocial Impact of DM 6,9
Patient Autonomy 7,10

SCORING: Strongly agree = 5, Agree = 4, Neutral = 3, Disagree = 2, Strongly Disagree = 1

MEAN SCORES: total scores/number of items answered

Volume 55 Number 4 Oct.-Dec., 2017 17

 Philippine Journal of Internal Medicine
The Incidence of In-Hospital Hypoglycemia and its Associated
Risk Factors Among Adult Filipino Patients with Diabetes
Mellitus in Chong Hua Hospital
Ma. Vircel Duyongco-Tiu, M.D.*; Imelda Lagula-Bilocura, M.D.**
Abstract
Introduction: Hypoglycemia is a burdensome complication
in the management of diabetes mellitus (DM), and has
been noted to be increasing. This study evaluated the
occurrence of hypoglycemia and identified its risk factors
among diabetic Filipino patients.
Methods: Census of Filipino non-pregnant adults with type 2
DM of Chong Hua Hospital, admitted and discharged from
January 2015 to June 2015 was taken. This study determined
the incidence rate of hypoglycemia (capillary blood glucose
<70 mg/dL), its severity, patients’ dietary status, medication,
and the common hospital areas where hypoglycemia
occurred. The clinical profiles of these patients were
analyzed and associated risk factors of hypoglycemia were
identified. Also, the incidence of congestive heart failure,
myocardial infarction, cerebrovascular disease, and all-
cause mortality among patients with hypoglycemia were
determined.
Results: Among 1,676 subjects, 8.9% had hypoglycemia
predominantly non-severe type (blood glucose 51-69
Introduction
Hypoglycemia is a dangerous complication in the
management of diabetes and precludes the achievement
of glycemic control. Its incidence has been noted to be
increasing and has added to the morbidity of the disease
with resultant increased medical expenses. Hypoglycemia is
defined as episodes of low plasma glucose concentrations,
enough to cause symptoms or signs1, and may expose the
individual to potential harm. According to the American
Diabetes Association (ADA), a blood serum glucose or
capillary glucose <70 mg/dl is determined as hypoglycemia.2
It has been noted that the incidence of hypoglycemia
is increasing. Among 1,718 adult patients admitted for
hyperglycemia or receiving insulin therapy, this adverse
*Fellow-in-training, Section of Endocrinology, Diabetes and Metabolism,
Department of Medicine, Chong Hua Hospital, Cebu City, Philippines
**Section Head, Section of Endocrinology, Diabetes and Metabolism,
Department of Medicine, Chong Hua Hospital, Cebu City, Philippines
Corresponding author: Vircel Duyongco-Tiu, M.D., Chong Hua
Hospital, Cebu City, Philippines
Email:vircel_du@yahoo.com
The PHILIPPINE JOURNAL OF INTERNAL MEDICINE is a peer reviewed journal and a copyrighted publication of the Philippine College of Physicians
Original Article
mg/dL). The identified risk factors for the development
of hypoglycemia were the following, age >65 years old
(52.7% vs 36.2%, p<0.001), diabetes duration of 8.56 years
(± 10.34 years), the presence of cardiovascular disease
(62.7% vs 48.6%, p<0.001), congestive heart failure (8.7% vs
4.4%, p=0.009) and stage III, IV, V kidney disease (32.7% vs
25.1%, p=0.043, 12% vs 5.5%, p=0.002, 12% vs 4.1%, p<0.001,
respectively), and the use of insulin whether combined
with oral therapy (25.3% vs 16.5%, p<0.006) or used alone
(34.7% vs 12.1%, p<0.001). Hypoglycemia occurred more
frequently in the non-ICU ward (82.7%). Only one patient
developed non-fatal myocardial infarction, one had non-
fatal cerebrovascular disease and one had congestive heart
failure. All-cause mortality rate was 4.7%
Conclusion: The notable incidence of in-hospital
hypoglycemia of 8.9% among diabetic patients should
be addressed to decrease the associated morbidity and
mortality.
Keywords: hypoglycemia, diabetes, diabetes mellitus
event occurred on 2.8% of all hospital days.3 In another study,
hypoglycemia events were observed in 7.7% of admissions in
a general ward.4 Point-of-care bedside glucose monitoring
in the hospitals in United States identified hypoglycemia
prevalence of 6.3% of patient-days for intensive care unit
(ICU) patients and 5.7% of patient-days for non-ICU patients.5
In fact, National Diabetes Inpatient Audit reported in 2012
that in England, 22.4% of inpatients experienced at least
one hypoglycemic episode. 6 An Asian study showed an
incidence of 1.29% among hospitalized Chinese diabetic
patients.7
Hypoglycemia can be classified as: mild, if with
autonomic symptoms and the patient can treat himself;
moderate, if with both autonomic and neuroglycopenic
symptoms but still patient can manage by himself; and
severe, if patient requires assistance from another person.8
The episodes of severe hypoglycemia are a small fraction
of the total hypoglycemia rate. The data from University
Hospital Consortium showed that the prevalence of severe
hypoglycemia ranged from three to 11%. 9 In unselected
populations, the annual prevalence of severe hypoglycemia
has been reported consistently at 30-40% in several
Volume 55 Number 4 Oct.-Dec., 2017 1
 Duyongco-Tiu M, et al.
large studies. 10 However, these reported incidences of
hypoglycemia varies considerably among studies.
Both insulin-induced and spontaneous hypoglycemia
inc reased th e ri sk f or m ort a l i ty a m on g h osp it a liz e d
patients.11 All three trials, Action to Control Cardiovascular
Risk in Diabetes (ACCORD), Action in Diabetes and
Vascular disease: PreterAx and Diamicron MR Controlled
Evaluation (ADVANCE), and Veterans Affairs Diabetes Trial
(VADT), clearly demonstrated that an episode of severe
hypoglycemia was associated with an increased risk of
subsequent mortality. A retrospective analysis of 4,368
admissions involving 2,582 diabetic patients admitted to the
general ward where indicated that severe hypoglycemia
was associated with increased length of stay, greater odds
of inpatient death, and death within one year of hospital
discharge. 12 Deaths of up to 10% of patients with severe
sulfonylurea-induced hypoglycemia have been reported.
These are thought to be the result of cardiac arrhythmias
triggered by an intense sympathoadrenal response resulting
from QT interval prolongation and reduced baroreflex
sensitivity.1 Thus, early recognition and prompt management
of hypoglycemia should be the proper practice to decrease
the patient’s morbidity and mortality.
Common risk factors for hypoglycemia include the
following: mismatch of insulin timing and amount or type
of carbohydrate intake; mismatch of oral secretagogues
without appropriate carbohydrate intake; history of severe
hypoglycemia; low glycosylated hemoglobin; presence of
altered consciousness; reduction of oral intake; new nothing
per orem (NPO) status; critical illness like hepatic, renal,
and heart failure.13Identification of these risk factors during
admission, with appropriate adjustments of diabetes mellitus
(DM) treatment regimens, will reduce the patient’s risk for
in-hospital hypoglycemia.
To the best of our knowledge, there are no published
studies about hypoglycemia in the Philippines. This study will
determine the incidence of in-hospital hypoglycemia and
identify its associated risk factors. The primary objective
of this study was to determine the incidence and risk
factors associated with hypoglycemia among the census
of admitted diabetic patients in the local setting. The
secondary objective of this study was to determine the
incidence of all-cause mortality and morbidity (myocardial
infarction, cerebrovascular disease and congestive heart
failure) of patients who had hypoglycemic event.
Methods
Study design and population
This is a cross-sectional analytic study utilizing a
retrospective review of charts of all the Filipino adults with
2 Volume 55 Number 4 Oct.-Dec., 2017
The Incidence of In-Hospital Hypoglycemia and its Associated Risk Factors
type 2 DM of Chong Hua Hospital (CHH), admitted and
discharged from January 2015 to June 2015.
Data collection and analysis
Patients with type 2 DM with recorded hypoglycemia
were identified by their patient identification number. The
chart retrieval and review was done through manual charts
scanned and stored at the hospital medical records section.
The clinical profile of these patients was collected and this
included the gender, age, body mass index (BMI), duration
of DM, available glycosylated hemoglobin (Diabetes Control
and Complications Trial standardized) and creatinine values
taken within one month of admission, and comorbidities
such as cardiovascular disease and heart failure, liver
cirrhosis, chronic kidney disease, and cancer. In the analysis
of risk factors, patient records with incomplete data (eg.
glycosylated hemoglobin or creatinine) were excluded
The information of only the first hypoglycemia occurrence
was analyzed as to the severity of hypoglycemia, patient’s
diet status, diabetic pharmacologic therapy, hospital area
of event, and the occurrence of congestive heart failure,
myocardial infarction (fatal or nonfatal), cerebrovascular
events (fatal or nonfatal), and all-cause mortality.
Hypoglycemia of <70 mg/dL was identified thru the
point-of-care capillary blood glucose monitoring by trained
nurses. The hospital-wide policy of only using the Lifescan’s
SureStepFlexx Meter (Johnson and Johnson Company),
which was calibrated daily at 12 midnight, standardized the
glucose monitoring of all inpatients. However, the frequency
and the timing of its determination were limited to the
medical decision of the attending physician.
Operational definition
1. Hypoglycemia – capillary blood sugar level of <70 mg/
dL according to the ADA.2
a. Non-severe hypoglycemia – capillary blood glucose
level between 51-69 mg/dL, with or without symptoms
b. Severe hypoglycemia – capillary blood glucose level
50 mg/dL and below, with or without symptoms
2. Body mass index (BMI) – calculated as weight in
kilograms over height in meters squared. This is classified
according to the Asian cut points as recommended by
the ADA 14:
• U nderweight – BMI <18 kg/m2
• N ormal – BMI 18-22.9 kg/m 2
• O verweight – BMI 23-24.9 kg/m 2
• O bese – BMI ≥ 25 kg/m2
3. Chronic kidney disease – estimated glomerular filtration
rate (eGFR) is calculated thru the Chronic Kidney
Disease Epidemiology (CKD-EPI) creatinine equation
(2009) 15 and is classified as follows:
Stage 1–normal eGFR of ≥ 90 ml/min/1.73 m2
 The Incidence of In-Hospital Hypoglycemia and its Associated Risk Factors Duyongco-Tiu M, et al.

Stage 2 – mildly decreased eGFR of 60-89 ml/ min/1.73 m2 Table I. Incidence of in-hospital hypoglycemia among adult
Stage 3 – moderately decreased eGFR of 30-59 ml/ Filipino patients with DM
min/1.73 m 2
Stage 4– severely decreased eGFR of 15-29 ml/min/1.73 m2 Hypoglycemia No. of patients Rate
Stage 5 – kidney failure with eGFR < 15 ml/min/1.73 m2 With Hypoglycemia 150 8.9
4. Cardiovascular disease – patients with documented
Without hypoglycemia 1,526 91.1
diagnosis of previous or present myocardial ischemia/
infarction, cerebrovascular diseases, peripheral arterial Total DM 1,676 100
occlusive disease
Hypoglycemia was noted more among younger patients
5. Congestive heart failure – patients with documented
(≤65 years old) who had higher glycosylated hemoglobin
diagnosis of congestive heart failure
(HbA1c) values (61% vs 43%, p=0.014). For the older age group,
6. Liver Cirrhosis – patients with documented diagnosis of
those with HbA1c above eight showed more hypoglycemia
liver cirrhosis
episodes but was not statistically significant, while those with
7. Cancer – patients with documented diagnosis of any
lower HbA1c levels experienced less hypoglycemia events
type of cancer
during admission.

Data management and statistical tools

Comorbidities such as stage III (32.7% vs 25.1%, p=0.043),
stage IV (12% vs 5.5%, p=0.002) and stage V (12% vs 4.1.%,
Data from patients were encoded in Excel spreadsheets
p<0.001) kidney disease, cardiovascular disease (62.7% vs
ver 2015. All patients’ categorical profiles were described
48.6%, p<0.001), and congestive heart failure (8.7% vs 4.4%,
in frequency and percentage while those continuous or
p=0.009) put patients at higher risk for the development of
quantitative profiles were expressed in mean and standard
hypoglycemia. The presence of liver cirrhosis (0.7%) and
deviation. Meanwhile, in comparing averages, Mann
cancer (12%) were factors for the event.
Whitney U non-parametric test was used while testing
association, Chi-square test of independence with 2x2
As noted in Table III, the 150 cases had the following
Fisher’s exact test was employed. Any associated p-values
dietary status during the hypoglycemia event: 84% were on
lesser than 0.05α were considered significant. IBMSPSS ver.
regular (oral) diet, 8% had nothing per orem, and 8% had tube
21 was used as statistical software.
feeding while in those 1,526 patients who did not experience
hypoglycemia, 95.4% had oral diet, 2.6% had tube feeding,

Results and two percent had nothing per orem.

Table IV shows that oral therapy alone did not show

Incidence of Hypoglycemia
higher incidence of hypoglycemia. There was no difference
between the use of sulfonylureas and other agents as
There was a total census of 1,676 patients with type
monotherapy. However, there was a lower incidence of
2 DM, admitted and discharged from January 1, 2015 to
hypoglycemia among those with multiple oral therapy
June 30, 2015, and had point-of-care blood glucose testing
independent of sulfonylurea use (5.3% vs 16.2%, p=0.001).
results. Only 150 patients experienced hypoglycemia and
Use of insulin, whether combined with oral hypoglycemic
the incidence rate was 8.9% (Table I). Among the 150 cases
agents (25.3% vs 16.5%, p=0.006), or alone (34.7% vs 12.1%,
of hypoglycemia, 88% (132/150) were categorized as non-
p<0.001) was significantly associated with the development
severe (capillary blood glucose 51-69 mg/dL), while 12%
of hypoglycemia. Among the combination therapy, the
(18/150) were severe (capillary blood glucose ≤ 50 mg/dL).
addition of sulfonylurea to an insulin regimen did contribute
to the hypoglycemia occurrence (eight percent vs. four
Clinical Profile
percent, p=0.034), while there is no significant difference as
to which insulin dependent type hypoglycemia occurred
Patients who were >65 years old had higher frequency
more frequently. Premix human insulin, combined with non-
of hypoglycemia (52.7% vs 36.2%, p<0.001). There was an
sulfonylurea oral agents, also had higher hypoglycemia
equal distribution of male and female patients and most of
events (4.7% vs1.8%, p=0.02).
them had longer duration (8.56 years ± 10.34 years) of type
2 DM, as seen in Table II.
Basal-bolus regimen with a rapid-acting insulin (11.3% vs
3.9%, p<0.001), premix human insulin (7.3% vs2.1%, p<0.001),
There was a greater proportion of patients belonging in
continuous insulin infusion with rapid-acting insulin (3.3% vs
the normal BMI category who experienced hypoglycemia.
0.1%, p<0.001) or short-acting insulin (1.3% vs 0.3%, p=0.037)
In contrast, those in the obese category, which was the
and the giving of rapid-acting insulin as rescue dose (2% vs
majority of our patients, showed the lowest risk of having
0.2%, p=0.001) were the treatment modalities observed to
low blood sugar levels.

Volume 55 Number 4 Oct.-Dec., 2017 3

Duyongco-Tiu M, et al. The Incidence of In-Hospital Hypoglycemia and its Associated Risk Factors

Table II. Clinical profile of patients

Without hypoglycemia With hypoglycemia Total

Characteristics n=1,526 (%) n=150 (%) n=1,676 (%) p-value
Sex 
Females 767(50.3%) 75(50%) 842(50.2%)
0.951
Males 759(49.7%) 75(50%) 834(49.8%)
Length of DM, average[SD] 5.28[7.47] 8.56[10.34] 5.56[7.83] <0.001
BMI status 
Normal 331(21.7%) 44(29.3%) 375(22.4%) 0.032
Underweight 13(0.9%) 2(1.3%) 15(0.9%) 0.550
Overweight 272(17.8%) 33(22%) 305(18.2%) 0.206
Obese 910(59.6%) 71(47.3%) 981(58.5%) 0.004
Age  
Average[SD] 61.63[12.67] 66.47[11.61] 62.06[12.65] <0.001
≤ 65 years old 974[63.8%] 71[47.3%] 1,045[62.4%] <0.001
HbA1c  N=696 N=49  N=745 
<7.0 275[40%] 15[31%] 290[39%] 0.217
7.1-8.0 121[17%] 4[8%] 125[17%] 0.095
>8.1 300[43%] 30[61%] 330[44%] 0.014
> 65 years old 552[36.2%] 79[52.7%] 631[37.6%] <0.001
HbA1c  N=342 N=50  N=392 
<8 263[77%] 31[62%] 294[75%] 0.023
8.1-9.0 33[10%] 8[16%] 41[10%] 0.171
>9.0 46[13%] 11[22%] 57[15%] 0.109
Kidney disease stage  
I 236(15.5%) 10(6.7%) 246(14.7%) 0.004
II 438(28.7%) 35(23.3%) 473(28.2%) 0.163
III 383(25.1%) 49(32.7%) 432(25.8%) 0.043
IV 84(5.5%) 18(12%) 102(6.1%) 0.002
V 63(4.1%) 18(12%) 81(4.8%) <0.001
Cardiovascular disease 742(48.6%) 94(62.7%) 836(49.9%) <0.001
Congestive Heart Failure 67(4.4%) 13(8.7%) 80(4.8%) 0.009
Liver cirrhosis 34(2.2%) 1(0.7%) 35(2.1%) 0.202
Cancer 189[12.4%] 18[12%] 207[12.4%] 0.891
Thyroid 19(1.2%) 3(2%) 22(1.3%)
Breast 28(1.8%) 1(0.7%) 29(1.7%)
Lung 17(1.1%) 4(2.7%) 21(1.3%)
Esophageal 3(0.2%) 0(0%) 3(0.2%)
Gastric 9(0.6%) 0(0%) 9(0.5%)
Liver 30(2%) 2(1.3%) 32(1.9%)
Cholangiocarcinoma 2(0.1%) 0(0%) 2(0.1%)
Pancreatic 5(0.3%) 1(0.7%) 6(0.4%)
Colon 35(2.3%) 2(1.3%) 37(2.2%)
Prostrate 7(0.5%) 1(0.7%) 8(0.5%)
Renal 7(0.5%) 2(1.3%) 9(0.5%)
Bladder 2(0.1%) 0(0%) 2(0.1%)
Ovarian 2(0.1%) 0(0%) 2(0.1%)
Cervical 0(0%) 2(1.3%) 2(0.1%)
Endometrial 6(0.4%) 0(0%) 6(0.4%)
Myeloma 5(0.3%) 0(0%) 5(0.3%)
Non hodgkins lymphoma 4(0.3%) 0(0%) 4(0.2%)
Sarcoma 4(0.3%) 1(0.7%) 5(0.3%)
Leukemia 3(0.2%) 0(0%) 3(0.2%)
Basal cell 2(0.1%) 1(0.7%) 3(0.2%)
Nasopharyngeal cancer 2(0.1%) 0(0%) 2(0.1%)
Squamous cell cancer of maxillary sinus 1(0.1%) 0(0%) 1(0.1%)

4 Volume 55 Number 4 Oct.-Dec., 2017

 The Incidence of In-Hospital Hypoglycemia and its Associated Risk Factors Duyongco-Tiu M, et al.

Table III. Dietary status of the patients at the time of hypoglycemic event

  Without hypoglycemia With hypoglycemia

Dietary status n=1,526 n=150
Oral diet 1,456(95.45) 126(84%)
Tube feeding 40(2.6%) 12(8%)
Nothing per orem 31(2%) 12(8%)

Table IV. Type of pharmacologic therapy at the time of hypoglycemic event

Without hypoglycemia With hypoglycemia

Type of pharmacologic therapy p-value
n=1,526 n=150
Composite 
Oral therapy 921[60.4%] 51[34%] <0.001
Combination of oral and insulin 252[16.5%] 38[25.3%] 0.006
Insulin 184[12.1%] 52[34.7%] <0.001
Specific types 
Oral monotherapy   
With sulfonylurea 83(5.4%) 7(4.7%) 0.303
Without sulfonylurea 331(21.7%) 7(4.7%) <0.001
Multiple oral therapy   
With sulfonylurea 260(17%) 29(19.3%) 0.141
Without sulfonylurea 247(16.2%) 8(5.3%) 0.001
Combination of insulin and oral therapy  
With sulfonylurea 61 (4%) 12(8%) 0.034
Basal insulin only 43(2.8%) 8(5.3%) 0.061
Basal-bolus (rapid-acting insulin) 7(0.5%) 2(1.3%) 0.119
Basal-bolus short-acting insulin 0(0%) 0(0%) 0.000
Premix analogue insulin 10(0.7%) 2(1.3%) 0.156
Premix human insulin 3(0.2%) 0(0%) 0.244
without Sulfonylurea 191(12.5%) 26(17.3%) 0.085
Basal insulin only 60(3.9%) 9(6%) 0.069
Basal-bolus (rapid-acting insulin) 38(2.5%) 6(4%) 0.136
Basal-bolus short-acting insulin 5(0.3%) 0(0%) 0.216
Premix analogue insulin 65(4.3%) 7(4.7%) 0.364
Premix human insulin 27(1.8%) 7(4.7%) 0.02
Insulin alone      
Basal insulin only 28(1.8%) 4(2.7%) 0.231
Basal-bolus (rapid-acting insulin) 60(3.9%) 17(11.3%) <0.001
Basal-bolus short-acting insulin 2(0.1%) 1(0.7%) 0.089
Premix analogue insulin 48(3.1%) 8(5.3%) 0.07
Premix human insulin 32(2.1%) 11(7.3%) <0.001
Rapid-acting insulin infusion 2(0.1%) 5(3.3%) <0.001
Short-acting insulin infusion 4(0.3%) 2(1.3%) 0.037
Rapid-acting insulin rescue dose 3(0.2%) 3(2%) 0.001
Short-acting insulin rescue dose 5(0.3%) 1(0.7%) 0.284
have significant hypoglycemia events. There were 124 cases
Discussion
(82.7%) of hypoglycemia recorded in the non-ICU ward but
only 26 cases (17.3%) were noted in the ICU ward.
This is the first local cross-sectional study on the
incidence of inpatient hypoglycemia and its associated
Among 150 (8.9%,n=1,676 census) patients
risk factors.
with hypoglycemia, one (0.7%) patient developed
cerebrovascular disease, one (0.7%) developed nonfatal
The rate of hypoglycemia among patients with DM in
myocardial infarction, while the other had congestive
this study was 8.9%. There were varied results from previous
heart failure (0.7%). Meanwhile, mortality rate of those who
studies with the same cut off point of <70 mg/dL of blood
experienced hypoglycemia was 4.7%.
glucose. One retrospective study of patients admitted to

Volume 55 Number 4 Oct.-Dec., 2017 5

 Duyongco-Tiu M, et al.
the general wards of an academic medical center showed
an incidence of 10.5%.12 Another study2 involving admitted
patients in both medical and surgical wards showed an
incidence of 28.6%, while an Asian study7 showed lower value
of 1.29%. A retrospective cohort study4 but with a lower cut
point of <50 mg/dL, among hospitalized patients in a general
ward, reported a 7.7% incidence.
In this study, hypoglycemia cases were classified as
non-severe (88%) and severe (12%). In the Asian study, only
0.29% presented with blood glucose ≤2.8 mmol/L (≤50 mg/
dL).7 Comparing our result to a report done in a university
hospital in the United States, severe hypoglycemia with
blood glucose of <40 mg/dL ranged at three to 11%. 9 In
another review of patients admitted to ICU, 1.9% had severe
hypoglycemia (<40mg/dL). 12 The slightly higher result in our
study may be due to a higher cut point of <50 mg/dL. An
accurate comparison of hypoglycemia occurrences among
these studies indeed would be difficult due to the different
criteria employed in each study.
Hypoglycemia is a common problem in old people with
DM.16 The vulnerability of the elderly to severe hypoglycemia
may be partially related to a progressive age-related
decrease in β-adrenergic receptor function and a high
number of clinical complications and comorbidities. 12
Indeed, the older patients of >65 years old in this study
were observed to have more hypoglycemia events (52.7%
vs 36.2%, p<0.001) than the younger age group. In a
different study2, patients aged ≥75 years were experiencing
more hypoglycemia episodes (60% vs 45.2%, p<0.01). The
predominance of older patients (>65 years old) and female
gender developing hypoglycemia were also noted in the
study of Quilliam. 17 The van Staa study also demonstrated a
higher rate of hypoglycemia in women as compared with
men. 17 This was not however detected in our study since
there was equal distribution of hypoglycemia episodes in
both genders. In other studies, sex did not also predispose
to hypoglycemia.18
We have observed that there was a greater proportion
of patients who had normal BMI who experienced
hypoglycemia while those in the obese category were at
lowest risk. Low BMI increased the risk of severe hypoglycemia
significantly in one study. 19 Obesity, however, was inversely
related with the risk of developing hypoglycemia, probably
due to increased insulin resistance and poorer DM control
as seen in one study.18
The mean duration of DM diagnosis was 8.56 years ±
10.34 years. In another study, patients with diabetes duration
of >10 years were more likely to report hypoglycemia
(13.9%) compared with those with shorter diabetes duration
(8.3%). 20 Older patients with longer duration of diagnosed
DM denoting insulin deficiency are at high risk for iatrogenic
hypoglycemia. 1,12
6 Volume 55 Number 4 Oct.-Dec., 2017
The Incidence of In-Hospital Hypoglycemia and its Associated Risk Factors
Intensive glucose control strategies implemented in
randomized control trial settings in patients with type 2
DM resulted in lower HbA1c and were associated with
an increased risk of hypoglycemia. Patients achieving
near-normal glycemia (HbA1c <6%) and those who were
poorly controlled (HbA1c ≥9) appeared to be at highest
risk for severe hypoglycemia.20 With the present advocacy
that HbA1c goals should be individualized, we divided
our population into the older age group (≥65 years old)
and the younger age group (<65 years old) and identified
hypoglycemia events in the different categories. Consistent
with the study of Lipska et al20, it was noted in our study that
in the younger group, those with HbA1c ≥8.1% had higher
rate of hypoglycemia (20%) and the lowest category (HbA1c
<7.0%) also had a significant rate of episodes (10%). In the
older group, however, only those with an HbA1c of <8%
showed higher risk for hypoglycemia (20.7%). The occurrence
of hypoglycemia in those with low HbA1c levels could be
a result of intensive treatment. The higher frequency noted
among the younger group with elevated HbA1c could
be due to a mismatch of intensive treatment and abrupt
change of diet in the hospital.
Studies have identified advanced age, malnutrition,
active cancer, end-stage renal disease, liver disease, and
congestive heart failure, as contributors to hypoglycemia
risk.21 Renal failure has been identified as an independent
risk factor for hypoglycemia in two studies. 17,18 The following
comorbidities were noted in our study which put patients
at risk for hypoglycemia: stage III, IV, V kidney disease
(32.7% vs 25.1%, p=0.043, 12% vs 5.5%, p=0.002, 12% vs 4.1%,
p<0.001, respectively) cardiovascular disease (62.7% vs
48.6%, p<0.001), , and congestive heart failure (8.7% vs 4.4%,
p=0.009). In another study, they have identified end-stage
renal disease (16.8% vs 8.8%, p<0.01), peripheral vascular
disease (27.6% vs 19.4%, p=0.02), and dementia (19.5% vs
11.6%, p<0.01) as common comorbidities seen in patients
with hypoglycemia.2 However, in one review, complications
of DM and other comorbidities, GFR, liver function test
abnormalities were not associated with a change in risk for
a hypoglycemic episode. 4 The different population studies
among these studies may have contributed to varied results.
A majority of our patients included in the study was on
regular diet which resulted to a higher recorded rate of
hypoglycemia (84%). Lower rates were noted among
those on tube feeding (eight percent) and on NPO
status (eight percent). Among those12 patients who had
hypoglycemia events while they were on NPO status, seven
patients were in preparation for a procedure (e.g. blood
extraction for lipid panel, ultrasound of the abdomen,
esophagogastroduodenoscopy, colonoscopy, surgery, etc.),
while five were in critical condition thus diet was withheld.
Most of them did not receive any hypoglycemic agents,
except for three who were on insulin infusion, one was given
a rescue of a subcutaneous rapid-acting analogue dose,
and one was given a sulfonylurea. This common error may
 The Incidence of In-Hospital Hypoglycemia and its Associated Risk Factors
be corrected by either scheduling patients first thing in the
morning or after a meal, reviewing patient’s medications
regularly, monitoring of blood glucose intensively when
placed on NPO and/or on insulin infusion, monitoring blood
glucose before the patient leaves the unit for the procedure,
and giving supplemental carbohydrates should blood
glucose are low or expected to decrease.13 We also noted
that patients on tube feeding (whether on NGT or PEG tubes)
had significant hypoglycemia rates.
Therapeutic hyperinsulinemia, whether by treatment
with an insulin secretagogue or with insulin, is a prerequisite
for the development of iatrogenic hypoglycemia. 1 In
this study, being on oral therapy alone recorded a low
incidence of hypoglycemia (34% vs 60.4%, p<0.001). This
was consistent with one study done in North Carolina (24%
vs 44%, p<0.0001).2 Monotherapy with a sulfonylurea (4.7% vs
5.4%, p=0.303) or another oral agent (4.7% vs 21.7%) did not
increase the incidence of hypoglycaemia in this study. This
contrasted with a study on the burden of sulfonylurea-related
hypoglycemia in United Kingdom in which it observed that
sulfonylurea caused 31.8% of all hypoglycemia readings. 6
Notably, oral therapy without the use of sulfonylurea showed
a lesser risk of hypoglycemia in our study.
Being on insulin therapy caused more events of
hypoglycemia during hospital stay. Combination with oral
agents (25.3% vs 16.5%, p=0.006) or used alone (34.7% vs
12.1%, p<0.001) caused most of the recorded hypoglycemia
events in this study. Ghazi observed the same in his study
that patients who used insulin, whether in combination with
oral therapy (14% vs 9.5%, p<0.0001) or used alone (51.6% vs
23.5%, p<0.0001) had more hypoglycemia episodes.2 In fact,
he observed that the use of either long- or intermediate-
acting insulin (76.7% vs 36.8%, p<0.0001) and insulin
infusion (5.9% vs 2.0%, p<0.01) were common causes of
hypoglycemia.2 In addition, a study by Garg et al. exhibited
the increased incidence of hypoglycemia among insulin
treated group (41.3%) than in the non-insulin treated group
(16.3%) with p<0.0001. 11
The non-ICU ward recorded more episodes of
hypoglycemia (82.7%) than the ICU ward. The greater
number of admission and fast turnover of patients in this
ward may have contributed to this figure. This number was
comparable with previous studies where a prevalence of five
to 32% in a non-ICU setting was noted among patients treated
with subcutaneous insulin.22 In contrast to the study of Swanson
et al.5 which analyzed measurements from the largest number
of US hospitals, the prevalence of hypoglycemia was 6.3% in
ICU patients and 5.7% in non-ICU patients.
We have detected that only few patients had significant
outcomes after the hypoglycemia event. There were seven
patients who died during their hospital stay and were all at a
grave state since admission. Five of them were resuscitated
Duyongco-Tiu M, et al.
upon arrival in the emergency room, while two of them were
in septic shock since admission. Four of them developed
severe hypoglycemia, of which three were on continuous
insulin infusion and only one was on NPO status. According
to Turchin4, inpatient mortality was 2.96% for patients who
had at least one hypoglycemic episode during the hospital
stay. In-patient mortality rate increased progressively from
1.9% for patients with lowest blood glucose of >39 mg/dL to
8.2% for those with lowest glucose of <30 mg/dL.4 Though the
categorization of severe and non-severe hypoglycemia in
this study varies with that of Turchin, nevertheless, a strong
relationship between increased risk for mortality and low
blood sugar levels (<50 mg/dL) was also noted in our study.
This study has several limitations. Though the total
study population was quite large, a longer timeframe (ex.
≥one year) would have identified the true incidence of
hypoglycemia in our locality. The frequency of blood glucose
determination which was not uniform across all patients could
have missed some episodes of asymptomatic hypoglycemia
relevant to the determination of hypoglycemia unawareness
which is common among the elderly population. Additionally,
the degree of distribution of hypoglycemia was based
only on numerical blood glucose values. Determining the
symptoms of hypoglycemia would have added to the
clinical relevance of the study. Also, some patients did not
have complete data (e.g. HbA1c or creatinine within one
month of admission) and their determination was limited to
the discretion of the attending physician. Other factors that
were not studied here include the dose of medications during
the hypoglycemia event, review of possible overlapping
medications (e.g. combination of gliclazide and glimepiride),
correlation of hemoglobin and HbA1c values, relationship
of severe hypoglycemia to inpatient mortality. Finally, the
generalizability of this single-center study may be limited.
Conclusion
In this study, we have focused on the total census
patients with type 2 DM, excluding the minors and the
pregnant patients. The incidence of hypoglycemia of 8.9%,
though predominantly of the non-severe type, is indeed
a realization that this should be addressed aggressively
to decrease the burden of DM management. The elderly,
longer duration of DM diagnosis, comorbidities like moderate
to end-stage kidney disease, cardiovascular disease and
congestive heart failure, and the use of insulin have been
identified as factors for hypoglycemia. These patients should
have intensive monitoring of blood glucose and regular
review of medications. The recorded consequences of
hypoglycemia in our study were not relevant, except for the
mortality rate of 4.7%. It is still noteworthy that these events
may happen because of hypoglycemia. Lastly, with these
findings, though not generalizable in our country, physicians
will now be vigilant in preventing hypoglycemia. This would
greatly help our patients in their struggle against DM.
Volume 55 Number 4 Oct.-Dec., 2017 7
 Duyongco-Tiu M, et al. The Incidence of In-Hospital Hypoglycemia and its Associated Risk Factors

References Risk of Severe Hypoglycemia in type 2 Diabetes. Diabetes Care.

Vol. 36. No. 11. (3535-3542). Nov 2013.
21. Maynard, G., Huynh, M. PharmD., Renvall, M. MSc. Iatrogenic
1. Polonsky, K. MD, et al. Williams Textbook of Endocrinology. 12th Inpatient Hypoglycemia: Risk Factors, Treatment, and Prevention.
ed. 2011. Chapter 34. Philip Cryer. Hypoglycemia. P1552-1570. Diabetes Spectrum. Vol. 21. No. 4 (241-247). Oct 2008.
2. Ghazi, A. MD, Landerman, L. PhD., Lien, L. MD., Impact of 22. Farrokhi, F. MD., Klindukhova, O. MD., Chandra, P. MD. Risk
Race on the Incidence of Hypoglycemia in Hospitalized Older Factors for Inpatient Hypoglycemia During Subcutaneous Insulin
Adults with Type 2 Diabetes. Clinical Diabetes. Vol. 31 No. 2, Therapy in Non-Critically Ill patients with Type 2 Diabetes.
66-72, April 2013. Journal of Diabetes Science and Technology. Vol. 6. Issue 5.
3. Braithwaite, S., Clark, L., Dacenko-Grawe, L., Prevention of Sept 2012.
Hospital Hypoglycemia by Algorithm Design: A Programming
Pathway for Electronic Order Entry, Diabetes – Damages and
Treatments. 2011. ISBN: 978-953-307-652-2, InTech.
4. Turchin, A. MD, MS, Matheny, M. MD, MS, MPH, Shubina,
M. SCD. Hypoglycemia and Clinical Outcomes in Patients with
Diabetes Hospitalized in the General Ward. Diabetes Care. 32(7):
1153-1157. July 2009.
5. Swanson, C. MD., Potter, Daniel, MA., Kongable, G. MSN, FNP.
Update on Inpatient Glycemic Control in Hospitals in the United
States. Endocrine Practice, 17(6);853-61, Nov-Dec 2011.
6. Rajendran, R., Kerry, C., Rayman, G., Temporal Patterns of
Hypoglycemia and Burden of Sulfonylurea-related hypoglycemia
in UK hospitals: A Retrospective Multicenter Audit of Hospitalized
Patients with Diabetes. BMJ Open. 2014; Vol. 4, Issue 7.
7. Cun-mei Yang, Yan-lan Ma, Jun Kang. Time and Department
Distribution of Hypoglycemia Occurrences in Hospitalized
Diabetic Patients. International Journal of Nursing Sciences. Vol.
2, Issue 3, 263-267, Sept 2015.
8. Clayton, D., MD, Woo, V, MD, Yale, JF, MD. Hypoglycemia.
Canadian Journal of Diabetes. 37. S69-S71. 2013.
9. Shomali, M., MD. Hypoglycemia in the Hospital. Journal of
Community Hospital Internal Medicine Perspectives. Vol 1, No.
2. 7217. July 18, 2011.
10. Stanisstreet, D. RGN, Walden, E. RGN, Jones, C. The Hospital
Management of Hypoglycemia in Adults with Diabetes Mellitus.
March 2010.
11. Garg, R., MD., Hurwitz, S. PhD., Turchin, A. MD. Hypoglycemia,
With or Without Insulin Therapy, is Associated with Increased
Mortality Among Hospitalized Patients. Diabetes Care. Dec. 17,
2012.
12. Seaquist, E. MD., Anderson, J. MD., Childs, B. ARNP.
Hypoglycemia and Diabetes: A Report of a Workgroup of the
American Diabetes Association and The Endocrine Society.
Diabetes Care 36:1384–1395, 2013.
13. Tomsky, D. MSN. Detection, Prevention and Treatment of
Hypoglycemia in the Hospital. Diabetes Spectrum. Vol. 18 No.1
39-44. Jan 2005.
14. Hsu, W. MD, Araneta, MR. MD., Kanaya, A. MD. BMI Cut Points
to Identify At-Risk Asian Americans for Type 2 Diabetes Screening.
Diabetes Care. 38(1): 150-158. Jan 2015.
15. Kasper, D. MD., et al. Harrison’s Principles of Internal Medicine.
19th edition. 2015. Chapter 335. Bargman, J. MD., Skorecki, K.
MD. Chronic Kidney Disease. P1813.
16. Shafiee, G. MD., Mohajeri-Tehrani, M. MD., Pajouhi, M. MD.
The Importance of Hypoglycemia in Diabetic Patients. Journal of
Diabetes & Metabolic Disorders. 11:17. 2012.
17. Quilliam, B. PhD. Simeone, J. PhD., Ozbay, B. PhD. The Incidence
and Costs of Hypoglycemia in Type 2 Diabetes. The American
Journal of Managed Care. Vol. 17, No. 10. (673-680). 2011.
18. Bodmer, M. MD., Meier, C. MD., Krahenbuhl, S. MD. Metformin,
Sulfonylureas, or Other Antidiabetic Drugs and the Risk of Lactic
Acidosis or Hypoglycemia. Diabetes Care. Vol. 31, No. 11. (2086-
2091). Nov 2008.
19. Samann, A., MD., Lehmann, T. MD, Heller, T. MD. A Retrospective
Study on the Incidence and Risk Factors of Severe Hypoglycemia
in Primary Care. Family Practice. 30 (3): 290-293. 2012.
20. Lipska, K. MD., Warton, M. MPH, Huang, E., MD. HbA1c and

8 Volume 55 Number 4 Oct.-Dec., 2017

 Philippine Journal of Internal Medicine
Hemodialysis Patients’ Compliance and Adherence Behaviors
to Renal Replacement Therapy in Two Dialysis Centers in Iloilo
City
Renato C. Ong Jr., R.M.T., M.D.*; Agnes Jean M. Villaflor, M.D.**, Patricio P. Palmes, M.D.***
Abstract
Introduction: Approximately 120 per million population
develop kidney failure, translating to about 10,000 Filipinos
needing to replace their kidney function per year. If without
the appropriate intervention, those having kidney failure
will surely die. The study aims to evaluate the compliance
of hemodialysis (HD) patients to renal replacement therapy
(RRT) in two dialysis centers in Iloilo City, and to compare the
prevalence of non-adherence in between groups.
Methods: A cross-sectional study where subjects answered
the End-Stage Renal Disease–Adherence Questionnaire
(ESRD-AQ).
Results: Of the 102 patients, 59.8% (n=61) were enrolled.
The mean age was 47 years with average HD vintage of 30
months. More females were non-adherent to HD treatment,
17.1% vs.15.4%; whereas more males were non-adherent
to the remainder descriptors (medications, 11.5% vs. 8.6%;
fluid restriction, 23.1% vs. 17.1%; and diet recommendations
30.8% vs. 25.7%). There were less non-adherent patients
than adherent ones (HD attendance, 9,803.92 vs. 50,000;
medications, 5,882.35 vs. 53,921.57; fluid restriction, 11,764.71
vs. 48,039.22; and diet, 16,666.67 vs. 43,137.25 per 100,000).
There were significant differences in their behaviors toward
Introduction
Registries in the United States and Europe scale show
increasing prevalence and incidence rates of end-stage
renal disease (ESRD). The prevalence being 479 to 1,500
cases per million inhabitants and the incidence being
75 to 308 cases per million inhabitants depending on the
region studied. 1,2 In 2008, archives from the Philippine
National Statistics Office revealed kidney diseases as the
10 th leading cause of morbidity and mortality. 3 From being
comparable to Southeast-Asian neighbors, the Philippines
having been regarded as a chronic kidney disease (CKD)
* Resident in Training, Department of Internal Medicine, West Visayas State
University Medical Center
**Training Officer, Department of Internal Medicine, West Visayas State
University Medical Center
***Chair, Department of Internal Medicine, West Visayas State University
Medical Center
Corresponding author: Renato C. Ong Jr., M.D., West Visayas State
University Medical Center, Iloilo City, Philippines
Email:r.ongjrmd@gmail.com
The PHILIPPINE JOURNAL OF INTERNAL MEDICINE is a peer reviewed journal and a copyrighted publication of the Philippine College of Physicians
Original Article
HD attendance (p=0.000); shortening of HD treatment
(p=0.000); duration of shortening HD (p=0.000); adherence
to medications (p=0.000); to fluid (p=0.000); and to diet
(p=0.000). Both groups demonstrated the same level of
perception and understanding towards the importance
of HD (p=0.306 and 0.096, respectively). There was no
significant difference in their perception to medications
(p=0.427); however, figures illustrate a significant difference
in their levels of understanding towards its importance
(p=0.001). Adherent subjects have better perception and
understanding in fluid restriction regimen and dietary
recommendations as data show significant differences in
between groups (p=0.000 and 0.000; and p=0.001 and 0.004,
respectively).
Conclusion: The compliance of adherent subjects to HD
treatment, medications, fluid restriction protocol and dietary
recommendations was more adequate. The non-adherent
subjects were less prevalent than adherent subjects.
Keywords: renal replacement therapy, end-stage renal
disease adherence questionnaire, adherence behaviors
and compliance
country, is now leading in incidence at 2.6 per 100,000 in
2003 to 9.75 per 100,000 having the in 2008. 4 According to
the Philippine Renal Disease Registry (2009), diabetes mellitus
(DM) was responsible for 42% of kidney diseases among
dialysis patients, while hypertension contributed another
25%, closely followed by kidney inflammation at 20%, with
slight male preponderance at 57% and with a mean age
of 53 years. 4,5 Approximately 120 per million population
develop kidney failure, translating to about 10,000 Filipinos
needing to replace their kidney function per year. Of
these, around 86% undergo dialysis, whereas only about
14% could afford transplantation, as these treatments are
expensive. 5,6 If without the appropriate intervention–either
renal replacement therapy (RRT) or kidney transplantation,
those having kidney failure will surely die.5 Emerging evidence
suggest that patient noncompliance with treatment
regimen undermines the effectiveness of medical care that
more often than not results in progression of the primary
disease which frequently leads to development of more
Volume 55 Number 4 Oct.-Dec., 2017 1
 Ong RC, et al. Hemodialysis Patients’ Compliance and Adherence Behaviors

complications. 7 Likewise, foregoing data indicate that way for improvement in the delivery of the health care
negative perception of disease and non-adherence to the system, and address these issues that can be controlled to
recommended treatment may lead to unfavorable clinical promote better adherence.
outcomes in patients on maintenance hemodialysis (HD).
However, there seems to be a paucity of researches that Administrative bodies can likewise gain knowledge of
addresses clinical outcomes in the end stage renal disease the drawbacks and difficulties encountered by these patients,
population as a function of patients’ illness perceptions and who happen to be are on the receiving end of the paradigm;
their degree of adherence to recommended treatment.8 such that, this study can light the way in the formulation of an
improved guideline for better health care delivery.
In the United States, over 485,000 people have
CKD, a progressive kidney disease that may lead to HD. The general objective of this study is to evaluate the
Hemodialysis involves a complex regimen of treatment, compliance of HD patients’ to RRT in two dialysis centers in
medication, fluid, and diet management. 8 Patients who Iloilo City, and to compare the prevalence of non-adherence
are on dialysis are well suited for studying compliance with in between groups. Specifically, to compare the adherence
therapy because treatment is prolonged and intensive, behaviors of HD patients among two dialysis centers,
and medical regimens are clear cut and easily determined with the following as subsets: HD treatment attendance,
with objective measures. 7 Khalil, et al. (2010) indicated that medications, fluid restrictions, and diet recommendations;
depressive symptoms are the most common psychological and to compare dialysis patients’ perception, and levels of
complication among patients with ESRD. Only little is known understanding to treatment adherence behaviors.
about the mechanisms responsible for this association;
however, depressive symptoms are considered a risk factor
for increased morbidity and mortality. 9 Also, other data
Methods
show that ESRD patients who are on maintenance HD with
This is a cross-sectional, analytic study that will be done
negative discernments of the condition, and who are non-
in two HD centers in Iloilo City. The end-stage renal disease
adherent to the recommended treatment may succumb
adherence questionnaire (ESRD-AQ) was utilized in one
to unfavorable clinical outcomes.10 In 2005, over 312,000
session. A minimum sample size of 43 is required to detect a
patients were underwent HD in the United States, where
significant difference at a power of 0.9 with 95% confidence
dialysis non-adherence rates range from 8.5% to 86%.8
using the G*Power Version 3.1.5.
Moreover, noncompliant behavior by these dialysis patients
not only endangers their life in the long run, but also results
Inclusion criteria
in negative effects within a day or two. Despite severe
A subject will be eligible for inclusion in this study if all of the
consequences, noncompliance with their medical regimen
following criteria apply at baseline:
is the norm for dialysis patients rather than the exception. 7
1. 19-years-old and above
According to Bame, et al. (1993), arbitrary progression of the
2. diagnosed with ESRD and treated with HD for at least
primary disease and a greater likelihood of complications
3 months
can result from patient nonconformity with treatment regime,
3. received HD for three to four hours per session, at least
which in turn emasculates the effectiveness of medical
once a week
care. Dialysis therapy treatment non-adherence, including
4. independent and performs self-care activities (such as
treatment, medication, fluid, and diet non-adherence,
ability to walk and eat without assistance);
significantly increases the risk of morbidity and mortality. 8
5. lliving in a home setting
There is a great paucity of research which addresses clinical
6. subject or his/her legally acceptable representative is
outcomes in the ESRD population, and the correlation
willing to provide written informed consent
between: the patients’ perceptions of their illness, and their
degree of adherence to recommended treatment, hence
Exclusion criteria
this study.
1. on peritoneal dialysis
2. uremic patients who are not able to give informed
The results of this study will benefit all ESRD patients. It
consent
will put forward strategies for provision of better medical
3. patients who are not able to answer the questionnaire
care thereby improving the quality life of their ESRD patients.
This can enhance compliance to the prescribed treatment
Data collection technique
regimen, thus translating into lesser complications. This
may lead to patients resuming their work if they are still
Eligible participants completed the ESRD-AQ for patients
able. Also, health care providers will similarly be aided in
requiring in-center HD. A paper-and pencil instrument
entertaining lesser morbid complications which arise from
designed to measure HD patients’ treatment adherence
non-adherence to the treatment protocol; increase their
behaviors in four dimensions: HD attendance, medication
awareness of the issues that surround these patients, paving

2 Volume 55 Number 4 Oct.-Dec., 2017

Hemodialysis Patients’ Compliance and Adherence Behaviors Ong RC, et al.

use, fluid restrictions, and diet recommendations.11 Kim et Table I. Demographic profile of hemodialysis patients enrolled in
al. (2010) generated the items based on in-depth literature this study
reviews and in consultation with clinical experts, such as
nephrologists and nephrology researchers, HD nurses, and Demographic Profile n (%)
renal dietitians. This questionnaire consists of 46 questions/ Total number of patients on hemodialysis 102
items divided into five sections. The first section pursues Hospital-based kidney unit 23 (22.5)
general information about patients’ ESRD and RRT-related Free-standing dialysis center 79 (77.5)
history (five items), and the remaining four sections ask Total number of patients enrolled 61 (59.8)
about treatment adherence to HD treatment (14 items),
Hospital-based kidney unit 15/61 (24.6)
medications (nine items), fluid restrictions (10 items), and Free-standing dialysis center 46/61 (75.4)
diet recommendations (eight items).
Gender

Scoring system of individual item in the questionnaire Males 26 (42.6)

A panel of expert clinicians and patients confirmed
content and face validity of the tool. Seven experts
(two nephrologists, a nurse practitioner, two HD nurses,
and two renal dietitians) with extensive clinical and
research experience in the care for patients with ESRD on
maintenance HD were invited to assess content validity
of the ESRD-AQ. Moreover, all scale scores were able to
discriminate clearly between adherent and nonadherent
patients, indicating that the instrument is a valid measure
of adherence behaviors.
In addition, the ESRD-AQ adjusts scores for question
numbers 14 (“During the last month, how many complete
dialysis treatments did you miss?”), 18 (“During the last month,
when your dialysis treatment was shortened, what was
the average numbers of minutes?”), and 26(“During the
past week, how often have you missed your prescribed
medicines?”), depending on the reasons for not adhering.
For example, patients with medical reasons for missing or
shortening the HD treatment (such as having HD access
problems or physical symptoms during HD) obtained a full
score.11
Interpretation of scores from among the questions
The adherence behavior subscale is scored by adding
the responses to questions 14, 17,18,26,and 46. The weighting
system for scores was determined based on the degree of
importance relevant to clinical outcome of each dimension.
For example, missing or shortening HD has been reported
to have a stronger association with mortality of patients
with ESRD than other components of adherence behavior;
therefore, it was given more weight in computing the
adherence scores.12,13
Females 35 (57.4)
Mean age ± SD (years) 47.57 ± 12.41
Age range (years) 22 – 76
Mean vintage months ± SD (months) 30.18 ± 33.80
Vintage range (months) 7 – 200
Data Analysis
All analyses were performed using SPSS version 20.0
and Epi Info™ Version 7.0. Prevalence and other frequency
measures were used to analyze qualitative data, whereas
t-test and Mann Whitney U were used in the quantitative
data analysis.
Ethical Considerations
In obtaining and documenting informed consent,
adherence to ICH GCP guideline E6 and to the ethical
principles that have their origin in the declaration of
Helsinki. Prior to the beginning of the trial, the ethics review
committee’s written approval/favorable opinion of the
protocol, written informed consent form and any other written
information to be provided to the subjects. Before any trial-
related procedure begins, written informed consent must
be obtained from the subject or his/her legally acceptable
representative. All research data will be confidential.
Results
There were a total of 102 patients were having HD
treatments at the Hospital-based Kidney Unit (n=23), and at
free-standing Dialysis Center (n=79). However, 59.8% (n=61)
patients satisfied the inclusion criteria and completed the
ESRD-AQ.

Translation of the questionnaire to local dialect

As shown in Table I, more than 75% of the participants
in this study came from the freestanding HD center. Females
For better comprehension among the local respondents,
constitute 57.4% (n=35) of the sample. The mean age of
this questionnaire was translated to the dialect “Hiligaynon”.
the subjects was 47.57 years ± 12.41 (standard deviation
It was pilot tested randomly among the CKD patients (n=30)
[SD]), with age range noted at 22 to 76 years. Since the
confined in the different wards of this medical center,
start of maintenance HD, the participants in this study had
namely medical, surgical and obstetrics/gynecology ward.

Volume 55 Number 4 Oct.-Dec., 2017 3

Ong RC, et al. Hemodialysis Patients’ Compliance and Adherence Behaviors

Table II. Sociodemographic data of study participants: adherers vs. non-adherers

Hemodialysis Medication Fluid Diet

Adherence Area A(n)/B(n) = 51/10 A(n)/B(n) = 55/6 A(n)/B(n) = 49/12 A(n)/B(n) = 44/17
Descriptor A B A B A B A B
n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%)
Gender
Male 22 (84.6) 4 (15.4) 23 (88.5) 3 (11.5) 20 (76.9) 6 (23.1) 18 (69.2) 8 (30.8)
Female 29 (82.9) 6 (17.1) 32 (91.4) 3 (8.6) 29 (82.9) 6 (17.1) 26 (74.3) 9 (25.7)
Age
Young 8 (80.0) 2 (20.0) 9 (90.0) 1 (10.0) 6 (60.0) 4 (40.0) 5 (50.0) 5 (50.0)
Middle-aged 38 (86.4) 6 (13.6) 40 (90.9) 4 (9.1) 37 (84.1) 7 (15.9) 34 (77.3) 10(22.7)
Older 5 (71.4) 2 (28.6) 6 (85.7) 1 (14.3) 6 (85.7) 1 (14.3) 5 (71.4) 2 (28.6)
Education level
High school or lower 1 (2.0) 0 (0.0) 1 (1.8) 0 (0.0) 1 (2.0) 0 (0.0) 0 (0.0) 1 (5.9)
Vocational school 3 (5.9) 0 (0.0) 3 (5.5) 0 (0.0) 2 (4.1) 1 (8.3) 2 (4.6) 1 (5.9)
Some college 8 (15.7) 1 (10.0) 8 (14.5) 1 (16.7) 8 (16.3) 1 (8.3) 6 (13.6) 3 (17.6)
College graduate or
39 (76.4) 9 (90.0) 43 (78.2) 5 (83.3) 38 (77.6) 10 (83.3) 36 (81.8) 12 (70.6)
higher
Marital status
Never married 9 (17.6) 0 (0.0) 9 (16.4) 0 (0.0) 6 (12.2) 3 (25.0) 6 (13.6) 3 (17.6)
Married 39 (76.5) 10 (100) 43 (78.1) 6 (100) 40 (81.6) 9 (75.0) 36 (81.8) 13 (76.5)
Separated, widowed 3 (5.9) 0 (0.0) 3 (5.5) 0 (0.0) 3 (6.1) 0 (0.0) 2 (4.5) 1 (5.9)
Current employment
Yes 7 (13.7) 1 (10.0) 8 (14.5) 0 (0.0) 6 (12.2) 2 (16.7) 6 (13.6) 2 (11.8)
No 44 (86.3) 9 (90.0) 47 (85.5) 6 (100) 43 (87.8) 10 (83.3) 38 (86.4) 15 (88.2)
Cause of kidney failure
Diabetes mellitus 22 (43.1) 5 (50.0) 26 (47.3) 1 (16.7) 22 (44.9) 5 (41.7) 20 (45.5) 7 (41.2)
Hypertension 14 (27.5) 3 (30.0) 15 (27.3) 2 (33.3) 14 (28.6) 3 (25) 14 (31.8) 3 (17.6)
Glomerulonephritis 11 (21.6) 2 (20.0) 10 (18.1) 3 (50.0) 10 (20.4) 3 (25) 7 (15.9) 6 (35.3)
Others 4 (7.8) 0 (0.0) 4 (7.3) 0 (0.0) 3 (6.1) 1 (8.3) 3 (6.8) 1 (5.9)
HD vintage (months)
Mean ± SD 5.7 ± 1.6 1.2 ± 0.4 6.0 ± 1.4 0.8 ± 0.4 5.5 ± 1.5 1.5 ± 0.5 4.9 ± 1.4 1.9 ± 0.6
Range 7 – 200 21 – 65 7 – 200 21 – 65 7 – 200 21 – 65 7 – 200 21 – 65

Table III. Chi-square tests for adherence of hemodialysis patients to the respective descriptors in this study when grouped according to age

Hemodialysis Medication Fluid Diet

Adherence area A(n)/B(n) = 51/10 A(n)/B(n) = 55/6 A(n)/B(n) = 49/12 A(n)/B(n) = 44/17
descriptor A B A B A B A B
n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%)
Young 8 (80.0) 2 (20.0) 9 (90.0) 1 (10.0) 6 (60.0) 4 (40.0) 5 (50.0) 5 (50.0)
Middle-aged 38 (86.4) 6 (13.6) 40 (90.9) 4 (9.1) 37 (84.1) 7 (15.9) 34 (77.3) 10(22.7)
Older 5 (71.4) 2 (28.6) 6 (85.7) 1 (14.3) 6 (85.7) 1 (14.3) 5 (71.4) 2 (28.6)
Total 51 (83.6) 10 (16.4) 55 (90.2) 6 (9.8) 49 (80.3) 12 (19.7) 44 (72.1) 17 (27.9)
χ2 1.10 0.18 3.14 3.02
df 2 2 2 2
P value 0.578 0.912 3.028 0.221
Numbers in parentheses indicate row percentages.

4 Volume 55 Number 4 Oct.-Dec., 2017

 Hemodialysis Patients’ Compliance and Adherence Behaviors Ong RC, et al.

Table IV. One-way ANOVA of respondents adherence to hemodialysis descriptors in this study when grouped according to age

Sum of squares df Mean square F p-value

Between age groups 7429.3 2 3714.6
Within age groups 1805.7 58 31.1 119.3 < 0.00001
Total 9234.9 60

Table V. Point prevalence of hemodialysis patients with the parameter descriptors

Adherent Non-adherent
Parameter descriptor Prevalence rate Prevalence rate
n (%) n (%)
cases per 100,000 cases per 100,000
Hemodialysis treatment 51 (83.6) 50,000.00 10 (16.4) 9,803.92
Medications 55 (90.2) 53,921.57 6 (9.8) 5,882.35
Fluid restriction protocol 49 (80.3) 48,039.22 12 (19.7) 11,764.71
Diet recommendations 44 (72.1) 43,137.25 17 (27.9) 16,666.67

Table VI. Summary of known group analysis on the questions that specifically address patients’ adherence behaviors

Adherers (n)/
Behavior to treatment t-test p-value
Non-adherers (n)
HD attendance 51/10 - 24.901 0.000
Shortening HD 56/5 - 12.241 0.000
Duration of shortening of HD 52/9 - 20.842 0.000
Adherence to medication 55/6 - 8.382 0.000
Adherence to fluid restrictions 49/12 - 12.857 0.000
Adherence to diet restrictions 44/17 - 10.843 0.000

Table VII. Summary of known group analysis on the questions that address patients’ perception and understanding levels of adherence
behaviors

Adherers (n)/ Mann-Whitney

Behavior to treatment Z p-value
Non-adherers (n) U
Perception 51/10 230.000 - 1.024 0.306
HD attendance
Level of understanding as to importance 51/10 205.000 - 1.664 0.096
Perception 55/6 131.000 - 1.335 0.427
Medication
Level of understanding as to importance 55/6 38.500 - 3.964 0.001
Perception 49/12 111.000 - 4.004 0.000
Fluid restrictions
Level of understanding as to importance 49/12 114.000 - 4.445 0.000
Dietary recommenda- Perception 44/17 191.500 - 3.316 0.001
tions Level of understanding as to importance 44/17 224.500 - 2.845 0.004

an average HD vintage of 30.18 ± 33.80 (SD) months, the
vintage range was from seven to 200 months.
Table II shows that there are more female subjects who
were non-adherent to HD treatment as compared to males
(n=6 [17.1%] vs. n=4 [15.4%], whereas there were more non-
adherent males to the remainder parameter descriptors
(medications n=3 [11.5%] vs. n=3 [8.6%]; fluid restriction n=6
[23.1%] vs. n=6 [17.1%]; and diet recommendations n=8
[30.8%] vs. n=9 [25.7%]) than females. Majority have finished
college or higher. More than 75% of these subjects were
also married. Likewise, data show that more than 80% of the
samples are not employed at present, and a little over 40%
of the enrolled patients in this study have diabetes mellitus
as the cause of their kidney failure.
Table III shows that majority of the respondents were
compliant to their HD schedules (83.6%, χ2 = 1.10, df = 2, p=
0.578), to the prescribed medications (90.2%, χ2 = 0.18, df =
2, p= 0.912), to the fluid restriction protocol (80.3%, χ2 = 3.14,
df = 2, p= 3.028), and to the dietary advices (72.1%, χ2 = 3.02,
df = 2, p= 0.221). The result shows that the difference in the
compliance among the three age groups: the younger (19
– 35 years old), the middle aged (30 – 60 years old) and the

Volume 55 Number 4 Oct.-Dec., 2017 5

 Ong RC, et al.
older (above 60 years old) was not statistically significant.
Likewise, Table IV shows that there is a significant difference
in the adherence of the respondents to the respective
descriptors when grouped according to age [F(2,58) = 119.3,
p = <0.00001].
According to the 2010 Census of Population and
Housing by the National Statistics Office, the Province of
Iloilo has a population of 2,230,195 comprising about 2.4%
of the whole Philippine population (92,337,852). With the
aforementioned data, the computed prevalence of HD
patients (in two dialysis centers) in Iloilo City is 4.57 cases
per 100,000 population (n=102).
Table V demonstrates the point prevalence (PP) of HD
patients with the parameter descriptors of this study. There
were more adherent subjects to the different parameter
descriptors of RRT than non-adherent ones. The prevalence
for non-adherence to diet recommendations is 16,666.67
cases per 100,000(n=17,27.9%), whereas the prevalence for
non-adherence to medications was only 5,882.35 cases per
100,000.
Table VI shows the summary of known group analysis
on the questions that specifically address patients’ adher-
ence behaviors. Quantitative data was analyzed using
t-test with the p-value set to be significant when less than
0.05, while Table VII summarizes the known group analysis
on the questions that address patients’ perception and un-
derstanding levels of adherence behaviors. Mann-Whitney
U was determined and the p-value was set at less than 0.05
for significance.
Discussion
End-stage renal disease is a growing public health
concern and non-adherence to treatment has been
associated with poorer health outcomes in this population.14
The Philippine Renal Disease Registry in its Annual Report for
2011 stated that there was an 8.9% increase in the number
of patients on dialysis from 8,922 in 2009 to 9,716 patients in
2010, where 9,133 (94%) were on HD and 583 (six percent)
on peritoneal dialysis. 15 The Philippines is a CKD country and
since 2008 took lead with 9.75 Filipinos having the disease.
Although HD effectively contributes to long term survival,
morbidity and mortality of dialysis patients remains high,
more commonly secondary to cardiovascular diseases.16-20
The 2003 US Renal Data System Annual Report shows that 32%
to 33% of patients on HD survive to the fifth year of treatment,
and 70% of patients who have kidney transplants are alive
after five years.21 Restriction of certain nutrients, and removal
of waste metabolites from the blood by regular dialysis are
the two pillars from which a HD regimen is based on. Central
to effective management of patients with ESRD is adherence
6 Volume 55 Number 4 Oct.-Dec., 2017
Hemodialysis Patients’ Compliance and Adherence Behaviors
to this therapeutic regimen. Adherence refers to “the extent
to which a person’s behavior – taking medication, following
a diet, and/or executing lifestyle changes - corresponds
[to] the agreed recommendations from a health care
provider.” 22 Successful HD depends on four factors: fluid
restriction, dietary guidelines, medication prescriptions,
and attendance at HD sessions.23 Fluid restrictions can be as
severe as a maximum 500 mL of fluid intake daily, depending
on the residual diuresis. Patients receiving HD report a
large preoccupation with thirst, rank fluid adherence as
distressing,24 and often embark on fluid and dietary binges.25
Prescribed dietary restrictions limit sodium, potassium, and
protein intake. The goals of the medication regimen are to
treat or prevent cardiovascular comorbid conditions and
keep a stable mineral blood balance, for instance by giving
phosphate binders,26 this regimen consists of an average of
12 different drugs.27 Attendance at the prescribed dialysis
sessions implies both regular attendance (no skipping of
sessions) and full completion of the sessions (no shortening
of a session).
Causes of kidney failure
Dialysis therapy treatment non-adherence, including
treatment, medication, fluid, and diet non-adherence,
significantly increases the risk of morbidity and mortality. The
causes of chronic kidney disease in the patients enrolled in
this study were diabetes mellitus (n=22, 43.1%), hypertensive
nephrosclerosis (n=14, 27.5%), glomerulonephritis (n=11,
21.6%), and others (n=4, 7.8%). This was reflective to that of
the national populace.4
Prevalence of non-adherence
Appointment non-adherence refers to data gathered
by the dialysis staff about missed and shortened treatments,
along with the total treatment time missed. Missed
treatments, the percentage of nonattendance, are the
number of sessions skipped compared with the number
of sessions prescribed during a specific time. Shortened
treatments are the percentage of the prescribed time of
the attended sessions a patient actually receives dialysis
or the percentage of appointments shortened by a certain
amount of time. The total missed treatment time covers both
the skipping and the shortening dimensions of appointment
non-adherence; this time is the percentage of time a patient
received dialysis compared with the total time prescribed in
both attended and unattended sessions. These definitions
provide a clear and easy measure of nonadherence and
are therefore recommended.
Prevalence of non-adherence to appointments
Various studies have documented prevalence to
appointment non-adherence. In studies in which the
delivered dialysis dose was determined by assessing
 Hemodialysis Patients’ Compliance and Adherence Behaviors
appointment non-adherence, the relationship between
the dose and higher mortality28-30 or higher blood pressure31
was significant. Skipping at least one dialysis session per
month has been associated with a 25% to 30% higher risk
of death. 28,29 Shortening frequently more than 10 minutes
(=three times per month) also has been associated with
increased mortality.28
In a study done by Hecking et al. (2004), the number
of sessions skipped in the month before patients were
enrolled in the study was taken from among the random
sample of kidney centers in France (20 centers, N=672,
n=20, PP=2,976.19 per 100,000), Germany (21 centers, N=571,
n=5, PP=875.66 per 100,000), Italy (20 centers, N=600, n=53,
PP=8,833.33 per 100,000), Spain (20 centers, N=570, n=38,
PP=6,666.67 per 100,000) and United Kingdom (20 centers,
N=620, n=78, PP=12,580.65 per 100,000).
In this study, there were 10 patients who were non-
adherent to the HD appointment from a total of 102 in two
dialysis centers, the computed prevalence was 9,803.92 per
100,000. Most of those who were classified as non-adherent
would miss their dialysis appointment due to financial
constraints (n=8), whereas two specified having difficulty
in transportation (these patients were from the Island of
Guimaras, and for the month prior the study was conducted,
storm breakthroughs frequented the whole of Panay).
Prevalence of non-adherence to medications
Non-adherence with the medication regimen is usually
assessed by using self-reports or pre-dialysis serum levels
of phosphate, although the degree to which the results
of assessment of phosphate-binding medication can be
extrapolated to the rest of the medication regimen (calcium
supplements, vitamins B and C, folic acid, cardiovascular
drugs) is not known. The weak correlation between self-
reports and phosphate measurements (r= −0.24)32 may be
due to the fact that factors other than taking medication
(dietary adherence, for example) also affect serum levels of
phosphate.33 Assessment of serum calcium, which is generally
low in cases of non-adherence, is a complementary method
for evaluating adherence to use of phosphate binders.
In a study by Lin and Liang (1997), 86 patients in two
dialysis centers in Taiwan were ask to self-report adherence
with medication intake, 15 patients claimed to have been
non-adherent, the computed prevalence was 17,441.86 per
100,000. Also, in another study by Curtin et al. (1999), self-
reports as well as electronic monitoring and patient-reported
pill count were used to evaluate 135 patients’ adherence to
anti-hypertensives or phosphate binders in 11 centers in the
United States in 6 weeks’ times. It was scored either as perfect
adherence, minor non-adherence: <20% of prescribed
medications not taken; or major non-adherence: >20% of
prescribed medications taken. For the self-reports, there was
Ong RC, et al.
47% major non-adherence, 45% minor non-adherence and
7.0% adherence for anti-hypertensives; and there was 73%
major non-adherence, 25% minor non-adherence for the
phosphate binders.
In this study, 9.8% (n=6) were non-adherent to the
medications, the computed prevalence rate was 5,882.35
per 100,000. There were more females who were non-
adherent as compared to males.
Prevalence of non-adherence to fluid restriction protocol
Non-adherence to fluid restrictions can lead to fluid
overload and possibly complications such as pulmonary
congestion. Fluid non-adherence can be assessed by
measuring a patient’s weight gain between two HD sessions,
called interdialytic weight gain (IWG), or weight loss during a
session, called intradialytic weight loss (IWL). Non-adherence
with fluid restrictions results in excess weight gain between
two dialysis sessions (IWG), which is lost again during a dialysis
session (IWL). Indirect measurement of non-adherence to
fluid restriction is also possible by self-report. Vlaminck et al.
(2002) did a study in 10 dialysis center at Flanders involving
564 patients where self-reports of fluid adherence in the
past 14 days were gathered. There were 72% (n=406) who
admitted at least a mild (score≥1) non-adherence.
In another study done by Kugler et al (2005), a total of
916 patients from six centers in Germany and 12 centers in
Belgium who self-reported fluid adherence for the past 14
days were included. Seventy-four per cent (n=678) admitted
at least a mild (score≥1) non-adherence.
In this study, 19.7% (n=12) were non-adherent to fluid
restriction protocol. The computed prevalence rate was
11,764.71 per 100,000. Most of the adherent patients have
claimed that they (n=40/49, 81.6%) have experienced
difficulty of breathing, and was either rushed to the dialysis
unit for an emergency HD or to the emergency room for
confinement, thus after that have been compliant to the
regimen prescribed thereafter.
Prevalence of non-adherence to diet recommendations
Dietary non-adherence has been assessed by using
indirect measures such as patients’ self-reports and direct
measures such as pre-dialysis serum levels of potassium,
phosphate, urea nitrogen, and creatinine as well as pre-
dialysis normalized protein catabolic rate. Non-adherence
with sodium intake guidelines is measured by determining
IWG or IWL, because excessive sodium intake causes thirst
and leads to fluid nonadherence. 34 Kugler et al. (2005)
demonstrated that there 81.4% of 916 patients from Germany
and Belgium were at least mildly non-adherent to the diet
recommendations.
Volume 55 Number 4 Oct.-Dec., 2017 7
 Ong RC, et al.
In this study, 27.9% (n=17) were non-adherent to the diet
recommendations, the computed prevalence was 16,666.67
per 100,000. There were also more females who were non-
adherent to the dietary restrictions. Also notable was the 18%
(n=11) who were unable to avoid certain restricted food.
Behaviors of patients to treatment
Table VI shows the summary of known group analysis on
the questions that specifically address patients’ adherence
behaviors. It shows that there is a significant difference in the
behaviors of adherent and non-adherent patients towards:
HD attendance (p=0.000); shortening of HD treatment
(p=0.000); duration of shortening of HD (p=0.000); adherence
to medications (p=0.000); adherence to fluid restrictions
(p=0.000); and adherence to dietary restrictions (p=0.000).
Perception and understanding levels of adherence behaviors
Table VII shows the summary of known group analysis
on the questions that address patients’ perception and
understanding levels of adherence behaviors. There was
no significant difference in the perception of both adherent
and non-adherent CKD patients towards HD attendance
(p=0.306), as do in their understanding towards the level of
importance of attending to the HD treatment on schedule
(p=0.096). Both adherent and non-adherent patients have
the same level of perception and understanding towards the
importance of HD in their condition. There was no significant
difference in the perception on adhering to the prescribed
medications for both the adherent and non-adherent
patients (p=0.427). Both parties perceived that they need to
take the prescribed medications because it was important.
However, there was a significant difference in the levels of
understanding on the importance of medications between
the adherent and non-adherent subjects (p=0.001). The
non-adherers know that it is important to take the prescribed
medications, but they are limited to do so either because
of the following: 13% due to financial constraints, they are
limited by the cost of the medications (n=8); 8.2% said they
forgot to take the medications (n=5); and 4.9% claimed
they forgot to order medications (n=3). Most correlate their
need to take the medications with how they feel and would
allocate their limited financial resources to other matters,
like tuition fees of their children, and food – but they know
that they need to take the prescribed medications.
There was a significant difference on the perception
and understanding the level of importance to follow the
fluid restriction regimen in both adherers and non-adherers
(p=0.000, and p=0.000 respectively). Both groups know that
they need to limit their fluid intake. For the dietary restrictions,
there was a significant difference on the perception and
understanding level of importance for both the adherers
and non-adherers (p=0.001, and p=0.004 respectively). Most
of the non-adherers claimed that they feel that they need
8 Volume 55 Number 4 Oct.-Dec., 2017
Hemodialysis Patients’ Compliance and Adherence Behaviors
more nutrients as they feel weak more often than usual.
Also, one compelling reason was that more often than not,
they don’t have the appetite hence they eat whatever they
crave for.
Recommendations
With the data gathered and interpreted, the following
recommendations are suggested: Firstly, the standard of
care should be afforded to all patients coming from all
walks of life. The quality of care should not be different
merely because the patient is chronically ill. Stricter
implementation of quality assurance and quality control in
health care delivery, alongside a more holistic approach
with interventions utilizing a cognitive or cognitive/
behavioral component. The behavioral model may consist
of positive reinforcement, shaping, and self-monitoring,
and the cognitive model may consist of a counseling
intervention designed to modify health beliefs. Secondly,
administrative reforms are needed to facilitate better
delivery of health care services to among patients. Also,
stricter implementation of quality assurance and quality
control to police excellent health care accessibility and
opportunity in all HD centers. Identify other government
agencies that can provide support to chronically ill patients.
And lastly, a larger-scale multi-center study done in both
hospital-based and free-standing HD centers to compare
their approaches and its effectiveness to control non-
adherence to RRT. To compare the adequacy of HD among
adherent and non-adherent patient who are on HD.
Conclusion
The compliance of adherent subjects to RRT was more
adequate compared to those of non-adherent ones. The
non-adherent subjects were less prevalent than adherent
subjects. When grouped according to age, there was no
significant difference in the compliance of the respondents
to the respective descriptors, however there was a
significant difference in their adherence thereof. There was
a significant difference in the behaviors of adherent and
non-adherent patients towards HD attendance, shortening
of HD treatment, duration of shortening of HD, adherence to
medications, adherence to fluid restrictions, and adherence
to dietary restrictions.
References
1. European Renal Association-European Dialysis and Transplant
Association. ERAEDTA Registry 2004 Annual Report.
Amsterdam, the Netherlands: Department of Medical Informatics,
Academic Medical Center, 2006.
2. United States Renal Data System (USRDS) USRDS annual data
report. 2009. Retrieved from http://www.usrds.org/adr.htm.
3. National Statistics Office. Top 10 Causes of Morbidity and
Mortality in the Philippines.2008.
 Hemodialysis Patients’ Compliance and Adherence Behaviors Ong RC, et al.

4. Roxas, G. No kidding matter. Medical Observer, September 2010. 24. Schneider MS, Friend R, Whitaker P, Wadhwa NK. Fluid non-
Retrieved from http://www.medobserver.com/archivearticle. compliance and symptomatology in end-stage renal disease:
php?ArticleID=224. cognitive and emotional variables. Health Psychol. 1991;
5. Department of Health. Philippine Renal Disease Registry for 10:209–215.
2009. 2009. 25. Hoover H. Compliance in hemodialysis patients: a review of the
6. Danguilan, RA. The burden of kidney disease in the Philippines. literature J Am Diet Assoc. 1989;89:957–959.
ABS-CBN News, July 7, 2008. Retrieved from http://www. 26. L o c a t e l l i F. T h e n e e d f o r b e t t e r c o n t r o l o f s e c o n d a r y
abscbnnews.com/views-andanalysis/07/29/08/burden-kidney- hyperparathyroidism. Nephrol Dial Transplant. 2004;19(suppl
diseasephilippines. 5): V15–V19.
7. Bame SI, Petersen N, Wray NP. Variation in hemodialysis patient 27. Manley HJ, Garvin CG, Drayer DK, et al. Medication prescribing
compliance according to demographic characteristics. Soc Sci Med. patterns in ambulatory hemodialysis patients: comparisons of
1993 Oct; 37(8):1035-43. USRDS to a large not-for-profit dialysis provider. Nephrol Dial
8. Matteson ML, Russell C. Interventions to improve hemodialysis Transplant. 2004; 19:1842–1848.
adherence: a systematic review of randomized-controlled trials. 28. Leggat JE Jr, Orzol SM, Hulbert-Shearon TE, et al. Noncompliance
Hemodial Int. 2010 Oct;14(4):370-82. doi: 10.1111/j.1542- in hemodialysis: predictors and survival analysis. Am J Kidney
4758.2010.00462.x. Epub 2010 Aug 27. Dis.1998; 32:139–145.
9. Khalil AA, Lennie TA, Frazier SK. Understanding the negative 29. Saran R, Bragg-Gresham JL, Rayner HC, et al. Nonadherence
effects of depressive symptoms in patients with ESRD receiving in hemodialysis: associations with mortality, hospitalization, and
hemodialysis. Nephrol Nurs J. 2010 May-Jun; 37(3):289-295, practice patterns in the DOPPS. Kidney Int. 2003; 64:254–262.
308; quiz 296. 30. Kimmel PL, Peterson RA, Weihs KL, et al. Psychosocial factors,
10. Kim Y, Evangelista LS. Relationship between illness perceptions, behavioral compliance and survival in urban hemodialysis patients.
treatment adherence, and clinical outcomes in patients on Kidney Int.1998; 54:245–254.
maintenance hemodialysis. Nephrol Nurs J. 2010 May-Jun; 31. Rahman M, Fu P, Sehgal AR, Smith MC. Interdialytic weight
37(3):271-80; quiz 281. gain, compliance with dialysis regimen, and age are independent
11. Denhaerynck K, Manhaeve D, Dobbels F, Garzoni D, Nolte C, predictors of blood pressure in hemodialysis patients. Am J Kidney
De Geest S. Prevalence and consequences of nonadherence to Dis. 2000; 35:257–265.
hemodialysis regimens. American Journal of Critical Care.2007; 32. Lin CC, Liang CC. The relationship between health locus of control
16(3):222–235. Quiz 236. and compliance of hemodialysis patients. Kaohsiung J Med Sci.
12. Leggat JE, Orzol SM, Hulbert-Shearon TE, Golper TA, Jones 1997; 13:243–254.
CA, Held PJ, Port FK. Noncompliance in hemodialysis: Predictors 33. Vlaminck H, Maes B, Jacobs A, Reyntjens S, Evers G. The dialysis
and survival analysis. American Journal of Kidney Diseases. 1998; diet and fluid nonadherence questionnaire: validity testing of a
32(1):139–145. self-report instrument for clinical practice. J Clin Nurs. 2001;
13. Saran R, Bragg-Gresham JL, Rayner HC, Goodkin DA, Keen 10:707–715.
ML, van Dijk PC, et al. Port FK. Nonadherence in hemodialysis: 34. Kaveh K, Kimmel PL. Compliance in hemodialysis patients:
Associations with mortality, hospitalization, and practice patterns multidimensional measures in search of a gold standard. Am J
in the DOPPS. Kidney International. 2003; 64:254–262. Kidney Dis.2001; 37:244–266.
14. Cukor D, Rosenthal DS, Jindal RM, Brown CD, et al. Depression
is an important contributor to low medication adherence
in hemodialyzed patients and transplant recipients. Kidney
International (2009) 75, 1223–1229; doi:10. 1038/ki.2009.51;
published online 25 February 2009.
15. Department of Health. Philippine Renal Disease Registry Annual
Report for 2011.
16. Locatelli F, Marcelli D, Conte F, et al. Survival and development
of cardiovascular disease by modality of treatment in patients with
end stage renal disease. J Am Soc Nephrol. 2001;12:2411–2417.
17. Chan CT. Cardiovascular effects of frequent intensive hemodialysis.
Semin Dial. 2004; 17:99–103.
18. Horl MP, Horl WH. Hypertension and dialysis. Kidney Blood
Press Res.2003; 26:76–81.
19. Dunbar-Jacob J, Foley S. A historical overview of medication
adherence. In: Dunbar-Jacob J, Erlen J, Schlenk E, Stilley C, eds.
Methodological Issues in the Study of Adherence. Pittsburgh, Pa:
School of Nursing, University of Pittsburgh; 2005.
20. Vanholder R, Massy Z, Argiles A, Spasovski G, Verbeke F,
Lameire N. Chronic kidney disease as cause of cardiovascular
morbidity and mortality. Nephrol Dial Transplant. 2005;
20:1048–1056.
21. Collins AJ, Kasiske B, Herzog C, et al. Excerpts from the United
States Renal Data System 2003 Annual Data Report: atlas of
end-stage renal disease in the United 11 States. Am J Kidney Dis.
2003;42(6 suppl 5): A5–A7.
22. Sabate E, ed. Adherence to Long-term Therapies: Evidence for
Action. Geneva, Switzerland: World Health Organization; 2003.
23. Wolcott DL, Maida CA, Diamond R, Nissenson AR. Treatment
compliance in end-stage renal disease patients on dialysis. Am J
Nephrol. 1986; 6:329–338.

Volume 55 Number 4 Oct.-Dec., 2017 9

 Philippine Journal of Internal Medicine
The Correlation of Body Mass Index With Fasting C-peptide
Levels of Newly Diagnosed Type 2 Diabetes Mellitus Filipino
Patients
Patrick Y. Siy, M.D.*; Oliver Allan C. Dampil, M.D.*; Joselynna A. Quimpo, M.D.*
Abstract
Introduction: Type 2 diabetes mellitus (DM) is one of
the leading non-communicable causes of death in the
Philippines with a prevalence of 5.4% and its pathogenesis
includes insulin resistance correlated with excess weight and
BMI. Asian-based studies have shown that serum C-peptide
is strongly associated with newly diagnosed diabetes and
has a linear increasing trend with BMI, hence, this study
aimed to determine the correlation of body mass index
(BMI) with fasting C-peptide levels in Filipino patients
with newly diagnosed type 2 DM. Also, to determine the
correlation of fasting C-peptide, markers of insulin secretion
and sensitivity (Homeostasis Model Assessment of beta cell
function and insulin resistance: HOMA-IR, HOMA-B) with
other metabolic parameters in newly diagnosed diabetics:
waist circumference, HbA1C, fasting blood sugar (FBS),
lipid profile.
Methods: This cross-sectional study included 35 treatment
naïve, newly diagnosed type 2 DM Filipino patients evaluated
with anthropometric measurements, fasting C-peptide,
and other metabolic parameters. The correlations among
fasting C-peptide, BMI, waist circumference, FBS, HbA1c,
Introduction
Type 2 diabetes mellitus (DM) is one of the leading
non-communicable causes of death in the Philippines and
the number of people being diagnosed with type 2 DM is
growing with a prevalence of 5.4%.1,2 Complex mechanisms
are involved in the pathogenesis of type 2 DM. This involves
an interplay of genetic and environmental risk factors which
contribute strongly to the development of insulin resistance,
as well as β-cell failure. 3 Uncontrolled diabetes mellitus can
lead to microvascular and macrovascular complications like
diabetic retinopathy, nephropathy, neuropathy, myocardial
infarction, hypertension and peripheral arterial disease.4
Insulin resistance has been considered to have an
important role in the pathogenesis of type 2 DM and an
*Section of Endocrinology, Diabetes and Metabolism, St. Luke’s Medical
Center
Corresponding author: Patrick Y. Siy, M.D., St. Luke’s Medical Center,
Quezon City, Philippines
Email:siy_patrick@yahoo.com
The PHILIPPINE JOURNAL OF INTERNAL MEDICINE is a peer reviewed journal and a copyrighted publication of the Philippine College of Physicians
Original Article
lipid profile, HOMA-IR, and HOMA-B were determined using
Pearson correlation.
Results: A significant positive relationship were observed
between BMI and HOMA-IR(r=0.335); C-peptide and waist
circumference (r=0.363); C-peptide and HOMA-B(r=0.357);
HOMA-IR and C-peptide (r=0.892); HOMA-IR and waist
circumference (r=0.438); HOMA-IR and triglycerides (r=0.543).
HOMA-B was negatively correlated with FBS and HbA1C (r=-
0.771, and r=-0.641, respectively). No correlation was seen
between BMI and C-peptide (p=0.61).
Conclusion: Body mass index (BMI) is not correlated
with fasting C-peptide levels in newly diagnosed type 2
DM Filipino patients. The positive relationship between
C-peptide, waist circumference, and HOMA-IR merits further
evaluation with larger studies.
Keywords: c-peptide, type 2 diabetes mellitus, body mass
index, insulin resistance
increase in body fat is generally associated with an increase
in risk of metabolic diseases. 5,6 An established risk factor for
developing type 2 DM is excess weight and most patients
with type 2 DM are obese.7 Also, the risk of developing type 2
DM for individuals who were overweight or obese was about
1.5 to five times higher than for individuals with normal body
mass index (BMI). 8 It must be noted that BMI is a powerful
and modifiable risk factor for diabetes.9
Since insulin resistance is involved in DM, the quantification
of insulin secretion and insulin sensitivity are important in the
assessment of beta-cell function in diabetes. The gold-
standard methods for evaluation are the hyperglycemic and
euglycemic-hyperinsulinemic clamp, but these tests are time
consuming, expensive and require trained personnel. Other
methods used to evaluate insulin secretion and sensitivity
include surrogate markers derived from basal measurements
(such as homeostasis model assessment (HOMA) indexes),
fasting insulin and C-peptide; and oral stimulation tests (with
glucose or mixed meals), intravenous stimulation tests (with
glucose, glucagon or arginine).10
Volume 55 Number 4 Oct.-Dec., 2017 1
 Siy PY, et al.
C-peptide can be used to compute for the HOMA
indices. It is a pancreatic peptide of about 31 residues and
is the middle segment of proinsulin. Equimolar insulin and
C-peptide are released on proteolytic cleavage of proinsulin.
C-peptide immunoassay has been used to assess pancreatic
beta cell function in diabetic patients with circulating insulin
antibodies or exogenous insulin. The half-life of C-peptide is
30 minutes, almost eight times that of insulin which makes it
a more stable parameter in assessing insulin secretion and
sensitivity.11 Recent studies have suggested that C-peptide is
not only a marker of beta cell function but is also biologically
active. C-peptide increases glucose utilization when studied
on type 1 diabetic patients.12
In a study done in Thailand, it showed that fasting serum
insulin and C-peptide levels progressively increased from
normal subjects to the diabetic subjects. Serum C-peptide
was also more strongly associated with newly diagnosed
diabetes than insulin, and was an independent factor
associated with newly diagnosed diabetic subjects.13 While
in China, they found that fasting C-peptide showed linear
increasing trend while HbA1C showed decreasing trend with
BMI. They also saw that underweight patients had the lowest
C-peptide and highest HbA1C while overweight patients
had the highest C-peptide, blood pressure, triglyceride but
lowest HbA1C levels.14 Interestingly, a study done in Denmark
showed that C-peptide concentrations below 0.4 nmol/L
would predict insulin dependence on patients who are
already on oral hypoglycemic agents.15
The correlation of BMI and C-peptide has been
mentioned in previous studies in other countries but there
are no local studies yet. This study aims to answer if BMI is
correlated with fasting C-peptide levels in Filipinos, newly
diagnosed with type 2 DM. Taking into consideration that the
pathophysiology of type 2 DM involves BMI, insulin sensitivity
and insulin resistance, this study would help improve the
knowledge on BMI, beta-cell function, insulin resistance
and severity of diabetes in newly diagnosed Filipino
patients and help in the decision on the treatment of these
patients. We would also want to determine if BMI could be
a surrogate marker for insulin resistance in place of the more
expensive C-peptide test. This study could also be used as
a reference for future research on correlating C-peptide
levels with initiation of insulin treatment and development
of complications on this subset of patients.
The general objective of this study is to determine the
correlation of BMI with fasting C-peptide levels in patients
with newly diagnosed type 2 DM. Specifically, this study
aimed:
1. To determine the correlation of fasting C-peptide
with other metabolic parameters in newly diagnosed
diabetics: waist circumference, HbA1C, FBS, lipid profile,
HOMA-IR, HOMA-B.
2. To determine the correlation of insulin secretion and
2 Volume 55 Number 4 Oct.-Dec., 2017
The Correlation of Body Mass Index with Fasting C-peptide Levels
sensitivity (HOMA-B, HOMA-IR) with waist circumference,
HbA1C, FBS, lipid profile.
Methods
Study design and subjects
This was a cross-sectional study approved by the
Institutional Review Board and Institutional Ethics Review
Committee of St. Luke’s Medical Center (SLMC), Quezon
City that included 35 treatment-naïve, newly diagnosed
type 2 DM Filipino patients seen at both the private clinics
and social service out-patient department of SLMC,
Quezon City, Philippines from August 2016-January 2017.
Endocrinologists, fellows-in-training and medical residents
informed the researchers on potential participants then
they were screened during out-patient visit, and asked to
participate in the study based on the inclusion and exclusion
criteria. Patients were included if they are adults (age more
than 18 years old) and newly diagnosed patients who
matched the American Diabetes Association (ADA) criteria16
for the diagnosis of type 2 DM within three months who are
also medication-naïve. They were excluded if the patients
were on anti-diabetic medications for other indications; on
steroid therapy; pregnant; with active infection; with chronic
kidney disease stage three, four and five (eGFR <60), since
there was higher levels of C-peptide compared to those
with stage one and two disease17; and with history of liver
disease since liver disease can cause alteration in levels of
C-peptide particularly in cirrhotic patients.18 The subjects
were recruited by consecutive sampling.
All participants signed the informed consent voluntarily
after thorough explanation on the nature of the research;
objectives, risks, and expected benefits to participation.
Participants were interviewed by the researcher.
Demographic information was collected, as well as medical
history and other related diseases, they then underwent a
physical examination. Height, weight, waist circumference,
and blood pressure were measured by the researcher using
the weighing scale, tape measure and sphygmomanometer
of the diabetes, thyroid and endocrine center at SLMC,
Quezon City.
Laboratory analysis
Blood samples were collected and processed by the
pathology department at SLMC, Quezon City. Complete
blood count was measured by electrical impedance using
the Sysmex XN-3000. Fasting blood sugar was measured
by hexokinase method using Dimension RXL Max with
versacell. Creatinine, lipid profile and SGPT were measured
using the same machine. C-peptide was measured by
chemiluminescence using Architect 1000ISR. HbA1C was
measured by HPLC using Biorad Variant II Turbo. HOMA-B
 The Correlation of Body Mass Index with Fasting C-peptide Levels Siy PY, et al.

Table I. The anthropometric and metabolic characteristics of participants

Characteristics Overall (n=35) Males (10) Females (25)

Age (years ± SD) 50 ± 9 50 ± 7 50 ± 10
Height (cm ± SD) 156.4 ± 9.8 164.8 ± 5.9 153 ± 9
Weight (kg ± SD) 70.1 ± 12.5 76.6 ± 11.3 67.5 ± 12
Body Mass Index (kg/m2 ± SD) 28.6 ± 4.1 28.3 ± 3.9 28.8 ± 4.1
Waist circumference (cm ± SD) 96.6 ± 7.8 97.2 ± 7.2 96.4 ± 8
Family History of Diabetes (with family history %) 60% 50% 64%
Systolic BP (mmHg ± SD) 128 ± 14 134 ± 17 126 ± 12
Diastolic BP (mmHg ± SD) 80 ± 7 83 ± 8 78 ± 5
Creatinine (mg/dL ± SD) 0.76 ± 0.19 0.95 ± 0.17 0.68 ± 0.14
SGPT (U/L ± SD) 49.8 ± 33 47 ± 25.8 50.9 ± 35.6
FBS (mg/dL ± SD) a
174 ± 63 208 ± 66 160 ± 56
HbA1C (% ± SD) 8.8 ± 2.3 10.1 ± 2.9 8.3 ± 1.9
Total Cholesterol (mg/dL ± SD) 220 ± 43 221 ± 53 220 ± 38
Triglycerides (mg/dL ± SD) 170 ± 114 227 ± 152 148 ± 85
HDL (mg/dL ± SD)b 46 ± 13 39 ± 8 49 ± 13
LDL (mg/dL ± SD) c
140 ± 34 134 ± 40 142 ± 30
C-peptide (ng/mL ± SD) 2.79 ± 1.03 2.76 ± 1 2.8 ± 1
HOMA-IR (IR ± SD) d
2.56 ± 0.97 2.78 ± 1 2.47 ± 0.95
HOMA-B (% ± SD) e
65.14 ± 40.39 51.49 ± 28.93 70.6 ± 42.95
Fasting blood sugar, bHigh Density Lipoprotein, cLow Density Lipoprotein, dHomeostasis Model Assessment of Insulin
a

Resistance, eHomeostasis Model Assessment of beta cell function

and HOMA-IR were computed using an online calculator and HOMA-B. Pearson’s correlation analyses were used for
downloaded from the University of Oxford website: https:// correlating HOMA-IR and HOMA-B with waist circumference
www.dtu.ox.ac.uk/homacalculator/. HbA1C, Lipid Profile, and FBS. A p-value of <0.05 was
considered statistically significant.
No further follow-up was required after all data
collection and laboratory extraction. Patients proceeded
with their regular check-up or follow-up with their respective
Results
physicians.
Mean age was 50 years in this set of newly diagnosed

type 2 DM patients. (Table I). The youngest subject included
Sample size calculation
in this study was 26 years of age. Almost a third of the
subjects were male. 80% (n=28) were obese, 17% (n=6) were
Sample size was computed using piface program for
overweight, and three percent (n=1) with normal BMI, based
linear regression. Given a correlation of 0.488, and assuming
on the Asia-Pacific guidelines on obesity, with a mean of
SD of one and error SD of one, 35 subjects were needed to
28.6 kg/m 2. Mean FBS was 174 with an HbA1C of 8.8 with
achieve 80% power at 0.05 alpha.
males having a higher HbA1C compared to females. More
than half of the participants had a first degree relative with
Statistical analysis
type 2 DM. The mean cholesterol, triglyceride, low-density
lipoprotein (LDL) were elevated and the mean high-density
Descriptive statistics was used to characterize the
lipoprotein (HDL) were below normal based on gender.
study population. Data were expressed as percentage and
mean±SD. These included the age, gender, family history
No correlation was seen between BMI and C-peptide
of diabetes, blood pressure, height, weight, BMI and waist
with a p-value of 0.61 but positive correlations with moderate
circumference. Statistical analyses were performed using
association were noted with BMI and HOMA-IR(r=0.335).
the SPSS software package. Pearson’s correlation analyses
C-peptide showed a linear positive correlation with waist
were used for correlating BMI with fasting C-peptide levels,
circumference (r=0.363). HOMA-IR was positively correlated
and were also used for correlating C-peptide levels with
with C-peptide with a strong association (r=0.892), and with
waist circumference, HbA1C, Lipid Profile, FBS, HOMA-IR
waist circumference with moderate association (r=0.438).

Volume 55 Number 4 Oct.-Dec., 2017 3

 Siy PY, et al. The Correlation of Body Mass Index with Fasting C-peptide Levels

Table II. Pearson’s correlations (95% CI) of C-peptide with BMI patients had a C-peptide level of <1.2 ng/mL (<4 nmol/L)
and other metabolic parameters indicating that these patients can still be treated with oral
hypoglycemic agents and there is a lower possibility for
C-peptide (r) HOMA-IRd (r) HOMA-Be (r) future insulin requirement.15
p-value p-value p-value
  (95% CI) (95% CI) (95% CI)
Insulin resistance calculated with HOMA-IR is correlated
0.320 0.335 0.025 positively with increasing BMI, more so with increasing waist
BMI 0.61 0.049 0.886 circumference. Studies showed different results regarding
(0.39-5.68) (0.055-0.569) (0.141-0.572)
waist circumference and BMI as predictors of insulin
0.892 0.357
resistance. Some studies suggest that waist circumference
C-peptide - <0.001 0.035
(0.742-0.964) (-0.138-0.570) could be a better predictor of insulin resistance and
cardiovascular risk while others showed no difference.22,23,24
0.363 0.438 0.061
Waist In this study, both BMI and waist circumference were
0.032 0.009 0.728
circumference
(0.136-0.583) (0.238-0.634) (-0.222-0.343) associated with HOMA-IR but waist circumference showed
-0.118 0.312 -0.771 a stronger statistical significance. This may provide us with
FBSa 0.5 0.068 <0.001 another parameter to consider on how to treat our patients
(-0.32-0.12) (0.36-5.91) (-0.880-0.653 with greater waist circumference seeing that it is correlated
-0.187 0.165 -0.641 with insulin resistance. Triglycerides were also associated
HbA1C 0.281 0.343 <0.001 with insulin resistance probably due to the physiology and
(-0.427-0.82) (-0.149-0.495) (-0.792-0.505)
interaction of triglycerides and insulin.
0.043 0.096 0.029
Total
0.806 0.584 0.869
Cholesterol Increasing HOMA-B in relation to a decreasing FBS and
(-2.33-0.385) (-0.234-.422) (-0.333-0.337)
HbA1C is the physiologic response of the body to decrease
0.173 0.543 -0.156
Triglycerides 0.119 0.001 0.372 glucose levels. This trend is seen during the early stages of
(-0.05-0.452) (0.252-0.75) (-0.354-0.29) type 2 DM where the pancreas still has enough beta cell
0.173 0.069 0.069 activity to compensate but cannot totally normalize the
HDLb 0.321 0.692 0.692 fasting blood glucose.
(-0.05-0.452) (-0.176-0.326) (-0.176-0.326)
-0.178 -0.334 0.282 Based on this study, BMI may not be a good surrogate
LDLc 0.306 0.05 0.101
marker in place of C-peptide in determining insulin resistance
(-0.43-0.078) (-0.565-0.063) (-0.086-0.569)
in Filipinos with newly diagnosed type 2 DM.
a
Fasting blood sugar, b High Density Lipoprotein, c Low Density
Lipoprotein, d Homeostasis Model Assessment of Insulin Resis-
tance, e Homeostasis Model Assessment of beta cell function Conclusion
HOMA-IR was also positively correlated with triglycerides
with strong association (r=0.543). HOMA-B was positively Body mass index (BMI) is not correlated with fasting
correlated with C-peptide (r=0.357), and negatively C-peptide levels in newly diagnosed type 2 DM Filipino
correlated with FBS and HbA1C (r=-0.771, and r=-0.641, patients. The researchers recommend further investigation
respectively). (Table II). on waist circumference since this may be used as a less
expensive way of determining insulin resistance and aid in

Discussion a more appropriate management of DM.

Unlike in the study done in China and Thailand13,14, this
cross-sectional studies showed no association between
the BMI and C-peptide. This non-association may be due
to differences in body composition of a person, a higher
BMI does not necessarily correlate to disturbed glucose
tolerance or increase in body fat percentage which could
affect C-peptide levels. 19 Also, although of the same
race, there might be ethnic differences which could have
contributed to the difference in the results of the studies.
Another factor to consider with the non-correlation of BMI
and C-peptide is the patient’s physical activity. It has been
shown that habitual physical activities are associated with
lower C-peptide levels. 20, 21 Some of these individuals may
have these activities hence altering the results. None of the
Acknowledgement
This study was funded by the research, and biotechnology
department of SLMC, Quezon City, Philippines.
References
1. Department of Health, Republic of the Philippines. Twenty years
of non-communicable disease (NCD) prevention and control in
the Philippines (1986-2006). 2009.
2. Paz-Pacheco E, Jimeno C. Diabetes Care in the Philippines.
Journal of the ASEAN Federation of Endocrine Societies,
2015;30(2):118-23
3. D’Adamo E, Caprio S. Type 2 diabetes in youth: epidemiology
and pathophysiology. Diabetes Care. 2011;34 Suppl 2:S161–5.
4. Sosale A, Prasanna Kumar KM, Sadikot SM, Nigam A, Sarita

4 Volume 55 Number 4 Oct.-Dec., 2017

 The Correlation of Body Mass Index with Fasting C-peptide Levels Siy PY, et al.

B, Zargar AH, et. al. Chronic complications in newly diagnosed 24. Elbassuoni E. Better association of waist circumference with
patients with type 2 diabetes mellitus in India. Indian Journal of insulin resistance and some cardiovascular risk factors than body
Endocrinology and Metabolism, 2014:18(3):355–360. mass index. Endocr Regul. 2013 Jan;47(1):3-14.
5. Mahler RJ, Adler ML. Type 2 Diabetes Mellitus: Update On
Diagnosis, Pathophysiology, And Treatment. Clinical Review 102.
J Clin Endocrinol Metab 1999, 84(4):1165-1171.
6. Bays HE, Chapman RH, Grandy S. The relationship of body
mass index to diabetes mellitus, hypertension and dyslipidaemia:
comparison of data from two national surveys. International
Journal of Clinical Practice, 2007:61(5):737-747.
7. Eckel RH, Kahn SE, Ferrannini E, Goldfine AB, Nathan DM,
Schwartz MW, et. al. Obesity and type 2 diabetes: what can be
unified and what needs to be individualized? J Clin Endocrinol
Metab 2011;96:1654–1663.
8. Schienkiewitz A, Schulze MB, Hoffmann K, Kroke A, Boeing
H. Body mass index history and risk of type 2 diabetes: results
from the European Prospective Investigation into Cancer and
Nutrition (EPIC)-Potsdam Study. The American Journal of Clinical
Nutrition, 2006:84(2):427–433.
9. Narayan KMV, Boyle JP, Thompson TJ, Gregg EW, Williamson
DF. Effect of BMI on lifetime risk for diabetes in the U.S. Diabetes
Care, 2007:30(6):1562–1566.
10. Cernea S, Dobreanu M. Diabetes and beta cell function: from
mechanisms to evaluation and clinical implications. Biochem Med
(Zagreb). 2013;23:266-280.
11. National Center for Biotechnology Information. PubChem
Compound Database; CID=16132309,https://pubchem.ncbi.nlm.
nih.gov/ compound/16132309 (accessed Feb. 2, 2016)
12. Wilhelm B, Kann P, Pfützner A. Influence of C-peptide on glucose
utilisation. Experimental Diabetes Research. 2008;2008:3
13. Chailurkit LO, Jongjaroenprasert W, Chanprasertyothin S,
Ongphiphadhanakul B. Insulin and C-peptide levels, pancreatic
beta cell function, and insulin resistance across glucose tolerance
status in Thais. J Clin Lab Anal. 2007;21:85–90.
14. Chan WB, Tong PC, Chow CC, So WY, Ng MC, Ma RC, et al. The
associations of body mass index, C-peptide and metabolic status in
Chinese Type 2 diabetic patients. Diabet Med. 2004;21:349–353.
15. Nielsen NV, Tronier B. C-peptide and insulin secretion in diabetes
mellitus treated with oral hypoglycaemic agents or diet alone.
A 3 years epidemiological cohort study on the Island of Falster,
Denmark. Diabetes Res. 1987 Mar;4(3):135-9.
16. American Diabetes Association. Standards of medical care in
diabetes 2015. Diabetes Care. 2015;38(Suppl 1):S8-S13.
17. Chen J, Muntner P, Lee H, Fonseca V, Batuman V, Whelton PK,
et. al. Insulin Resistance and Risk of Chronic Kidney Disease in
Nondiabetic US Adults. J. Am. Soc. Nephrol. 2003;14:469-477.
18. Gragnoli G, Signorini AM, Tanganelli I. Plasma levels of insulin,
C-peptide and glucagon in liver cirrhosis. J Endocrinol Invest.
1981Jan-Mar;4(1):1-5.
19. Gomez-Ambrosi J, Silva C, Galofre JC, Escalada J, Santos S, Gil
MJ, et al. Body adiposity and type 2 diabetes: increased risk with
a high body fat percentage even having a normal BMI. Obesity
(Silver Spring) 2011;19: 1439–1444.
20. Huus K, Åkerman L, Raustorp A, Ludvigsson J. Physical Activity,
Blood Glucose and C-Peptide in Healthy School-Children, a
Longitudinal Study. PLoS ONE. 2016; 11(6):e0156401.
21. Larsen J, Dela F, Madsbad S, Galbo H. The effect of intense
exercise on postprandial glucose homeostasis in Type II diabetic
patients. Diabetologia (1999) 42: 1282-1292.
22. Huang LH, Liao YL, Hsu CH. Waist circumference is a
better predictor than body mass index of insulin resistance
in type 2 diabetes. Obesity Research & Clinical Practice.
2012;6(4):e314-e320.
23. Farin HM, Abbasi F, Reaven GM. Body mass index and waist
circumference both contribute to differences in insulin-mediated
glucose disposal in nondiabetic adults. Am J Clin Nutr. January
2006;83(1):47-51.

Volume 55 Number 4 Oct.-Dec., 2017 5

 Philippine Journal of Internal Medicine
Diagnosis of Gestational Diabetes Mellitus Using the
International Association of the Diabetes and Pregnancy Study
Groups Criteria and Adverse Pregnancy Outcomes Among a
Cohort of Filipino Women: An Association Analysis
Kristine S. de Luna, M.D.* and Elaine C. Cunanan, M.D.**
Abstract
Introduction: Locally, there is no unified set of diagnostic
criteria for gestational diabetes mellitus (GDM) and this can
lead to potential confusion on the part of the physician and
the patient as well. Moreover, whether the adoption of the
International Association of the Diabetes and Pregnancy
Study Groups (IADPSG) threshold values for GDM diagnosis
among Filipino women is appropriate is still unclear. This study
serves to give a clinically important insight whether utilizing
the abovementioned diagnostic criteria is appropriate in
the local setting or not. The study aims to determine the
association of the threshold values set up by the IADPSG to
diagnose GDM with adverse pregnancy outcomes among
a cohort of Filipino women.
Methods: A retrospective analysis of medical files of the
women diagnosed with GDM using the IADPSG criteria from
January 2013 to March 2016 was done. The results of seventy-
five gram oral glucose tolerance test (75-g OGTT) were
recorded. The association between each IADPSG threshold
values (fasting blood glucose of ≥92 mg/dL, one-hour post
glucose load of ≥180 mg/dL, two-hour post glucose load
of ≥153 mg/dL) used to define GDM and maternal and
perinatal outcomes were determined.
Results: One hundred twenty women with GDM were
included in the analysis. Each of IADPSG-defined cut-off
Introduction
Over the years, around the world, various sets of
diagnostic criteria have been formulated to detect
gestational diabetes mellitus (GDM) resulting in the lack
of a unified consensus on how this condition should be
diagnosed. Locally, two diagnostic criteria can be used
to interpret GDM based on 75-g OGTT values. One is the
International Association of Diabetes and Pregnancy Study
Groups (IADPSG) criteria that is being endorsed by the Unite
for Diabetes Philippines and widely applied. 1-3 The patient
*Fellow-in-training, Section of Endocrinology, Diabetes, and Metabolism,
Department of Medicine, University of Santo Tomas Hospital
**Consultant, Section of Endocrinology, Diabetes, and Metabolism,
Department of Medicine, University of Santo Tomas Hospital
Corresponding author: Kristine S. de Luna, M.D., University of Santo
Tomas Hospital, Manila, Philippines
Email:adobe0328@yahoo.com
The PHILIPPINE JOURNAL OF INTERNAL MEDICINE is a peer reviewed journal and a copyrighted publication of the Philippine College of Physicians
Original Article
values was not significantly associated with increased
likelihood of having adverse maternal outcomes namely:
hypertensive disorders of pregnancy, miscarriage, primary
cesarean section, operative vaginal delivery, and maternal
death. Similarly, the likelihood of perinatal outcomes namely:
macrosomia, perinatal death, prematurity, birth injuries,
congenital anomalies, neonatal hypoglycemia, jaundice,
low APGAR score, acute respiratory distress syndrome, and
infection were not significantly higher even if these cut-off
values were met.
Of note, high odds ratio was noted for neonatal
hypoglycemia at FBS >92 mg/dL and <92 mg/dL and the low
Apgar Score in first minute at >153 mg/dL and <153 mg/dL
even though they were statistically not significant.
Conclusion: We did not find a statistically significant positive
association between IADPSG threshold values and specified
adverse maternal and perinatal outcomes.
Keywords: gestational diabetes mellitus, IADPSG criteria,
75-gram oral glucose tolerance test, adverse pregnancy
outcomes
needs to undergo three blood extractions to obtain the
baseline fasting blood glucose (FBS), one-hour post-glucose
load, and two-hour post-glucose load values that might pose
inconvenience and added expense to our usually resource-
poor patients.
Historically, each of the three 75-g OGTT diagnostic
thresholds is arbitrarily chosen based on Hyperglycemia
Adverse Pregnancy Outcomes (HAPO) trial, where increasing
maternal hyperglycemia showed strong associations
with increasing birth weight and other outcomes such
as prematurity, birth injury, neonatal intensive care unit
(NICU) admission, hyperbilirubinemia, and preeclampsia. 4-6
However, due to the absence of any clear threshold of
glucose concentration at which risk of adverse outcomes
increased, the group reached a consensus that the
thresholds for diagnosing GDM would be: the glucose
Volume 55 Number 3 4 Oct.-Dec., 2017 1
 De Luna KS & Cunanan EC
values at which the odds ratios (ORs) reached 1.75 for
birth weight greater than the 90th percentile, percent
infant body fat (based on skinfolds) greater than the 90th
percentile, and concentration of C-cord peptide greater
than the 90 th percentile. 5,7 Several other adverse pregnancy
outcomes especially perinatal death were not taken into
consideration due to the technical limitation of the HAPO
trial for its analysis. In addition, only 29% were Asians in this
trial based on self-reporting1,4 thus questioning applicability
of the IADPSG criteria to Filipinos. The studies of Urbanozo1
and Serafica-Hernandez3 bear similar findings with the HAPO
study. In line with these findings, authors hypothesized that
there will be an association between IADPSG threshold
values and specified adverse maternal and perinatal
outcomes. However, one expert noted that there was a
diverse rate of GDM incidence among Asian groups leading
to the theory that there may be differences in pregnancy
outcomes among these groups.1 The Philippine Obstetrics
and Gynecological Society (POGS) system can be used
and requires only two blood extractions to get the fasting
blood glucose and two-hour post-glucose load values. The
adoption of two systems in the diagnosis of GDM can add
to potential diagnostic confusion and therapeutic dilemma
(due to same FBS cut-off value but different two-hour post-
glucose load cut-off value) especially if the patient is being
seen by two specialties that usually happen. The issues above
seem to have important clinical implication with regards to
formulating a unified set of diagnostic criteria that may be
more suitable to the Filipino population and more intelligible
to the health care providers.
We therefore aimed to determine the association of
IADPSG-defined cut-off values to diagnose GDM to adverse
pregnancy outcomes among a cohort of Filipino women.
The finding of our study will give a clinically important insight
whether adopting this set of diagnostic criteria is appropriate
in the local setting.
Methods
Study design and setting
This was a retrospective review and analysis of out-
patient and in-patient medical records of Filipino women
identified with GDM using the IADPSG criteria who attended
and delivered at the University of Santo Tomas Hospital (USTH)
pay and clinical division from January 2013 to March 2016.
The pay division which is equivalent to the private section
of a hospital, is attended by more financially-able patients,
while the clinical division, due to its lower fees is attended
by patients with a limited budget. GDM was diagnosed
according to this set of criteria if at least one 75-g OGTT value
equal or exceeds the following thresholds: FBS of 92 mg/dL,
one-hour post-glucose load of 180 mg/dL, and two-hour
post-glucose load of 153 mg/dL. Patients had 75-g OGTT
2 Volume 55 Number 4 Oct.-Dec., 2017
Diagnosis of Gestational Diabetes Mellitus using the IADPSG
in different laboratories since they were usually advised by
their physician to have the blood test in a location that is
convenient for them. Data from the medical charts of their
corresponding neonates were also gathered and analyzed.
The study was reviewed and approved by the Institutional
Review Board of the USTH prior to its implementation.
Participants
Inclusion criteria for this study were the following: women
whose GDM were diagnosed using IADPSG criteria, women
18 years old and above, and singleton pregnancy. On the
other hand, exclusion criteria for this study were the following:
diagnosis of pre-gestational diabetes mellitus (DM) or overt
DM, women whose medical files contained insufficient data
to be included in the analysis, and women whose neonate
had missing and incomplete medical files.
Over a three year and three-month period, 153 women
were identified as having GDM. Thirty-three medical records
were excluded due to insufficient data (n= 30), and diagnosis
of twin pregnancy (n= 3) which left a total of 120 files suitable
for analysis
Study variables and definition of terms
Maternal antepartum characteristics gathered were
the following: maternal age at delivery, parity, height
in centimeters (cm), weight in kilograms (kg),body mass
index (BMI) (which was calculated as weight divided by
height squared in kg/m 2), 75-g OGTT values in milligrams
per deciliter or mg/dL (which included FBS, one-hour post-
glucose load, and two-hour post-glucose load), family
history of diabetes mellitus (DM), macrosomia in the previous
pregnancy, polycystic ovary syndrome (PCOS), chronic
hypertension, dyslipidemia, pre-diabetes (which included
a diagnosis of impaired fasting blood glucose or impaired
glucose tolerance prior to pregnancy), GDM in the previous
pregnancy, and treatment modality of GDM (whether
treated with diet and physical activity or supplemental
insulin).
The following adverse maternal pregnancy outcomes
were collected: hypertensive disorders of pregnancy (which
included gestational hypertension, pre-eclampsia and
eclampsia), 8 miscarriage, primary cesarean section, and
operative vaginal delivery (deliveries where either forceps
or ventouse was used to deliver fetal head),9 and maternal
death.
The following adverse perinatal outcomes were
collected: prematurity (defined as having gestational age at
delivery of <37 weeks),9 macrosomia (defined as birth weight
more than 3.6 kg as set by the ASEAN Federation of Endocrine
Society Study Group for Diabetes in Pregnancy2 or having
a notation of LGA in the chart), low APGAR score taken
 Diagnosis of Gestational Diabetes Mellitus using the IADPSG De Luna KS & Cunanan EC

at one minute and at five minutes (defined as having an

Table I. Summary of maternal antepartum profiles (N=120)
APGAR score of less than seven),10 neonatal hypoglycemia
(defined as blood glucose value of less than 40 mg/dL 11 or Antepartum profiles Data
having a notation of such condition in the chart), jaundice, Maternal age (years) 31.88 + 5.4*
perinatal death (term used for fetal and infant deaths), 12
Parity
acute respiratory distress syndrome, congenital anomalies, Primiparous 38 (31.93)**
infection, and birth injury. Other data recorded were Multiparous 81 (68.07)**
gestational age at delivery in weeks, birthweight in kilograms, Height (cm) 155.57 + 9.91*
capillary blood glucose (CBG)value taken at first hour of life Weight (kg) 68.80 + 12.27*
in mg/dL, and APGAR score taken at one minute and at five
BMI (kg/m2) 28.88 + 8.86*
minutes.
75-g OGTT values (mg/dL)
FBS 95.14 + 20.36*
1-hour post-glucose load 186.15 + 48.98*
Statistical analysis 2-hour post-glucose load 166.74 + 54.82*
Mode of Treatment
Descriptive statistics was used to summarize the clinical Diet and Physical Activity 64 (53.33)**
characteristics of the study population. Frequency and Supplemental Insulin 56 (46.67)**
percentage was used for nominal variables, and mean Family history of DM 70 (58.33)**
and standard deviation (SD) for interval/ratio variables. PCOS 12 (10)**
Median and range was used for ordinal variables. Binary Diagnosis of pre-DM prior to pregnancy 2 (1.67)**
Chronic hypertension 12 (10)**
logistic regression analysis was used to determine the
Dyslipidemia 1 (0.83)**
significant maternal and perinatal factors associated with GDM in previous pregnancy 20 (16.67)**
blood glucose parameters of 75-g OGTT. A p-value of <0.05 Macrosomia in previous pregnancy 17 (14.17)**
was considered significant. All data were entered using *Mean and Standard deviation
**Frequency and percentage
the Microsoft Excel for Mac 2011 (Version 14.6.5). Statistical
analysis was carried out using STATA 12.0 software. Table II. Summary of maternal outcomes (N=120)

Maternal outcomes Frequency (%)

Results Hypertensive disorders of pregnancy 11 (9.17)
Miscarriage 0
From January 2013 to March 2016, 153 women were Primary Cesarean section 50 (41.67)
diagnosed as having GDM, while 3122 women had no
Operative vaginal delivery 3 (2.5)
GDM. A total of 120 women with GDM were included in the
Maternal death 0
analysis after fulfilling the inclusion criteria. Table I shows the
maternal antepartum profile of 120 participants in the study. Table III. Summary of perinatal profiles of study participants (N = 120)
The participants had a young mean age. Two-thirds of the
participants (n=81) were multigravid. They also had a high Perinatal profiles Data
mean BMI of 28.88 kg/m 2. In terms of 75-g OGTT values, they Birth weight (kg) 3.05 + 0.61*
had mildly elevated parameters: mean FBS of 95.14 mg/dL, Macrosomia 16 (13.33)**
mean one-hour post-glucose load value of 186.15 mg/dL,
Gestational age at delivery (weeks) 37.82 + 2.14*
and mean two-hour post-glucose load value of 166.75 mg/
Premature 14 (11.67)**
dL. More than half of the participants had family history of
diabetes mellitus. The most common maternal comorbidity APGAR score
1st minute 8 (2 to 8)***
was previous GDM (n=20), macrosomia (n=17), chronic 5th minute 9 (4 to 9)***
hypertension (n=12), and PCOS (n=12).
Perinatal death 3 (2.50)**
Jaundice 40 (33.33)**
Table II shows the summary of maternal outcomes. There
were no cases of serious outcomes such as miscarriage and CBG at 1st hour of life 65 (21 to 175)***
maternal death. Few women had hypertensive disorders of Neonatal hypoglycemia 5 (4.16)**
pregnancy (n=11, 9.17%). In terms of mode of delivery, almost Congenital anomalies 5 (4.16)**
half of the participants underwent primary CS (n=50, 41.67%) Acute respiratory distress syndrome 2 (1.67)**
while only 2.5% (n=3) underwent forceps-assisted vaginal
Infection 18 (15)**
delivery.
Birth injuries 1 (0.83)**
*Mean and standard deviation
Table III shows the perinatal profile of study participants.
**Frequency and percentage
The mean birth weight was normal at 3.05 kg. Among the ***Median and range

Volume 55 Number 4 Oct.-Dec., 2017 3

 De Luna KS & Cunanan EC Diagnosis of Gestational Diabetes Mellitus using the IADPSG

Table IV. Proportion and association of adverse pregnancy outcomes in relation to IADPSG-defined FBS threshold value
for GDM diagnosis (N = 120)

FBS ≥ 92 mg/dL FBS < 92 mg/dL

Maternal outcomes n=61 n=59 OR (CI)* p-value
Frequency (%)
Hypertensive disorders of pregnancy 5 (8.20) 6 (10.17) 0.79 (0.23-2.74) 0.71
Miscarriage 0 0 - -
Primary cesarean section 23 (41.07) 27 (45.76) 0.83 (0.39-1.73) 0.61
Operative vaginal delivery 1 (1.75) 2 (3.39) 0.51 (0.04-5.77) 0.59
Maternal death 0 0 - -
Perinatal outcomes
Macrosomia 9 (15.79) 8 (14.04) 1.15 (0.41-3.22) 0.79
Perinatal death 1 (1.75) 2 (3.39) 0.51 (0.04-5.77) 0.59
Prematurity 6 (10.71) 8 (13.79) 0.75 (0.24-2.32) 0.62
Birth injuries 0 1 (1.72) - -
Congenital anomalies 2 (3.51) 3 (5.17) 0.67 (0.11-4.15) 0.66
Neonatal hypoglycemia 4 (8.51) 1 (2.27) 4 (0.43-37.26) 0.22
Jaundice 21 (36.84) 19 (32.76) 1.20 (0.56-2.58) 0.65
Low APGAR score (<7)
1st minute 5 (8.77) 6 (10.53) 0.82 (0.23-2.85) 0.75
5th minute 3 (5.26) 4 (7.02) 0.74 (0.16-3.45) 0.70
Acute respiratory distress syndrome 0 2 (3.45) - -
Infection 9 (15.79) 9 (15.52) 1.02 (0.37-2.79) 0.97
*OR- odds ratio; CI- confidence interval

neonates in the study, the mean maturity was 37.82 weeks. Table VI shows that a two-hour glucose post-load value
Only sixteen neonates (13.33%) were macrosomic while 14 of ≥153 mg/dL, was associated with six times more likelihood
were born premature (11.67%). Three perinatal deaths (2.5%) (OR=6.61) of having an infant with a low one-minute APGAR
were noted. Five neonates (4.16%) were noted to have score. Women with this glucose value were twice as likely to
congenital anomalies. have macrosomic (OR=2.09), and premature infants (OR=
2.34). Moreover, a smaller increased rate of undergoing
Table IV shows that women with an FBS of ≥92 mg/ primary CS (OR=1.96), and having jaundiced infants
dLhad four times the odds of having infants with neonatal (OR=1.56) was observed. Similar to the earlier findings, these
hypoglycemia. However, this was not statistically significant values did not reach statistical significance.
(p=0.22). There also seemed to have a non-significant and
small increase in the likelihood of having macrosomic infants
(OR=1.15, p=0.79), neonatal jaundice (OR=1.20, p=0.65), and
Discussion
neonatal infection (OR= 1.02, p=0.97).
The results indicate that the rate of developing adverse
maternal and perinatal outcome among women whose 75-g
As shown below in Table V, one-hour post-glucose load
OGTT values reached the IADPSG-defined cut-off values was
value of ≥180 mg/dL was associated with small increase
not significantly increased. This is contrary to the two local
in the odds of having hypertensive disorders of pregnancy
studies showing an association of specified 75-g OGTT values
(OR=1.09, p=0.89). There appeared to have a 1.71 times
with some of the adverse pregnancy outcomes.1,3 Urbanozo
increase in the likelihood of giving birth to jaundiced
et al., demonstrated an increase in the risk of having large
infants among these women. In terms of other perinatal
for gestational age (LGA) neonate with FBS of ≥92 mg/
outcomes, reaching this one-hour post-glucose load value
dL.1 In addition, the study showed an increase in the risk of
was associated with minimal increase in the likelihood of
having primary CS with one-hour post-glucose load value
having macrosomia (OR=1.46, p-value=0.48), prematurity
of ≥ 180 mg/dL. Their findings are also in agreement with
(OR= 1.28, p-value=0.67), neonatal hypoglycemia (OR=1.37,
study by Black et al and Brankica et al. that elevated FBS
p-value=0.74), low five-minute APGAR score (OR=1.31,
was associated with higher risk of LGA. 13,14 However, they
p-value=0.73), and infection (OR=1.22, p-value=0.70).
found that elevation of post-load values was associated with
However, all these values did not reach statistical
higher risk of pre-term delivery, gestational hypertension, and
significance.
hyperbilirubinemia. On the other hand, Serafica-Hernandez

4 Volume 55 Number 4 Oct.-Dec., 2017

Diagnosis of Gestational Diabetes Mellitus using the IADPSG De Luna KS & Cunanan EC

Table V. Proportion and association of adverse pregnancy outcomes in relation to IADPSG-defined 1-hour glucose post-
load threshold value for GDM diagnosis (N = 120)

1-hour post-load 1-hour post-load

≥ 180 mg/dL < 180 mg/dL
Maternal outcomes (n=63) (n=57) OR (CI)* p-value

Frequency (%)
Hypertensive disorders of pregnancy 6 (9.52) 5 (8.77) 1.09 (0.32-3.8) 0.89
Miscarriage 0 0 - -
Primary cesarean section 25 (41.67) 25 (45.45) 0.86 (0.41-1.79) 0.68
Operative vaginal delivery 1 (1.67) 2 (3.57) 0.46 (0.04-5.19) 0.53
Maternal death 0 0 - -
Perinatal outcomes
Macrosomia 10 (17.24) 7 (12.50) 1.46 (0.51-4.15) 0.48
Perinatal death 1 (1.67) 2 (3.57) 0.46 (0.04-5.19) 0.53
Prematurity 8 (13.56) 6 (10.91) 1.28 (0.41-3.96) 0.67
Birth injuries 0 1 (1.79) - -
Congenital anomalies 2 (3.39) 3 (5.36) 0.62 (0.10-3.86) 0.61
Neonatal hypoglycemia 3 (6.25) 2 (4.65) 1.37 (0.22-8.59) 0.74
Jaundice 24 (40.68) 16 (28.57) 1.71 (0.79-3.73) 0.18
Low APGAR score (<7)
1st minute 6 (10.34) 5 (8.93) 1.18 (0.34-4.1) 0.80
5th minute 4 (6.90) 3 (5.36) 1.31 (0.28-6.13) 0.73
Acute respiratory distress syndrome 2 (3.39) 0 - -
Infection 10 (16.95) 8 (14.29) 1.22 (0.45-3.37) 0.70
*OR- odds ratio; CI- confidence interval

Table VI. Proportion and association of adverse pregnancy outcomes in relation to IADPSG-defined 2-hour glucose post-
load threshold value for GDM diagnosis (N = 120)

2-hour post-load ≥ 2-hour post-load <

153 mg/dL 153 mg/dL
Maternal outcomes (n=78) (n=42) OR (CI)* p-value

Frequency (%)
Hypertensive disorders of pregnancy 6 (7.69) 5 (11.90) 0.62 (0.18-2.16) 0.45
Miscarriage 0 0 - -
Primary cesarean section 36 (49.32) 14 (33.33) 1.96 (0.88-4.28) 0.10
Operative vaginal delivery 3 (4.05) 0 - -
Maternal death 0 0 - -
Perinatal outcomes
Macrosomia 13 (18.06) 4 (9.52) 2.09 (0.64-6.90) 0.23
Perinatal death 3 (4.05) 0 - -
Prematurity 11 (15.28) 3 (7.14) 2.34 (0.61-8.94) 0.21
Birth injuries 1 (1.37) 0 - -
Congenital anomalies 3 (4.11) 2 (4.76) 0.86 (0.14-5.35) 0.87
Neonatal hypoglycemia 5 (8.47) 0 - -
Jaundice 28 (38.36) 12 (28.57) 1.56 (0.69-3.53) 0.29
Low APGAR score (<7)
1st minute 10 (13.89) 1 (2.38) 6.61 (0.82-53.63) 0.08
5th minute 7 (9.72) 0 - -
Acute respiratory distress syndrome 1 (1.37) 1 (2.38) 0.57 (0.03-9.35) 0.69
Infection 13 (17.81) 5 (11.90) 1.60 (0.53-4.86) 0.40
*OR- odds ratio; CI- confidence interval

Volume 55 Number 4 Oct.-Dec., 2017 5

 De Luna KS & Cunanan EC
et al., found a weak association between FBS and birth
weight.3 However, they found that the one-hour post-glucose
load is a significant predictor of birth weight. A European
study yielded a similar finding wherein one-hour post-glucose
level from 75-g OGTT may predict LGA babies. 14 In addition,
FBS was found to also predict the said outcome. 9 Although
the study population generally had a high metabolic risk
profile to develop GDM or overt DM that can eventually lead
to adverse pregnancy outcomes, each adverse maternal
and perinatal outcome was not significantly increased. We
then attributed our results to several reasons. First, the mean
age of women in our study can be considered as somewhat
young and low risk for developing undesirable pregnancy
outcomes. Second reason is that the knowledge of a
healthcare provider of elevated 75-g OGTT value/s could
lead to provision of appropriate treatment (whether with diet
and physical activity or supplemental insulin), blood glucose
monitoring, and recommendation of timely follow-up to the
patient. These measures might prevent adverse pregnancy
outcomes. The other reason might be due to achievement
of glycemic targets of the women throughout pregnancy as
this was proven to reduce the incidence of some adverse
pregnancy outcomes. Supporting these notions are the
two large randomized trials done in Australia and United
States. 15,16 The Australian Carbohydrate Intolerance Study
in Pregnant Women (ACHOIS) trial group demonstrated a
reduction in birth injury and perinatal death with treatment
of GDM.15 On the other hand, a different trial showed that
treatment of such condition reduced the risks of fetal
overgrowth, shoulder dystocia, cesarean delivery, and
hypertensive disorders.16 However, two studies demonstrated
that despite GDM treatment, the association of specific
adverse pregnancy outcomes to 75-g OGTT values
persisted. 9,17 Disse et al., found in their study that delivery
of LGA infants was more frequent in women with elevated
FBS.17 These women received treatment as part of the study
protocol. Another study, found a persistence of antenatal
complications women diagnosed with GDM using IADPSG
criteria despite treatment.9 Due to these conflicting study
results, whether treatment of GDM can offset the association
of 75-g OGTT values to adverse pregnancy outcomes needs
to be verified. The neonatal population in our study was
noted to have a normal mean birth weight and maturity.
An infant with a normal birth weight and maturity has a low
risk of developing perinatal complications. Moreover, only
a small percentage of the neonates were premature, and
macrosomic. Another logical explanation might be due
to appropriate maternal weight gain during pregnancy.
Notwithstanding, the mean BMI of these women were
classified as obese. It is an accepted fact that excessive
maternal weight gain during pregnancy leads to higher
incidence of delivery of LGA infants.18,19 A study by Ray et
al. further showed that maternal weight gain also leads
to higher incidence of cesarean delivery, gestational
hypertension, NICU admission, and preterm birth. 18 Chen
et al. also found that maternal BMI and weight gain have
6 Volume 55 Number 4 Oct.-Dec., 2017
Diagnosis of Gestational Diabetes Mellitus using the IADPSG
additive effects on the delivery of LGA infants. 19 In addition,
we were only able to gather the latest recorded weight of
the subjects prior to delivery to compute for the BMI. It is
somewhat plausible to assume that majority of the subjects
might have a low or normal pre-pregnancy BMI. Lastly, the
small sample size of the study might have an impact on the
degree of statistical significance.
The retrospective nature of the study limits the type of
information that can be gathered from the medical charts.
In addition, some medical charts were either unable to be
retrieved or found. The earlier mentioned variables such as
pre-pregnancy BMI, maternal glycemia during pregnancy,
patient compliance to treatment and follow-up, and
maternal weight gain which might have significant impact
with respect to reduction in the incidence of adverse
pregnancy outcomes can be addressed by performance
of a prospective study involving a larger sample size. The
authors also recommend inclusion of non-GDM patients for
comparison. Performance of 75-g OGTT following a uniform
protocol in one laboratory would also be appropriate.
Patterning the study design to that of HAPO trial, taking
into account the additional variables would provide a more
thorough evaluation of the appropriateness of adopting
the IADPSG criteria in the local setting. If ethically feasible,
inclusion of untreated women with GDM in the study would
give information whether treatment had an impact on the
lack of significant association between IADPSG-defined
cut-off values and adverse pregnancy outcomes. The
economic and long-term impact of GDM on the mother
and infant using this set of criteria may also be studied as
well. In fact, studies in other countries comparing IADPSG
criteria to other diagnostic approaches showed discrepant
results with respect to pregnancy outcomes. Other showed
decrease in adverse pregnancy outcomes with the usage
of the IADPSG criteria.20-23 While another study demonstrated
an increase in the rates of adverse pregnancy outcomes.24
Two local studies comparing it to POGS criteria showed no
difference with regards to adverse maternal and perinatal
outcomes.1,3 Furthermore, a systematic study was done that
demonstrated the high inconsistency of the IADPSG criteria.25
Despite the limitations of the study, we were able to
include women regardless of their socioeconomic status as
the medical files were gathered from both pay and clinical
division of the institution. This adds to the generalizability of
the results. We were also able to analyze several adverse
maternal and perinatal outcomes that might have an
association with 75-g OGTT cut-off values.
Conclusion
In conclusion, the study did not find a statistically
significant positive association between IADPSG threshold
values and adverse maternal and perinatal outcomes.
 Diagnosis of Gestational Diabetes Mellitus using the IADPSG De Luna KS & Cunanan EC

However, the study findings have important clinical outcomes of pregnancies complicated by mild gestational diabetes
implications with regards to finding the suitable diagnostic mellitus differ by combinations of abnormal oral glucose tolerance
approach to GDM in the local setting. test values. Diabetes Care, 33(12):2524-2530, 2010.
14. Brankica K, Valentina VN, Slagjana SK, Sasha JM: Maternal

References 75-g OGTT glucose levels as predictive factors for large-for-

gestational age newborns in women with gestational diabetes
mellitus. Arch EndocrinolMetab, 60(1):36-41, 2016.
1. Urbanozo H, Isip-Tan IT: Association of gestational diabetes
15. Crowther CA, Hiller JE, Moss JR, McPhee AJ, Jeffries WS,
mellitus diagnosed using the IADPSG and the POGS 75 gram
Robinson JS for the Australian Carbohydrate Intolerance Study
oral glucose tolerance test cut-off values with adverse perinatal
in Pregnant Women (ACHOIS) Trial Group: Effect of treatment
outcomes in the Philippine General Hospital. JAFES, 29(2):157-
of gestational diabetes mellitus on pregnancy outcomes. N Engl J
162, 2014.
Med, 352:2477-2486, 2005.
2. Jimeno C, for the Technical Review Committee of the UNITE for
16. Eunice Kennedy Shriver National Institute of Child Health and
DM Clinical Practice Guidelines on the Diagnosis and Management
Human Development Maternal-Fetal Medicine Units Network:
of Diabetes: A summary of the Philippines UNITE for diabetes
A multicenter, randomized trial of treatment for mild gestational
clinical practice guidelines for the diagnosis and management of
diabetes. N Engl J Med, 361:1339-13348, 2009.
diabetes. Part I: Screening and diagnosis of DM. JAFES, 26(1):
17. Disse E, Graeppi-Dulac J, Joncour-Mills G, Dupuis O, Thivolet
26-30, 2011.
C: Heterogeneity of pregnancy outcomes and risk of LGA neonates
3. Serafica-Hernandez SA, Espina-Tan C, Tremendal MA,
in Caucasian females according to IADPSG criteria for gestational
Diaz-Roa LJ: Local versus international criteria in predicting
diabetes mellitus. Diabetes Metab, 39:132-138, 2013.
gestational diabetes mellitus-related pregnancy outcomes. Philipp
18. Ray JG, Vermeullen MJ, Shapiro JL, Kenshole AB: Maternal
J ObstetGynecol, 38(1):33-42, 2014.
and neonatal outcomes in pregestational and gestational diabetes
4. The HAPO Study Cooperative Research Group. Hyperglycemia
mellitus, and the influence of maternal obesity and weight gain:
and adverse pregnancy outcomes. N Engl J Med, 358(19):1991-
the DEPOSIT study. QJM, 94:347-356, 2001.
2002, 2008.
19. Chen Q, Wei J, Tong M, Yu L, Lee AC, Gao YF, Zhao M:
5. International Association of Diabetes and Pregnancy Study
Associations between body mass index and maternal weight gain
Groups Consensus Panel: International Association of Diabetes
on the delivery of LGA infants in Chinese women with gestational
and Pregnancy Study Groups recommendations on the diagnosis
diabetes mellitus. J Diabetes Complications, 29:1037-1041, 2015.
and classification of hyperglycemia in pregnancy. Diabetes Care,
http://dx.doi.org/10.1016/j.jdiacomp.2015.08.017
33(3):676-682, 2010.
20. Hung T-H, Hsieh T-T: The effects of implementing the
6. Leary J, Pettitt DJ, Jovanovic L: Gestational diabetes guidelines
International Association of Diabetes and Pregnancy Study Groups
in a HAPO world. Best Pract Res ClinEndocrinolMetab, 24:673-
Criteria for diagnosing gestational diabetes on maternal and
685, 2010.
neonatal outcomes. PLoS ONE, 10(3):e0122261, 2015.
7. Farrar D, Fairley L, Santorelli G, Tuffnell D, Sheldon TA,
21. Sibartie P, Quinlivan J: Implementation of the International
Wright J, van Overveld L, Lawlor DA: Association between
Association of Diabetes and Pregnancy Study Groups Criteria: not
hyperglycemia and adverse perinatal outcomes in south Asian and
always a cause for concern. J Pregnancy, 2015:1-5, 2015. http://
white British women: analysis of data from the Born in Bradford
dx.doi.org/10.1155/2015/754085
Cohort. Lancet Diabetes Endocrinol, 3:795-804, 2015.
22. Duran A, Saenz S, Torrejon MJ, Bordiu E, del Valle L, Galindo
8. Gongora MC, Wenger NK: Cardiovascular complications of
M, Perez N, Herraiz MA, Izquierdo N, Rubio MA, Runkle
pregnancy. Int J MolSci, 16:23905-23928, 2015. DOI: 10.3390/
I, Perez-Ferre N, Cusihuallpa I, Jimenez S, de la Torre NG,
ijms161023905
Fernandez MD, Montanez C, Familiar C, Calle-Pascual AL:
9. Nayak PK, Mitra S, Sahoo JP, Daniel M, Mathew A, Padma,
Introduction of IADPSG criteria for the screening and diagnosis
A: Feto-maternal outcomes in women with and without gestational
of gestational diabetes mellitus results in improved pregnancy
diabetes mellitus according to the International Association of
outcomes at a lower cost in a large cohort of pregnant women: the
Diabetes and Pregnancy (IADPSG) diagnostic criteria. Diabetes
St. Carlos Gestational Diabetes Study. Diabetes Care, 37:2442-
and Metabolic Syndrome: Clinical Research and Reviews, 7:206-
2450, 2014. DOI: 10.2337/dc14-0179
209, 2013.
23. Wu ET, Nien FJ, Kuo CH, Chen SC, Chen KY, Chuang LM, Li
10. Leuthner SR, Das UG: Low APGAR scores and the definition of
HY, Lee CN: Diagnosis of more gestational diabetes lead to better
birth asphyxia. Pediatr Clin North Am, 51:737-745, 2004.
pregnancy outcomes: comparing the International Association of
11. Jain A, Aggarwal R, Sankar MJ, Agarwal R, Deorari AK, Paul
the Diabetes and Pregnancy Study Group Criteria, and the Carpenter
VK: Hypoglycemia in the newborn. Indian J Pediatr, 77:1137-
and Coustan Criteria. J Diabetes Investig, 7:121-126, 2016. DOI:
1142, 2010.
10.1111/jdi.12378
12. Barfield WD, the Committee on Fetus and Newborn: Clinical
24. O’Sullivan EP, Avalos G, O’Reilly M, Dennedy MC, Gaffney
reports- standard terminology for fetal, infant, and perinatal deaths.
G, Dunne F on behalf of the Atlantic DIP collaborators:
Pediatrics, 128:177-181, 2011. DOI: 10.1542/peds.2011-1037
Atlantic Diabetes in Pregnancy (DIP): the prevalence and
13. Black MH, Sacks DA, Xiang AH, Lawrence JM: Clinical
outcomes of gestational diabetes mellitus using new diagnostic

Volume 55 Number 4 Oct.-Dec., 2017 7

 De Luna KS & Cunanan EC Diagnosis of Gestational Diabetes Mellitus using the IADPSG

criteria. Diabetologia, 54:1670-1675, 2011. DOI: 10.007/s00125-

01102150-4
25. Wendland EM, Torloni MR, Falavigna M, Trujillo J, Dode MA,
Campos MA, Duncan BB, Schmidt MI: Gestational diabetes and
pregnancy outcomes- a systematic review of the World Health
Organization (WHO) and the International Association of Diabetes
in Pregnancy Study Groups (IADPSG) diagnostic criteria.
BMC Pregnancy Childbirth, 12:23, 2012. DOI: 10.1186/1471-
2393/12/23/prepub

8 Volume 55 Number 4 Oct.-Dec., 2017

 Philippine Journal of Internal Medicine
Relationship of Average Daily Glycemic Index and Glycemic
Load with Body Mass Index among Filipinos in the Rural Setting
Hderbert A. Arellano, M.D.*; Mark Anthony S. Sandoval, M.D.**; Elizabeth Paz-Pacheco, M.D.**; Jundelle Romulo Jalique, R.N.***
Abstract
Introduction: While the relationship between obesity and
caloric intake is widely accepted, the role of glycemic
index (GI) and glycemic load (GL) to body mass index (BMI)
remains equivocal. This study seeks to determine the daily
glycemic index (GI) and glycemic load (GL) of usual diet
of rural-dwelling Filipinos, and their relationship with body
mass index (BMI).
Methods: This is a cross-sectional study reviewing the data of
139 adults from San Juan, Batangas. Average daily GI and
GL were calculated from two-day food recall questionnaires.
Spearman’s rank test was used to determine correlation
of daily GI and GL with BMI; the mean BMI was compared
among GI and GL tertiles using one-way ANOVA. Partial least
squares regression was used to determine the contribution
of food items to daily GI and GL.
Results: No overall correlation was observed between daily
GI or GL and BMI using Spearman’s rank. However, BMI was
Introduction
The alarming growth of the obesity pandemic has
inevitably driven research agenda towards preventive
measures and nutritional interventions.1 One particular point
of interest was the relationship of obesity with consumption
of food with high glycemic index (GI) and glycemic load
(GL). GI can be defined as the ratio of the blood glucose
response over time from a certain food item against the
same quantity of available carbohydrate in a reference
such as a glucose drink; while glycemic load refers to the
estimated amount of available carbohydrate in the quantity
of a food item consumed multiplied by its GI.
*Fellow-in-training, Section of Endocrinology, Diabetes and Metabolism,
Department of Medicine, University of the Philippines – Philippine General
Hospital
**Consultant and Faculty member, Section of Endocrinology, Diabetes
and Metabolism, Department of Medicine, University of the Philippines –
Philippine General Hospital
***Biotatistician, Division of Research, Department of Education, Training
and Research, Philippine Heart Center
Corresponding author: Hderbert A. Arellano, M.D., University of the
Philippines – Philippine General Hospital, Manila, Philippines
Email:dochdarel@gmail.com
The PHILIPPINE JOURNAL OF INTERNAL MEDICINE is a peer reviewed journal and a copyrighted publication of the Philippine College of Physicians
Original Article
higher with increasing GI tertiles (p<0.0001) and GL tertiles
(p=0.0108) among the males, but not females. Bread, coffee-
mix and sweets were major contributors to daily GI, while rice,
bread/pastries and sweetened beverages were to daily GL.
Leafy vegetables negatively contributed to both.
Conclusion: There is a positive relationship observed between
daily GI and BMI, and daily GL and BMI among the men,
but not women, in this population. Staple food with high GI
like bread/pastries and sweetened beverages contributed
most to both daily GI and GL, with the addition of rice for
daily GL. Among Filipinos with marginal daily caloric intake,
optimizing carbohydrate quality (low GI or GL) rather than
limiting its quantity may be more appropriate. Future studies
of prospective design and using objective methods of food
intake reporting are recommended.
Keywords: glycemic index, glycemic load, body mass index,
obesity
The implication of GI or GL in energy assimilation
and expenditure appears to be broad. In human models,
consumption of low-GI diet can enhance glycogen reserve
in trained athletes, may lessen voluntary food intake and
increase counter-regulatory hormone levels in teenage boys,
can increase protein retention among hyperinsulinemic men,
and even may attenuate weight gain during pregnancy.2
Studies have demonstrated that the GI of mixed meals
is consistent with mean GI for individual food items, and
average daily GI can be estimated by adding the products
of the GI of each particular food and its carbohydrate
content and the number of servings, and dividing this sum the
total carbohydrate intake.3 In a metaanalysis examining low-
GI diets among diabetic individuals, an absolute reduction of
0.43% points in A1c is observed favoring low GI diets.4 Despite
limited evidence, most international authorities in diabetes
worldwide like American Diabetes Association (ADA) and
even local guidelines advocate limiting intake of food with
high GI and replacing them with those with low GI. However,
how GI or GL relates to measures of obesity in the general
population is uncertain.
Although the idea of higher GI or GL predicting a higher
body mass index (BMI) is popular and seemingly intuitive,
Volume 55 Number 3 Oct.-Dec., 2017 1
 Arellano HA, et al.
the available evidence does not unanimously support this.
On one hand, some studies have found that BMI is positively
correlated with both daily glycemic index and load.5-6 On
the other hand, more recent investigations involving Spanish
and Italian cohorts concluded the relationship is inverse.7-8
Whether these patterns are confounded by unaccounted
variables, or are simply specific to the particular population
being observed is unclear.
In Southeast Asia, a study in Singapore looked into the GI
of the most commonly consumed food and beverages in the
region and found that nine out of fifteen items included were
of medium to high GI.9 In the Philippines, however, no previous
studies have assessed the relationship of GI or GL with BMI
to our knowledge. Like that of its neighboring countries,
the Filipino cuisine is largely based on carbohydrates,
particularly with high GI sources like rice that is staple for
most regions in the country as seen in the report by the World
Food Programme.10 Because previous investigations have
determined that Asians are at risk for metabolic disorders
at lower BMI, tend to develop post-prandial hyperglycemia
earlier on, and have more profound beta cell dysfunction,11
dietary interventions are of utmost importance among Asian
population, including Filipinos. In order to make appropriate
recommendations on dietary modifications in terms of GI and
GL, it is important to examine its relationship with markers of
obesity in this population in order to understand its impact
on the increasing prevalence of metabolic diseases like
diabetes and other non-communicable diseases (NCD).
Objectives
• To determine the average daily GI and GL of the
usual carbohydrate intake of Filipinos living in a rural
community
• To determine the relationship of average daily GI and
GL with BMI among Filipinos living in a rural community
• To determine the relative contribution of specific food
items and food groups to average daily GI and GL
Methods
The study follows a cross-sectional analytic design.
The investigators utilized the baseline data gathered in the
original study by Sandoval and colleagues 12, entitled An
Intensive Community-Based Lifestyle intervention Program
for the prevention of type II diabetes mellitus among Some
Filipinos in San Juan, Batangas, Philippines. In its preliminary
phase (phase IVA), 139 rural residents were selected using
stratified random sampling of the adult (>18 years old)
population grouped according to geographical clusters
(different villages or barangays), age group and sex. The
subjects selected were relatively healthy, non-pregnant
individuals. In the original study, they were interviewed
by trained nutritionists and physicians using a standard
two-day, 24-hour food recall, verified by a food frequency
2 Volume 55 Number 4 Oct.-Dec., 2017
Relationship of Average Daily Glycemic Index and Glycemic Load
questionnaire with amount recall for the previous two
weeks. This study included all 139 respondents after verifying
completeness of needed data.
Using NCSS-PASS 2013, the minimum sample size needed
to determine relationship of BMI and GI/GL was calculated to
be 112 based on r=0.2615 with alpha level= 5% and power=
80%, with a final estimate of 134 to account for incomplete
data.
Clinical data (age,sex) and anthropometric measure-
ments (weight, height, and body mass index) were recalled
from the electronic database of the original study and
recorded for analysis. The participants were classified using
BMI (kg/m 2 ) criteria of World Health Organization Asia
Pacific Perspective (WHO-APP) as underweight (less than
18.5), normal (18.5-22.9), overweight (23-24.9), obese I (25-
29.9), or obese II (30 and above). 13 For purposes of analysis,
the last three categories were grouped into a single entity
(overweight/obese). 12 The level of physical activity (in
Metabolic Equivalents [MET]-min/week) was determined
in the original study using International Physical Activity
Questionnaire, and participants were classified as having
either low, moderate or high physical activity.
Dietary Assessment
The accomplished two-day, 24-hour food recall forms
of each participant were reviewed. The total caloric intake
together with specific macronutrient composition, dietary
fiber content and alcohol consumption were duly noted.
Using the book Glycemic index of commonly consumed
carbohydrates foods in the Philippines published by the
Food and Nutrition Research Institute (FNRI) as a guide,
the glycemic index of each carbohydrate consumed was
identified. 14 For food items not listed in mentioned source,
reliable international publications were consulted, and if
none was available, the GI of the most similar food item
identified was appropriated. To calculate for the average
daily GI (GId), the following formula was used: 7 GId = {Ʃ[GIf
x (CHOf x nf)/CHOT]}; where GIf is the identified GI of food
item, CHOf is the amount of carbohydrates per serving of
food item in grams, nf is the number of servings of food item
consumed per day, and CHOT is the total daily carbohydrate
intake in grams. This was done for all food items consumed
containing at least three grams of carbohydrates. Likewise
the daily glycemic load (GLd) was calculated by multiplying
the GId by the CHOT and dividing the product by 100.
Identification of underreporters
An underreporter (UR) was defined as an individual who
selectively reports caloric intake that is less than the minimum
amount required to maintain one’s present weight. The ratio
of reported daily energy intake to basal metabolic rate
(EI:BMR) was calculated for this purpose. The Mifflin-St Jeor
 Relationship of Average Daily Glycemic Index and Glycemic Load Arellano HA, et al.

Equation (MSJE) as used to estimate the basal metabolic

Table I. Clinical characteristics of study participants
rate.15 The cut-off for underreporting (Goldberg-Black cut-
off) was based on the proposed lower limit for EI:BMR by  Characteristics (mean ± SD) Men (n=70) Women (n=69) p-value
Goldberg and Black as follows: among men, 1.06, 1.19 and
Age (year), 39 ± 26 39 ± 16 0.638
1.33 for assumed low, moderate and high physical activity
BMI (kg/m 2) 21.5 ± 5.2 22.1 ± 5.1 0.510
levels (PAL), respectively; for women, 1.06, 1.11 and 1.23,
Underweight, n (%) 14 (20) 11(16)
respectively. These limits have a sensitivity of 0.74 in men
Normal, n (%) 32 (45.7) 29(42) 0.798
and 0.67 in women, and specificity of 0.97 in men and 0.98
Overweight/Obese, n (%) 24 (34.3) 29 (42)
in women for detection of underreporting.16 Participants with
Average Total Calories 1666.5 ± 975.0 1336.0 ± 515.0 <0.001
EI:BMR less than the designated cut-off were identified as (Kcal/day)
UR. Average Carbohydrate Intake 73.9 ± 12.6 71.7 ± 11.4 0.121
(g/day)
Statistical Analysis Average Protein intake 12.6 ± 5.1 12.7 ± 5.0 0.601
(g/day)
Data encoding was done in MS Excel, while data Average Fat Intake 10.4 ± 11.0 15.8 ± 9.6 0.001
analysis was performed in Stata SE version 13 and SAS (g/day)
version 9. Normally distributed quantitative variables were Fiber intake 6.2 ± 2.4 8.1 ± 2.8 <0.001
(g/1000 kcal),
summarized as mean ± SD, and non-normally distributed
Leisure time physical activity 3840 2422 0.006
quantitative variables as median and inter-quartile range. (LTPA) (Metabolic equivalents (280-33,012) (28-19,146)
Categorical variables were tabulated as frequency and [MET]-min/week), median
percentage. Spearman’s rank correlation was used to (interquartile range)
analyze overall relationship of daily GI and GL with BMI. Low n (%) 5 (7.2) 8(11.6)
Comparison of characteristics between males and females Moderate, n (%) 22 (31.4) 39(56.5) 0.184
were performed using Wilcoxon rank sum test for continuous High, n (%) 43 (61.4) 22(31.9)
variables, and Fisher’s exact test for categorical variables. 44 (62.8) † 29 (42.0) †
Underreporters n (%)
Comparison of the daily GI and GL across BMI classification 20 (28.7)‡ 11(15.7) ‡
was performed using one-way ANOVA. The data for each Glycemic index 64±2.2 64.0±4.5 0.902
gender was then divided into tertiles based on the GI and Glycemic load (g/day) 195.2±61.4 152.4±41.8 <0.001
GL. Comparison of different characteristics across GI and GL †
Using physical activity level (PAL) specific cut-offs,
tertiles were analyzed using kruskal wallis test for continuous
‡
Using universal cut-off for EI:BMR (<0.9)
variables and fisher’s exact test for categorical variables.
Partial least squares (PLS) regression, a special type of daily GI was 63 (male and female), while average daily GL
regression wherein several variables are analyzed and was 182g and 144g for males and females respectively.
regressed while ranking was done to identify contribution of
various food items to daily GI and GL. Level of significance Using Spearman rank test, rho coefficient of 0.0348
was set at five percent. (p=0.6839) and 0.1537 (p=0.0708) were obtained when
correlating GI with BMI and GL with BMI of all participants,
Ethical Consideration respectively. After the participants were classified into three
BMI groups (underweight, normal, overweight/obese), the
The study was conducted in accordance to the mean daily GI and GL were compared across categories
stipulations of Declaration of Helsinki and Good Clinical relationship showing non-significant differences for both
Practice. The protocol was reviewed and duly approved (Table II).
by the University of the Philippines Regulatory Ethics Board
(UPM-REB) in April 2016. Confidentiality was maintained. Due to lack of accepted cut-off for daily GI and GL
Original documents were secured under lock and key, while (unlike that for individual food item, i.e. low GI <55) and the
electronic databases were password-protected. likelihood of observing a non-linear relationship, earlier studies
have used tertiles or quintiles to describe the distribution of
variables in specific populations.7-8 Participants were grouped
Results into tertiles according to their average daily GI and GL.
The mean BMI, age, daily GI, total daily caloric intake and
The clinical characteristics and dietary parameters macronutrient distribution, fiber intake and level of physical
were as summarized in Table I. The sample was relatively activity were compared across tertiles. BMI was observed
young (x̅ =39 years) and lean (BMI 21.5=males; 22=females). to be higher with increasing GI tertiles in males (p=<0.0001)
Average total caloric intake and fiber intakes were low. but not in females; age varied significantly among GI tertiles
Majority of participants have at least moderate level of in females (see Table III). Among the GL tertiles, significant
physical activity (92.8%=males; 88.4%=females). Average differences were noted in the mean total energy intake in

Volume 55 Number 4 Oct.-Dec., 2017 3

 Arellano HA, et al. Relationship of Average Daily Glycemic Index and Glycemic Load

Table II. Comparison of daily GI and GL among BMI categories
Overweight/
Underweight Normal
N=139 Obese
n=25 n=61
n=53
Daily GI (mean) 64.4 ± 3.1 63.9 ± 2.6 63.9 ± 3.8
Daily GL (mean) 157.2 ± 51.5 172.8 ± 59.9 182.9 ±57.9
†
Using one-way ANOVA
both males and females, while the percentage of energy
reported from carbohydrate intake differed significantly
among females only. As in the case of GI tertiles, BMI of males
was noted to be higher with increasing glycemic load tertiles,
while age was higher in the lower GL tertiles (Table IV). No
such pattern was seen among the female participants. This
suggests that as men get older, their GLd decreases. Since
GLd was computed by adding up the products of GI and
the available carbohydrates in a food item, it is expected
that as the GLd tertile increases, total energy intake and the
intake of carbohydrate in relation to total calories would
also increase. Among females, the percentage fat intake
was observed to decrease with increasing GL tertile.
The relative contributions of the different food items to
both daily GI and GL were evaluated by assigning a factor
(PLS) to each item to that indicated the vector of influence.
p-value A factor closer to one signified a greater impact on the
whole, the weight diminishing as value approaches zero;
0.741 † while a negative sign indicates the direction of influence
is inverse (i.e. predicts lower daily GI or GL). The results are
0.0954 †
summarized in Table V. Bread, sweets and coffee mixes
contributed to higher daily GI in both males and females.
The analysis was unable to define the contribution of rice
to daily GI due to the narrow range of the daily GI values
and because the entire sample consumed said food item,
rendering its influence neutral (GI values are fixed despite
the amounts consumed). On the contrary, intake of nuts/
legumes, pasta, root crops and chocolate are associated
with lower daily GI for both sexes, with the addition of fruits
for men. As expected, rice contributed most to daily GL due
to the large amounts consumed, followed by bread, pastries,
fruits, corn and coffee mixes, with nuts and soda as added
contributors in women. Among the negative contributors
to daily GL are leafy vegetables for both sexes and nuts/
legumes for males only.

The underreporting rates using the Goldberg-Black cut- Discussion

offs were higher than expected (52.5% overall), compared
to prior reports (19.7-24.7%). 5,7 However, utilizing a lower To our knowledge, this is the first study to explore the
universal cut-off that was used in a Korean survey (<0.9), 17 relationship of GI and GL with BMI among Filipinos. A positive
the UR rate approximated the earlier reports (22.3%). relationship was observed between GI and BMI, and GL and

Table III. Glycemic index tertiles in relation to clinical and dietary parameters

Men Women
 
1 st tertile GI 2 nd tertile GI 3 rd tertile GI p 1 st tertile GI 2 nd tertile GI 3 rd tertile GI p
 
(n= 37) (n=10) (n=23) (n= 24) (n=23) (n=22)

Mean daily 61.7 63.3 66.6   60.3 63.5 67.8  

Glycemic Index (61.4,62.0) (63.2,63.5) (65.8,67.3) (59.1,61.5) (63.2,63.8) (66.9,68.7)

Body mass index 21.4 22.5 24.0 23.1 22.4 22.3

<0.0001† 0.8026
(kg/m 2) (19.9, 23.0) (20.6,24.5) (19.9,28.0) (20.9,25.2) (20.3,24.5) (20.7,23.9)
40.6 41.3 44.3 39.8 37.8
Age (years) 0.8487† 47.9 (42.3,53.5) 0.0321
(30.9,50.2) (35.2,47.4) (38.4,50.2) (34.3,45.3) (31.3,44.3)

Total Energy 1817.1 1830.9 1567.0 1347.2 1478.2 1279.5

0.3823† 0.2145
(kcal/day) (1453.8, 2180.3) (1592.1,2069.8) (1307.8,1826.1) (1188.6,1505.8) (1290.9,1665.5) (1154.1,1405.0)

Carbohydrates 70.3 74.6 70.4 69.8

0.7043† 73.1 (69.0, 77.3) 71.9 (69.2,74.7) 0.3304
(%) (63.5,77.1) (71.3,77.9) (63.5,77.2) (66.7,72.9)
15.9 12.4 16.7 13.2 14.6
Protein (%) 0.1011† 12.4 (11.1, 13.7) 0.4051†
(10.8,21.1) (11.3,13.5) (11.1,22.4) (11.6,14.8) (12.5,16.6)
11.7 11.1 11.5 17.0 13.5
Fat (%) 0.9226† 14.5 (10.9, 18.1) 0.1415†
(8.0,15.4) (8.2,14.0) (8.2,14.9) (14.4,19.6) (11.3,15.6)
Fiber 6.6 6.4 6.7 8.7 9.1
0.8191† 7.8 (6.5, 9.2) 0.5954†
(g/1000 Kcal) (5.3,7.9) (5.5,7.4) (5.6,7.9) (7.7,9.8) (7.3,10.8)

LTPA 6958.2 6756.5 5992.2 2646.4 3391.9 (2154. 3301.9

0.9377† 0.5303†
(MET-min/week) (2777.8,11138.6) (4036.9, 9476.1) (3137.1,8847.4) (1886.3,3406.4) 1,4629.7) (1795.1,4808.7)

One-way ANOVA was used to analyze the differences among tertiles except marked (†) where Kruskal Willis test was used; significant differences are in bold letters. Values
are expressed in median with interquartile range in parentheses.

4 Volume 55 Number 4 Oct.-Dec., 2017

 Relationship of Average Daily Glycemic Index and Glycemic Load Arellano HA, et al.

Table IV. Glycemic load tertiles in relation to clinical and dietary parameters

  Men Women

1 st tertile GL 2 nd Tertile GL 3 rd tertile GL p 1 st tertile GL 2 nd Tertile GL 3 rd tertile GL p

  (n=17) (n=19) (n=34) (n=29) (n=28) (n=12)

Glycemic 119.9 162.9 251.0   116.6 160.9 218.9  

Index (112.0,127.7) (156.8,169.0) (237.3, 264.7) (109.7,123.5) (155.3,166.6) (200.1,237.8)
Body Mass 19.9 22.3 24.4 22.6 22.5 23.0
0.0108 0.7392
Index (kg/m 2) (18.0,21.9) (20.3,24.2) (21.5,27.2) (20.7, 24.5) (20.7,24.3) (21.1,24.9)
49.3 47.8 35.3 44.7 42.8 36.6
Age (year) 0.0030 0.3442
(40.4,58.2) (40.6,55.0) (30.6,40.0) (38.6, 50.8) (37.7,47.8) (30.7,42.5)

Total Energy 1005.6 1544.3 2217.9 1055.5 1499.5 1719.2

<0.0001 <0.0001
(kcal) (910.2,1100.9) (1390.4,1698.2) (20135.6,2400.1) (969.0,1142.0) (1391.0,1607.9) (1600.6,1837.9)

Carbo- 77.5 66.0 72.9 69.4 71.1 77.1

0.0813 0.0082†
hydrates (%) (74.3,80.7) (57.5,74.5) (69.2,76.5) (67.2,71.6) (67.9,74.3) (72.8,81.3)
14.4 18.8 12.6 13.5 14.3 11.9
Protein (%) 0.1008 0.3008
(12.9,15.9) (10.7,27.0) (11.6,13.6) (12.1,14.9) (12.3,16.2) (10.3,13.5)
8.2 12.8 12.1 17.1 14.6 11.0
Fat (%) 0.1561 0.0151†
(5.7,10.8) (9.0, 16.6) (9.3,14.9) (15.1,19.1) (12.1,17.2) (7.1,15.0)
Fiber (g/ 7.0 6.2 6.6 9.1 8.4 8.2
0.9932 0.9063
1000 Kcal) (5.2,8.8) (5.6,6.7) (5.7,7.5) (7.4,10.7) (7.4,9.5) (6.5,10.0)

LTPA (MET- 7166.3 7174.5 5907.7 2794.8 3188.8 3490.8

0.9014 0.5085
min/week) (3040.8,11291.8) (3196.0,11153.0) (3702.1,8113.4) (1986.2,3603.3) (2341.3,4036.4) (204.6,6777.1)

Kruskal Wallis test was used to analyze the differences among tertiles except marked (†) where one-way ANOVA was used; significant differences are in bold letters.
Values are expressed in median with interquartile range in parentheses.

BMI, but among male participants only; that may be due to
differences in dietary patterns between sexes. Commonly
consumed food items like bread contributed largely to both
GI and GL, while rice was most implicated for GL.
Traditionally, each carbohydrate source can be
described in terms of its ability to affect blood glucose
level after consumption known as its GI. Food items whose
GI is less than 55 are considered low GI foods, while those
with GI of 55-69 and ≥70 are moderate and high GI food,
respectively.13 In a practical sense, this concept was devised
to simplify the notion of “available carbohydrates” that it
may be easily applied to evaluate and likely optimize dietary
patterns; and therefore, identify which food item one should
“eat less of” due to higher glucose content. Its application
to lifestyle intervention among diabetics is supported by
observed modest improvement in glycemic control and is
reflected in the ADA guidelines.
The investigations of Lau (2006) and Murakami (2007)
both reported positive correlation of BMI with GI and GL;5-6
however, other studies have opposite results.7-8 Those that
support a positive correlation hypothesize that this may be
related to hyperinsulinemia that promoted fat oxidation and
greater carbohydrate oxidation. Satiety may also play a role,
as it has been postulated by Lavin that low GI diets may not
only dampen glycemic excursion but may also bring about a
more sustained stimulation of the gut due to slower digestion
and release of nutrients, thereby producing a prolonged
activation of satiety centers in the brain.18 Our investigation
found a positive relationship for both daily GI and daily GL
with BMI among men. The fiber intake in females in the study
is higher on average by a little more than two gram per 1000
kcal of energy intake (p=<0.001). This may mask the influence
of daily GI to BMI, as shown in the study by Murakami where
dietary fiber was negatively correlated to obesity. 6 The
finding of higher percentage of fat intake among lower GL
in women may also suggest that higher relative fat intake
may decrease the drive for consumption of more glucose in
the diet, although this cannot be confirmed at the moment
as without additional data. Physical activity level did not
vary among the GI and GL groups. Since majority of study
population have moderate to high physical activity, low-
activity subjects are under-represented that may render its
effect difficult to observe.
The nutritional status of this population markedly differed
from the data provided by the latest National Nutrition
and Health Survey (NNHeS) in 2013, where the combined
prevalence of obese/overweight in the Philippines was 31.1%
(overall population). The survey used the WHO definition of
overweight and obesity (BMI 25-29.9 and ≥30, respectively)
rather than the WHO-APP definitions used in this study.
Applying WHO definitions, the combined prevalence of
overweight/obese for this study was only 20% (38% using
WHO-APP criteria). Similarly, it was lower than the estimates
for CALABARZON region (33.5%) where San Juan, Batangas
was located. Conversely, the overall rates of chronic energy

Volume 55 Number 4 Oct.-Dec., 2017 5

 Arellano HA, et al. Relationship of Average Daily Glycemic Index and Glycemic Load

Underreporting as described by Lau in his study is a

Table VIII. Factor loading for GI and GL diet pattern scores
potential yet often undervalued source of bias.5 In this group,
(regression coefficients)
overall UR rate using Goldberg-Black criteria was 52.5%
Glycemic index Glycemic load pattern (62.8=male; 42.0=female), higher than that reported by Lau
Food items pattern factor loading factor loading
(24.7%), 5 which included more than 12,000 participants. As
Men Women Men Women
previously indicated, when a universal cut-off was applied,
Grains & cereals      
Rice 0.00001 0.00001 0.98203* 0.84992* the number is reduced to 22.3% (male =28.7; female=15.7%).
Rice products 0.08618 0.18127 0.05747 0.18923 However, the former criteria were based on observations
Pasta/noodles -0.10596‡ -0.12052‡ 0.07591 0.14416 among Caucasians, 20-22 and has not been validated for
Root crops -0.27414‡ -0.39342‡ 0.063 0.04221 Filipinos. A similar sex bias for underreporting was seen
Corn -0.0443 0.05456 0.09884* 0.09996* in an earlier study which noted more male participants
Bread/crackers 0.29297* 0.16750* 0.22187* 0.33222* underestimating their caloric intake.23 A lower cut-off then
Pastries/cakes 0.12573 -0.04638 0.14153* 0.24291*
may be more fitting but needs validation. Likewise, method
Junk food/chips 0.09903 -0.27756 0.05023 -0.01591
of basal metabolic rate (BMR) estimation has its inherent
Fruits & Vegetable        
limitations that can only be overcome by calorimetric
Fruits -0.27441‡ -0.06258 0.10703* 0.16526*
Leafy vegetables -0.07151 0.01074 -0.00490‡ -0.01866‡ measurement, and its use among Asians is likely to
Starchy vegetables -0.12787 0.08149 0.03761 0.01882 overestimate values. Hence, further investigation is needed
Nuts/legumes -0.33762‡ -0.34131‡ -0.01642‡ 0.14606 to verify these cut-offs in order to draw more meaningful
Dairy products         conclusions with their use.

Milk/yogurt 0.02125 -0.04427 -0.00094 0.0053

Chocolate -0.14658 -0.19422 0.02102 0.06651 As expected, the food items that predicted higher
Ice cream -0.05786 0.00693 0.05092 -0.00967 daily GI (bread, pastries, coffee mixes, soda/sweets) were
Creamer -0.00038 -0.00666 0.01069 0.04245 naturally food items with high individual GI (>55), while
Simple sugars         items with low GI (<55) like nuts/legumes, pasta/noodles
Table sugar 0.18283 -0.17245 0.066 0.07388 and root crops are associated with lower daily GI. Similarly,
Candy/sweets/syrup 0.17170* 0.23240* 0.00258 0.02713 food items with the greatest relative contribution to daily
Beverages        
GL were of high GI. These results reflect the typical diet
Juices 0.04696 -0.08142 0.04497 0.09215
Soda -0.06001 0.18206 0.04015 0.19396 of Filipinos, with rice, corn and root crops as staple foods,
Coffee mix 0.42292* 0.19081* 0.09526* 0.20897* breads and pastries as snacks, and abundance of tropical
fruits and vegetables. The Batangas province in particular
*Major positive contributors to GI and GL, ‡the major negative contributors. was known for its flourishing coffee plantations during the
deficient or underweight individuals were higher in our study Spanish era, and coffee drinking is commonplace among its
than that of national and regional (18% vs. 10% vs. 9.85%, dwellers to this day. However, many of the residents of San
respectively). 19 Juan have favored instant mixes over brewed coffee. Dietary
modifications for weight management in this population
The distinctiveness of this population from that of would likely include cutting down on servings of rice, bread
earlier reports was not limited to differences in nutritional and pastries, and replacing them with items of lower GI,
status. As emphasized earlier, the sample population was as well as moderation on intake of sweetened beverages,
relatively leaner (BMI x̅ =22.6) with a lower obesity rate coffee mixes and fruits.
(20%). The participants were also relatively young and more
physically active. Compared to the reports by Lau, Mendez There are several limitations to this study. In the
or Rossi,5,7,8 the participants of this study reported a markedly calculation of daily GI and GL, a few necessary assumptions
lower daily caloric intake (x̅ =1547 kcal/day) and a higher were made with regards to assigning corresponding GI values
percentage of carbohydrates consumption (ranging 63-77% to food items that did not appear in the local resource. The
of total calories). This pattern offers a rare perspective to the authors had consulted international resources to resolve
consequence of the carbohydrate quality (GI, GL) to obesity this issue. Also, it was assumed that the reported dietary
in a population that consumes high carbohydrate diets and information was accurate and represented the usual dietary
where caloric excess is uncommon. Understandably, these intake. Thirdly, the study was limited to evaluating association
differences may have important implications regarding the between daily GI or GL and BMI, and not causality. Fourth,
dietary recommendations for such individuals. Intervention BMI was used as the sole measure of obesity; it would be
involving caloric restriction may have limited role here given interesting to see if similar patterns would be observed when
the higher prevalence of energy deficient individuals, and other parameters such as waist circumference or waist-to-hip
dietary advice reasonably should emphasize quality of food ratio (WHR) are used to define obesity. Lastly, underreporting
choices over actual quantity. This highlights the importance rate using Goldberg-Black criteria was determined to be
of a tailored medical nutrition therapy to suit individual high, but the applicability of such criteria to this population
needs. is uncertain.

6 Volume 55 Number 4 Oct.-Dec., 2017

 Relationship of Average Daily Glycemic Index and Glycemic Load
Conclusions
The results of this investigation suggest that there is
likely a positive relationship between daily GI and BMI,
and between daily GL and BMI among the males in this
population. This relationship was not seen in the female
population, although differences between the dietary
patterns between the sexes particularly dietary fiber or fat
intake may have influenced the results. Majority of the food
items that are considered staple this population are of high
GI and contribute to higher daily GI and GL.
Recommendations
Although the study has its limitations, it paves the
way for further research that explores this subject. Further
investigations are needed to determine applicability of
Goldberg-Black criteria among Filipinos and to set relevant
cut-offs for its use. A prospective study employing reliable
methods of energy reporting is also ideal. Likewise, we
recommend a study focusing on urban population, as there
are likely to be differences in nutritional status and dietary
patterns.
Acknowledgements
Special thanks to Dr. Cecilia Jimeno for a comprehensive
technical review of this protocol and to Ms. Dolores Santos
for her help with the SAS program.
References
1. Popkin B, Adair L, Ng SW. Now and then: The global nutrition
transition: the pandemic of obesity in developing countries.
Nutrition Review, 70(1): 3–21, 2012.
2. Brand-Miller J, Holt S, Pawlak D, McMillan J. Glycemic index
and obesity. American Journal of Clinical Nutrition, 76:281-285S,
2002.
3. Schulze, M, Liu S, Rimm E, Manson J, Willet W, Hu F. Glycemic
index, glycemic load, and dietary fiber intake and incidence of type
2 diabetes mellitus in younger and middle aged women. American
Journal of Clinical Nutrition, 80:348-56, 2004.
4. Brand-Miller, J, Hayne S, Petocz P, Colaguiri S. Low glycemic
index diets in the management of Diabetes. Diabetes Care,
26:2261-67, 2003.
5. Lau C, Toft U, Tetens I, et al. Association between dietary
glycemic index, glycemic load, and body mass index in the Inter99
study: is underreporting a problem? American Journal of Clinical
Nutrition, 84:641-45, 2006.
6. Mukarami, K, Sasaki S, Okubo H, et al. Dietary fiber intake,
glycemic index and load and body mass index: a cross-sectional
study of 3931 Japanese women aged 18-20 years. European Journal
of Clinical Nutrition, 61:986-95, 2007.
7. Mendez M, Covas MI, Marrugat J, Vila J, Schroder H. Glycemic
index, glycemic load, and body mass index in Spanish adults.
Arellano HA, et al.
8.
American Journal of Clinical Nutrition, 89:316-22, 2009.
Rossi M, Bosetti C, Talamini R, et al. Glycemic index and
glycemic load in relation to body mass index and waist to hip
ratio. European Journal of Nutrition,49:459-64, 2010.
9. Sun L, Lee DE, Tan WJK, et al. Glycemic index and glycemic
load of selected popular foods consumed in Southeast Asia. British
Journal of Nutrition, 113:843-48, 2015.
10. Fernandez-San Valentin C, Berba Jr J. Philippine Food and
Nutrition Security Atlas. Makati : World Food Programme, 2012.
11. Yoon KH, Lee JH. Epidemic obesity and type 2 diabetes in Asia.
Lancet, 368:1681-88, 2006.
12. Sandoval M, Paz-Pacheco E, Ardena G, et al. Socioeconomic
realities in a rural Filipino community lead to volunteer bias in a
survey of diabetes, prediabetes and metabolic syndrome. Social
Medicine, 10:1, 2016.
13. Florentino R, Duante C, Valendria, F. The applicability of the
proposed Asian and WHO anthropometric cut-off points for the
assessment of overweight and obesity among Filipino adults.
Philippine Association for the Study of Overweight and Obesity
Convention, 2005.
14. Food and Nutrition Research Institute - Department of
Science and Technology. Glycemic index of commonly consumed
carbohydrates foods in the Philippines. Taguig : DOST, 2011.
15. Mifflin M, St Joer S, Hill L, Scott B, Daugherty S, Koh Y. A
new predictive equation for resting energy expenditure in healthy
individuals. American Journal of Clinical Nutrition, 51:241-7,
1990.
16. Black AE. The sensitivity and specificity of the Goldberg cut-off
for EI:BMR for identifying diet reports of poor validity. European
Journal of Clinical Nutrition, 54:395-404, 2000.
17. Kye S, Kwon S, Lee S, et al. Under-reporter of energy intake
from 24-hour dietary recalls in the Korean National Health and
Nutrition Examination Survey. Osong Public Health Res Perspect,
5(2):85-91, 2014.
18. Lavin JH, Wittert GA, Andrews J, et al. Interaction of insulin,
glucagon-like peptide 1, gastric inhibitory polypeptide and
appetite in response to intraduodenal carbohydrate. American
Journal of Clinical Nutrition, 68:591-8, 1998.
19. 8th National Nutrition Survey. http://endo-soc.ph.org/news.
Accessed July 6, 2016.
20. Goldberg G and Black A. Assessment of the validity of reported
energy intakes - review and recent developments. Scandinavian
Journal of Nutrition, 42:6-9, 1998.
21. Stice E, Palmrose CA, Burger KS. Elevated BMI and male sex
are associated with greater underreporting of caloric intake as
assessed by doubly labeled water. Journal of Nutrition, 10:2418-
8, 2015.
22. Millen A, Tooze J, Subar A, Kahle L, Schatzkin A, Krebs-Smith
S. Differences between food group reports of low energy reporters
and non-low energy reporters on a food frequency questionnaire.
Journal of American Dietary Association, 7:1194-203, 2009.
23. Huang T, Roberts S, Howarth N, McCrory M. Effect of
screening out implausible energy intake reports on relationships
between diet and BMI. Obesity Research, 13:1205-17, 2005.
Volume 55 Number 4 Oct.-Dec., 2017 7
 Philippine Journal of Internal Medicine
Development and Validation of the Filipino Version of the
Coronary Artery Disease Education Questionnaire Version 2
(FILIPINO CADE-Q II)
Lucky R. Cuenza, M.D.*; Bernard Benjamin Albano, M.D.**; Joseph Michael Ramirez, M.D.**; Raphael Magbag, PTRP***, Benjamin Jose Quito, M.D.****;
Edgardo Ebba, M.D.****; Leandro Bongosia, M.D.***
Abstract
Introduction: There is currently a lack of validated tools that
measure knowledge level as an outcome of the educational
component of cardiac rehabilitation programs in our local
setting. The researchers aim to culturally adapt and validate
a questionnaire that was designed to assess patients’
knowledge about coronary artery disease and participation
in cardiac rehabilitation programs, the second version
of the Coronary Artery Disease Education Questionnaire
(CADE-Q II).
Methods: Qualified translators did two independent
translations of the questionnaire. After back translation, the
questions were reviewed and modified by a committee of
experts. The final Filipino version was tested in a pilot study.
For psychometric validation the tool was administered to
109 patients enrolled in a cardiac rehabilitation program.
Criterion validity was assessed with regards to differences
in educational attainment and patient characteristics.
Spearman rank was used to correlate patient’s level of
knowledge with number of sessions attended. Internal
consistency was assessed by use of cronbach’s alpha.
Introduction
Cardiac rehabilitation (CR) is an evidence-based
program recommended for patients with cardiovascular
disease which involves a multidisciplinary approach of
physical activity, lifestyle modifications, nutritional and
risk factor management with the aims of improving
survival and quality of life. 1 One of its core components is
patient education which helps promote knowledge and
understanding of their disease. 2 Education is essential to
enable the patient to make decisions regarding their health
status which is important in the adoption of a healthy lifestyle
and behavioral changes.3
*Clinical Research Fellow in Cardiac Rehabilitation, Philippine Heart Center,
Quezon City, Philippines
**Adult Cardiology Fellow, Department of Adult Cardiology, Philippine Heart
Center, Quezon City, Philippines
*** Physical Therapist, Lead Coordinator, Section of Cardiac Rehabilitation,
Philippine Heart Center, Quezon City, Philippines
**** Consultant, Section of Cardiac Rehabilitation, Philippine Heart Center,
Quezon City, Philippines
Corresponding author: Lucky R. Cuenza , M.D., Philippine Heart
Center, Quezon City, Philippines
Email:baldyboy_182001@yahoo.com
The PHILIPPINE JOURNAL OF INTERNAL MEDICINE is a peer reviewed journal and a copyrighted publication of the Philippine College of Physicians
Original Article
Results: The final version of the questionnaire had 30
questions arranged in five domains consisting of medical
condition, risk factors, exercise, nutrition, and psychosocial
risk. Patients who were college graduates had significantly
higher mean scores than non college graduates. The
number of cardiac rehab sessions attended had a weak
but statistically significant correlation with knowledge.
(spearman rho 0.35, p=0.007). The overall internal consistency
of the questionnaire was good (α=0.75)
Conclusion: The CADE-Q II questionnaire cross culturally
adapted in Filipino is a valid and reliable tool which can
be used to assess Filipino patients’ knowledge about
their disease when participating in cardiac rehabilitation
programs.
Keywords: coronary artery disease, patient education,
health knowledge, cardiac rehabilitation
Studies have shown that patients with heart disease
seek knowledge on their disease, treatment options and
overall prognosis.4 Likewise in order to plan and deliver an
effective CR educational intervention, it is important to
have adequate information of the knowledge of patients
regarding their condition. However the reality is that the
education component of the CR program is frequently
overlooked and there are currently no validated tools for use
to assess the patient’s knowledge level with regards to CR
program participation and its components in our local setting.
The Coronary Artery Disease Education Questionnaire
(CADE-Q) was initially developed to assess the level of
patients’ knowledge regarding coronary artery disease.5
Then the second version of the questionnaire, the CADE-Q
II was an update that was psychometrically validated to
include all the core components of CR such as nutrition
and psychosocial aspects. 6 There has been no validated
questionnaire regarding patient’s knowledge of CR and
coronary artery disease for Filipinos. If translated and
validated in Filipino the CADE-Q II can be a useful tool
to assess the patient’s knowledge gaps and evaluate
educational delivery in CR for Filipinos.
Volume 55 Number 3 Oct.-Dec., 2017 1
 Cuenza LR, et al.
Objectives of the study
1. To translate and culturally adapt the second version
of the CADE-Q II into the Filipino language (Tagalog)
2. To determine the validity and reliability of the Translated
Filipino version of the CADE-Q II questionnaire
Methods
The study utilized a cross-sectional analytical design. The
study population's crteria is as follows:
Inclusion criteria:
1. Type of subject: patients with coronary artery disease
who were referred and enrolled in the Comprehensive
CR Program of the Philippine Heart Center (PHC) (post
coronary artery bypass graft, post percutaneous
catheter intervention, stable angina on optimal
medical treatment)
2. Gender: male or female above 19 years of age
Exclusion criteria:
1. Subjects who cannot read or speak Tagalog as the first
and daily language
2. Subjects with any visual, cognitive or psychiatric
condition that will prevent the individual from
answering the questionnaire
3. Subjects who refused to give informed consent
We hypothesized that the translated Filipino version of
the CADE-Q II will be a valid instrument to assess patient’s
knowledge, while the null hypothesis is that the questionnaire
will be unreliable to determine the level of patient knowledge
regarding heart disease and CR. We also hypothesize that
the number of cardiac sessions attended will be correlated
with the CADE-Q II scores attained.
The CADE-Q II was initially developed and validated
by the authors in Canada for patients undergoing CR. The
questionaaire is self administered and originally had 31 items
covering five different domains: medical condition, risk
factors, exercise, nutrition and psychosocial risk. Each item
had four alternatives that correspond to knowledge level:
A correct statement which showed complete knowledge,
a correct statement showing incomplete knowledge, an
incorrect statement showing wrong knowledge and an “I
don't know” option indicating a lack of knowledge. Scores
of knowledge items were given three points if they were
perceived correct and zero if they were wrong. Responses
were given a rating of one point if it pertained to incomplete
knowledge while the other two responses had a numerical
weight of zero points.
The original authors of the CADE-Q II (Ghisi et al.) were
contacted via email and they gave permission to carry out
the translation of the questionnaire in our native language.
The initial process of translation and cultural adaptation
2 Volume 55 Number 4 Oct.-Dec., 2017
Development and Validation of the Filipino CADE-Q II
was carried out to provide the CADE-Q II for the Filipino
population. The original English questionnaire followed the
protocol proposed by Gullemin et al.7 of initial translation from
English to the native Filipino language of Tagalog followed
by back translation and initial review. The translation was
done by a committee of experts in bilingual translation from
Sentro ng Wika of the University of the Philippines.
An expert panel assessed the content validity of the
translated questionnaire. The panel consisted of the primary
author, three cardiology consultants specializing in CR and
three cardiology fellows. Included in the focused group
were the physician and staff of the PHC section of CR who
ensured proper wording of questions, appropriateness of the
content, clarity, sequence and how the data will be sought
from the respondents. The final draft of the questionnaire
consisted of translated questions covered the same five
different domains: medical condition, risk factors, exercise,
nutrition and psychosocial risk. Many items were adapted
to Filipino culture and what was typically learned during
the education sessions of the CR program of the PHC. One
question in the exercise domain pertaining to exercising
during the winter months was deleted for a total of 30 items.
No further deletions or modifications were made and this
final version was used for validation. (Appendix A)
The study was conducted in the PHC section of CR
where patients with heart disease are referred for the
secondary prevention program. The mode of administration
of the questionnaire was self-administered. Initially a pilot
translated draft was given to 20 subjects for establishment
of face validity. Any of the questions that were perceived to
be vague due to grammatical rewording were rephrased.
After the initial validation a re test was done after two weeks
using the same subjects. The questionnaire return rate for the
pilot study was 100%. The final respondents to be analyzed
were invited for participation. They were asked for informed
consent and the complete objectives of the study were
disclosed. Patient profiles were determined through interview
by the investigators. Scores of knowledge items were given
three points if they were perceived correct and zero if they
were wrong. Unsure responses were given a rating of one
point (Appendix B). The sums of the scores were computed to
represent the mean total knowledge, with a highest possible
score of 90 points representing excellent knowledge.(Table I)
Since using cronbach’s alpha yielded a very small
sample size because the power was high, the sample
size calculation was based on Hair and Anderson’s
recommendations8 of a sample of 10 participants per item
or at least 100 participants in determination of responses
from a questionnaire or survey.
Descriptive statistics included measures of central
tendency (mean and their standard deviation) for
continuous variables and percentage-frequency distribution
 Development and Validation of the Filipino CADE-Q II Cuenza LR, et al.

Table I. Classification of the patient’s level of knowledge Table II. Characteristics of the study respondents
according to the questionnaire scores
Characteristic (n=109) Total n (%) Mean scores P-value
or ±SD ±SD
Sum of the scores Percentage Classification of
(points) knowledge Age 57.1± 9.4
81-90 90-100 Excellent Sex (Male) 82(75)
63-80 70-89 Good Body Mass Index 25.1± 3.5
45-62 50-69 Acceptable History of previous CABG 93(85.3) 64.3 ± 3.3 0.2142
27-44 30-49 Little knowledge History of previous PCI 12 (11) 60.1 ± 1.2
<26 <30 Insufficient knowledge Stable CAD 4 (3.7)

for categorical data. Spearman rank correlation was LVEF 55.7 ± 11.1
used to determine the correlation between number of College graduate 74 (67.9%) 61.7 ± 1.5 0.034
sessions attended and knowledge score. Criterion validity Number of sessions 5.8 ± 3.8
was assessed thru comparing the CADE-Q II scores by Hypertension 77 (70.6) 61.1 ± 1.3 0.153
participant’s level of education using T-test. This criterion
Dyslipidemia 69 (63.3) 62 ± 1.3 0.021
was applied as there has been evidence that individuals
with lower level of education have lower knowledge about Diabetes 40 (36.9) 57.6 ± 2.1 0.332
their health and disease.9 Statistical significance will be set at Aspirin/Clopidogrel 104 (95.4)
p-value of <0.05. For internal consistency Cronbach’s alpha Beta Blocker 90 (82.6)
was used with a minimum value of 0.610 All analyses were Calcium Channel Blocker 31(28.4)
performed using STATA version 13 software.
Statin 96 (88.1)
ACEI/ARB 72 (66.1)
The study was conducted in compliance with the
ethical principles set forth in the declaration of Helsinki. Nitrates 52 (47.7)
Prior to study initiation, there was a review and approval of
the study protocol and informed consent and subsequent
amendments by the PHC Institutional Ethics Review Board
(PHC IERB). Signed informed consent was taken from each
respondent prior to study participation. The investigator
preserved the confidentiality of all subjects taking part
in the study and ensured that the subject's anonymity is
maintained.

Results
The characteri sti cs of the stud y p op ul a tion a re
shown in Table I. A total of 109 patients were analyzed.
The patients’ average age was 57.1±9.4 years and 75% Figure 1: Correlation of number of sessions with CADE-Q scores
were males. Majority had risk factors such as hypertension
had a weak but statistically significant correlation with the
(70.6%) and dyslipidemia (63.3). There were 93 (85.3%) who
level knowledge based on CADE-Q II scores thus rejecting
were post coronary artery bypass patients, 74 (67.9%) were
one of our null hypothesis (Figure 1).
college graduates and the mean number of cardiac rehab
sessions participated was 5.8±3.8. The mean total CADE-Q
The mean scores per area are shown in Table III.
II scores were compared by educational attainment level,
Patients had the greatest knowledge related to their
the procedure that they underwent and co-morbidities. It
medical condition while the area of nutrition showed the
was shown that patients who were college graduates had
least knowledge. Out of a possible perfect score of 90
significantly higher mean scores than non college graduates
points, the mean score of all the participants was 60.1±11.5,
indicating higher knowledge (x̅ =61.7±1.5, p= 0.034). Patients
which generally indicated knowledge of 67% or higher and
with dyslipidemia were also noted to have higher mean
classified as acceptable knowledge. The reliability of each
scores (p=0.021). There were no significant differences in
area was assessed using cronbach’s alpha. Individually four
mean scores with regards to other comorbidities or whether
of the five subsets demonstrated internal reliability that was
the patient underwent percutaneous catheter intervention
generally lower than acceptable. The overall scale had
or coronary artery bypass. Using spearman rank correlation
good internal consistency with an alpha of 0.75 enabling us
(ρ=0.35, p=0.007) it was shown that the number of sessions
to reject the null hypothesis.11

Volume 55 Number 4 Oct.-Dec., 2017 3

 Cuenza LR, et al.
Table III. Mean scores and cronbach’s alpha per area of the
questionnaire.
Area Mean CADE-Q II Cronbach
score per area Alpha
Medical Condition 14.9 ± 3.5 0.53
Risk Factors 10.5 ± 2.9 0.41
Exercise 12.2 ± 3.4 0.63
Nutrition 11.8 ± 4.1 0.51
Psychosocial Risk 10.6 ± 2.9 0.47
Total 60.1 ± 11.5 0.75
Discussion
Translation and validation studies of health questionnaires
do not only entail simple semantic and literal analysis. It is
necessary that the language and idiomatic expressions be
conceptually adapted particularly to the culture that it aims
to target and apply the instrument for.12 While the Philippines
is composed of multiple islands, ethnicities and dialects, 96%
of Filipinos speak and understand Tagalog13 so we opted to
use it for our translation process. These aspects along with
other social and cultural differences were all considered in
the study.
The Filipino version of the CADE-Q II showed overall
good internal consistency and reliability. The psychometric
properties of the translated version are consistent with the
original CADE-Q II not just in internal consistency (α=0.75) but
also in relation to criterion validity. This supports the use of this
tool in assessment of knowledge of patients with coronary
artery disease who are in a CR program.
Regarding participant characteristics, it was noted that
patients with a higher educational attainment have higher
scores (x̅ =61.7±1.5). This relationship has also been observed
in other studies 14 indicating that knowledge is mediated
by an individual’s education as well as economic status.
It must be noted that although the level of educational
attainment presented significant differences in total scores,
other factors such as comorbidities and type of procedure
must be analyzed in relation to CR participation, as they
can have an impact on the attainment of knowledge of
coronary patients. 15 The higher mean scores of patients
with dyslipidemia may be multifactorial and may indicate
better compliance to statin medications and follow up in
these patients although larger studies are warranted. It has
been shown that patients with higher knowledge regarding
dyslipidemia has had a more positive attitude towards its
management.16
There are some limitations to this study that need to
be pointed out. First, this was a single center study where
generalizability may be limited. Secondly, while the overall
reliability of the scale is good, some of the domains performed
4 Volume 55 Number 4 Oct.-Dec., 2017
Development and Validation of the Filipino CADE-Q II
lower than acceptable. This may require further assessment
by use of other psychometric evaluation methods such as
exploratory factor analysis. Finally, it is worth noting in our
study that there is a statistically significant correlation with
the number of sessions attended with the level of knowledge,
providing some evidence that the duration and attendance
in a cardiac rehab program directly influences a patient’s
level of knowledge.17 Future research is needed to assess
whether this translated tool will be affected by CR as an
intervention, such that participation in cardiac rehab will be
associated with increased knowledge and in turn improved
awareness and outcomes.
A multifaceted CR program consists not just the
exercise component but also the educational component.
The association between CAD and knowledge can be
collaborated to promote proper lifestyle and risk factor
modification as well as optimize treatment and compliance.18
It has been shown that when all facets of CR are applied in
a systematic fashion, including proper patient education,
it can have a significant impact on recovery, reduction of
admissions, quality of life improvement and mortality. 19 The
Filipino version of the CADE-Q II is a useful tool capable of
measuring the level of knowledge of patients which can
potentially be a target goal in CR programs.
Conclusion
The results of the study shows that the Filipino translation
of the CADE-Q II has adequate validity and reliability
in assessing the Filipino patient’s knowledge regarding
coronary artery disease who participate in CR. The
questionnaire is a useful tool to evaluate a patient’s overall
level of knowledge as well as improve the educational
component of CR programs.
Acknowledgments
The authors would like to thank the Cardiac Rehabilitation
Staff of the PHC for their invaluable contributions in the
conduct of this study.
References
1. Balady GJ, Ades PA, Bittner VA, Franklin BA, Gordon NF,
Thomas RJ, Tomaselli GF, Yancy CW. Referral, enrollment,
and delivery of cardiac rehabilitation/secondary prevention
programs at clinical centers and beyond: a presidential advi-
sory from the American Heart Association. Circulation. 2011:
published online before print November 14, 2011, 10.1161/
CIR.0b013e31823b21e2
2. Leon AS, Franklin BA, Costa F, Balady GJ, Berra KA,
Stewart KJ, Thompson PD, Williams MA, Lauer MS. Cardiac
rehabilitation and secondary prevention of coronary heart disease:
an American Heart Association scientific statement from the
 Development and Validation of the Filipino CADE-Q II Cuenza LR, et al.

Council on Clinical Cardiology (Subcommittee on Exercise, S, Oh P, et al. Degree and correlates of cardiac knowledge
Cardiac Rehabilitation, and Prevention) and the Council on and awareness among cardiac inpatients. Patient Educ Couns.
Nutrition, Physical Activity, and Metabolism (Subcommittee on 2009;75(1):99-107.
Physical Activity), in collaboration with the American Association 17. Roter DL, Steshefsky-Margalit R, Rudd R. Current perspectives
of Cardiovascular and Pulmonary Rehabilitation. [published on patient education in the US. Patient Education Counseling
correction appears in Circulation. 2005;111:1717.] Circulation. 2001; 44: 79-86
3. Froelicher ES. Multifactorial cardiac rehabilitation: education, 18. Thompson DR, Lewin RJP. Coronary disease: management of
counseling, and behavioral interventions. In: Wenger NK, Smith the post myocardial infarction patient:rehabilitation and cardiac
LK, Froelicher ES, Comoss PM, editors. Cardiac rehabilitation. neurosis. Heart 2000; 84:101-105
New York, Dekker, 1999: 187–191.Suaya JA, Shepard DS,
Normand SL, Ades PA, Prottas J, Stason WB. Use of cardiac
rehabilitation by Medicare beneficiaries after myocardial infarction
or coronary bypass surgery. Circulation. 2007;116:1653–1662.
4. Danish Regions, Copenhagen Hospital Corporation and
Ministry of Health. Patienternes vurdering af landets sygehuse
[Patients’ assessment of Denmark’s hospitals]. Glostup,
Copenhagen County, 2000.
5. De Melo G, Oh P, Thomas S, Benetti M, Development and
validation of an English version of the Coronary Artery Disease
Education Questionnaire (CADE-Q), Eur J Prev Cardiol. 2013
Apr;20(2):291-300. doi: 10.1177/2047487312437061.
6. De Melo G, Grace S, Thomas S, Evans M, Oh P, Development
and Validation of the second version of the Coronary Artery
Disease Education Questionnaire (CADE Q II), Patient Educ
Couns, 2015 Mar;98(3):378-83
7. Guillemin F, Bombardier C, Beaton D, Cross Cultural Adaptation
of Health related Quality of Life Measures:literature review and
proposed guidelines. J Clin Epidemiol. 1993;46(12):1417-32
8. Hair JF, Anderson RE. Multivariate data analysis. New Jersey:
Prentice Hall; 1998, pp. 91-153, 660-706
9. Potvin L, Richard L, Edwards AC. Knowledge of cardiovascular
disease risk factors among the Canadian population:relationships
with indicators of socioeconomic status. Canadian Medical
Association 2000; 162:S5-11
10. Dancey CP, Reidy J. Statistics without maths for Psychology:
using SPSS for Windows. 3rd ed. London: Prentice Hall; 2005.
11. Ghisi GLM, Leite CM, Durieux A, Schenkel IC, Assumpção
MS, Barros MM, et al. Validação para o português do MargerI
CaRdiac preventiOn- Questionnaire (MICRO-Q). Arq Bras
Cardiol. 2010;94(3):372-8.
12. Educational Characteristics of the Filipinos (Special Release
No. 153) (2005)
13. Sommaruga M, Vidotto G, Bertolotti G, Pedretti RF, Tramarin
R. A self-administered tool for the evaluation of the efficacy of
health education interventions in cardiac patients. Monaldi Arch
Chest Dis. 2003;60(1):7-15.
14. Ghisi GLM, Oh P, Thomas S, Benetti M, Development and
validation of the English Version of the Coronary Artery Disease
Education Questionniare (CADE Q). European Journal of
Preventive Cardiology 2013; 20:291-300
APPENDIX A:
15. Alahmari AS, Alrashed FM, Afnan RA, Khozam SA,
AlsharaniMM, Mahdi BA et al. (2016); Knowledge, Attitude The Filipino CADE-Q II Questionnaire
And Practice Towards Dyslipidemia among Patients Attending Ikaw ay inaanyayahan na sagutan itong questionnaire na ito
Primary Healtch Care Centers Abha City, Saudi Arabia. Int. J. of dahil ikaw ay kasama sa isang programa ng cardiac rehabilitation.
Adv. Res. 4 (11). 1937-1946] Ang inyong kaalaman tungkol sa inyong kondisyon, mga gamot at
mga salik ng dahilan ng inyong sakit sa puso ay isang mahalag-
16. Kayaniyil S. Ardern CI, Winstanley J, Parsons C, Brister

Volume 55 Number 4 Oct.-Dec., 2017 5

Cuenza LR, et al. Development and Validation of the Filipino CADE-Q II

ang aspeto ng inyong pag galing.

Gusto naming malaman ang inyong kasalukuyang nalalaman tungkol sa inyong sakit.
Ang layunin ng pagsagot ninyo ng questionnaire na ito ay:
• Alamin ang inyong kabuuang kaalaman ng pasyente tungkol sa kanyang sakit sa puso
• Alamin ang inyong tiyak na kaalaman na nauukol sa inyong medikal na kondisyon, mga kasanhian ng sakit, ehersisyo, nutrisyon, at mga
sikososyal na aspeto.
Ang mga tanong ay nakalathala sa pamamagitan ng sumusunod na pamamaraan:
• may mga pagpipilian na apat na posibleng kasagutan
• bawat sagot ay may katugon na antas ng kaalaman
- Sagot na nagpapakita ng sapat na kaalaman
- Sagot na nagpapakita ng hindi hustong kaalaman
- Sagot na nagpapakita ng maling kaalaman
- Sagot na nag papakita ng kulang na kaalaman
Bawat sagot ay may katugon na puntos at ang kabuuan nito ang magsasaad ng iyong kaalaman
Mga direksiyon sa pagsagot:
• Ang mga tanong ay nakagrupo sa iba’t ibang saklaw ng kaalaman
Pakisagutan po ang lahat ng mga katanungan kung ano sa tingin ninyo ang tamang sagot. At huwag po mang iwan ng bahagi na hindi nasa-
gutan.
Maaari pong piliin ang sagot na “hindi ko alam” kapag hindi sigurado sa sagot.
• Pagkatapos sagutan pakibalik po ang questionnaire sa taong nagbigay sa inyo. Ang mga laman at kasagutan na inyong ilalagay ay bolun-
taryo at mananatiling konpidensyal

Unang Saklaw: Medikal na Kondisyon (Medical Condition)

Question 1
Ang Coronary Artery Disease ay:
a) Sakit sa ugat ng puso na pagkakaroon ng matigas na deposito ng calcium sa ugat ng puso dahil sa katandaan
b) Sakit sa ugat ng puso na nangyayari sa pagtanda ng tao na mataas ang kolesterol o paninigarilyo.
c) Sakit na nagbabara ang ugat sa puso. Ito ay naiimpluwensiyahan ng mga pagkain, bisyo at lahi at konektado ito sa pamamaga ng ugat
ng puso.
d) Hindi ko alam

Question 2
Ang Angina (pagsakit ng dibdib) ay nangyayari:
a) Kapag masyadong mabigat ang trabaho ng masel ng puso
b) Kapag ang masel ng puso ay hindi nakakakuha ng sapat na dugo at oxygen upang gumana ng mabuti
c) Kapag ang utak ay hindi nakakakuha ng sapat na oxygen.
d) Hindi ko alam

Question 3
Sa taong may coronary artery disease o sakit sa ugat ng puso, ano ang karaniwang paglalarawan o deskripsyon sa angina (pagsakit ng
dibdib)?
a) Pagsakit ng ulo pagkatapos kumain
b) Pagsakit ng dibdib kapag kumikilos o may ginagawa o kahit nakapahinga, na maaari din maradaman sa may braso, sa likod o sa leeg
c) Pagsakit ng dibdib habang kumikilos o may ginagawa
d) Hindi ko alam

Question 4
Ang atake sa puso ay nangyayari:
a) Kapag nag bara ang ugat sa puso
b) Kapag bumilis ang tibok ng puso dahil sa stress.
c) Kapag biglang nagbara ang ugat na pinagdadaluyan ng dugo papunta sa masel ng puso. Kung hindi ma ayos ang pagdaloy ng dugo,
mapipinsala ang bahagi ng puso na walang daloy ng dugo.
d) Hindi ko alam

Question 5
Ang pinakamainam na pinanggagalingan ng impormasyon para maintindihan ng pasyente ang kanyang mga gamut ay:
a) Ang doctor, ang cardiac rehab team, ang pharmacist at iba pang impormasyon mula sa mga healthcare professional
b) Ang mga nababasa natin sa internet

6 Volume 55 Number 4 Oct.-Dec., 2017

 Development and Validation of the Filipino CADE-Q II Cuenza LR, et al.

c) Ang doctor at ang cardiac rehab team

d) Hindi ko alam

Question 6
Ang mga gamut katulad ng aspirin at clopidogrel ay mahalaga sapagkat:
a) Pinapababa nya ang blood pressure
b) Pinalalabnaw ang dugo
c) Binabawasan ang aktibidad ng mga platelets sa dugo kaya mas mainam ang pagdaloy ng dugo sa ugat ng puso
d) Hindi ko alam

Question 7
Ang mga gamut na “statin” tulad ng atorvastatin, rosuvastatin, or simvastatin, ay may mabuting epekto sa katawan sa pamamagitan ng:
a)pagpapababa ng masamang kolesterol o LDL cholesterol sa dugo
b) Binabawasan ang paggawa ng masamang kolesterol o LDL cholesterol sa atay, pinapababa ang LDL cholesterol sa dugo at tinatangal
ang kolesterol para hindi maipon sa mga ugat.
c) binabawasan ang pag ipon ng kolesterol sa dugo
d) Hindi ko alam

Ikalawang Saklaw: Kasanhian ng Sakit (Risk Factors)
Question 1
Ang mga sanhi ng sakit sa puso na maaaring mabago at maagapan ay:
a) altapresyon, kolesterol at paninigarilyo
b) Edad, may sakit sa puso ang lahi, at kasarian
c) altapresyon, mabuti (HDL) at masamang (LDL) kolesterol, paninigarilyo at pagkakalantad sa usok ng sigarilyo, katabaan, malaking tiyan o
waistline
d) Hindi ko alam

Question 2
Ang mga hakbang upang ma kontrol and kolesterol sa katawan ay :
a) Iwasan ang pagkain ng itlog
b) Alamin ang antas ng mabuting kolesterol (“good cholesterol o HDL”) at ng masamang kolesterol (“bad cholesterol o LDL”), paginom ng
tamang gamut, pag kain ng pagkain na maraming fiber, pagbawas ng pagkain ng matataba, at pag ehersisyo ng mga limang beses sa isang
lingo
c) Alamin ang antas ng kolesterol at paginom ng gamut sa kolesterol na binigay ng doktor
d) Hindi ko alam

Question 3
Ang mga hakbang upang ma kontrol ang altapresyon ay:
a) Damihan ang paginom ng gatas sa dyeta
b) Bawasan ang pagkain ng maaalat at paginom ng gamot para sa altapresyon o high blood
c) Bawasan ang pagkain ng maaalat at ang asin sa pagkain na mas kaunti pa sa 2000 mg o isang kutsarita sa isang araw, pag ehersisyo,
paginom ng gamot sa altapresyon, at pagtuto ng mga pamparelax na aktibidad para mabawasan ang aburido
d) Hindi ko alam

Question 4
Ang unang hakbang sa pag control ng mga kasanhian ng sakit sa puso tulad ng altapresyon o kolesterol ay:
a) Alamin kung maaari kang magkaroon ng mga sanhi ng sakit
b) Magpacheck up upang alamin ang antas o level ng kasanhian ng sakit sa puso
c) Magkaron ng adhikain o hangarin na ma kontrol ang mga kasanhian
d) Hindi ko alam

Question 5
Ang mga hakbang upang maiwasa ang diabetes ay:
a) Diet na mabuti sa puso, mag ehersisyo ng 150 minuto sa isang lingo at panatilihing mainam ang pangagatawan

Volume 55 Number 4 Oct.-Dec., 2017 7

 Cuenza LR, et al. Development and Validation of the Filipino CADE-Q II

b) Bawasan ang carbohydrates tulad ng kanin at ang pagkain ng matataba sa dyeta.

c) Kung ikaw ay may lahi ng diabetes, maaari kang magkaroon din nito dahil hindi mo ito maiiwasan
d) Hindi ko alam

Ikatlong Saklaw: Ehersisyo (Exercise)

Question 1
Ano ang mahahalagang aspeto ng pag sailalim ng ehersisyo?
a) Pagalam kung ano ang maaaring kainin bago mag ehersisyo
b) Gaano katindi, gaano katagal, gaano kadalas at anong klaseng ehersisyo ang dapat gawin
c) Gaano katindi at gaano katagal ang pag ehersisyo
d) Hindi ko alam

Question 2
Sa isang tao na may sakit sa puso, mahalaga ang pag warm up bago simulant ang pag ehersisyo sapagkat:
a) Unti unti nitong pinapabilis ang tibok ng puso, maaaring bawasan ang pagsakit ng masel at bawasan ang pagkakataon ng angina o pag-
sakit ng dibdib
b) Para tumagal ang ginagawa nating ehersisyo
c) Hinahanda nya ang katawan para sa maayos na pag ehersisyo
d) Hindi ko alam

Question 3
Ang pulso ay matatagpuan:
a) sa may kamay sa may pulsuhan malapit sa hinlalaki
b) sa may kamay malapit sa hinliliit
c) sa may pulsuhan sa kamay o sa ugat ng leeg sa gilid
d) Hindi ko alam

Question 4
Ang mga kabutihan na maidudulot ng paggawa ng resistance training (pagbubuhat ng weights o ng pabigat) ay:
a) Nagpapalakas ng katawan at ng mga masel
b) Nagpapabagal ng tibok ng puso
c) Nagpapalakas ng masel, nagpapaganda ng kakayahan na gawin ang mga aktibidad na pang araw araw, nakakabuti ng blood sugar
d) Hindi ko alam

Question 5
Kung sumasakit ang dibdib habang naglalakad na ehersisyo, ang tamang gawin ay:
a) Bilisan lalo ang paglakad at tingnan kung mawawala ang sakit
b) Bagalan ang lakad at huminto mag ehersisyo
c) Bagalan ang paglakad. Kung hindi mawala ang sakit sa loob ng isang minute huminto sa pag ehersisyo. Kung higit isang minuto pa at
hindi pa rin nawawala ang sakit, maaaring uminom ng gamut sa ilalim ng dila na nitroglycerin. Kung hindi pa rin nawawala ang sakit, humingi
ng konsulta at tulong
d) Hindi ko alam

Question 6
Paano malalaman kung nasa tamang antas o gaano katindi ang pag ehersisyo?
a) Ang heart rate o ang bilang ng tibok ng puso ay umaabot sa target, ang paglarawan ng pasyente sa hirap ng ehersisyo ay “medyo mahi-
rap” (RPE of 13) at nakapagsasalita ang pasyente
b) Ang heart rate o ang bilang ng tibok ng puso ay umaabot sa target
c) matinding pawis at pagod na nararamdaman
d) Hindi ko alam

Ikaapat na Saklaw: Nutrisyon (Nutrition)

Question 1
Ano any pinakamagandang pinanggagalingan ng omega 3 sa pagakain?

8 Volume 55 Number 4 Oct.-Dec., 2017

 Development and Validation of the Filipino CADE-Q II Cuenza LR, et al.

a) bacon at hotdog
b) Pasta at noodles
c) mga malalansang isda tulad ng tuna, salmon at tawilis
d) Hindi ko alam

Question 2
Ang mga halimbawa ng trans fat ay:
a) pagkain ng itlog
b) mga cake at biskwet
c) margarina o mantikilya
d) Hindi ko alam

Question 3
Ano ang mainam na paraan upang mag dagdag ng fiber sa dyeta?
a) kumain ng wheat bread
b) Uminom ng juice
c) Kumain ng prutas at gulay
d) Hindi ko alam

Question 4
Alin sa mga sumusunod na pagkain ang pinakamaraming laman na asin:
a) pasta at noodles
b) mga sawsawan tulad ng gravy at soy sauce
c) Prutas at gulay
d) Hindi ko alam

Question 5
Anong kombinasyon ng pagkain ang nakakapagpababa ng altapresyon?
a) Karne, mga manok at isda
b) Prutas at gulay
c) Prutas at gulay, pag kain ng whole wheat at pagkain ng hindi maalat o maraming asin
d) Hindi ko alam

Question 6
Kapag nagbabasa ng mga label ng pagkain, ano ang pinakamahalagang tinitingnan o binibigyan ng pansin
a) gaano karami ang laman ng taba
b) pangalan ng brand
c) serving size o gaano kalaki ang nilalaman ng putahe
d) Hindi ko alam

Question 7
Gaano karami dapat ang kinakain na prutas at gulay?
a) mga pito hanggang sampu (7 to 10) na servings sa isang araw
b) isang beses lang sa isang araw
c) Kung gaano karami ang kaya
d) Hindi ko alam

Ikalimang Saklaw: Sikolohikal (Psychosocial Risk)

Question 1
Alin sa mga sumusunod ang epektibong pamamahala ng stress?

Volume 55 Number 4 Oct.-Dec., 2017 9

 Cuenza LR, et al. Development and Validation of the Filipino CADE-Q II

a) Paghinga ng malalim
b) Iwasan ang pakikipagkomunikasyon
c) Pag relax at huwag gaano magalala, pakikisama ng mabuti sa iba, pag ehersisyo, paghinga ng malalim
d) Hindi ko alam

Question 2
Anung klaseng stress ang napagalaman na may kaugnayan sa atake sa puso?
a) Talamak na stress sa buhay, mga malungkot na nangyari sa buhay, mahirap makatulog, kalumbayan o pagiging matamlay
b) Talamak na stress sa tirahan o sa trabaho and pakiramdam ng kalumbayan
c) Stress ng pag ehersisyo
d) Hindi ko alam

Question 3
Alin sa mga sumusunod ang naglalarawan ng mga paraan upang maiwasan ang kalumbayan o depression?
a) Uminom ng gamut sa depression at panatilihing mag ehersisyo
b) Mag ehersisyo, alagaan ang sarili, maayos na pananaw sa buhay, at kung kailangan uminom ng tamang gamot
c) Mahirap malunasan ang ang sakit sa puso dahil sa depresyon o kalumbayan
d) Hindi ko alam

Question 4
Mahalagang huwag balewalain ang sakit sa pagtulog na malakas na paghilik o ang “sleep apnea” dahil:
a) maaaring magkaroon ng pang matagalang sakit sa baga
b) Ito ay konektado sa mataas na altapresyon, abnormal na pagtibok ng puso at mataas na pagkakataon na magkarron ng atake o sakit sa puso
c) Maaaring magkaroon ng mas malubhang sakit sa puso
d) Hindi ko alam

Question 5
Ang “Chronic stress” o stress na talamak o matagal na at mahirap na lunasan ay maaaring mailarawan na:
a) mga kasalukuyang tension o kahirapan sa isang bahagi ng iyong buhay
b) Mga nangyayari sa bahay, sa trabaho o sa iyong lovelife na dahilan ng iyong pagiging iritable, aburido o hirap makatulog
c) Stress dahil sa ingay ng paligid o ng kapitbahay
d) Hindi ko alam
\
Maraming salamat po sa inyong partisipasyon!

10 Volume 55 Number 4 Oct.-Dec., 2017

Development and Validation of the Filipino CADE-Q II Cuenza LR, et al.

APPENDIX B.
CADE-Q II Scores

Alternatives
Question A B C D
Area: Medical Condition
1 0 1 3 0
2 1 3 0 0
3 0 3 1 0
4 1 0 3 0
5 3 0 1 0
6 0 1 3 0
7 1 3 0 0
Area: Risk Factors
1 1 0 3 0
2 0 3 1 0
3 0 1 3 0
4 1 3 0 0
5 3 1 0 0
Area: Exercise
1 0 3 1 0
2 3 0 1 0
3 1 0 3 0
4 1 0 3 0
5 0 1 3 0
6 3 1 0 0
Area: Nutrition
1 1 0 3 0
2 0 3 1 0
3 1 0 3 0
4 1 3 0 0
5 0 1 3 0
6 1 0 3 0
7 3 0 1 0
Area: Psychosocial Risk
1 1 0 3 0
2 3 1 0 0
3 1 3 0 0
4 0 3 1 0
5 1 3 0 0

Volume 55 Number 4 Oct.-Dec., 2017 11

 Philippine Journal of Internal Medicine
Neurosyphilis(Ocular Syphilis) with Bilateral Temporal Lobe
Atrophy in an HIV Patient: A Case Report
Vaughn Caesar L. Edulan, M.D.*; Jeremyjones Robles, M.D.*; Carmela Remotigue, M.D.*
Abstract
Introduction: Before the advent of antibiotics, syphilis was
known to be one of the most common infections affecting
approximately 10% of the adult population worldwide. One
of its devastating complications is neurosyphilis, which has
a broad set of manifestations. Some patients may present
with blurring of vision in the setting of an ongoing syphilis
infection known as ocular syphilis. In the advent of increasing
incidence of human immunodeficiency virus (HIV) infection,
co-infection with it may further obscure its manifestations or
may even cause synergistic effects.
Case Presentation: Presenting a case of a 26-year-old
male patient who complained of bilateral fronto-occipital
headache with progressive blurring of vision and scaly
reddish to brown maculopapular lesions affecting the limbs
prominently the soles and palms. CT scan showed cerebral
atrophy prominently on the temporal lobe bilaterally. Mental
Introduction
The incidence of syphilis and its complications such as
neurosyphilis has declined markedly since the introduction
of penicillin therapy. However, after the appearance of
acquired immunodeficiency syndrome (AIDS) in 1981, it
has increased in number due to the rising incidence of
human immunodeficiency virus (HIV) and the sexual habits
of individuals. High risk individuals include those men having
sex with men, intravenous drug users and commercial sex
workers.
Syphilis is a sexually acquired infection, which is
characterized by episodes of active clinical disease
interrupted by periods of latent infection if left untreated.
Studies suggest that HIV infection modulates the clinical
presentation of syphilis with greater organ involvement,
atypical and florid skin rashes, and more rapid progression to
neurosyphilis. The results of serologic tests for syphilis may also
be modified in HIV-infected patients. Furthermore, emerging
data suggest that syphilis may have a negative impact on
HIV viral load. 1
*Department of Internal Medicine, Cebu Velez General Hospital, Cebu City,
Philippines
Corresponding author: Vaughn Caesar L. Edulan, M.D., Cebu Velez
General Hospital, Cebu City, Philippines
Email:vaughncaesaredulan@gmail.com
The PHILIPPINE JOURNAL OF INTERNAL MEDICINE is a peer reviewed journal and a copyrighted publication of the Philippine College of Physicians
Case Report
status exam was normal. Neurosyphilis was confirmed by CSF
studies and patient tested positive for HIV infection. Patient
was then started on aqueous crystalline benzathine penicillin
G four million units every four hours for ten days and was
discharged with improved condition and no neurocognitive
deficits. . He was advised to have CD4 count and other work
up for his HIV infection as outpatient.
Conclusion: The reported incidence of neurosyphilis is
increasing in the advent of HIV infection. The deficiency of
a clear epidemiology, pathophysiology and complications
of cerebral atrophy in neurosyphilis patients co-infected
with HIV necessitates further studies to elucidate the proper
approach to this preventable and treatable disease.
Keywords: syphilis; neurosyphilis; ocular syphilis; cerebral
brain atrophy
Recently, early neurosyphilis is more common than late
neurosyphilis, and is most frequently seen in patients with
HIV infection. This association may simply reflect the fact
that syphilis is most common in men who have sex with men,
many of whom are HIV-infected, or it may reflect a true
difference in vulnerability1,2
Neuroimaging findings of neurosyphilis include cortical
and subcortical infarcts, cortical atrophy, hydrocephalus,
leptomeningeal enhancement associated with clinical
meningitis and arteritis. However, only few case reports
have presented with mesiotemporal abnormalities.3 In HIV,
neuroimaging findings include cortical and subcortical
atrophy most common on the frontal and temporal lobes.
Early stage of HIV most commonly affect the frontal lobe
and later affects the other lobes of the brain.4
Case Presentation
This is a case of a 26-year-old male who presented with
bilateral frontal and occipital headache, two out of 10 in
pain scale, occurring approximately twice per week for five
months now. In the succeeding months, he complained of
progressive blurring of vision on the left eye which progressed
to the right. He sought consult from an ophthalmologist and
was prescribed with steroids of unrecalled dose.
Volume 55 Number 3 Oct.-Dec., 2017 1
 Malundo AFG, et al. Neurosyphilis (Ocular Syphilis) with Bilateral Temporal Lobe Atrophy

Patient was newly diagnosed with HIV after one month

of recurrent headache. Patient has no known comorbidities.
He is an intravenous drug user at the age of 16 and has a
history of one male and five female sexual partners with
first sexual contact at the age of 17. He has no previous
hospitalizations, surgeries or blood transfusion.

On physical examination, vital signs were stable.

Pertinent findings included non-blanching, scaly, non-
pruritic, maculopapular lesions on the extremities and a
healed ulcer over the penile shaft with bilateral inguinal
lymphadenopathy. Patient had unremarkable central
nervous system findings.

On admission, CT scan of the brain plain was done

which showed mild cerebral volume loss, more pronounced
in both temporal lobes. There were no signs of increased
intracranial pressure (ICP). Lumbar puncture was done with
cerebrospinal fluid studies showing lymphocytic pleocytosis,
increased protein and decreased glucose. CSF IgG was
elevated and treponema pallidum immunofluorescence
was positive all consistent with neurosyphilis. Patient was
started with penicillin G, four million units, every four hours
for 10 days and was discharged improved. Figure 3. Algorithm for the diagnosis of Neurosyphilis coinfected with HIV 11

eye symptoms. However, its incidence in South-East Asia is

Discussion
Neurosyphilis is the invasion of the central nervous
system by treponema pallidum which is observed in five to
10% of untreated patients and may occur at any stage of
the disease. Neurosyphilis can be classified into early forms
and late forms. The early forms typically affect the cerebro-
spinal fluid (CSF), meninges, and vasculature, while the late
forms affect the brain and spinal cord parenchyma. The
duration of infection is important for it denotes the degree
of reversibility of damage done to the brain. The diagnosis
of the early stage of syphilitic infection is complex as many
patients present either with nonspecific symptoms or are
asymptomatic. According to a study by Bordon et al. 1995,
incidence of neurosyphilis co-infected with HIV increased
to 23.5% from 10% in HIV negative patients.
inconsistent on other countries such as Singapore and Japan
have several cases unlike in South China wherein it occurs
rarely even with high incidence of syphilis.7 Currently, there
are no studies regarding its prevalence in the Philippines.
After 10-30 years of infection, the patient can manifest
a condition known as general paresis which is character-
ized initially with forgetfulness and personality change. Most
affected individuals experience progression of deficits in
memory and judgment leading to severe dementia. Less
often, patients may develop psychiatric symptoms such as
depression, mania, or psychosis. These patients have also
been found to have cerebral atrophy or the cortical thinning
of the temporal and fronto-parietal regions bilaterally, most
prominent in the temporal regions.4

In patients with early neurosyphilis, they may present

asymptomatically or may have evidence of concomitant
primary or secondary syphilis. Ocular syphilis is one of its mani-
festations presenting in one third of patients with neurosyphilis
with blurring of vision as its most common symptom. This can
involve almost any eye structure such as the anterior uvea,
and posterior uvea or both uvea, but posterior uveitis is the
most common and presents with diminished visual acuity.5,6
In patients co-infected with HIV infection, studies show that
they have severe and diffuse form of inflammation such as
panuveitis and has a faster course of blurring of vision such
as with this patient. It is indicated therefore to test for ocular Figure 1. Left foot of the patients showing erythematous, exfoliating
syphilis and neurosyphilis for patients with syphilis having maculopapular rash

2 Volume 55 Number 4 Oct.-Dec., 2017

 Neurosyphilis (Ocular Syphilis) with Bilateral Temporal Lobe Atrophy
Human immunodeficiency virus (HIV) infected individuals
develop AIDS dementia complex (ADC) when in advanced
HIV infection is advanced. Advanced HIV infection is defined
as a CD4 count of <200 cells/uL by the Centers for Disease
Control and Prevention (CDC). If the test is unavailable, one
can use the clinical staging by the World Health Organiza-
tion (WHO) which include: recurrent pneumonia, HIV wasting
syndrome, chronic herpes simplex infection, extrapulmonary
tuberculosis and esophageal candidiasis which are all absent
in this patient. ADC presents with cerebral atrophy defined as
a decrease in the total gray matter and parietal cortex vol-
umes and increased total ventricular volumes in the parietal,
temporal and frontal lobes particularly the hippocampus.8
Patients having this disease present with neurocognitive
impairment which is not present in our patient. The degree
of cerebral brain atrophy is correlated with a low CD4 count
and chronicity of HIV infection.
Cerebrospinal fluid abnormalities of neurosyphilis include
of lymphocytic pleocytosis, elevated protein, decrease
glucose and a positive non-treponemal and treponemal
test. However, there is a different approach in patients co-
infected with HIV. An algorithm on how to diagnose neuro-
syphilis coinfected with HIV is in Figure 3. The current dilemma
is whether to do a lumbar puncture to test for neurosyphilis.
Lumbar puncture should be done on individuals with
known syphilis in the following situations: neurologic or oph-
thalmic signs or symptoms in any stage of syphilis, evidence
of active tertiary syphilis affecting other parts of the body,
treatment failure (including failure of serum nontreponemal
tests to fall appropriately) in any stage of syphilis, HIV infec-
tion with late latent syphilis or syphilis of unknown duration.9
The treatment of neurosyphilis including ocular syphilis is
aqueous crystalline benzathine penicillin G three to four
million units every four hours for 10-14 days. 10 The response
of this treatment to patients with neurosyphilis coinfected
with HIV is still effective. 11
Our patient, a 26-year-old male, presented with bilateral
fronto-occipital headache with blurring of vision bilaterally.
Patient was diagnosed with HIV and syphilis recently and
not on treatment. The presence of blurring of vision may
signify that patient may have ocular syphilis and so lumbar
puncture was indicated. Lumbar puncture showed decrease
Figure 2. CT scan of the brain of a normal 26 year old male (Left).
CT scan of the the patient with cerebral brain atrophy (Right)
Edulan VC, et al.
in glucose, elevated protein, lymphocytic pleocytosis and
a positive CSF treponema pallidum immunofluorescence
which clinched the diagnosis of neurosyphilis. CT scan of the
brain showed bitemporal lobe atrophy which may either be
caused by neurosyphilis or with HIV itself. However, cerebral
atrophy in these diseases usually occur in advance stages
with corresponding neurocognitive deficits which was absent
in this patient. Unfortunately, CD4 and T-cell count was not
taken which could have been an important predictor for
HIV associated brain atrophy. This case may lean toward
the synergistic effect of both neurosyphilis and HIV towards
brain atrophy.
Conclusion
The co-infection of neurosyphilis in an HIV patient is
relatively rare with an increasing incidence in Asia and
worldwide. The sequelae may lead to unpredictable course
of manifestations and signs. In patients who have ocular
syphilis and a more progressive course, it is recommended
to do HIV testing.
Cerebral bitemporal lobe atrophy has been proven to
be one the complications of advanced neurosyphilis with its
corresponding neurocognitive manifestations. Therefore, the
researchers recommend, that further investigation be done
in relation to the possible synergistic effect of neurosyphilis
when coinfected with HIV to cerebral bitemporal lobe at-
rophy. Further studies should emphasize the importance of
early recognition and treatment to prevent irreversible brain
damage in an otherwise curable disease.
References
1. Abara et al. Syphilis Trends among Men who have Sex with Men
in the United States and Western Europe: A Systematic Review of
Trend Studies Published between 2004 and 2015
2. Chen SY, Gibson S, Katz MH, et al. Continuing increases in
Sexual Risk Behavior and Sexually transmitted Diseases among
Men who have Sex with Men: San Francisco, California, 1999-2001,
USA. Am J Public Health 2002; 92:1387.
3. Mehrabian et al. Neurosyphilis with Dementia and Bilateral
Hippocampal Atrophy on Brain Magnetic Resonance Imaging 2012.
4. Cohen et al. Effects of Nadir CD4 Count and Duration of Human
Immunodeficiency Virus Infection on Brain Volumes in the highly
active Antiretroviral Therapy Era 2010; 16:25-32.
5. Taylor MM, Aynalem G, Olea LM, et al. A Consequence of the
Syphilis Epidemic among Men who have Sex with Men (MSM):
Neurosyphilis in Los Angeles, 2001-2004. Sexually Transmitted
Disease 2008; 35:430
6. Poliscli R, Vidal JE, Penalva Dc Oliveira AC, Hernandez AV.
Neurosyphilis in HIV-Infected Patients: Clinical Manifestation,
Serum Venereal Disease Research Laboratory Titers and associated
factors to symptomatic Neurosyphilis. Sexually Transmitted
Diseases 2008; 35:425.
Volume 55 Number 4 Oct.-Dec., 2017 3
 Edulan VC, et al. Neurosyphilis (Ocular Syphilis) with Bilateral Temporal Lobe Atrophy

7. Fonollosa A, Giralt J. Pelegrin L., Sanchez-Dalmau B, Segura

A, Garcia-Arumi J and Adan A. Ocular Syphilis-back again:
Understanding recent increases in the incidence of Ocular
Syphilitic Disease. OculImmunoInflamm 2009; 17: 207-12.
8. Richard P. Knudsen. Neurosyphilis. Medscape 2015.
9. Stokes JH, Beerman H, Ingraham NR. Modern Clinical
Syphilology: Diagnosis, Treatement, Case Study, 3rd edition, WB
Saunders, Philidelphia 1944.
10. Kasper: Harrisons Principles of Internal Medicine 19th edition
2015, New York, USA.
11. Marra, Christina et al.: Neurosyphilis. March 2013.

4 Volume 55 Number 4 Oct.-Dec., 2017

 Philippine Journal of Internal Medicine
Disease Characteristics of Behcet’s Disease Among Filipino
Patients Seen in Rheumatology Clinics
Juneth Ria R. Limgenco-Hipe, M.D.*; Evelyn O. Salido, M.D.**; Ester G. Penserga, M.D.**
Abstract
Introduction: Behcet's disease (BD) sometimes called
behcet's syndrome or silk road disease is an immune-
mediated systemic vasculitis. This condition remains a clinical
challenge for physicians. There are many reports, mostly case
series and nationwide surveys, on clinical manifestations
of BD from different parts of the world. In the Philippines
where BD is rare and underreported, physicians might not be
familiar with the clinical manifestations of this disease. The
aim of this research is to describe the disease presentation of
BD among Filipinos to increase awareness and avoid delay
in diagnosis which might pose a threat for the development
of irreversible, sometimes fatal complications.
Methods: A manual search was done for medical records
with diagnosis of BD in the clinics of rheumatology staff of
PGH. The diagnosis of BD was based on the 2006 International
Criteria for BD. We noted the demographic data, clinical
manifestations, results of ancillary procedures, treatment and
outcomes. The study follows a descriptive design.
Results: There were 31 patients with the diagnosis of BD
found from the manual search. Most of them were female
(77%). The mean age at diagnosis was 38.6 years ± 10.4 (SD)
and the mean time duration from onset of first symptom
to diagnosis was 41 months (range three to 180 months).
Three patients had a family member who also had BD (10%).
Introduction
Behcet’s disease (BD) sometimes called behcet’s
syndrome, morbus behcet, behcet-adamantiades or silk
road disease is an immune-mediated systemic vasculitis that
often presents with mucous membrane ulceration and ocular
involvement. BD was originally seen along the Silk Road,
going from East (China) to West (Spain and Portugal), but
due to trade and colonization, it is now seen everywhere in
the world.3 There are many reports, mostly case series and
nationwide surveys, on clinical manifestations of BD from
different parts of the world. There is difficulty in comparing
*Fellow-In-training, Section of Rheumatology, Department of Internal
Medicine, University of the Philippines-Philippine General Hospital
**Consultant, Section of Rheumatology, Department of Internal Medicine,
University of the Philippines-Philippine General Hospital
Corresponding author: Juneth Ria R. Limgenco-Hipe, M.D., University
of the Philippines – Philippine General Hospital, Manila, Philippines
Email:junethria@yahoo.com
The PHILIPPINE JOURNAL OF INTERNAL MEDICINE is a peer reviewed journal and a copyrighted publication of the Philippine College of Physicians
Original Article
The most common features of the disease were oral ulcers
(94%), ocular manifestation (68%), and cutaneous disease
(65%). The pathergy test was positive in 17%.The most
common treatments prescribed were oral steroids (74%),
colchicine (58%), and NSAIDs (48%). There was symptom
control or improvement in a third of patients but there were
still symptom recurrence in some. Thirteen patients (42%)
had recurrent oral ulcerations while 23% had recurrence
of skin lesions. Two of the patients (six percent) developed
blindness. There was no death recorded.
Conclusion: There is an average delay of three years in the
diagnosis of BD that hinders appropriate early treatment.
Moreover, BD remains to be a clinical challenge for
physicians. While a third of the cohort had good outcomes,
half still had symptom recurrences and the occurrence of
blindness in two patients underlines the potential of the
disease to disable. We recommend expansion of the cohort
to include the BD patients of other rheumatologists in the
Philippines to have an idea on the actual prevalence and
incidence of how this uncommon disease in our locality, and
to have a better understanding of its clinical presentation
and disease management in our country.
Keywords: bechet's disease, bechet's syndrome
the case series with the nationwide surveys because of
the difference in patient selection. According to a review
done by Davatchi et al., clinical manifestations are much
similar in nationwide surveys, while they may differ in case
series. The difference is mainly due to the specialty of the
centers. Ocular manifestations are more often reported
from ophthalmology centers, while mucocutaneous
manifestations are more reported from dermatology centers.
The new International Criteria for Behcet’s Disease (ICBD
2006) is as follows:
Symptoms Points
Oral aphthosis 2
Genital aphthosis 2
Ocular lesion 2
Skin lesions 1
Vascular manifestation 1
Positive pathergy test 1
Total score ≥ 3 = classify a patient with BD
98.2% sensitivity, 95.6% specificity, 97.3% accuracy5
Volume 55 Number 4 Oct.-Dec., 2017 1
 Limengco-Hipe JR, et al. Disease Characteristics of Behcet’s Disease Among Filipino Patients

Behcet’s disease (BD) carries an overall mortality rate as All patient information were anonymized and kept
high as 16% at five years. Rupture of coronary or pulmonary confidential. There were no conflicts of interest for this study.
arterial aneurysm carries a high mortality rate. Saadoun
et al. studied mortality data from 187 patients fulfilling the
Results
international criteria for BD from a single center in France.
The mortality rate at one year and five years was 1.2% and
There were 31 patients (77% are female) with the
3.3%, respectively. The main causes of death included major
diagnosis of BD. The mean age at diagnosis was 38.6 years
vessel disease (arterial aneurysm and Budd-Chiari syndrome,
± 10.4 (SD) and the mean duration from onset to diagnosis
43.9%), cancer and malignant hemopathy (14.6%), central
was 41 months (range three to 180 months) while mean
nervous system involvement (12.2%), and sepsis (12.2%). 
disease duration from diagnosis to latest follow-up was 55.6
 
months (range one to 192 months). Three patients had a
In the Philippines where BD is rare and underreported,
family history of BD (10%). Two patients with a relative with
physicians might not be familiar with the clinical manifestations
BD were diagnosed less than one year but one patient was
of this disease. Patients may be misdiagnosed to have
diagnosed after four years.
sexually transmitted diseases unresponsive to antibiotics,
refractory gout, sudden blindness of unknown cause, or
Table I show the clinical features included in the 2006
aphthous ulceration due to vitamin deficiency. This inability
International Criteria for BD. The most common feature of the
to recognize the disease will definitely increase morbidity
disease is oral ulcer (94%). The ocular manifestations seen are
and, possibly, mortality. There is no publication about
uveitis and visual impairment. The cutaneous findings consist
the disease characteristics of BD among Filipinos and it is
of folliculitis, erythema nodosum, and pustulosis. Vascular
interesting to discover any differences from other countries
events like arterial thrombosis, DVT, and superficial phlebitis
that also have BD. We hope that this study can contribute
are seen. Pathergy test is positive in only 17% of patients. The
to the knowledge about BD among Filipinos and aid in
average ESR is 44.22 ± 27.84 (SD) mm/hr and the peripheral
facilitating its recognition among our countrymen.
white blood cell count is 8.38 ± 2.19 (SD) x 109/L.

Behcet’s disease  (BD) is uncommon and its prevalence

The most common treatments prescribed were oral
in our country is not known. Its presentation mimics other
steroids (74%) and colchicine (58%, Table II). There was
common diseases and recognition is often a clinical challenge
symptom control or improvement without any recurrence in
for physicians. Through this publication, the authors hope that
a third of patients with mean follow-up of one year. There
physicians may learn of the disease, recognize it, and refer
were recurrences in patients that were followed up with
to the appropriate subspecialties. The study aims to describe
mean duration of five years. Thirteen patients (42%) had
the characteristics of BD among Filipinos.
recurrent oral ulcerations while 23% had recurrence of skin
lesions. Two of the patients (six percent) already presented

Methods with blindness on consult. There was no death recorded.

(Table III)

The study follows a descriptive design and includes

patients diagnosed with BD fulfilling the 2006 International Discussion
Criteria for Behcet’s Disease (ICBD) seen in clinics of
rheumatology consultants of the Philippine General Hospital Behcet’s disease (BD) is classically characterized as a
(PGH) - longest practice duration of 26 years; 1988 to 2014. triad of recurring aphthous oral ulcers, genital ulcers, and
Non-probability sampling was used in the selection of uveitis. It is more frequent and severe in persons of Eastern
participants. Mediterranean and Asian descent than those of European
Table I. Clinical features of 31 patients with BD included in the study
A manual search was done for medical records with
Features Frequency (%)
diagnosis of BD in the clinics of rheumatology consultants of
PGH. The diagnosis of BD was based on the 2006 International Mouth ulcers 29 (94)
Ocular lesions/findings 21 (68)
Criteria for BD. We noted the demographic data (gender,
Visual impairment 16
age at onset of BD; age at diagnosis, family history of BD), Uveitis 5
clinical manifestations, results of ancillary procedures (ESR, Skin lesions 20 (65)
WBC count, and pathergy test), treatment, and outcomes. Erythema nodosum (EN) 12
Pustulosis 5
Statistical Analyses: Descriptive statistics including frequency Folliculitis 3
tables Genital ulcers 18 (58)
Vascular 3 (10)
DVT 1
The conduct of this study was approved by the University
Venous insufficiency 1
of the Philippines Medical Research Ethics Board (UPMREB). APAS 1

2 Volume 55 Number 4 Oct.-Dec., 2017

 Disease Characteristics of Behcet’s Disease Among Filipino Patients
Table II. Treatment received by the 31 BD patients included in our
study
Treatment received Frequency (%)
Steroids 23 (74)
Colchicine 18 (58)
NSAIDs 15 (48)
Cyclophosphamide 10 (32)
Methotrexate 10 (32)
Azathioprine 2 (6)
Table III. Outcomes of 31 BD patients included in our study
Outcomes Frequency (%)
Improved (w/o any recurrences) 9 (30)
Recurrent oral ulceration 13 (42)
Recurrent skin lesions 7 (23)
Blindness 2 (6)
Recurrent genital ulceration 1 (3)
descent. There are nationwide surveys of BD in five countries
namely, Iran, Japan, China, Korea, and Germany (Table IV).
The male to female ratios are variable-male predominance
in Germany, China and Iran while female predominance
in Japan and Korea. Our study likewise shows a female
predominance. The mean age at onset is 32 years in our
study and similar to that in the surveys mentioned.
Oral aphthosis is the most constant symptom of BD, seen
in nearly every patient. Oral aphthous lesion can be seen
anywhere on the oral mucosa and presents as a painful,
round or oval ulceration with well-defined borders. In each
attack, there may be from one to several aphthous lesions,
and the number varies in different attacks. Most of the time,
two or more lesions may be seen. The healing process is
spontaneous and usually takes one or two weeks. This symptom
was seen in 93-99% of patients in the five nationwide surveys
mentioned and in 94% of patients in our cohort.
Genital ulcers are usually larger than oral ulcers, heal
slower, and recur less frequently. In females, they are often
wider than 10 mm and deeper than the oral aphthosis. They
are seen on the vulva, vagina, and rarely on the cervix. In
males, they are usually seen on the scrotum. Genital ulcers
were found in 58% of our cohort and in 64-83% of the five-
country surveys.
Anterior uveitis (AU) is a common ocular manifestation of
BD. It produces pain, photophobia, and visual disturbance.
The progress of AU follows the classical rule of attack and
remission. A single attack will usually cure spontaneously
without producing any sequela. Successive attacks lead
to cataract formation and, less frequently, to glaucoma.
Posterior uveitis (PU) and retinal vasculitis (RV), however, are
the main causes of blindness in BD. Blindness was seen in
11% of the eyes in patients with pan uveitis and/or retinitis.5
Ocular findings were present in 68% of our cohort, similar to
Iran, Japan, Korea, and Germany. China had the lowest
occurrence of ocular findings (35%).
Limengco-Hipe JR, et al.
The most frequent skin lesion in BD is pseudo-folliculitis,
better known as behcet’s pustulosis. It is a vasculitis
characterized by a dome shaped (non-acuminated) sterile
pustule on a round erythematous–edematous base. Erythema
nodosum (EN), usually frequent and relapsing, is the second
most frequent skin lesion. It is characterized by painful
multiple subcutaneous nodules of varying sizes preferentially
located on the lower limbs. Often, they have more erythema
and edema around the lesions than the classic erythema
nodosum. Skin aphthoses are painful, punched out, yellowish
narcotizing ulceration usually seen peri-anal skin, buttock, the
trunk, the axilla, the submammary space, and the interdigital
spaces and leaves a scar after healing. Skin manifestations
were seen in 65% of our cohort and in 67-87% of patients in
the five-country surveys.
Pathergy phenomenon is a hypersensitivity of the skin
to trauma. A papule, or a pustule, will appear at the site
of trauma, surrounded by erythema. The skin is punctured
perpendicular or diagonally with a 25- or 21-gauge needle
with one drop of normal saline. The reaction is best seen 24 to
48 hours after the puncture. The degree of reaction, which will
classify the pathergy test as positive, is not yet standardized
and this phenomenon is not constant during the course of
the disease. The frequency of the pathergy phenomenon has
decreased during the past decades, decreasing its value as
a diagnostic finding. This was seen in 34-56% of the patients
surveyed, compared to only 17% of our cohort.
Vascular involvement was seen in 10% of the Philippine
cohort, one case each of DVT, anti-phospholipid antibody
syndrome, and venous insufficiency. This was present in eight
to 13% in the surveys but quite low in Korea (1.8%). (Table III)
Laboratory findings are usually nonspecific and reflect
an inflammatory state. Elevated erythrocyte sedimentation
rate (ESR) seen in our cohort corroborates the presence of
active disease.
Immunosuppressive drugs are used to control BD.
Symptomatic therapy is directed at specific symptoms.
Topical measures (i.e., local corticosteroids) should be the first
line of treatment for isolated oral and genital ulcers. Acne-like
lesions are usually of cosmetic concern only. Thus, topical
measures as used in acne vulgaris are sufficient. Colchicine
is preferred when the dominant lesion is erythema nodosum
and this has also been used to prevent mucocutaneous
relapse. Joint involvement may respond to prednisone, local
corticosteroid injections, and nonsteroidal anti-inflammatory
drugs.7 Azathioprine is widely accepted as a steroid-sparing
agent and the initial agent for ocular involvement in BD. It
should be used together with systemic steroids for any patient
with BD and inflammatory eye disease affecting the posterior
segment.
Volume 55 Number 4 Oct.-Dec., 2017 3
 Limengco-Hipe JR, et al. Disease Characteristics of Behcet’s Disease Among Filipino Patients

Table III. Comparison of clinical features of behcet’s disease in the Philippine cohort and in five nationwide surverys

Clinical Features Philippines Iran9 Japan10 China11 Korea12 Germany13

(%) n=31 n=5059 n= 3316 n=1996 n=1527 n=590

Male to female ratio 0.36 1.19 0.976 1.34 0.63 1.40

Oral ulcer 94 97 98 93 99 98
Genital 58 65 73 76 83 64
Skin 65 67 87 69 84 81
Ocular 68 56 69 35 51 53
Vascular 10 9 9 8 2 13
Pathergy 17 54 44 nm 56 34
Legend: nm-not mentioned
Iran, analysis of 5059 cases. Arch Iranian Med 7:9–14
8. Nakae K, Masaki F, Hashimoto T et al (1993) Recent epidemiological
Conclusion features of Behcet's Disease in Japan. In: Godeau P, Wechsler B (eds)
Behcet's Disease. Elsevier Science Publishers B.V, Amsterdam, pp
Behcet’s disease remains a clinical challenge for 145–151
9. Zhang Z, Peng J, Hou X, Dong Y (2006) Clinical manifestations of
physicians. There is an average of three years’ delay in
Behcet's Disease in Chinese patients. APLAR J Rheumatol 9:244–247
diagnosis that hinders institution of early treatment. While 10. Bang D, Lee JH, Lee ES et al (2001) Epidemiologic and clinical
a third of the cohort had good outcomes, half still had survey of Behcet's Disease in Korea: the first multicenter study. J
symptom recurrences and the occurrence of blindness in two Korean Med Sci 16:615–618
patients underlines the potential of the disease to disable. 11. Altenburg A, Papoutsis N, Orawa H et al (2006) Epidemiologie
und Klinik des MorbusAdamantiades-Behçet in Deutschland—
We recommend expansion of the cohort to include the
AktuellepathogenetischeKonzepte und therapeutischeMöglichkeiten.
BD patients of other rheumatologists in the Philippines to J DtschDermatolGes 4:49–66
have an idea on the actual prevalence and incidence of 12. Fereydoun Davatchi, Farhad Shahram, Cheyda Chams-
how this uncommon disease in our locality, and to have a Davatchi, Hormoz Shams, AbdolhadiNadji, MassoomehAkhlaghi,
better understanding of its clinical presentation and disease TaherehFaezi, Zahra Ghodsi, AlirezaFaridar, FarimaAshofteh,
BaharSadeghiAbdollahi. Behcet’s disease from east to west.
management in our country.
ClinRheumatol (2010) 29:823–833
13. Davatchi F, Shahram F, Chams C et al (2005) Behcet's Disease.
Acknowledgement ActaMedicaIranica 43:233–242
14. Davatchi F, Chams-Davatchi C, Shahram F et al (2007) Pathergy
The authors would like to thank the following for their test in Behcet's Disease: change in incidence over the time. APLAR J
Rheumatol 10:333–335
valuable contribution to our study: Dr. Tom Edward N. Lo,
15. Calis M, Ates F, Yazici C, Kose K, Kirnap M, Demir M, et al.
Dr. Jose Paolo P. Lorenzo, Dr. Therese Lladoc-Natividad, Dr. Adenosine deaminase enzyme levels, their relation with disease activity,
Geraldine Zamora-Racaza, Dr. Bernadette Heizel Manapat- and the effect of colchicine on adenosine deaminase levels in patients
Reyes and Dr. Michael L. Tee with Behçet's disease. Rheumatol Int. Aug 2005;25(6):452-6.
16. Hatemi G, Silman A, et al. European League Against Rheumatism
(EULAR) recommendations for the management of Behcet disease
References:
1. Neville BW, Damm DD, Allen CM, Bouquot JE. (2008). Oral &
maxillofacial pathology (3rd ed.). Philadelphia: W.B. Saunders. p. 336.
ISBN 978-1416034353.
2. "Glossary,". Archived from the original on 19 April 2009. Retrieved
2009-03-28.
3. Davatchi F, Shahram F &Davatchi C & Shams H. Behcet’s disease:
from east to west. ClinRheumatol (2010) 29:823–833, DOI 10.1007/
s10067-010-1430-6
4. International Team for the Revision of the International Criteria for
Behcet's Disease (ITR-ICBD) (2006) Evaluation of the International
Criteria for Behcet's Disease (ICBD).ClinExpRheumatol 24(suppl
42):S13
5. Posadas, Augusto. Behcet Disease. Medscape Reference. http://
emedicine.medscape.com/article/329099-overview. 2011
6. Saaduon, D, Wechsler B, Desseaux K, Le Thi Huong D, Amoura
Z, Resche-Rigon M, Cacoub P. Mortality in Behcets disease. Arthritis
Rheum. 2010 Sep;62(9):2806-12. doi: 10.1002/art.27568.
7. Shahram F, Nadji A, Jamshidi AR et al (2004) Behcet's Disease in

4 Volume 55 Number 4 Oct.-Dec., 2017

 Disease Characteristics of Behcet’s Disease Among Filipino Patients Limengco-Hipe JR, et al.

APPENDIX A
Disease Characteristics of Behcet’s Disease among Filipino Patients seen in Rheumatology Clinics
Data Collection Form
ID No. Case #
Initials: Age:
Sex 0 = Male 1 = Female
Smoking: 0=never; 1=present; 2=past Age at onset of symptoms: _____
Alcohol: 0=never; 1=present; 2=past Age at diagnosis: _____
Date of diagnosis: _____
Family hx of BD: Duration of disease (in years): _____
0=none; 1= positive
Specify which family member:
Clinical Manifestations: Investigations done:
Yes No
ESR : 0-yes,1- no Result _____
Criteria Features: CRP: 0-yes, 1-no Result _____
Oral aphthosis/mouth ulcers WBC: 0-yes, 1-no Result _____

Genital aphthosis /ulcers Pathergy: 0-done, 1-not done

0-positive, 1-negative
Skin lesions/Cutaneous (follicultis,
erythema nodosum, pustulosis, Medications:
ulceration)
Yes No
Ocular lesions/Ophtha findings Colchicine
(uveitis, retinal vasculitis, visual NSAIDs
impairment) Steroids
DMARDs
Vascular (arterial thrombosis, DVT, Cytotoxic
superficial phlebitis) MTX
AZA
Non-criteria features:
Musculoskeletal (arthralgia, arthri- Outcomes: check if any of the following occurred during the
tis, back pain) course of treatment
Yes No
Neurologic (behavioral problems,
seizures, headache, Improvement
aphasia, hemiplegia, cerebellar Death
syndromes, myelopathy)
Blindness
Visual impairment
Recurrent oral ulceration
Recurrent genital ulcer
Recurrent skin lesion

APPENDIX B

WRITTEN INFORMED CONSENT FORM

I ______________________________, give my full consent to allow Dr. Juneth Ria Limgenco-Hipe, Rheumatology fellow-in-training, to get
necessary data from my patient’s chart for her research entitled DISEASE CHARACTERISTICS OF BEHCET’S DISEASE AMONG FILIPINO
PATIENTS SEEN IN RHEUMATOLOGY CLINICS under the direct supervision of Dr. Evelyn O. Salido and Dr. Ester G. Penserga.
I hereby declare:
That I fully understood the purpose of this study.
That my participation in this study is purely voluntary and without compensation in any form.
That all the information about the patients’ data will remain confidential except for the researchers conducting and the authorized
member of the research team.
That I am aware that the overall result of the study may be published in local or international journals.

____________________________ ____________________
Signature over printed name of
PGH Rheumatology staff Date

Volume 55 Number 4 Oct.-Dec., 2017 5

 Philippine Journal of Internal Medicine
Successful Reduction in Thyroid and Nodule Volumes in Large
Solitary and Multinodular Goiters with Serial 131Iodine Therapy
April Melody T. Abcede, M.D.*; Sjoberg A. Kho, M.D.**; Bien J. Matawaran, M.D.**; Leilani B. Mercado-Asis, M.D.**
Abstract
Introduction: 131Iodine therapy is effective in nodular non-
toxic goiter with enhanced effects using recombinant
thyroid stimulating hormone (rTSH). The eventual fibrosis
of the thyroid tissue and blood vessels ligates the vascular
supply of the nodule. The study aims to show the successful
reduction of thyroid and nodule volumes in large solitary and
multinodular goiters using serial low dose 131iodine therapy
(10mCi) at three to six months interval.
Methods: A retrospective analytical study was done from
January 2010 to December 2012 and included twenty three
patients with enlarged solitary and multinodular (nodule/s
≥2cm) non-toxic goiter (females: age range 35-65yrs) given
serial 131iodine therapy (eight to10mCi) at three to six-month
interval. Before each course, serum thyroid stimulating
hormone (TSH) was done to document hypothyroidism
while thyroid gland and nodule sizes were monitored by
ultrasonographic measurements serially with each 131iodine
therapy. Relief of compressive symptoms was monitored on
follow-up at clinic.
Results: Thyroid size reduced by 38-40% from baseline after
first radioactive iodine (RAI) and by 33-39% after the second
Introduction
Levothyroxine suppression therapy has been an
initial practice for prevention or growth reduction of
thyroid nodules. Studies have shown a moderate (50%-
60%) reduction in goiter volume primarily within the first
three months of treatment. 1 Surgery has still been widely
considered the standard therapy for patients with very large
compressive goiters.2 However, it is not a favorable option
among elderly people suffering from cardiovascular or other
disabling disorders rendering them unsuitable for surgery.
Several European studies have shown that radioactive iodine
(RAI) resulted in significant goiter size reduction among
**Fellow, Department of Endocrinology & Metabolism University of Santo
Tomas Hospital
**Consultant, Department of Medicine, Section of Endocrinology and
Metabolism University of Santo Tomas and University of Santo Tomas
Hospital
Reprint request to:Prof. Leilani B. Mercado-Asis, M.D., Ph.D., MPH,
lanibmasis@gmail.com, Contact # (02)7313001 local 2455
The PHILIPPINE JOURNAL OF INTERNAL MEDICINE is a peer reviewed journal and a copyrighted publication of the Philippine College of Physicians
Original Article
RAI. Thyroid nodules reduced by 63-69% and 11-25% serially.
Significant reduction was noted after the first RAI. One
subject underwent third RAI with 80-85% overall reduction in
nodule size. All patients developed post-RAI hypothyroidism
and overall had greater than 50% increase in levothyroxine
replacement dose after the last RAI. Significant relief of
compressive symptoms was noted by 91% post-therapy.
Four thyroid nodules disappeared which resulted in reduced
total number of thyroid nodules from 29 to 25 nodules post
serial RAI.
Conclusion: Serial 131 iodine therapy proved to have
thyroid and nodule size reduction by more than 70% in
this study. Among patients who do not consent or have
contraindications to surgery, serial 131iodine therapy may be
considered a safe and effective non-surgical alternative.
Keywords: serial RAI, large multinodular goiter, solitary
nodular goiter eduction
patients with nontoxic multi-nodular goiter.3,4 In a study by
Sia-Atanacio and Mercado-Asis, 131iodine therapy given at
a mean dose of 14mCi on patients with nodular non-toxic
goiter less than 2.0 cm showed complete disappearance of
nodules in 20 patients and 38% and 29% size reduction on
thyroid nodules and thyroid lobes respectively. 5 Being the
only non-surgical alternative treatment for large multinodular
goiter, RAI offers a mean thyroid volume reduction of
approximately 40-50% one year after treatment. 4,6 In
comparison to levothyroxine suppression therapy used
for thyroid nodule size one centimeter or less, it did not
offer benefit 6 and improvement in obstructive symptoms
(dyspnea, dysphagia) in the majority of patients with large
nodules.7,8
The intention to avoid dose dependent side effects done
in an out-patient clinic among elderly patients favored the
administration of low dose (8.0-10mCi) oral 131iodine therapy
in serial doses at three to six months interval. To date, there
have been few reported studies done on low dose serial
Volume 55 Number 4 Oct.-Dec., 2017 1
 Abcede AM, et al.
131
iodine therapy for large non-toxic goiters. Current trends
and studies are geared towards prior administration of
recombinant human thyroid stimulating hormone TSH (rhTSH)
with low doses of 131iodine therapy. In countries where rhTSH
is not readily available and use of low iodine preparation
is a common practice, serial low dose (eight to 10mCi)
131
Iodine therapy may prove to be effective in reduction
of multinodular goiter even with nodules more than two
centimeters.
The selection of the best therapeutic option for a patient
with multinodular goiter will depend on several factors,
including size and location of the goiter, the presence and
severity of compressive symptoms. Surgical complications
such as injury to the recurrent laryngeal nerve, trachea, and
parathyroid glands are more common in patients with large
and substernal goiters. 9 Levothyroxine therapy treatment
is particularly avoided in postmenopausal women with
evidence of low bone mass, in the elderly and in those with
cardiac disease, in whom the risk of this therapy generally
outweighs its uncertain benefits. 1 131Iodine therapy when
used to treat thyroid disease undergoes organification within
the gland. It emits beta particles with a path length of only
two to three millimeters destroys follicular cells by causing
DNA damage and cellular necrosis. Routine monitoring for
thyroid volume reduction includes ultrasound imaging, CT
scan or magnetic resonance imaging (MRI). The achieved
thyroid volume reduction ranges from 30-40% after the first
year (with half of the effect appearing within the first three
months) and from 50% to 60% after the third year.10
Methods follow-ups at the clinic. An endocrinologist evaluated for
Study population and design
Patients with large solitary and multinodular goiter
(≥2cm on either of the thyroid lobes) seen at the clinic from
2011 to 2013 who were biochemically and clinically euthyroid
underwent serial low dose RAI therapy. These patients were
unsuitable for surgery due to other medical problems.
Included are those who did not consent for surgery.
Seventeen subjects had large (≥2cm) solitary nodule while
six had multinodular goiter. Subjects with a median age of
47 yrs (range 37-69yrs) completed two consecutive 131iodine
therapies at eight to 10mCi at three to six months interval.
Patients were monitored for the first two weeks post RAI then
every two months thereafter. Close subjective correlation to
relief of compressive symptoms were recorded in the clinic
on follow-up visits.
131
Iodine therapy
131
Iodine was given as a single oral dose at the outpatient
department isolation room in accordance to the official
irradiation regulations. Since the side effects of 131 iodine
therapy are dose dependent, low dose (eight to 10mCi) was
2 Volume 55 Number 4 Oct.-Dec., 2017
Successful Reduction in Thyroid and Nodule Volumes
administered to avoid painful transient thyroiditis and swelling
which may occur within the first few weeks after treatment. A
second dose was given after three to six months.
Thyroid function
Thyroid stimulating hormone (TSH) was taken as an
initial test and recorded at baseline, after first and second
treatment. TSH was also done for the third time after 131iodine
therapy for one patient who had three RAI dose treatment.
Relative hypothyroidism developed after low doses of
131
iodine were given serially. Levothyroxine replacement
therapy was adjusted based on serial TSH results.
Thyroid imaging
Neck palpation was done on every patient and was
correlated with ultrasound imaging findings. This was the only
imaging modality used for baseline and serial measurements
of both thyroid lobes and nodules. The same machine and
reader was assigned to give measurements for all serial
ultrasound imaging however the reader was blinded to
the procedure done on all subjects. The baseline TSH on
all subjects were not below the lower limit of the reference
range, thyroid scintigraphy was not done in these subjects.
Compressive symptoms
Subjective complaints of compressive symptoms such
as difficulty breathing, swallowing and choking sensation
were all recorded prior to RAI as well as on subsequent
relief of compressive symptoms after serial RAI therapy and
compared it from previous subjective findings.
Statistical analysis
Categorical data were summarized using frequency
with percentage distribution, while numerical data were
summarized using mean. In addition, percent change
was computed. To determine significant change, paired
t-test was used; and Pearson product-moment correlation
coefficient was used to determine significant correlation.
Data were processed using Microsoft Excel and analyzed
using open sourced statistical software. An associated
p-value less than 0.05 was considered significant.
Results
Baseline characteristics of study group
From 2011 to 2013, 23 subjects were gathered where
21 (82%) were females and two (18%) were males. The
baseline characteristics are shown in Table I. The mean (±SD)
age group was 43 (±15.5) years, and the range was 37-75
years. Six subjects had multinodular goiter with compressive
 Successful Reduction in Thyroid and Nodule Volumes Abcede AM, et al.

Table I. Demographic distribution and baseline clinical

profile of subjects with large nodular and multinodular goiter

Baseline Characteristics Baseline

Sex (M/F) 2/21
Age (years) 43 ± 15.5
Total number of subjects 23
Number of subjects with 1 nodule 17
Number of subjects with 2 nodules 6
Biggest thyroid lobe size (cc) 24.209
Biggest thyroid nodule size (cc) 6.990
Baseline TSH 1.30 ± 0.48 Figure. 3 Thyroid function status (TSH) and hormone replacement after serial low
dose131iodine therapy
FNAB (all are negative) (-)
reduction in size to 4.79-5.38 cc after the first RAI and
symptoms while seventeen had large solitary nodules. subsequently to 2.91-3.60 cc after the second RAI (10mCi)
Baseline TSH on subject population was at 1.30 uIU/L (± 0.48). at three to six-month interval. At baseline, 29 nodules were
All subjects were clinically and biochemically euthyroid noted with an average volume at 3.27-3.41 cc. The figures
with no history of previous thyroid surgeries and absence of below showed the decreased volume of the nodules from
malignant features at baseline ultrasonographic findings. All baseline, then at 0.98-1.21 cc after first RAI, then at 0.87 0.91
patients had benign histopathologic findings on fine-needle cc after the second RAI. The highest response of thyroid
aspiration biopsy. nodule volume is observed after the first course of treatment.
Moreover, a reduction in total number of nodules was
Thyroid and nodule size reduction observed with disappearance of three nodules after the first
RAI and subsequently one nodule after the second RAI was
After the first RAI, there was a decrease in thyroid size observed (Figure 2).
by 38-40% from the baseline and further by 33-39% decrease
after the second RAI (Figure 1). The average thyroid volume Thyroid function
at baseline measurement was 7.79-9.03 cc with significant
Baseline TSH prior to serial 131 iodine therapy was at
1.30uIU/L (Table I). Subsequent increase in TSH levels to
2.98 after first RAI and 3.79 after second RAI (Figure 3).
Maintenance levothyroxine was at a mean dose of 65-70
mcg per day (Figure 3). Treatment of post-RAI hypothyroidism
with Levothyroxine therapy ensures better quality of life along
with relief of compressive symptoms. On the account of
high possibility of developing hypothyroidism, levothyroxine
therapy was started even after the first RAI treatment and
maintained with continued titration guided by serial TSH
monitoring until subsequent follow-ups.
Figure 1. Reduction of Thyroid Lobes after Serial Low Dose 131Iodine Therapy

Figure. 4 Improvement of compressive symptoms after serial low dose 131Iodine

therapy
Figure. 2 Reduction of Number of Thyroid Nodules and Size after Serial Low Dose
131
Iodine Therapy

Volume 55 Number 4 Oct.-Dec., 2017 3

 Abcede AM, et al.
Compressive symptoms
Six subjects with multinodular goiter had significant
improvement of compressive symptoms noted by
disappearance of choking sensation immediately after
the first RAI. Relief of compressive symptoms was noted
immediately after the first RAI with disappearance of choking
sensation. Subsequent relief of dysphagia and dyspnea
was fully noted after the second RAI (Figure 4). One patient
reported with partial relief of symptoms eventually had
complete relief six months after second dose of RAI.
Discussion
The recent use of recombinant TSH (rTSH) as enhancers
pronounced the effectiveness of RAI by enhancing
radioactive iodine uptake (RAIU). Dietary iodine restriction
is still widely used as pre-treatment thyroid enhancer. In
correlation to decreased iodine pool, it is still widespread
that many areas in the Philippines are still considered to
be iodine deficient. We have proven the effectiveness of
131
iodine therapy in solitary and multinodular non-toxic goiter
without rTSH on the premise that thyroid function must be
normal among population with relative iodine deficiency.
Radioiodine causes direct injury to the thyroid follicles and
eventually diffuses fibrosis of the thyroid tissue and blood
vessels eventually resulting in ligated blood supply to the
thyroid nodules. Overall, outcome will be a reduction of total
thyroid volume and shrinkage or disappearance of nodules.
This is a retrospective descriptive study done on 23
patients with enlarged solitary and multinodular goiters
(nodules ≥2.0cm) with a median age of 43 years old (range
35-65 years) who were clinically & biochemically euthyroid.
All patients had normal TSH and fT4 ensuring an intact iodine
trapping mechanism. All had benign ultrasonographic
features and negative fine-needle aspiration biopsy
(FNAB). Subjects completed two consecutive 131 iodine
therapy at 8-10mCi at interval of three to six months. An
overall reduction in size by 60% on thyroid gland and 73%
reduction on thyroid nodules. There was significant of
compressive symptoms has been emphasized in this study.
The disappearance of four thyroid nodules after the second
RAI remarkably depicts the ongoing process of fibrosis of
thyroid tissues and blood vessels causing shrinkage and
eventually dissolution of nodules within six-month period.
The important distinction here is that low dose serial 131iodine
therapy was found to have significant reduction both on
the enlarged goiter and nodule size. Knowing the dose-
dependent side effects of radioactive iodine, administration
at low doses abates even minor symptoms making this
procedure comfortable for the patient. For patients who are
inoperable due to cardiovascular or other disorders, serial
low dose 131iodine therapy is a good alternative for relief of
symptomatic patients.
4 Volume 55 Number 4 Oct.-Dec., 2017
Successful Reduction in Thyroid and Nodule Volumes
Thyroid scintigraphy was not performed in this study.
These nodules could appear cold or warm on thyroid scan.
In some cases it could even be a hot nodule but with an
unsuppressed TSH. This is possible in the background of
iodine deficiency more often seen in many iodine deficient/
insufficient areas including the Philippines. In this study,
patients were considered to have normal and intact iodide
trapping mechanism along with a normal TSH. However,
TSH may remain normal or unsuppressed even with an
autonomous functioning nodule in the background of iodine
deficiency because of the low proliferation rate of thyroid
epithelial cells and the low synthesis rate of thyroid hormones
by iodine-depleted thyroid glands. 11 Thus, it remains to be
one of the limitations in this study that thyroid scintigraphy
was not part of the initial thyroid assessment in the aspect of
function and detection of areas of possible autonomously
functioning thyroid nodules (AFTN) despite non-suppressed
TSH. Anti-thyroperoxidase (TPO) antibodies are usually taken
in support of high clinical suspicion for thyroiditis through
history but because of its cost and limited availability it was
not done on these set of patients. Instead, an fine needle
aspiration biopsy (FNAB) was done on all subjects which in
case of thyroiditis would show lymphocytic infiltrates in an
enlarged gland confirming autoimmune thyroiditis.
Conclusion
Serial 131iodine therapy proved to have successful goiter
and nodular size reduction by more than 50% even among
patients with enlarged nodular non-toxic goiter. Among
patients who did not consent or have contraindications to
surgery, serial 131iodine therapy may be considered a safe
and effective nonsurgical alternative.
Acknowledgements
In the accomplishment of this paper, I would like to
express my gratitude to the research committee, Dr Julie Li-
Yu, Dr. Elaine Cunanan, and Dr. Julie C. Visperas commented
on the ethical issues of this research paper.
References
1. Ross DS. 1992 Thyroid hormone suppressive therapy of sporadic
nontoxic goiter. Thyroid 2:263-269.
2. Allo MD, Thompson NW. 1983 Rationale for the operative
management of substernal goiters. Surgery. 94:967-977.
3. Nygaard B, Faber J, Hegedus L, Hansen JM 1996 131Iodine
treatment of nodular non-toxicgoitre. Eur J Endocrinol 134:15-20.
4. N y g a a r d B , H e g e d u ̈ s L , G e r v i l M , H j a l g r i m H , S o e -
JensenP,HansenJM1993 Radioiodinetreatment of multinodular
non-toxic goiter. BMJ 307:828 – 832
5. Sia-Atanacio, Mercado-Asis L.2011 Radioactive iodine therapy is
effective in diffuse and nodular non-toxic goiter. Phil. J. Internal
Medicine, Vol 49 Number 2Apr-Jun
6. Wesche MF, Tiel-V Buul MM, Lips P, Smits NJ, Wiersinga
WM 2001 A randomized trial comparing levothyroxine with
radioactive iodine in the treatment of sporadic nontoxic goiter. J
Clin Endocrinol Metab 86:998 –1005
 Successful Reduction in Thyroid and Nodule Volumes Abcede AM, et al.

7. Huysmans DA, Hermus AR, Corstens FH, Barentsz JO,

Kloppenborg PW 1994 Large compressive goiters treated with
radioiodine. Ann Intern Med 
121:757–762
8. Bonnema SJ, Bertelsen H, Mortensen J, Andersen PB, Knudsen
DU, Bastholt L, Hegedu ̈ s L 1999 The feasibility of high dose
iodine 131 treatment as an alternative to surgery in patients with a
very large goiter: effect on thyroid function and size and pulmonary
function. J Clin Endocrinol Metab 84:3636-3641
9. Pieracci FM, Fahey 3rd TJ 2007 Substernal thyroidectomy is
associated with increased morbidity and mortality as compared
with conventional cervical thyroidectomy. J Am Coll Surg 205: 1–7
10. Braverman LE, Cooper DS 2013 Werner & Ingbar’s The Thyroid: A
fundamental and clinical text 10th ed. Thyroid diseases: nontoxic
diffuse and multinodular goiter. In: Graf H, Mandel SJ, Langer
JE, Kaplan M. 10th ed. Wolters Kluwer/Lippincott Williams &
Wilkins 635 649
11. Hillenhinrichs H, Emrich D. Euthyroid goiter with and without
functional autonomy in the euthyroid phase: a comparison.
Nuklearmedizin. 1998;37:95-100

Volume 55 Number 4 Oct.-Dec., 2017 5

 Legal Prescription
Package Insert, Drug Labeling and Standard of Care
Atty. Rodel V. Capule M.D.*
“Package Insert [in FDA approved drugs] is the
document defining information that is supplied with
prescription drug products by the Marketing Authorization
Holder,” 1 whereas “Patient Information Leaflet is the
document defining information that is supplied with non-
prescription drug products by the Marketing Authorization
Holder.” 2 The Patient Information Leaflet is intended for
use by patients and is written in layman’s language. 3 On
the other hand, “labels and labeling materials are the
primary sources of information for consumers. They provide
useful information such as those dealing with the safe
and effective use of a drug product (e.g. indication(s),
pharmacologic class and dosage), and information
dealing with quality (e.g. manufacturing and expiration
dates, registration number, and manufacturer).” 4 “Drug
labeling is part of a comprehensive regulatory scheme
inextricably connected to drug approval.” 5 Take note that
[FDA] approval “doesn’t play a part in defining the drug’s
standard of care or how it is prescribed”. 6 Furthermore,
when the FDA approves a drug or device for sale and
marketing, it does so only with respect to the indicated
uses. 7
In the case of Lucas, et. al. v. Dr. Tuaño 8 complainants
alleged that respondent physician did not heed the
warning stated in the literature [package insert] of the
drug and thus should be held liable for the resulting
injuries. However, the Supreme Court dismissed the case
pointing out that petitioners’ complaint for damages
is merely anchored on a statement in the literature
[package insert]. If no standard is established through
expert medical witnesses, then courts have no standard
by which to gauge the basic issue of breach thereof by
the physician or surgeon. Another court 9 reached the
same conclusion - the Physicians’ Desk Reference (PDR)
and package inserts does not standing alone establish a
standard of care, but rather, [only] prima facie 10 proof of
proper use …” but when it is offered in conjunction with
expert testimony xxx that combination may be sufficient
to establish the standard of care.
Even granting, for the sake of argument, that a doctor
deviated from the drug manufacturer’s recommendation,
such deviation from such recommendations is [only] prima
facie evidence of negligence . . . .” 11 This is so, because
the term “negligent act or omission” consistently has been
used to refer only to breach and never to causation. 12
Hence, without further explanation, an alleged “breached
of the standard of care” but without any foundation to
establish causation will not be enough to compel the court
to rule against a respondent doctor.
*Dr. R.V. Capule is an attorney specializing in medical malpractice,
physical injuries and food torts. He is a law professor of Legal Medicine at
Arellano University School of Law and a consultant in Legal Medicine at
Adventist Medical Center-Manila and Makati Medical Center.
Philippine Journal of Internal Medicine
This is not to say that other FDA labeling must be
ignored. “The FDA-approved label may also include
‘contraindications’ and ‘warnings and precautions.’
A ‘contraindication’ is a ‘situation [] in which the drug
should not be used because the risk of use . . . clearly
outweighs any possible therapeutic benefit.’ ‘Warnings
and precautions’ are descriptions of ‘clinically significant
adverse reactions . . , other potential safety hazards .
. . , limitations in use imposed by them . . . , and steps
that should be taken if they occur,’ as well as any other
-information regarding any special care to be exercised by
the practitioner for safe and effective use of the drug…” 13
R eferences
1. Revised Rules and Regulations Governing the Generic
Labeling Requirements of Drug Products for
Human use, AO – 2016-ooo8, Office of the Secretary,
Department of Health, Republic of the Philippines.
Marketing Authorization (MA) - an official document issued
by the competent drug regulatory authority (DRA) for the purpose
of marketing or free distribution of a product after evaluation for
safety, efficacy, and quality, and containing, inter alia: the name
of the product; the pharmaceutical dosage form; the quantitative
formula (including excipients) per unit dose; the shelf-life and
storage condition(s); and packaging characteristics, specific
information on which authorization is based (e.g. “The product(s)
must conform with all the details provided in the application and as
modified in subsequent correspondence.”), the product information
approved for health professionals and the public, the sales category,
the name and address of the holder of the authorization, and the
period of validity of the authorization. In the Philippines, the
MA is in the form of a Certificate of Product Registration (CPR).
Marketing Authorization Holder (MAH) - the company or
corporate or legal entity in the field of pharmaceuticals in whose
name the MA for a drug product has been granted. This party is
responsible for all aspects of the product, including quality and
compliance with the conditions of the MA. The authorized holder
must be subjected to legislation in the country that issued the MA,
which normally means being physically located in that country.
In the Philippines, the MAH may either be a manufacturer or
distributor (exporter, importer or wholesaler).
2. Definition of Terms, (32), id.
3. Definition of Terms, (33), id.
4. I. Rationale, id.
5. Kurer, et. al. v. Parke, Davis & Company, and Warner-Lambert
Company 679 N.W.2d 867 (2004)
6. “On-Label vs. Off-Label Drug Prescribing” by Heather Claverie,
29 IG Living | December-January 2016 | IGLiving.com
7. Mark Herrmann and Pearson Bownas; “Keeping the Label out
of the Case”, 103:477, Northwestern University Law Review
Colloquy 2009
8. G.R. No. 178763, April 21, 2009
9. Harvey v. O’Donoghue, 530 A.2d 1141 (1987)
 Philippine Journal of Internal Medicine Legal Prescription

10. Prima facie evidence is defined as:

Evidence good and sufficient on its face. Such evidence as, in the
judgment of the law, is sufficient to establish a given fact, or the
group or chain of facts constituting the party’s claim or defense,
and which if not rebutted or contradicted, will remain sufficient.
Evidence which, if unexplained or uncontradicted, is sufficient to
sustain a judgment in favor of the issue it supports, but which may
be contradicted by other evidence (emphasis supplied). Wa-acon v.
People of the Philippines, G.R. No. 164575 December 06, 2006.
11. Winkjer v. Herr, 277 N.W.2d 579 (1979)
12. Grier v. AMISUB of South Carolina, Inc.,725 S.E.2d 693 (2012)
13. Mark Herrmann and Pearson Bownas; “Keeping the Label out
of the Case”, 103:477, Northwestern University Law Review
Colloquy 2009
 Philippine Journal of Internal Medicine
Efficacy of Ranolazine in Lowering HbA1c in Patients with Type
2 Diabetes Mellitus: A Meta-analysis
Everly Faith Ramos, M.D.*; Angelique Bea Uy, M.D.*; Aldrin B. Loyola, M.D.**
Abstract
Introduction: Cardiovascular diseases and diabetes mellitus
(DM) are two disease entities that commonly coexist in a
single patient. Ranolazine is an active piperazine derivative
approved by FDA in 2006 as an anti-anginal medication. It
was noted to have HbA1c lowering effects in the trials on
angina. The proposed mechanism of action is the inhibition
of glucagon secretion by blocking the Na v1.3 isoform
of sodium channels in pancreatic alpha cells leading to
glucagon- and glucose-lowering effects. HbA1c lowering
to a target of 6.5% in type 2 diabetes patients has been
shown to reduce risk of microvascular complications. The
objective of this study is to determine the efficacy and safety
of Ranolazine in HbA1c lowering as an add-on therapy to
existing anti-diabetic regimen.
Methods: A comprehensive literature search in PubMed,
The Cochrane Central Register of Controlled Trials, the
ClinicalTrials.gov website, Google Scholar databases and
EMBASE databases were made using the search terms
“Randomized controlled trial”, “Ranolazine,” “HbA1c,” and
“glycosylated hemoglobin”, as well as various combinations
of these, was done to identify randomized control trials. No
restriction on language and time were done. The authors
extracted data for characteristics, quality assessment
and mean change in HbA1c after at least eight weeks of
treatment with ranolazine. The program RevMan 5.3 was
used to generate the statistical analysis of the data.
Results: Six RCTs were included to make up a total of
1,650 diabetic patients. Five studies had moderate risk of
bias assessment while one had low risk of bias assessment
Introduction
Diabetes mellitus (DM) is one of the most common non-
communicable diseases worldwide. It is a chronic disease
that shows rising global disease burden, morbidity and mor-
tality rates. By the year 2030, it is predicted that diabetes will
be the seventh leading cause of death in the world and the
primary cause of blindness, amputation and kidney failure.
*Resident in Training, Department of Medicine, University of the Philippines-
Philippine General Hospital
**Consultant, Section of Adult Medicine, Department of Medicine, University
of the Philippines-Philippine General Hospital
Corresponding author: Everly Faith Ramos, M.D., University of the
Philippines – Philippine General Hospital, Manila, Philippines
Email:everlyfaith.ramos@gmail.com
The PHILIPPINE JOURNAL OF INTERNAL MEDICINE is a peer reviewed journal and a copyrighted publication of the Philippine College of Physicians
Meta-Analysis
and hence was not included in the analysis. The overall
analysis showed an HbA1c reduction of 0.35% 0.68 to -0.03,
p-value=0.03) however, the population was heterogenous
(I 2=100%). The heterogeneity was not eliminated by sensitivity
analysis.
Discussion: The results showed a statistically significant
lowering of HbA1c with ranolazine. However, the population
was heterogenous. The sources of heterogeneity could be
the (1) differences in the level of glycemic control among
subjects as indicated by baseline HbA1c levels, (2) the
current anti-diabetic regimen of the study patients, i.e.
whether or not they are on insulin therapy, (3) the presence
or absence of ischemic heart disease and (5) duration of
ranolazine therapy, and (4) the presence or absence of
chronic kidney disease. When the analysis excluded the
population with combination insulin therapy and ranolazine,
the effect becomes non-significant. Thus, the HbA1c
lowering effect may have been from the insulin therapy
rather than the ranolazine.
Conclusion: Ranolazine as anti-diabetic therapy shows
statistically significant HbA1c lowering effect. It can be a
potential treatment option for patients with both DM and
angina pectoris. However, well-designed, prospective trials
are still recommended to determine the effect on a less
heterogenous population. Likewise, more studies are needed
to determine its safety.
Keywords: ranolazine, HbA1c
In patients afflicted with the disease, about 50-80% die of
cardiovascular diseases. 1
Glycosylated hemoglobin (HbA1c) test has been used
as a measure of the average level of blood glucose in the
past 60–120 days. HbA1c target of 6.5% is recommended for
diabetic patients on the basis that it lowers the risk of
developing diabetic complications. The UK Prospective
Diabetes Study (UKPDS) established that intensive control
of blood glucose in type 2 diabetes reduced the risk
of microvascular complications, especially diabetic
retinopathy, in patients with type 2 diabetes, while it did not
find any effect on cardiovascular events.2
Volume 55 Number 3 July-Sept., 2017 1
 Ramos EF, et al.
Ranolazine([(+)N-(2,6-dimethylphenyl)-4(2-hydroxy-
3-(2-methoxyphenoxy)-propyl)-1-piperazineacetamide-
dihydrochloride]) is an active piperazine derivative approved
by FDA in 2006 for chronic angina. In experimental studies in
canine myocytes and guinea pig hearts, ranolazine showed
a concentration, voltage, and frequency-dependent
inhibition of late sodium current. The delayed or incomplete
inactivation of late sodium current is implicated in the heart
failure model of canine ventricular myocytes and is noted to
be increased in conditions associated with the pathological
milieu of ischemia.3,4 This in turn prevents intracellular sodium
overload that causes intracellular calcium influx through
the Na +-Ca ++exchanger that is responsible for contractile
dysfunction and cellular injury.
In the conduct of clinical trials evaluating the efficacy
of ranolazine as an anti-anginal agent, HbA1c lowering was
also observed among diabetic patients included in the study
population. This putative anti-diabetic property of ranolazine
has been tested in animal studies which yielded the following
plausible mechanisms of action: (1) ranolazine was found to
lower fasting and non-fasting glucose levels and preserve
pancreatic beta cells in streptozotocin-treated mice and
Zucker diabetic fatty rats and (2) ranolazine inhibits glucagon
secretion by blocking the Na v1.3 isoform of sodium channels
in pancreatic alpha cells leading to glucagon- and glucose-
lowering effects.5
The hypothesis generated in these observations
triggered the conduct of randomized controlled trials
evaluating ranolazine as add-on medication to existing
anti-diabetic regimen. To date, there is no published meta-
analysis on the effect of ranolazine on HbA1c lowering. Since
cardiovascular diseases and DM are two disease entities
that commonly coexist in a single patient. If proven to be
an effective anti-diabetic agent, ranolazine can become a
primary regimen for patients with chronic angina and DM.
Moreover, the glucagon-producing alpha cells as the target
of action of ranolazine offers a novel therapeutic target in
treating DM.
This study aims to answer the clinical question: among
patients with type 2 DM, how effective is ranolazine in lowering
HbA1c? This is a systematic review and meta-analysis on the
effect of ranolazine in the glycemic control of patients with
DM. Specifically, the study aimed to determine the effect of
ranolazine on the HbA1c levels of diabetic patients. It also
aimed to identify potential adverse events with its use.
Methods
This study included randomized control trials which
evaluated the effect of ranolazine on HbA1c levels of adult
patients with DM, expressed as mean change after at least
12 weeks of intervention.
2 Volume 55 Number 3 July - Sept., 2017
The Efficacy of Ranolazine in Lowering HbA1c
Figure 1. Study flow diagram. Study identification and selection process.
A systematic literature search on PubMed, The Cochrane
Central Register of Controlled Trials, the ClinicalTrials.gov
Website, Google Scholar databases and EMBASE databases
using the search terms “Randomized controlled trial”,
“Ranolazine,” “HbA1c,” and “glycosylated hemoglobin”, as
well as various combinations of these, was done to identify
potential studies. Cross-checking of references and citations
in review articles were carried out. Gilead Sciences was
contacted to obtain data on one unpublished randomized
control trial done on diabetic patients. No language or time
restriction was implemented. Only adult human trials were
included. Figure 1 shows the literature search algorithm.
Included studies met the following specifications: (1) RCT
design, (2) patients with Type 2 DM diagnosed by a fasting
plasma glucose ≥126 mg/dl, HbA1c ≥ 6.5%, random blood
glucose of ≥200 mg/dl with symptoms of hyperglycemia,
two-hour oral glucose tolerance test of ≥200 mg/dl; (3)
inclusion of subjects randomized to either placebo or
ranolazine on top of current anti-diabetic regimen. The
exclusion criteria are as follow: critically-ill patients, post-
operative patients and patients with type 1 DM. Studies
which reported mean HbA1c change after the pre-specified
duration of treatment is included in the analysis. Mean HbA1c
change was derived for studies which did not directly report
this outcome
The primary endpoint is (1) mean change, expressed
as least squares mean, in HbA1c after at least 12 weeks of
ranolazine treatment (2) incidence of hypoglycemia and
other adverse events with ranolazine therapy. No secondary
outcomes were sought.
Results were expressed as weighted mean differences
with their 95% CI computed. We evaluated heterogeneity
across included studies using Chi 2 and I 2 statistics. Studies
with an I2 statistic of 25 to 50% were considered to have low
 The Efficacy of Ranolazine in Lowering HbA1c
Figure 2. Funnel plot analysis.
heterogeneity, those with an I2 statistic of 50-75% to have
moderate heterogeneity, and those with an I2 statistic of
greater than 75% to have high degree of heterogeneity.
In cases of heterogeneity, the random effects model was
used. Subgroup analysis for the following groups were done:
ranolazine dose of at least 1,000 mg BID, ranolazine on top
of oral anti-diabetic agents, ranolazine in prospective trials
in diabetic patients i.e., post hoc analyses of angina trials
excluded.
All statistical analyses were performed using Review
Manager Version 5.3. A p-value of less than 0.05 was
considered statistically significant. Sensitivity analyses
were performed using the one-study-out method in order
to address the influence of each study by testing whether
deleting each individually would significantly change the
pooled results of the meta-analysis. Additionally, the random
effect model was applied to all outcomes to assess if there
were changes in the final effect.
Two reviewers (EFP and ABU) independently extracted
data from the identified RCTs. Assessment of eligibility of
studies were be done by applying the selection criteria.
The Cochrane’s Collaboration’s tool for assessing risk of
bias were used to assess the quality of the included RCTs.
Disagreements were resolved by consensus or, if necessary,
by a third party.
Results
Study selection and characteristics
The search strategy identified a total of 13 potential
articles (Figure 1). After removing duplicates and articles
that did not meet inclusion criteria, we screened 11 titles
and abstracts. Of these, 11 were selected for further review.
Ultimately, six RCTs satisfied all inclusion criteria. All selected
studies were published in journals as full english manuscripts.
One unpublished study from Gilead Sciences was included
in this review. Data were obtained from clinicaltrials.gov.
Ramos EF, et al.
Two studies, namely, Timmis and the unpublished from
Gilead Sciences were eventually not included in the analysis
because the results were not expressed as mean change in
HbA1c i.e., in least squares mean. The remaining four RCTs
make up for a total of 1,650 diabetic patients. The excluded
studies include that of Arnold and Kosiborod since HbA1c
was not included in the study outcome, Kloner and Patel
being review articles, and Khera an editorial. Funnel plot
analysis (Figure 2) showed high quality, precise studies but
with potential risk of bias.
Table 1 shows the characteristics of the studies included
in this systematic review and meta-analysis. Two studies were
post hoc analyses of HbA1c data obtained from the diabetic
population in ranolazine angina trials (MERLIN-TIMI 36 and
CARISA). 10 Three studies had HbA1c lowering in diabetic
patients as primary outcome.
The dose of ranolazine in the studies was either 500
mg, 750 mg or 1,000 mg taken twice daily per orem except
that of Chisholm et al. which gave an initial dose of 1,000
mg intravenously before shifting to oral administration. The
duration of treatment varied, with the shortest being at eight
weeks and the longest at 24 weeks. Common outcome
measures were change from baseline in HbA1c, fasting
blood sugar and two-hour post prandial glucose. Six studies
were judged to have low risk of bias while one had high risk
of bias (Table II).
Quantitative data synthesis
The overall analysis included a total of 1,650 patients.
It showed high heterogeneity with an I2 of 100%. The results
showed that ranolazine lowers HbA1c by 0.35% (-0.68 to -0.03,
p-value=0.03)(Figure 3). Figure 4 shows analysis excluding
Timmis 2005. This study had insulin as baseline anti-diabetic
treatment and contributed the smallest population but the
largest effect on HbA1c lowering. The result showed a trend
favoring ranolazine however, this was not signficant (p=0.31).
Figure 5 shows analysis excluding Yue MAO which is the
outlier in the overall analysis. The result showed a greater
effect favoring ranolazine with an HbA1c lowering of 0.5%
(-0.64 to -0.37, p-value=<0.00001). It also minimally lowered
the heterogeneity with an I2 of 98%.
Figure 6 shows the analysis including only the Yue GAO
and Yue MAO studies. These studies were prospective trials on
ranolazine as add-on therapy to either Glimeperide (GAO)
or Metformin (MAO). They were done by the same authors
and had similar inclusion and exclusion criteria. The result
showed that ranolazine had no effect on HbA1c lowering,
however this was not statistically significant (p=0.99) and had
high heterogeneity I2=100%.
Volume 55 Number 3 July-Sept., 2017 3
 Ramos EF, et al. The Efficacy of Ranolazine in Lowering HbA1c

Table I. Characteristics of included studies

Study Population Intervention Outcome measure Outcome Methodology Limitations

Eckel RH, et al. 5 Patients with Type 2 Ranolazine 500 mg BID • 24-week change -0.56 ±0.014 Randomized, Mean
Diabetes Care Diabetes Mellitus with uptitrated to 1000 mg BID from baseline in double-blind, difference
2015 HbA1c 7-10% (N=465) after 7 days vs Placebo HbA1c placebo derived
• Treatment naïve • Change from base- controlled
• Washed off of all line in FSG
antihyperglycemic • Proportion of sub-
therapy for 90 days jects with HbA1c
• Placebo (N=232) <7.0%
• Ranolazine (N=233) • Change from base-
line in 2-h post-
prandial glucose
Timmis AD, et CARISA Trial Diabetic population • 12-week change Randomized, Post hoc
al. 6 Patients with CAD and • Placebo + non-insulin from baseline in -0.19 ±0.16 double-blind, analysis of
European Heart a minimum 3-month medication (N=38) HbA1c as least- 3-group parallel data from
Journal 2006 history of exertional • Placebo + insulin (N=11) squares mean in 0.42 ± 0.26 trial angina trial
angina (N=823) • Ranolazine 750 mg BID Diabetic patients -0.54 ± 0.15
• Diabetes Mellitus + non-insulin medication as post hoc (p=0.087)
(N=189) (N=54) analysis
• Ranolazine 750 mg BID + -0.41 ± 0.23
insulin medication (N=13) (p=0.016)
• Ranolazine 1000 mg BID
+ non-insulin medication -0.74 ± 0.15
(N=52) (p=0.007)
Ranolazine 1000 mg BID +
insulin medication (N=11) -0.63 ± 0.3
(p=0.008)
Chisholm JW, MERLIN-TIMI 36 Trial • Placebo + insulin medica- 4-month change in • A1c 6-<8% Randomized, Post hoc
et al.7 • Patients with NSTE- tion (N=217) HbA1c from baseline group double-blind, analysis of
Diabetes Care ACS (N=6560) • Placebo + antihyperglyce- as retrospective 0.28% placebo data from
2010 • Diabetic patients micmonotherapy (N=385) exploratory analysis (p=0.045) controlled angina trial
(N=1734) • Placebo + antihyperglyce-
• Diabetic patients with mic dual therapy (N=218) • A1c ≥8-10%
A1c measurements • Placebo + 3 or more 0.59%
at randomization and antihyperglycemic drugs (p=0.001)
month 4 (N=1477) (N=38)
• Placebo + no antidiabetic • HbA1c ≥6.5-
drug (N=128) 10%
• Ranolazine 1000 mg -0.39%
BID + insulin medication (p=0.007)
(N=193)
• Ranolazine 1000 mg +
antihyperglycemicmono-
therapy (N=335)
• Ranolazine 1000 mg +
antihyperglycemic dual
therapy (N=204)
• Placebo + 3 or more
antihyperglycemic drugs
(N=34)
• Ranolazine 1000 mg + no
antidiabetic drug (N=134)
Gilead Sciences Patients 18-75 • Placebo + Mean and LSM 0.03% (0.949) Randomized,
Yue (GAO) years with Type 2 Glimeperide 2-4 mg/ change at 24 weeks double-blind,
NCT01494987 Diabetes Mellitus day OR in: placebo-
on Glimeperide/ Glipizide/Glyburide/ • HbA1c controlled
Pettus J, et al.8 Glipizide/ Glyburide/ Glibenclamide≥7.5 mg/ • FSG
Diabetes, Glibenclamide (N=431) day OR Gliclazide> 160 • 2-h PP
Obesity and mg/day (N= 216) • FSG-corrected -0.47%
Metabolism • Ranolazine 1000 mg 2-h PP glucose (0.971)
2016 BID + Glimeperide 2-4 rise
mg/day ORGlipizide/ • Mean glucose
Glyburide/ Gliben- for 3h after
clamide≥7.5 mg/day OR mixed meals
Gliclazide> 160 mg/day
(N= 215)

4 Volume 55 Number 3 July - Sept., 2017

 The Efficacy of Ranolazine in Lowering HbA1c Ramos EF, et al.

Table I. Characteristics of included studies (continuation)

Gilead Sciences Patients 18-75 years • Placebo + Metformin Mean and LSM -0.2% (0.949) Randomized,
Yue (MAO) 8 with Type 2 Diabetes ≥1500 mg/day (N=222) change at 24 weeks double-blind,
NCT01555164 Mellitus on Metformin • Ranolazine 1000 mg BID in: placebo-
≥1500 mg/day for ≥90 + Metformin ≥1500 mg/ • HbA1c -0.37% controlled
Pettus J, et al. days (N=442) day (N=220) • FSG (0.916)
Diabetes, • 2-h PP
Obesity and • FSG-corrected
Metabolism 2-h PP glucose
2016 rise
• Mean glucose
for 3h after
mixed meals
Gilead Patients with Type • Placebo on top of Mean change at -0.08% Randomized, Significant
Sciences 9 2 Diabetes Mellitus non-insulin antidiabetic 12 weeks in(least (0.142) double-blind, drop-out
NCT01163721 on non-insulin therapy (N=41) squares mean): placebo- rate
antidiabetic therapy • Ranolazine 1000 mg BID • HbA1c controlled
Unpublished (N=80) on top of non-insulin anti- • FSG Data on
diabetic therapy (N=39) • 2-h PP -0.61% baseline
(0.142) antidiabetic
therapy not
available

Table II. Assessment of risk of bias of individual studies

Study Randomization Allocation Performance Detection Attrition Reporting Overall

concealment bias bias bias bias grading of bias

Eckel RH, et al. Low Unclear Low Low Unclear Low Moderate
Diabetes Care 2015

Timmis AD, et al. Low Unclear Low Low Unclear Low Moderate
European Heart Journal 2006
Chisholm JW, et al. Low Unclear Low Low Unclear Low Moderate
Diabetes Care 2010
Gilead Sciences Low Unclear Low Low Drop-out Low Moderate
Yue (GAO) rate 13%
NCT01494987

Pettus J, et al.
Diabetes, Obesity and
Metabolism 2016
Gilead Sciences Low Unclear Moderate Low Drop-out Low Moderate
Yue (MAO) rate 17%
NCT01555164

Pettus J, et al.
Diabetes, Obesity and
Metabolism 2016
Gilead Sciences Low Unclear Low Low Drop-out Low High
NCT01163721 rate 25%

Unpublished

Figure 3. Overall analysis of the effect of ranolazine on HbA1c

Volume 55 Number 3 July-Sept., 2017 5

 Ramos EF, et al. The Efficacy of Ranolazine in Lowering HbA1c

Figure 4. Sensitivity analysis excluding Timmis 2005

Figure 5. Sensitivity analysis excluding Yue MAO 2014

Figure 6. Sensitivity analysis comparing the studies Yue GAO and Yue MAO.

Figure 7. Sensitivity analysis of ranolazine 1000 mg BID dose.

A sensitivity analysis on the effect of ranolazine 1000 mg

D iscussion
dose was done to determine if there is any dose-response
relationship (Figure 7). It showed that ranolazine lowered
This is a systematic review and meta-analysis on the
HbA1c by 0.42% (-0.76 to -0.07, p-value=0.02). This difference,
effect of ranolazine on HbA1c levels among patients with
however was not statistically significant from the effect in
type 2 DM. To our knowledge this is the first meta-analysis
the overall analysis.
of RCTs to examine such efficacy and safety. This study
included a total of 1,650 diabetic patients from five RCTs.
Qualitative data synthesis
The analysis generated the following results: (1) there is a
trend favoring the effect of ranolazine on HbA1c lowering,
Only two studies reported adverse events, summarized
(2) the magnitude of the lowering did not increase when
in Table III. The studies did not report significant differences in
analysis was limited to higher doses of the drug, i.e. 1000 mg
the occurence of adverse events between the study groups.
BID, (3) the exploration of the safety profile of ranolazine is
still limited.

6 Volume 55 Number 3 July - Sept., 2017

 The Efficacy of Ranolazine in Lowering HbA1c
Table III. Adverse events reported on ranolazine treatment.
Adverse effect Number of Study
events
Discontinuation due to 21/364 (5.8%) Eckel, et al.
adverse events Timmis, et al.
Any AE 97/232 (41.8%) Eckel, et al.
Hyperglycemia 19/232 (8.2%) Eckel et al.
Constipation 27/364 (7.4%) Eckel, et al.
Timmis, et al.
Dizziness 12/364 (3.3%) Eckel, et al.
Timmis, et al.
Nausea 14/364 (3.8%) Eckel, et al.
Timmis, et al.
Angina 4/132 (3.0%) Timmis, et al.
Asthenia 6/132 4.5% Timmis, et al.
The results, although statistically significant, should be
taken with caution as the population is very heterogenous.
The studies included in this review were both post hoc
analysis of data obtained from diabetic patients included
in angina trials of ranolazine as well as two prospective
studies which evaluated the effect of ranolazine on HbA1c
when used as add-on therapy to baseline anti-diabetes
medications. While the baseline characteristics of the
population studied in the angina trials showed no significant
differences, isolating the diabetic subgroup from this
population may have removed the effect of randomization.
Specifically, the sources of heterogeneity could be the (1)
differences in the level of glycemic control among subjects
as indicated by baseline HbA1c levels, (2) the current anti-
diabetic regimen of the study patients, i.e. whether or not
they are on insulin therapy, (3) the presence or absence
of ischemic heart disease and (5) duration of ranolazine
therapy, and (4) the presence or absence of chronic kidney
disease. Ranolazine, being a relatively new drug do not have
established pharmacokinetic and drug interaction profile
yet. Its interaction with the different baseline anti-diabetic
medications of the patients could have also contributed
to heterogeneity. Heterogeneity was not eliminated even
when sensitivity analysis was performed.
The sensitivity analysis excluding Timmis 2005 differed
because it showed non-significant HbA1c lowering with
ranolazine treatment Figure 4. Although it was a relatively
small study contributing only 112 patients, the ranolazine
added to insulin arm of this study contributed the highest
reduction in HbA1c at 1.05% (-1.28 to -0.82). The greater
lowering in HbA1c observed in this arm, therefore, could
have been from the insulin therapy and not from ranolazine.
In the pooled analysis, it was noted that the study Yue
MAO favors placebo (Figure 3). It was also expected that
heterogeneity will decrease when the Yue GAO and Yue
MAO studies were compared. Upon review, the authors
Ramos EF, et al.
concluded that the difference in the result stemmed from
the study design. The investigators in Yue MAO adjusted the
metformin doses in the intervention group to account for the
theoretical pharmacokinetic interaction between metformin
and ranolazine. This was based on Phase I clinical studies in
patients with type 2 DM showing a 1.53-fold increase in plasma
Metformin concentration among patients taking ranolazine
1000 mg and Metformin 1000 mg. 11 This dose adjustment in
the study design resulted in the possible underdosing of the
medications and this translated into an increased HbA1c.
Thus, when the Yue MAO and Yue GAO were compared
(Figure 6), heterogeneity was not eliminated despite having
similar baseline patient characteristics. In conclusion, the
attempt to cluster the two studies because they were the
only ones done prospectively on diabetic patients not in
angina trial, was an unfair comparison.
Only two studies (Eckel et al. and Timmis et al.) reported
adverse events and the observation period spanned only
12-24 weeks. Pettus et al. cited that the study of Eckel et
al. have established cardiovascular safety of ranolazine
among patients with type 2 DM. However, the authors
believe that further studies are needed because of the
limited follow-up duration and population size. ranolazine’s
drug interaction with Metformin, as well as the other anti-
diabetic medications, if indeed clinically significant should
be investigated.
Conclusion
Ranolazine as an anti-diabetic therapy shows statistically
significant HbA1c lowering effect. It can be a potential
treatment option forpatients with both DM and angina
pectoris. However, well-designed, prospective trials are
still recommended to determine the effect on a less
heterogenous population. Likewise, more studies are needed
to determine safety.
References
1. Diabetic fact sheet 2015-2016 retrieved from www.cdc.gov/
chronicdisease/resources/publications/aag/diabetes.htm.
2. King, P., Peacock, I., and Donnelly, R. (1999). The UK Prospective
Diabetes Study (UKPDS): clinical and therapeutic implications for
type 2 diabetes. British Journal of Clinical Pharmacology, 48(5),
643–648. http://doi.org/10.1046/j.1365-2125.1999.00092.
3. Hasenfuss G. and Maier L.S. (2008). Mechanism of action of the
new anti-ischemia drug ranolazine. Clin Res Cardiol 97(4): 222-6.
4. Chaitman, B.R. (2006). Ranolazine for the treatment of chronic
angina and potential use in other cardiovascular conditions.
Circulation 113(20).
5. Eckel, R. H., Henry, R. R., Yue, P., Dhalla, A., Wong, P.,
Jochelson, P., … Skyler, J. S. (2015). Effect of Ranolazine
Monotherapy on Glycemic Control in Subjects With Type 2
Diabetes. Diabetes Care, 38(7), 1189–1196. http://doi.org/10.2337/
Volume 55 Number 3 July-Sept., 2017 7
 Ramos EF, et al. The Efficacy of Ranolazine in Lowering HbA1c

dc14-2629
6. Timmis AD, Chaitman BR, Crager M. (2006). Effects of
ranolazine on exercise tolerance and HbA1c in patients with
chronic angina and diabetes. Eur Heart J. 27(1):42-8. Epub 2005
Sep 21.
7. Chisholm, J. W., Goldfine, A. B., Dhalla, A. K., Braunwald, E.,
Morrow, D. A., Karwatowska-Prokopczuk, E., & Belardinelli,
L. (2010). Effect of Ranolazine on A1C and Glucose Levels
in Hyperglycemic Patients With Non-ST Elevation Acute
Coronary Syndrome. Diabetes Care, 33(6), 1163–1168. http://doi.
org/10.2337/dc09-2334
8. Pettus, J., McNabb B., Eckel, R.H., Skyler, J.S., Dhalla, A.,
Guan, S., Jochelson, P., Belardinelli, L. and Henry, R.H. (2016).
Effect of ranolazine on glycaemic control in patients with type 2
diabetes treated with either glimepiride or metformin. Diabetes
Obes Metab. 18(5):463-74. doi: 10.1111/dom.12629. Epub 2016
Feb 23.
9. Gilead Sciences. A Phase 2, Randomized, Double­b lind, Placebo­
controlled, Parallel­g roup Exploratory Study to Access the
Metabolic Effects of Ranolazine When Added to Ongoing Non­
Insulin Antidiabetic Therapy in Subjects With Type 2 Diabetes
Mellitus. clinicaltrials.gov NCT01163721 retrieved February 2016.
10. Morrow DA, Scirica BM, Chaitman BR, McGuire DK, Murphy
SA, Karwatowska-Prokopczuk E, McCabe CH, Braunwald E
(2009). Evaluation of the glycometabolic effects of ranolazine in
patients with and without diabetes mellitus in the MERLIN-TIMI
36 randomized controlled trial. Circulation 119(15):2032-9. doi:
10.1161/CIRCULATIONAHA.107.763912. Epub 2009 Apr 6.
11. Zack, J., Berg, J., Juan, A., Pannacciulli, N., Allard, M., Gottwald,
M., Zhang, H., Shao, Y., Ben-Yehuda, O. and Jochelson, P. (2015),
Pharmacokinetic drug–drug interaction study of ranolazine and
metformin in subjects with type 2 diabetes mellitus. Clinical
Pharmacology in Drug Development, 4: 121–129. doi:10.1002/
cpdd.174

8 Volume 55 Number 3 July - Sept., 2017

 Philippine Journal of Internal Medicine
Prognostic Impact of Coronary Collaterals in Acute Coronary
Syndrome (PICC-ACS): A Meta-analysis of Observational
Studies
John Daniel A. Ramos, M.D.*; Jaime Alfonso M. Aherrera, M.D.*; Lowe L. Chiong, M.D.**; Mark A. Vicente, M.D.*; Felix Eduardo R. Punzalan, M.D.**; Richard
Henry P. Tiongco, M.D.**
Abstract
Introduction: The coronary collateral circulation (CCC) is an
alternative source of blood supply in coronary artery disease
(CAD). The prognostic value of the presence of CCC at
the time of acute coronary syndrome (ACS) is undefined
with regards to hard outcomes, particularly reduction in
mortality. The study's aim is to determine if the presence of
CCC demonstrated by coronary angiography during an ACS
is associated with a reduction in mortality.
Methods: We conducted a systematic search of studies
using MEDLINE, EMBASE, ScienceDirect, Scopus, and
Cochrane Central Register of Controlled Trials databases
in all languages and examined reference lists of studies.
The inclusion criteria were 1) observational; 2) population
included adults >19 years old with an acute coronary
syndrome; 3) reported data on mortality in association
with the presence or absence of CCC on angiography;
and 4) should have controlled for confounders by using
logistic regression analysis. Study quality was assessed
using the Newcastle-Ottawa Quality Assessment Scale for
observational studies. The outcome of interest was reduction
Introduction
The coronary collateral circulation (CCC) is an
important adaptation of the myocardium to prevent
damage from ischemic injury. Collaterals are usually
part of the microcirculation, existing as arterial-arterial
anastomotic connections. As an adaptation to injury, they
have a propensity to remodel into components of the
macrocirculation with a decreased resistance to blood
flow.1 These collateral arteries provide an alternative source
of blood supply to the ischemic or threatened myocardium.
Using the Rentrop grading system for CCC, grades of
collateral filling from the contralateral vessel were: 0=none
(ie. No visible filling of any collateral channels); 1=filling
of side branches of the artery to be dilated via collateral
channels without visualization of the epicardial segment;
*Fellow-in-training, Section of Cardiology, Department of Medicine,
University of the Philippines-Philippine General Hospital
**Section of Cardiology, Department of Medicine, University of the
Philippines-Philippine General Hospital
Corresponding author: John Daniel A. Ramos, M.D., University of the
Philippines – Philippine General Hospital, Manila, Philippines
Email: johndanielramos.md@gmail.com
The PHILIPPINE JOURNAL OF INTERNAL MEDICINE is a peer reviewed journal and a copyrighted publication of the Philippine College of Physicians
Meta-Analysis
in all-cause mortality, assessed using Mantel-Haenzel analysis
of random effects to compute for risk ratios.
Results: Pooled analysis from 11 identified trials with 8,370
subjects showed that among patients with ACS who
underwent coronary angiography, the presence of CCC
showed a trend towards benefit in terms of mortality, but
was not statistically different from those without CCC [RR
0.65, (95% CI 0.38 to 1.12), p<0.0001, I 2=74%]. In those ACS
patients with CCC treated with PCI, a significant reduction
in mortality was found [RR 0.43, (95% CI 0.29 to 0.64), p<
0.0001, I 2=0%].
Conclusion: The presence of CCC during ACS showed a
trend towards mortality reduction. Further, among patients
treated with PCI, those with CCC had an incrementally
significant reduction in mortality compared to those without
CCC.
Keywords: coronary collaterals, acute coronary syndrome
2=partial filling of the epicardial segment via collateral
channels; 3=complete filling of the epicardial segment
of the artery being dilated via collateral channels.2 It has
been demonstrated in past studies that in patients with
myocardial infarction, CCCs have a relevant protective
role regarding smaller infarct size, preservation of cardiac
function, reduction in post-infarct ventricular dilation, and
reduction of post-infarct aneurysm formation.3
A meta-analysis on the impact of CCCs on mortality
among patients with coronary artery disease (CAD) was
published in 2011. A total of 12 studies with 6,529 patients
were included in the analysis. Overall, the presence of high
collateralization showed a reduced mortality compared to
those with low collateralization. These effects were driven
by significant reduction in mortality for those patients with
stable CAD [RR 0.59 (CI 0.39, 0.89), p=0.012]; however, the
reduction among patients with acute myocardial infarction
(AMI) was not significant [RR 0.63 (0.29, 1.39), p=0.257]. 4
Intuitively, CCC should have a positive impact on
the outcomes of patients with ACS. However, studies
Volume 55 Number 3 July-Sept., 2017 1
 Ramos JDA, et al.
have conflicting results. As described previously, the ACS
subgroup of the most recent meta-analysis did not show a
significant reduction in mortality.4 Among patients with ACS,
surrogate end-points such as infarct size, systolic function,
ventricular dilatation and post-infarct aneurysm formation
have positive results in relation to the presence of CCC.3
Analysis of studies specifically intended to determine the
effect of CCC on hard outcomes such as mortality among
patients with ACS is imperative.
In this study, we wanted to specifically look at the impact
of CCC in ACS patients. In the meta-analysis described
above, Meier failed to reach a statistically significant result
for AMI, and attributed this to the limited statistical power of
the subgroup (small sample sizes). 4 We wanted to address
this limitation by pre-specifying this important subgroup of
patients, obtain more relevant studies, and increase the
number of ACS patients analyzed. The researchers aim
to determine if the presence of CCC demonstrated on
coronary angiography during an ACS is associated with a
reduction in mortality.
Methods
We conducted a meta-analysis following the proposed
reporting guidelines of the Meta-analysis for Observational
Studies in Epidemiology (MOOSE) group.
Literature Search
We conducted a systematic search of studies using
MEDLINE, EMBASE, Science Direct, Scopus, Google Scholar,
and Cochrane Central Register of Controlled Trials databases
with no language restrictions. The search terms used were
coronary collateral circulation, acute coronary syndrome,
and mortality (in both free text and MESH strategies when
using MEDLINE). We also searched for local studies on the
topic, both published and unpublished. We reviewed the
reference lists of original and review articles, and related
links of the relevant publications. The titles and abstracts of
all the studies were individually screened and the full texts of
relevant articles were obtained, when available. Authors of
studies were contacted when there was no available full text.
Study Selection
Studies were included if they are 1) observational; 2)
population included adults >19 years old with an acute
coronary syndrome; 3) reported data on mortality in
association with the presence or absence of CCC on
angiography, and 4) should have controlled for confounders
by using logistic regression analysis. Four reviewing authors
independently evaluated the eligibility of each study
included in this meta-analysis. The validity and quality of
each study was assessed using the Newcastle-Ottawa
2 Volume 55 Number 3 July - Sept., 2017
Prognostic Impact of Coronary Collaterals in Acute Coronary Syndrome
Qu a lit y A s s e s s me n t S c a le f or O bs e rv a t ional Studies
(Appendix 1). Disagreements were resolved by discussion
and a consensus among the reviewers.
Data Collection and Analysis
Relevant information such as patient and study
characteristics, data on the presence or absence of CCC,
and mortality outcomes were then extracted independently
by the three authors using a data collection table. We
assessed the prognostic value of coronary collaterals in ACS
using Mantel-Haenzel statistical analysis of random effects
to compute for risk ratios, with 95% confidence intervals,
and generate forest plots. Heterogeneity was assessed
through the I2 test. Subgroup analysis would be carried out by
excluding those studies that involved only thrombolysis as a
management. Likewise, data from the remaining studies will
be extracted to include only those patients who underwent
PCI. Studies were treated as statistical outliers if the k minus
1 estimate produced a 95% CI that did not overlap with the
95% CI of the aggregated estimate. P < 0.05 was considered
statistically significant. Publication bias was examined using
funnel plot analysis.
Analyses were carried out using Review Manager
(RevMan) 5.3 (The Nordic Cochrane Centre, The Cochrane
Collaboration, Copenhagen).
Results
Search for Studies and Strategy
Our MEDLINE search yielded a total of 111 potential
articles. Search from other databases, from reference lists,
and local studies yielded additional 33 studies. We evaluated
a total of 144 titles and abstracts. Out of these, 133 were
rejected for relevance. The full articles of the remaining 11
articles5-15 were obtained and reviewed. All met the specified
inclusion criteria. A summary of the search strategy is shown
in Figure 1.
Figure 1. Summary of search strategy
 Prognostic Impact of Coronary Collaterals in Acute Coronary Syndrome
Study Characteristics and Quality
Data were reviewed from the 11 studies5-15 included.
Table I summarizes the pertinent data of the studies included.
Studies included were mostly on ST-elevation myocardial
infarction (STEMI) patients who were managed accordingly
via thrombolysis or percutaneous coronary intervention (PCI).
The presence or absence of extensive CCC were classified
using the Rentrop classification. Most were observational
prospective studies. All of the included studies rated highest
quality in the Newcastle-Ottawa Quality Assessment Scale
for Observational Studies, and had high agreement among
the reviewers (Appendix A).
Mortality and the Presence or Absence of Coronary
Collateral Circulation
Pooled analysis from 11 identified trials showed that
among patients with ACS who underwent coronary
angiography, the presence of CCC showed a trend
towards benefit in terms of mortality, but was not statistically
different from those without CCC [RR 0.65, (95% CI 0.38 to
1.12), p<0.0001] (Figure 2). Funnel plot analysis showed no
evidence of publication bias (Appendix B). There was high
heterogeneity with this analysis (I2=74%).
Sensitivity analysis did not reveal a statistical outlier
(Appendix C). Subgroup analysis was done by extracting the
data for only those patients who had undergone PCI (i.e.
those patients who were managed medically or thrombolysis
were excluded). This analysis showed that those patients with
an ACS and CCC treated with PCI had a significant reduction
in mortality as compared to those with an ACS without CCC
treated with PCI [RR 0.43, (95% CI 0.29 to 0.64), p<0.0001]
(Figure 3). Data was homogenous (I2=0%). Funnel plot also
showed no evidence of publication bias (Appendix D).
Discussion
This meta-analysis of 11 observational studies, consisting
of 8,370 patients, demonstrates that among all patients
with acute coronary syndromes, the presence of CCC on
angiography does not significantly predict reduction in
overall mortality; but with a trend towards benefit. These
results were similar to the meta-analysis 4 cited earlier:
extensive CCCs significantly reduces mortality in CAD, but
this reduction was driven primarily by the effects of CCCs
on stable CAD (rather than on ACS).
In the advent of recent and larger studies done during
the PCI era, when patients with ACS were treated with early
invasive strategy or primary PCI, the presence of extensive
CCC was associated with lower overall mortality in the
secondary analysis done in our review. With the presence of
CCC among PCI-treated ACS patients, there was significant
Ramos JDA, et al.
relative reduction of 57%. The subgroup analysis clearly
indicate reduced mortality of ACS with extensive CCC.
Potential Mechanisms of Survival Benefit
Coronary collateral circulation (CCC) provides an
alternative blood supply to the myocardium during ischemia
or infarction.1 They are anastomotic channels that develop
in the heart as an adaptation to ischemia. 1 Survival benefits
in ACS may have stemmed from surrogate outcomes,
demonstrated by earlier studies. Notably, majority of these
studies have shown that extensive CCC preserves LV
function,12-14, 5 reduces infarct size,16 and prevents formation
of left ventricular aneurysms.17 Meier (2011) 4 cites his own
study showing that coronary collaterals reduce QT interval
prolongation, a risk factor for fatal arrhythmias, during acute
vessel occlusion.
Potential Implications in Management
Our meta-analysis demonstrated that among patients
with ACS and CCC on coronary angiography, there is a trend
towards reduction in mortality. We have also demonstrated
that among patients with ACS and CCC on angiography,
managed with PCI, a significant reduction in mortality
occurred.
These findings may affect current practice in
management of ACS, especially with regards to timelines
of revascularization among patients with ST elevation
myocardial infarction (STEMI). In the presence of CCC,
STEMI patients may not necessarily rapidly develop infarcted
myocardium as previously predicted. The presence of CCC
may prolong the viability of injured myocardium at risk when
its blood supply is occluded. Given the mortality benefit in
our review, the presence of extensive CCC may rationalize
performance of delayed revascularization, even in patients
with STEMI past the “golden period” of viability.
The idea on inducing coronary collateral growth as
a possible therapeutic strategy has also been explored.
The induction of collateral growth has been demonstrated
in several small experimental and clinical studies, using
granulocyte-macrophage colony-stimulating factor and
external counterpulsation, 18-20 but this remains largely
hypothetical and is unknown whether such strategy would
translate to improved survival.4
Another important implication of our study is on
determining the patient who most likely would have
good collateralization sans a coronary angiogram. Pre-
angiographic clinical factors have been explored in
an effort to predict which patients might have better
prognoses because of the presence of good coronary
collateral formation, both in stable CAD and ACS. Akgullu
et al. (2014) showed that ejection fraction < 55% and mean
Volume 55 Number 3 July-Sept., 2017 3
 Ramos JDA, et al. Prognostic Impact of Coronary Collaterals in Acute Coronary Syndrome

Table I. Study characteristics

No. Author Patients Rentrop Outcome Type of study Intervention

classification of
CCC
Observational
1 Williams 1976 5 Acute MI 0 versus 1-3 In-hospital death Thrombolysis
Prospective
2 Habib 1990 6 STEMI 0 versus 1-3 Death at 6 months Review of Database (TIMI) Thrombolysis
3 Castellano 1999 7
Anterior STEMI 0 versus 1-3 In-hospital death Observational All PCI
Observational
4 Nicolau 1999 8 STEMI 0-1 versus 2-3 Death at 3 years Thrombolysis
Prospective
Observational
5 Antioniucci 2002 ­9 STEMI 0-1 versus 2-3 Death at 6 months All PCI
Prospective
Observational Thrombolysis
6 Monteiro 2003 10 STEMI 0 versus 1-3 Death at 15 months Prospective and PCI
7 Sorajja 2007 11 STEMI 0-1 versus 2-3 Death at 6 months Review of Database (Emerald) All PCI
Observational
8 Desch 2010 12
STEMI 0-1 versus 2-3 Death at 6 months All PCI
Prospective
Observational
9 Wang 2011 13 Anterior STEMI 0 versus 1-3 Death at 1 year All PCI
Prospective
Moderate to high Review of Database (ACUITY Thrombolysis
10 Meier 2014 14 0 versus 1-3 Death at 1 year
risk ACS Trial) and PCI
Observational
11 Yaylak 2015 15 Inferior STEMI 0 versus 1-3 In-hospital death All PCI
Prospective

Figure 2. Forest Plot of All Trials (PCI and Thrombolysis)

Figure 3. Forest Plot of Trials that Included Only PCI.

Data from Meier and Monteiro were re-analyzed.
Data of only those who had undergone PCI were included in this sub-analysis.

4 Volume 55 Number 3 July - Sept., 2017

 Prognostic Impact of Coronary Collaterals in Acute Coronary Syndrome
platelet volume > nine femtoliter are predictive of coronary
collateral development in patients with stable CAD.21 In a
cohort of acute MI patients, a history of angina pectoris was
a significant predictor of collateral development. 22 In non-ST
elevation MI patients (NSTEMI), a high neutrophil-lymphocyte
ratio (NLR) may predict good collateral development. 23 It
would be interesting to pursue this type of study in our local
setting.
Limitations
By virtue of the clinical question to be answered, most
studies included are observational studies. The inherent
limitations of observational studies cannot be eliminated,
and this is evident in the observed heterogeneity in the
primary analysis.
This is to be expected given the observational nature
of the included studies. Factors likely contributing to this
heterogeneity include different study design (retrospective
versus prospective design), different clinical settings and/
or patient characteristics (e.g. timing of STEMI, type of
ACS included), varying primary outcomes (e.g., time to
follow-up), different study sizes, and different methods of
determining the presence or absence of extensive CCC
and the method of dichotomization i.e. some studies used
an all-or-none classification (Rentrop 0 vs. 1-3) 5-7, 10, 13-15, while
some used a low-or-high approach (Rentrop 0-1 vs 2-3). 8-9,
11-12.
The precision of some of the included studies, especially
the larger ones, may have conferred an artificially high I2. We
were able to mitigate this heterogeneity by pre-specifying a
subgroup and sensitivity analysis. Removing outliers would be
the first step in correcting for heterogeneity for this reason,
as this removed the possible effect of an artificially high I 2.
As shown in our sensitivity analysis, however, not one of the
studies included was a statistical outlier. In our study, the
heterogeneity appears to be attributable primarily to the
treatment strategy, as shown in the subsequent subgroup
analysis. In the subgroup analysis done by excluding the
studies that used thrombolysis as therapy and limiting the
analysis only to those that utilized PCI, we achieved a
homogenous data set.
Conclusion
The presence of CCC during ACS showed a trend
towards mortality reduction. After exclusion of those treated
with thrombolysis, patients with extensive CCC treated with
PCI was associated with a significant reduction in mortality
compared to those without extensive CCC. The presence
of extensive CCC may prolong the viability of injured
myocardium at risk when its blood supply is totally occluded.
Findings in this meta-analysis may guide physicians in
management, especially in patients with ACS who are
candidates for revascularization via PCI.
Ramos JDA, et al.
References
1. Chilian WM, Penn MS, Pung YF, et al. Coronary collateral
growth – back to the future. Journal of molecular and cellular
cardiology 2012. 52 (905-911).
2. Rentrop KP, Cohen M, Blanke H. Change in collateral channel
filling immediately after controlled coronary artery occlusion by
an angioplasty balloon in human subjects. 1985, JACC 5:3(92)
3. Seiler C. The human coronary collateral circulation. Eur J Clin
Invest 2010;40: 465 – 476.
4. Meier P, Hemingway H, Lansky A, et al. The impact of the
coronary collateral circulation on mortality: A meta-analysis.
European Heart Journal 2011.
5. Williams DO, Amsterdam EA, Miller RR, Mason DT. Functional
significance of coronary collateral vessels in patients with acute
myocardial infarction: relation to pump performance, cardiogenic
shock and survival. Am J Cardiol 1976;37: 345 – 351. 

6. Habib GB, Heibig J, Forman SA. Influence of coronary collateral
vessels on myocardial infarct size in humans: Results of phase-I
Thrombolysis in Myocardial Infarction (TIMI) Trial. Circulation
1990; 76.
7. Perez-Castellano N, Garcia E, Abeytua M. Influence of collateral
circulation on In-hospital death from anterior acute myocardial
infarction. 1998; JACC 31:512-8.
8. Nicolau JC, Nogueira PR, Pinto MA, Serrano CV Jr, Garzon
SA. Early infarct artery collateral flow does not improve long-
term survival following thrombolytic therapy for acute myocardial
infarction. Am J Cardiol 1999;83:21 – 26. 

9. Antoniucci D, Valenti R, Moschi G, Migliorini A, Trapani
M, Santoro GM, Bolognese L, Cerisano G, Buonamici P,
Dovellini EV. Relation between preinter- vention angiographic
evidence of coronary collateral circulation and clinical and
angiographic outcomes after primary angioplasty or stenting for
acute myocardial infarction. Am J Cardiol 2002;89:121 – 125. 

10. Monteiro P, Antunes A, Goncalves LM, Providencia LA. Long-
term clinical impact of coronary-collateral vessels after acute
myocardial infarction. Rev Port Cardiol 2003;22:1051 – 1061. 

11. Sorajja P, Gersh BP, Mehran R. Impact of collateral flow on
myocardial reperfusion and infarct size in patients undergoing
primary angioplasty for acute myocardial infarction. 2007; Am
Heart J 152(2):379-84
12. Desch S, Eitel I, Schmitt J, Sareban M, Fuernau G, Schuler
G, Thiele H. Effect of coronary collaterals on microvascular
obstruction as assessed by magnetic reson- ance imaging in patients
with acute ST-elevation myocardial infarction treated by primary
coronary intervention. Am J Cardiol 2009;104:1204 – 1209. 

13. Wang B, Han Y, Li Y, et al. Coronary collateral circulation:
Effects on outcomes of acute anterior myocardial infarction after
primary percutaneous coronary intervention. J Geratr Cardiol
2011; 8:93-98
14. Meier P, Lansky AJ, Fahy M, etal. The impact of the coronary
collateral circulation on outcomes in patients with acute coronary
syndromes: results from the ACUITY Trial. 2014; Heart
100(8):647-51
15. Yaylak B, Altintas B, Ede H, et al. Impact of coronary collateral
Volume 55 Number 3 July-Sept., 2017 5
 Malundo AFG, et al. Prognostic Impact of Coronary Collaterals in Acute Coronary Syndrome

circulation on in-hospital death in patients with Inferior ST
elevation myocardial infarction. Cardiology research and practice
2015; 242686
16. Rentrop KP, Feit F, Sherman W, et al. Late thrombolytic therapy
preserves left ventricular function in patients with collateralized
total coronary occlusion. J Am Coll Cardiol 1989; 14(1):58-64.
17. Hirai T, Fujita M, Nakajima H, et al. Importance of collateral
circulation for prevention of left ventricular aneurysm formation
in acute myocardial infarction. Circulation 1989;79-791-796.
18. Seiler C, Pohl T, Wustmann K, Hutter D, Nicolet PA, Windecker
S, Eberli FR,Meier B. Promotion of collateral growth by
granulocyte-macrophage colony-stimulating factor in patients
with coronary artery disease: a randomized, double-blind, placebo-
controlled study. Circulation 2001;104:2012–2017.
19. Zbinden S, Zbinden R, Meier P, Windecker S, Seiler C. Safety
and efficacy of subcutaneous-only granulocyte-macrophage
colony-stimulating factor for collateral growth promotion
in patients with coronary artery disease. J Am Coll Cardiol
2005;46:1636–1642.
20. Gloekler S, Meier P, de Marchi SF, Rutz T, Traupe T, Rimoldi
SF, Wustmann K, Steck H, Cook S, Vogel R, Togni M, Seiler
C. Coronary collateral growth by external counterpulsation: a
randomised controlled trial. Heart 2010;96:202–207.
21. Akgullu Ç, Eryılmaz U, Murat OI, Gungor H, Avcil M, et
al. (2014) Predictors of Well Developed Coronary Collateral
Circulation in Patients with Stable Angina Pectoris. J Clin Exp
Cardiolog 5: 305. doi:10.4172/2155-9880.1000305
22. Fujita M, Nakae I, Kihara Y, et al. Determinants of Collateral
Development in Patients with Acute Myocardial Infarction Clin.
Cardiol. 1999; 22 (9): 595-599
23. Tenekecioglu E, Yilmaz M, Karaagac K, et al. Predictors
of coronary collaterals in patients with non ST-elevated acute
coronary syndrome: the paradox of the leukocytes. Centr Eur J
Immunol 2014; 39 (1): 83-90.

Appendix A.
Newcastle-Ottawa Quality Assessment Scale for Cohort Studies†.

SELECTION OUTCOMES ASSESSMENT

Representativeness Selection Ascertainment Demonstration that Assessment Follow-up Adequacy

SOURCE of the Exposed of the of Exposure outcome of interest was COMPARABILITY of Outcome Period of Follow-up
Cohort Nonexposed not present at start of Long Enough Period Among
Cohort study for Outcome Cohorts
to Occur

Williams 1976 * * * * ** * * *
Habib 1990 * * * * ** * * *
Castellano1999 * * * * ** * * *
Nicolau 1999 * * * * ** * * *
Antioniucci 2002 * * * * ** * * *
Monteiro 2003 * * * * ** * * *
Sorajja 2007 * * * * ** * * *
Desch 2010 * * * * ** * * *
Wang 2011 * * * * ** * * *
Meier 2014 * * * * ** * * *
Yaylak2015 * * * * ** * * *
†- a study is graded highest quality if it has a total of 9 stars

6 Volume 55 Number 3 July - Sept., 2017

Prognostic Impact of Coronary Collaterals in Acute Coronary Syndrome Ramos JDA, et al.

APPENDIX B APPENDIX D

Funnel plot of the primary analysis showing no evidence of publication Funnel plot of the secondary analysis showing no evidence of publica-
bias. Lower standard errors indicate better precision and larger study size. tion bias. Lower standard errors indicate better precision and larger study size.

APPENDIX C

Sensitivity analysis with risk ratios for mortality. Each line represents a re-analysis of the data with exclusion of one study (inclusion of 10 studies only) at a
time to assess the influence of this particular study on the overall result. A study was treated as statistical outlier if the k minus 1 estimate (where k is the number of studies)
produced a 95% CI that did not overlap with the 95% CI of the aggregated estimate. None of the studies met the qualifier for a statistical outlier.

Study RR 95% CI
Removing Antoniucci 2002 0.69 (0.39, 1.21)
Removing Desch 2010 0.68 (0.39, 1.19)
Removing Habib 2010 0.58 (0.32, 1.06)
Removing Meier 2014 0.56 (0.30, 1.02)
Removing Monteiro 2003 0.64 (0.36, 1.15)
Removing Nicolau 1999 0.55 (0.31, 1.00)
Removing Perez-Castellano 1998 0.72 (0.42, 1.24)
Removing Sorajja 2007 0.65 (0.37, 1.15)
Removing Wang 2011 0.71 (0.41, 1.21)
Removing Williams 1976 0.69 (0.41, 1.18)
Removing Yaylak 2015 0.72 (0.42, 1.23)

Random Effects Model 0.65 (0.38, 1.12)

Volume 55 Number 3 July-Sept., 2017 7

 Philippine Journal of Internal Medicine
Weathering an Adenosine Insensitive Right Ventricular Outflow
Tract Ventricular Tachycardia (Ado-insensitive RVOT VT) Storm
in an Adolescent Female: A Case Report
Jose Eduardo DL. Duya, M.D.*; Nashiba Daud, M.D.*; Joerelle V. Mojica, M.D.*; Dioscoro DC. Bayani II, M.D.* Muriel A. Morilla, M.D.*; Giselle G. Gervacio,
M.D.*; Michael Joseph Agbayani, M.D.*; Louisa Go, M.D.**; Olympia Q. Malanyaon, M.D.**
Abstract
Introduction: Ventricular tachycardias (VT) are commonly
associated with structural heart disease. However, 10% of
VTs have no identifiable cause. Right ventricular outflow
tract ventricular tachycardia (RVOT VT), a small subgroup
of idiopathic VTs localized in the right ventricular outflow
tract is highly sensitive to adenosine (ADO). Only 11% of
RVOT VT is ADO-insensitive, posing a diagnostic challenge.
We present a peculiar case of an ADO-insensitive RVOT-VT
storm and the challenges of recognizing and managing it
in a resource-limited setting.
Case summary: A 15-year-old female, asthmatic, com-
plained of palpitations, lightheadedness, chest pain and
dyspnea a few hours prior to admission. She had a similar
episode a month ago, which necessitated ER admission,
electrical cardioversion and amiodarone.
On admission, she was tachycardic but normotensive.
She had diffuse wheezes. Cardiac exam was normal. ECG
revealed a wide complex tachycardia (WCT). Work-up
revealed a normal chest x-ray, thyroid function tests and
electrolytes. Echocardiogram showed a structurally normal
heart. She was managed as a case of viral myocarditis
and SVT with aberrancy. Vagal maneuvers and adenosine
was given which slowed down the tachycardia. She was
Introduction
Ventricular tachycardias (VT) are commonly associated
with structural heart disease. However, 10% of patients with
VT have no identifiable structural or metabolic causes. In
structurally normal hearts, VT commonly arises from the
outflow tracts.1
Right ventricular outflow tract ventricular tachycardia
(RVOT VT) comprises a small subgroup of idiopathic VTs
that is localized in and around the right ventricular outflow
*Section of Cardiology, Department of Medicine, University of the
Philippines-Philippine General Hospital
**Section of Pediatric Cardiology, Department of Pediatrics, University of
the Philippines-Philippine General Hospital
Corresponding author: Jose Eduardo DL. Duya, M.D., University of the
Philippines – Philippine General Hospital, Manila, Philippines
Email: joeyduya@gmail.com
The PHILIPPINE JOURNAL OF INTERNAL MEDICINE is a peer reviewed journal and a copyrighted publication of the Philippine College of Physicians
Case Report
then started on IV anti-arrhythmics however, sustained
symptomatic VT recurred on the same day. ECG analysis
showed a WCT, LBBB, AV dissociation with positive QRS
complexes in inferior leads suggestive of VT originating from
the RVOT. RVOT VT storm was considered and adenosine
(maximum dose) was given. The patient did not revert to
sinus, hence, ADO-insensitive RVOT VT was considered.
Cardioversion terminated the VT storm.
On electrophysiology study, the VT was induced/
localized at the RVOT via 3D mapping. Ablation of the RVOT
focus was performed, immediately terminating the VT. Post
ablation, the patient was asymptomatic and was discharged
improved with excellent prognosis.
Discussion: This case report highlights two things. The
ECG remains a reliable tool in recognizing and localizing
VTs clinically. Secondly, it highlights the importance of
prompt recognition of ADO-insensitive RVOT VT because
its management and prognosis is very different from the
common causes of VT.
Keywords: ventricular tachycardia, arrhythmia, electro-
cardiogram, VT ablation
tract (80% of all locations). 7 The arrhythmogenesis is due
to calcium-dependent delayed after depolarizations that
can lead to an underlying automatic focus, hence the
tachycardia. 1 Usually manifesting at 30-50 years of age,
exercise and emotional stress can trigger outflow tract VTs.1
Its hallmark is its sensitivity to adenosine (ADO), a drug that
causes suppression of atrioventricular conduction. 2 While
adenosine is typically recommended as class one treatment
for the management of stable supraventricular tachycardia3,
the sensitivity of RVOT VT to adenosine differentiates it from
the typical VT consistent with its triggered mechanism.2 This
feature is a useful clinical information because adenosine
can be given to undifferentiated wide complex regular
tachycardias as a diagnostic tool, since majority of RVOT
VT and aberrantly conducted supraventricular tachycardia
will convert to sinus upon giving adenosine.4 Exceptionally,
only 11% of sustained RVOT VT is ADO-insensitive, posing a
diagnostic challenge.
Volume 55 Number 3 July-Sept., 2017 1
 Duya JE, et al.
Figure 1. Cardiac monitor display showing a regular wide complex tachycardia (rate of
300 beats/min)
When compared to VT from structural heart disease,
the prognosis for RVOT VT is generally favorable, but there
is potential for developing PVC-related cardiomyopathy
from the tachycardia and, rarely, sudden cardiac death. 1
While the disease can be suppressed with calcium channel
blockers and anti-arrhythmic drugs, the long term and
definitive management is to ablate the automatic focus
where the ventricular tachycardia arise. Hence, prompt
recognition and early ablation is curative and holds a low
risk of serious complications.7
We present a peculiar case of an ADO-insensitive RVOT
VT storm and the challenges in recognizing and managing
it in a resource-limited hospital setting.
Case summary
This is a case of a 15-year-old female, known asthmatic,
who had multiple doses of salbutamol nebulization for asthma
exacerbation prior to consult. She complained of persistent
palpitations, lightheadedness, chest pain and dyspnea a
few hours prior to admission. She had a similar episode of
incessant palpitations a month prior, which necessitated
emergency room (ER) admission and electrical cardioversion.
The patient was managed as a case of supraventricular
tachycardia (SVT). She was started on oral amiodarone and
was discharged improved. She has no family history of a similar
disease or sudden cardiac death. Her developmental history
is at par with age. She was a high school student, who denied
vices and use of recreational drugs.
On admission at the emergency room, the patient was
awake and coherent yet in cardiorespiratory distress. She was
tachycardic (240 beats/min), normotensive (110/70 mmHg),
tachypneic (30 cycles/min) and non hypoxemic (SpO 2 98%).
She had no anterior neck mass or distended neck veins. Chest
examination revealed wheezes on bilateral lung fields. No
rales was noted. She had an adynamic precordium, soft heart
sounds, undisplaced apex beat and no murmur. Abdominal
physical examination was unremarkable. The peripheral
pulses were faint. Cardiac monitoring revealed a regular wide
complex tachycardia (Figure 1).
She was initially managed as a case of myocarditis with
symptomatic supraventricular tachycardia with aberrancy
by the primary service. Vagal maneuvers were employed
2 Volume 55 Number 3 July - Sept., 2017
Weathering an Adenosine Insensitive Right Ventricular Outflow
Figure 2. Chest x- ray findings revealed a normal cardio-thoracic ratio, absence
of pulmonary congestion or pulmonary parenchymal infiltrates
and adenosine (0.2 mg/kg, maximum dose of 12 mg) was
given which slowed down the tachycardia to 180 beats/min
only momentarily. She was then started on IV amiodarone
(5mg/kg) and diltiazem (1.5 mg/kg/day). Work-up revealed
a normal chest x-ray (Figure 2), thyroid function tests,
serum electrolytes, urinalysis and complete blood count.
Echocardiogram showed a structurally normal heart with
acceptable systolic function. Echocardiographic features
of arrhythmogenic right ventricular cardiomyopathy such as
bulging dyskinesia of the right ventricle, dilated right ventricle
or reduced right ventricular systolic function were absent.
Despite the amiodarone drip, sustained symptomatic
ventricular tachycardia recurred on the 13th hour of intensive
care unit stay, yet she remained hemodynamically stable
with no signs of central and peripheral hypoperfusion.
(Figure 3) The patient was referred to Adult Cardiology –
Electrophysiology for opinion and co-management.
Detailed analysis of the electrocardiogram (ECG)
showed a wide complex tachycardia (QRS complexes
>0.12 msec), with left bundle branch block morphology, AV
dissociation with positive QRS complexes in inferior leads,
suggestive of VT tachycardia originating from the RVOT. The
patient was diagnosed with ventricular tachycardia storm
(VT storm) and was given adenosine (maximum dose) since
majority of RVOT VT are adenosine sensitive. However, the
patient did not revert back to sinus, hence, ADO-insensitive
RVOT VT was considered. Synchronous cardioversion (0.1
joule/kg) under intravenous sedation with propofol was
Weathering an Adenosine Insensitive Right Ventricular Outflow Duya JE, et al.

Figure 3. ECG findings of wide complex regular tachycardia, left bundle branch block morphology, signs of AV dissociation (blue arrow) with positive QRS
complexes in inferior leads suggestive of ventricular tachycardia originating from the right ventricular outflow tract

Figure 4. ECG findings post cardioversion revealed sinus arrhythmia, prolonged QT, peaked T waves, early repolarization change and non specific ST T
wave change.
performed, which terminated the VT storm and converted
the rhythm back to sinus (Figure 4). Post cardioversion, the
patient’s ECG revealed sinus arrhythmia, prolonged QT,
peaked T waves, early repolarization change and non-
specific ST T wave changes. The prolonged QT interval was
attributed to the drug effect of amiodarone.
Due to the presentation of ventricular tachycardia
storm, the patient was offered radiofrequency ablation of
the automatic RVOT focus for definitive management. A
cardiac EP study is a minimally invasive procedure that tests
the electrical conduction system of the heart to assess the
electrical activity and conduction pathways of the heart.
The study is indicated to investigate the cause, location of
origin and ablate the foci of the tachycardia. The patient
underwent an electrophysiology study. The ventricular
tachycardia was induced and localized at the RVOT via
three dimensional (3D) electroanatomical mapping. (Figure
5 and 6)
Radiofrequency ablation of the RVOT focus was
performed, immediately terminating the tachycardia (Figure
7). Post ablation, the patient was asymptomatic, with no VT
recurrence and was discharged improved with excellent
prognosis. The electrocardiogram post radiofrequency
ablation was normal. The patient has been asymptomatic
during the three-month follow up. Presently, all the anti-
arrhythmic medications have been discontinued with no
recurrence of the arrhythmia.
Discussion
The ECG remains an accessible and reliable tool in
recognizing and localizing RVOT VT. The challenge in diag-

Volume 55 Number 3 July-Sept., 2017 3

 Duya JE, et al. Weathering an Adenosine Insensitive Right Ventricular Outflow

Figure 6. Three dimensional electroanatomical mapping of the right ventricle The

Figure 5. Three dimensional electroanatomical mapping of the right ventricle. different colors illustrate the various activation time of the right ventricle. The red
An anatomic model of the heart showing the orientation of the right ventricle and focus on the right ventricular outflow tract shows the site of the earliest endocardial
its outflow tract. activation time during VT induction.

nosing the patient’s ECG tracing is to first identify if this is

a ventricular tachycardia or an aberrantly conducted su-
praventricular tachycardia (SVT with a pre-existing bundle
branch block). A baseline ECG during sinus rhythm could
have been very helpful in clinching the diagnosis, however,
it was not available for this patient.

If you look closely in the ECG (Figure 8), it is a wide QRS

tachycardia (> 0.12 msec). The regularity of the tachycardia
favors VT. Upon institution of vagal maneuvers, the tachy-
cardia slowed down from a rate of 300 to 180 beats/minute
but was not terminated. SVTs are typically slowed down by
vagal maneuvers and by administration of adenosine. Look-
ing closely at lead II, there is evidence of atrio-ventricular
dissociation as evidenced by the P wave pointed by the Figure 7. Three dimensional electroanatomical mapping of the right ventricle.
The green circles represent the areas ablated in the RVOT. Below the diagram is an
blue arrow. This finding favors the diagnosis of ventricular intracardiac ECG tracing. Note that on the left side is the induced ventricular tachy-
tachycardia. cardia. Upon ablation of the RVOT focus (green dots) there was abrupt termination
of VT occurring within 10 seconds

Understanding of this anatomic framework aids in

understanding the electrocardiographic manifestation of
outflow tract VT. The outflow tracts are superior structures,
and activation originating from these sites is directed inferi-
orly, thereby producing a QRS appearance that is strongly
positive in the inferior leads (II, III, and aVF) and negative
wave in aVL and aVR1. In the patient’s tracing, there was an
LBBB morphology signifying that the site of VT origin is from
the right side. There are positive QRS complexes on leads II,
III and AVF while negative QRS complexes on aVL and AVR
consistent with a RVOT origin. Additional leads (particularly
leads V1 and I) can further refine the ECG localization within Figure 8. ECG wide QRS tachycardia (> 0.12 msec)
the outflow tracts.1
was a deep S wave on V1 consistent with an RVOT origin.
Lead V1 is right-sided and anterior lead. Since the The ECG localization of RVOT VT was confirmed during the
RVOT is anterior and leftward within the body, when the electrophysiology study with 3D anatomic mapping.
impulse begins in the RVOT and spreads away posteriorly
and leftward, V1 should manifest a predominantly negative Cytosolic calcium overload mediated by increased
complex.5 Looking at our patient’s tracing (Figure 9), there levels of cyclic adenosine monophosphate (cAMP) lead
to delayed afterdepolarizations which, when reaching

4 Volume 55 Number 3 July - Sept., 2017

 Weathering an Adenosine Insensitive Right Ventricular Outflow
Figure 9. Patient's ECG localization
the cardiomyocyte threshold, may cause another action
potential during the relative refractory period of the ven-
tricle and may initiate a tachycardia. 7 The effectiveness
of adenosine in terminating this triggered activity lies
on its pharmacologic property of reducing cAMP. Beta
agonists drugs such as salbutamol nebulization in this
patient, increased the serum catecholamine levels. Both
exogenous and endogenous catecholamines increase
cAMP concentration through the modulation of adenyl-
ate cyclise and facilitate tachycardia induction7, hence
the RVOT VT storm was precipitated in this patient.
Albeit very rare, ADO-insensitive RVOT VT was well
documented in this case as manifested by the lack of ap-
propriate response to adenosine. In a study done by Cheung
in 2014, 46 patients with inducible sustained RVOT VT were
given adenosine and their clinical and electrophysiologic
characteristics were compared. Five out of 41 patients
(11%) had ADO insensitive RVOT VT. The electrophysiology
study findings between ADO sensitive and ADO insensitive
RVOT VT were similar6. The variant of ADO insensitive of
RVOT VT has been linked to somatic myocardial mutations
involving the A1 ADO receptor-associated cyclic adenosine
monophosphate-mediated pathway.6 Genetic testing was
not performed in our patient to confirm this theory, because
studies did not reveal significant phenotypic / electrophysi-
ologic differences between ADO sensitive and ADO insen-
sitive RVOT VT. Clinically, the presence of ADO insensitive
RVOT VT limits the use of pharmacologic therapy in events
of ventricular tachycardia. Since the patient is young and
lacks structural heart disease, ablation was identified as the
best long term solution for the RVOT VT.
Therapy is directed by the calcium-dependent delayed
after-depolarizations that can lead to an underlying auto-
matic focus. Although RVOT VT shows a better response to
antiarrhythmic drugs than structural VT, their overall efficacy
Duya JE, et al.
is moderate with 30 to 40% recurrences. Calcium channel
blockade (verapamil or diltiazem) and beta blockers can be
effective first line therapies, however, their efficacy has been
proven to be from 25 to 50% with a synergistic effect when
administered in combination.8 Other alternative therapies
such as flecainide, sotalol and amiodarone can be used
however long term to life long therapy is not preferred in
very young patients.
The automatic focus can be targeted for ablation by
identifying the site of ventricular tissue that is activated earli-
est by a PVC. Catheter ablation of the automatic focus is an
effective therapeutic option (class one, level of evidence C).1
Acute success rate after radiofrequency ablation has been
reported to be over 80%. After successful ablation, a 5% of
VT recurrences has been reported, the majority within the
first year and successfully ablated with a second procedure.9
In the patient, we plan to monitor VT recurrence by closely
following up this patient.
This case highlights the practical importance of prompt
recognition of adenosine insensitive RVOT VT, because the
management and prognosis is very different from the com-
mon causes of VT. By correctly managing this arrhythmia,
long term complications such as tachycardia related car-
diomyopathy and sudden death will be prevented.
Conclusion
This case highlights the practical importance of prompt
recognition of adenosine insensitive RVOT VT, because the
management and prognosis is very different from the com-
mon causes of VT. By correctly managing this arrhythmia,
long term complications such as tachycardia related car-
diomyopathy and sudden death will be prevented.
Volume 55 Number 3 July-Sept., 2017 5
 Duya JE, et al. Weathering an Adenosine Insensitive Right Ventricular Outflow

Patient’s Perspective

The patient has had several emergency room visits due
to palpitations and pre-syncope. Despite repeated consults,
the patient and her mother has been unsatisfied with the
diagnosis previously given as the symptoms would always
recur despite anti-arrhythmics given. Thru radiofrequency
ablation, it offered the patient a more lasting and possibly
permanent solution to this arrhythmia and they were satisfied
with the results.

R eferences
1. Gard, J.J. Asirvatham, S. Outflow tract ventricular tachycardia.
Tex Heart Inst J. 2012; 39(4): 526–528.
2. Klabundle, R. Adenosine. Cardiovascular Pharmacology
Concepts. Available online: http://cvpharmacology.com/antiarrhy/
adenosine
3. Page, R. et. al. 2015 ACC/AHA/HRS Guideline for the
Management of Adult Patients With Supraventricular Tachycardia.
A Report of the American College of Cardiology/American Heart
Association Task Force on Clinical Practice Guidelines and the
Heart Rhythm Society. J Am Coll Cardiol. 2016;67(13):e27-e115.
doi:10.1016/j.jacc.2015.08.856
4. Marill, KA et.al. Adenosine for wide-complex tachycardia:
efficacy and safety. Crit Care Med. 2009 Sep;37(9):2512-8. doi:
10.1097/CCM.0b013e3181a93661.
5. Asirvatham SJ. Correlative anatomy for the invasive
electrophysiologist: outflow tract and supravalvar arrhythmia. J
Cardiovasc Electrophysiol 2009;20(8):955–68.
6. Cheung JW. et.al. Adenosine-insensitive right ventricular
tachycardia: novel variant of idiopathic outflow tract tachycardia.
Heart Rhythm. 2014 Oct;11(10):1770-8. doi: 10.1016/j.
hrthm.2014.06.014. Epub 2014 Jun 12
7. Reviriego, S.M. Merino, J.L. Ventricular Tachycardia in patients
without apparent structural heart disease: Focus on Ventricular
Outflow Tract Tachycardia. ESC Council for Cardiology Practice.
VOL.8, N°11 - 18 NOV 2009
8. Zipes DP, Camm AJ, Borggrefe M, Buxton AE, Chaitman B,
Fromer M, et al. ACC/AHA/ESC 2006 guidelines for management
of patients with ventricular arrhythmias and the prevention
of sudden cardiac death: A report of the American College of
Cardiology/American Heart Association Task Force and the
European Society of Cardiology Committee for Practice Guidelines
(Writing Committee to Develop Guidelines for Management of
Patients with Ventricular Arrhythmias and the Prevention of Sudden
Cardiac Death). J Am Coll Cardiol 2006; 48: e247–e346.
9. Aliot EM, Stevenson WG, Almendral-Garrote JM, et al.
European Heart Rhythm Association / Heart Rhythm Society
Expert Consensus on Catheter Ablation of Ventricular Arrhythmias.
Europace 2009; 11: 771–817.

6 Volume 55 Number 3 July - Sept., 2017

 Philippine Journal of Internal Medicine
The Role of Prophylactic Renin-angiotensin System Inhibitors
for the Prevention of Anthracycline-induced Cardiotoxicity
Among Adult Cancer Patients: A Meta-analysis
Karen Anjela M. Mondragon, M.D.*; Jhoanna Rose H. Velasquez, M.D.*; Danielle Benedict L. Sacdalan, M.D.**; Lauro L. Abrahan IV, M.D.***
Irisyl O. Real, M.D.**; Felix Eduardo R. Punzalan, M.D.***
Abstract
Introduction: Anthracycline is a cornerstone in the treatment
of various cancers. One major limitation to its use is
cardiotoxicity. Renin angiotensin system (RAS) inhibitors
have been shown to attenuate myocardial injury, initial
data is promising in its use as prophylaxis for anthracycline-
induced cardiotoxicity. The aim of the study is to determine
effectiveness of prophylactic RAS inhibitors in preventing
anthracycline-induced cardiotoxicity and adverse cardiac
events among adult cancer patients
Methods: Systematic search of databases PUBMED, MEDLINE,
EMBASE, and CENTRAL was done. Selection criteria were:
1) randomized controlled trials (RCT) 2) adult cancer patients
with normal ejection fraction and without heart failure
symptoms 3) RAS inhibitors as prophylaxis versus placebo
4) development of cardiac events, all-cause mortality
and left ventricular ejection fraction (LVEF) reduction as
outcomes. Two reviewers independently assessed the trials.
Disagreements were resolved with a third reviewer. Test for
effect of intervention, heterogeneity, trial quality and risk of
bias were assessed using the Cochrane Review Manager
Software version 5.3.
Results: Five RCTs involving 530 adult patients, with average
age of 50± two years old, and average follow-up from six
Introduction
Anthracyclines remain to be one of the cornerstones
in the treatment of various hematologic and solid
cancers. 1 It is among the most widely used and accepted
chemotherapeutic regimen for both adult and pediatric
population. However, one major limitation to its use is its
established acute and chronic cardiac toxicity.2-4 Billingham
and collaborators and Mackay and collaborators, both
demonstrated the structural effect of this drug class on the
*Department of Medicine, University of the Philippines-Philippine General
Hospital
**Section of Oncology, Department of Medicine, University of the
Philippines-Philippine General Hospital
**Section of Cardiology, Department of Medicine, University of the
Philippines-Philippine General Hospital
Corresponding author: Karen Anjela M. Mondragon, M.D., University
of the Philippines – Philippine General Hospital, Manila, Philippines
Email: k.montevirgen@yahoo.com
The PHILIPPINE JOURNAL OF INTERNAL MEDICINE is a peer reviewed journal and a copyrighted publication of the Philippine College of Physicians
Meta-Analysis
months to three years were included. Combined clinical
outcomes of heart failure, cardiac events and all-cause
mortality showed an RR of 0.27[95%CI 0.18, 0.40],p<0.00001,
in favor of RAS inhibitors. There is same benefit in LVEF
preservation with mean difference of 4.37%[95%CI 1.20,
7.55;p=0.007]. Exploratory subgroup analysis showed
significant benefit in LVEF preservation with combined
RAS inhibitor and beta-blocker, with mean difference
of 2.45%[95%CI 1.27, 3.63]. There is overall significant
heterogeneity (I2=95%). Excluding one article with high-risk
population, after sensitivity analysis, showed same benefit
but reduced heterogeneity.
Conclusion: Renin angiotensin system (RAS) inhibitors may
be used as prophylaxis for cardiotoxicity. As prophylaxis,
it reduced the clinical outcome of cardiac events, heart
failure, and all-cause mortality among cancer patients
needing anthracycline. Combined RAS inhibitor and beta-
blocker limits LVEF reduction.
Keywords: renin-angiotensin system, anthracyclin-induced
cardiotoxicity
myocardium, leading to a dose-dependent and potential
irreversible cardiac dysfunction leading to heart failure.5-6
There have been varying definitions for cardiotoxicity
induced by anthracyclines, as a consequence, there is lack
of a consensus definition for cardiotoxicity.7 Cardiotoxicity
may be predicted by a baseline left ventriular ejection
fraction (LVEF) less than 50% or a reduction in LVEF by
more than 10% during treatment, or to a level less than 50%
during or after treatment.8 The European Society of Medical
Oncology (ESMO) guidelines state that a decline of LVEF to
<50%, the chemotherapy should be put on hold for three
weeks to reassess and treat left ventricular (LV) dysfunction,
while at an LVEF of <40% it should be discontinued and other
options be considered.7-9
At present, there is no accepted regimen to provide
cardioprotection from damage induced by anthracyclines.7,8,10
Modification of anthracycline structure, dosing regimen and
Volume 55 Number 3 July-Sept., 2017 1
 Mondragon KAM, et al. The Role of Prophylactic Renin-angiotensin System Inhibitors

schedules all geared toward mitigating its effects have been General Objectives
encouraged and prescribed, but despite this, cardiotoxicity
continues to be a problem. 11 Symptomatic patients are To determine the efficacy of giving prophylactic RAS
managed as cases of overt heart failure with referral to a inhibitors in preventing anthracycline-induced cardiotoxicity
cardiologist being advocated by guidelines. 7,12 Dexrazoxane and adverse cardiac events among adult cancer patients
is an iron chelator that reduces the incidence of contractile
dysfunction and is advocated by some.7,11 However, because Specific Objectives
dexrazoxane can potentially reduce tumor response rates
and the lack of a significant effect on improving overall 1. Primary Endpoint: To measure the efficacy of RAS
survival has prevented the administration of this drug from inhibitors in preventing the occurrence of adverse
becoming a universal practice.11 cardiac events (sudden death, death resulting from a
cardiac cause, overt heart failure, and life-threatening
Data from experimental models suggest that the arrhythmias requiring treatment) during the 6 months
cardiac renin-angiotensin system (RAS) plays an important and one-year follow-up.
role in the development of anthracycline-induced 2. Secondary Endpoint: To measure the efficacy of
cardiomyopathy and that treatment with RAS inhibitors RAS inhibitors in preventing chemotherapy-
protects against chemotherapy-induced cardiotoxicity. induced cardiotoxicity defined as an absolute
Potential mechanisms identified are reduction in the decrease >10 percent units in rest LVEF associated
formation of reactive oxygen species and preservation with a decline below the normal limit value (50%).
of mitochondrial respiratory efficiency all of which leads
to attenuation of myocardial dysfunction and irreversible
damage. The positive outcomes of animal studies have led
Methods
to postulation that these drug classes specifically angiotensin
The study was reported in adherence to the Preferred
converting enzyme (ACE) inhibitors and angiotension
Reporting Items for Systematic Reviews and Meta-Analyses
receptor blocking agents (ARBs) may have a potential role
(PRISMA) proposed by the Cochrane collaboration. The
in cardioprotection in patients who will receive anthracycline
methods of the analysis and inclusion criteria were specified
therapy.13-16
in advance and documented in a protocol available from
the corresponding author upon request. All references and
Several systematic reviews and meta-analyses
authors were acknowledged and identified properly.21-22
regarding anthracycline-induced cardiotoxicity and
various cardioprotective agents had been published in
Electronic searches
recent years. 17-19 These covered patients from both adult
and pediatric populations who were diagnosed with
Two independent researchers (K.M.M. and J.H.V.)
different cancer types. Taken together these studies used
systematically searched MEDLINE, CENTRAL (Cochrane
varying outcome measures to document cardiotoxicity.
Central Register of Controlled Trials) and Embase for
In the systematic review and meta-analysis of Kalam and
relevant studies using a combination of Medical Subject
collaborators the following drugs had similar efficacy in
Headings (MeSH) term and corresponding free-text terms
reducing anthracycline-induced cardiotoxicity: dexrazoxane,
using the search terms “anthracyclines”, “cardiomyopathy”,
beta-blockers, statins, and angiotensin antagonists.18
“cardiotoxicity” “Heart Failure”, “Renin-Angiotensin Sytem
Inhibitors”, “Angiotensin-Converting Enzyme Inhibitors”, and
In the latest systematic review and meta-analysis of Yun
“Angiotensin-Receptor Antagonist”.
et al, they were able to show an association among groups
given beta-blockers and/or ACE inhibitors with higher LVEF
The researchers also looked into the World Health
compared with the control group. Exploratory subgroup
Organization International Clinical Trials Registry Platform,
analysis also showed benefit in giving prophylactic agents to
Current Controlled Trials (http://www.controlled-trials.com
those with higher cumulative dose of anthracyclines versus
webcite), ClinicalTrials.gov and the Clinicaltrialsregister.
those with lower cumulative dose.20
eu for potentially eligible studies including completed and
ongoing RCTs, which could possibly post their interim results
In recent years, several newer studies on the potential
online. There was no restriction regarding to language and
role of RAS inhibitors in limiting cardiotoxicity had since
publication period.
been published specifically for the adult population of
cancer patients receiving anthracyclines. This review was
Other resources
conducted to systematically analyze all available data from
randomized controlled trials on the role of RAS inhibitors
The researchers also reviewed the reference lists of
in preventing anthracycline-induced cardiotoxicity and
all full-text papers and correspond with all trial authors to
adverse cardiac events among adult cancer patients.

2 Volume 55 Number 3 July - Sept., 2017

 The Role of Prophylactic Renin-angiotensin System Inhibitors
identify any trials that we may have missed. The reference
sections and citation lists of the retrieved literature, including
original research articles, reviews, editorials and letters were
also reviewed for potentially relevant studies.
Eligibility criteria
The included studies met all of the following criteria:
1. A randomized controlled trial as study design
2. Study population of patients with any type of cancer
ages 19 years old and above with normal ejection
fraction (EF) and no history of heart failure symptoms
who will be receiving any anthracycline containing
chemotherapy regimen
3. Renin Angiotensin System (RAS) Inhibitors either alone
or in combination with other cardioprotective agents,
as prophylactic intervention arm versus placebo.
Prophylaxis was defined as administration of intervention
prior to any evidence of clinical heart failure and/or
reduction of EF to less than 50%.
4. Primary outcome of measures include either change in
EF from baseline to a predefined follow up period and
a primary clinical endpoint – cardiac events, all cause
mortality. The differences in types and preparation of
anthracycline, dosing regimen, treatment duration,
length of follow up, length and timing of intervention
were taken into account but as long as they fulfill the
four predefined criteria they were eligible for inclusion.
Studies which included patients who already have known
cardiac dysfunction or previous chemotherapy-related heart
failure or cardiac dysfunction, EF < 50% or multiple organ
failure were excluded from the analysis. Studies with outcome
measures that did not include measurement of EF were also
excluded in the articles for review. For the purpose of this
study, the researchers focused on measurement of EF and
clinical endpoints as primary outcomes.
Data extraction and quality assessment
After duplicate studies were removed and articles
were screened based on the inclusion criteria, the authors
reviewed the full-text articles independently. The eligibility
of each study was determined by consensus among the
authors. Eligible studies were reviewed independently and
data were extracted based on the cochrane data extraction
template.
Selection of studies
Two members of the review team (K.M.M. and J.H.V.)
independently triaged the titles and abstracts identified by
the search to remove those that are clearly inappropriate.
The remaining papers were found to have clear inclusion
criteria applied to them. Disagreements about study inclusion
were resolved by discussion with a third review author. All
Mondragon KAM, et al.
trials excluded from the review were given reasons for
exclusion, such as ‘not a randomized trial’ or ‘inappropriate
control’. All randomized controlled trials (RCTs) in languages
other than English were to be translated into English,
however none of the included trials were found to be in a
non-English text.
Data extraction and analysis
Two reviewers (K.M.M. and J.H.V.) independently
extracted data from each study with uniform electronic
forms specifically created for this study and the following
data were extracted and recorded: trial characteristics
(country, details of study procedure, sample size, study
period, follow-up duration and funding), intervention
characteristics, patient characteristics (inclusion criteria,
background treatment, age, gender). (Appendix 1)
Risk of bias assessment
The bias risk of individual studies were assessed with
the domains recommended by the cochrane collaboration
tool including random sequence generation, allocation
concealment (selection bias), blinding of participants
and personnel (performance bias), blinding of outcome
assessment (detection bias), incomplete outcome data
(attrition bias), and selective reporting (reporting bias).
Statistical method
The aggregate data from each study were summarized
by entering the data in the Cochrane Review Manager
Software version 5.3.To examine the outcomes, the inverse
variance fixed-effect model was used to calculate the
weight mean difference (WMD) and 95% CI interval if there
was no significant or substantial heterogeneity; otherwise,
the random effects model was used. Both the maximally
adjusted and unadjusted effect sizes with 95% CIs were
recorded, if available. Any discrepancies were resolved
by discussion or consensus with a third reviewer (DLS), the
data extracted from each study was carefully checked by
another reviewer (LLA) before performing final analyses.
Heterogeneity between studies was assessed using
Cochran Q test (based on pooled RR from the Mantel–
Haenszel test) and also by using the I2 statistic interpreted as
I2 Iess than 0-30% was assessed as minimal heterogeneity, 30%
to 50% as moderate and >50% as substantial heterogeneity
A forest plot was constructed to show the overall
effect of intervention against control in all the studies
grouped together. Data were also analyzed by subgroups
of either single RAS inhibitor or in combination with another
cardioprotective agent.
Volume 55 Number 3 July-Sept., 2017 3
 Mondragon KAM, et al. The Role of Prophylactic Renin-angiotensin System Inhibitors

Table I. Summary of the studies included

Study No. of Age Study Design Type of cancer Anthracycline and Intervention Follow Up
pts dosage
Cardinale, 114 E: 47±11 Prospective, Acute myeloid Varied Anthracy- Enalapril Cardiac evaluation was
et. al 2006 C: 44±13 randomized leukemia cline regimens and performed at baseline
clinical study Breast cancer dosing (Epirubicin, and at one, three, six,
Ewing’s sarcoma Idarubicin, etc.) and 12-month
Hodgkin’s disease
Myeloma
Non-Hodgkin’s
lymphoma
Georgako- 147 E: 47.4±16.2 Prospective, parallel Lymphoma Doxorubicin Metoprolol or 36-month
poulos, 2010 C: 49.1±19.4 group, ~380mg/m2 – as the Enalapril or no follow up
randomized, maximal cumulative concomitant
controlled study dose treatment
Dessi, 49 E: 52.9±9 Phase II placebo Endometrium Epirubicin 400 ± 30 Telmisartan 18-month
et. al 2013 C: 53±10 (PLA)-controlled Salivary gland (SD) mg/m2 – as follow-up
randomized trial Non Hodgkin’s the maximal cumu-
lymphoma lative dose
Breast
Ovary
Lung (NSCLC)
Bosch, 90 E: 49.7±13.9 Randomized, con- Hematological Varied regimens Enalapril and six months
et. al 2013 C: 50.9±13.2 trolled study malignancies and dosing of AC Carvedilol
E: 139 ± 188 mg/m2
C: 133 ± 182 mg/m2
Gulati, 130 E: 51.7±10.7 2x2 factorial, Breast Cancer Epirubicin Candesartan six months
et. al 2016 C: 50.8±9.2 randomized, and Metoprolol
placebo-controlled,
double-blind
Abbreviations: E – experimental; C - Controlled

Results
During the search, there were 28 studies derived from the
search terms used, and an additional two studies were found
from other sources and references through other studies.
A total of nine studies were screened, however one study
that was listed at clinical trials.gov was unpublished and
could not be retrieved even after contacting the primary
investigator. A total of nine full articles were subjected for
review. Among the nine studies, four were excluded. 23-26
Two of the four were found to be preliminary trials of a more
recent study already obtained, and the other article was
excluded due to absence of desired measured outcome.36-37
A total of five studies were included for qualitative and
quantitative synthesis. (Figure 1 and Table I)

The remaining five studies were all randomized controlled

Figure 1. PRISMA flowchart of study selection
trials (n=530), with an average follow-up of 15.6 months.
Average age of patients was 50 ± two years and patients
had varied oncologic diseases requiring anthracycline
regimens, but majority had lymphoma and breast cancer.
Baseline characteristics were cited in all studies, and all studies
included patients of normal EF, without baseline heart failure
and coronary disease (Table I). 22-27

Enalapril was used in three studies as preventive

therapeutic agent. However, in one of those studies,
Enalapril and Carvedilol were used in combination. The

4 Volume 55 Number 3 July - Sept., 2017

 The Role of Prophylactic Renin-angiotensin System Inhibitors
Figure 2. Risk of bias assessment
two other studies used an angiotensin-receptor blocker
(telmisartan and candesartan) as preventive therapy.
Risk of bias (Figure 2) was assessed in all the included
trials. The study of Georgakopoulous et al had unclear risks
because there was no mention of blinding of the outcome
assessment, of allocation concealment, and of blinding
of participants. 29 Blinding of the outcome assessment may
have significant effect in the measurement of LVEF, however
blinding of participants and allocation concealment were
not found to significantly affect the objective outcome
being measured, which was the change in LVEF post
chemotherapy.
Effect of preventive therapy on EF is depicted in Figure
3. In the forest plot the mean difference in the reduction of
EF from baseline to six months of follow up was compared
between the control arm and the intervention of either RAS
inhibitors alone or in combination with a beta blocker. The
average time frame of follow up which was reported in all
of the studies included were six months and has been the
basis of comparison in this review.
Subgroup analysis was done based on the combination
of agents. Combined agents of RAS inhibitor with a
beta-blocker (Carvedilol) showed benefit in preventing
cardiotoxicity with a significant mean difference of 2.45 [95%
CI 1.27, 3.63]. Control groups were found to have significant
Mondragon KAM, et al.
reduction in LVEF by 2.45% compared with the group given
combined agents of RAS inhibitor with another drug as
prophylaxis. Subgroup analysis of RAS alone showed mean
difference of 5.37 [95% CI -5.61, 16.34] when compared with
the control group; although nonsignificant with a p=0.34. This
was also found to have significant heterogeneity at I2=95%.
The combined effect of all five trials had an overall mean
difference of 4.37 [95% CI 1.20, 7.55], p=0.007. There was also
an overall significant heterogeneity among all the five trials
with an I2 of 95% (Figure 3).
Sensitivity analysis was done to determine the effect of
removing the study by Cardinale et al study and its effect
on the overall outcome. This yielded with an overall mean
difference of 2.24 [95% CI 1.21, 3.27], p<0.0001. Heterogeneity
was also decreased to I2=50%. Despite the adjustment, there
is still benefit of limiting the reduction in LVEF by a mean
difference of 2.20%. (Figure 4)
In terms of clinical endpoint, Compared to the
intervention group, the control group had a higher incidence
of death, heart failure symptoms or LVEF <50% and/or
decrease by 10% from baseline with an overall RR 0.27 [95%
CI 0.18, 0.40], p<0.00001. This was represented by two of the
five trials gathered that compared clinical endpoints with
the use of RAS inhibitor. (Figure 5)
D iscussion
This meta-analysis explored the role of RAS inhibitors to
prevent anthracycline-induced cardiotoxicity. The principal
finding of this meta-analysis is that RAS inhibitors, with or
without beta-blockers, are able to reduce the combined
clinical outcome of heart failure, cardiac events, and all-
cause mortality. Two of the five trials included were able to
demonstrate this result.27,28 One of which used a combina-
tion of RAS inhibitors with beta-blocker, 28 while the other
study made use of RAS inhibitor alone. 27 The heterogeneity,
although significant, does not affect the overall result since
both studies clearly showed benefit in decreasing the risk of
cardiac events.
Overall, there was a significant LVEF preservation among
those given RAS inhibitors. However, this was particularly
significant in the exploratory subgroup analysis of combined
RAS inhibitors and beta-blockers. In the meta-analysis of Yun
et al. they were able to demonstrate an association of beta-
blocker treatment and/or angiotensin antagonist treatment
with higher LVEF compared with control.20 The combination
of beta-blocker and angiotensin antagonist treatment as
prophylaxis, however, was demonstrated only by the study
of Cardinal.27 The addition of the study of Gulati in this meta-
analysis further strengthens the benefit of combined beta-
blocker with RAS inhibitor.
Volume 55 Number 3 July-Sept., 2017 5
 Mondragon KAM, et al.
Figure 3.
Figure 4. Forest plot showing the sensitivity analysis without the study of Cardinale 2006.
Figure 5. Forest plot showing control and treatment group and risk ratio for each study based on adverse cardiovascular outcomes death, heart failure symptoms or
LVEF <50% and/or decrease by 10% from baseline
The subgroup analysis of RAS inhibitor alone showed
potential benefit, but was largely affected by heterogeneity.
Several factors were identified to be potential sources of this
heterogeneity.
First was the difference in the type of anthracycline used.
Among the included studies variability in the anthracycline
investigated was noted. One study investigated only
doxorubicin 26 while two others looked at epirubicin. 27,32
The fourth included study did not mention a specific
anthracycline.24 In this meta-analysis data from the single
doxorubicin study showed a non-significant trend in favor
of the control over the treatment intervention. This could
be explained by differences among the anthracycline
compounds in terms of their cardiotoxicity. In particuIar, it
had been shown that the risk of clinical cardiotoxicity was
lower with epirubicin compared to doxorubicin.19
6 Volume 55 Number 3 July - Sept., 2017
The Role of Prophylactic Renin-angiotensin System Inhibitors
Second was the dosage of anthracycline used. Toxicity
from this class of agents was driven not only by type but
also by cumulative dosing with higher doses increasing
the likelihood and severity of heart failure. 5,6 Of the studies
considered, three gave the cumulative anthracycline doses
of participants, while the study of Bosch and collaborators28
did not. The study of Georgakopolous and collaborators26
used doxorubicin at a cumulative dose approaching the
recommended lifetime limit of the drug (~400-550 mg/m2). 29
Meanwhile, the studies of Dessi and collaborators and Gulati
and collaborators30,31 both used epirubicin but at different
doses: for the former 400 mg/m 2 and for the latter 240,
360, or 400 mg/m 2, respectively. Notably, the equivalent
dose of epirubicin could be estimated by multiplying the
doxorubicin dose by two.12 Thus the Georgakopolous and
collaborators study used an estimated dose of about 800
mg/m2 of epirubicin.29 This higher dose compared to other
studies might further explain the results of this study in favor
 The Role of Prophylactic Renin-angiotensin System Inhibitors
of the control over the treatment group. Moreover, the lack
of uniform dosing given that anthracyclines cause toxicity at
higher doses made comparisons of RAS inhibitor treatment
effect more difficult to assess. In addition, considering that all
doses given were within the acceptable range of doses for
both doxorubicin and epirubicin could there be a ‘threshold
dose’ where cardioprotection would no longer be effective?
Third was the presence of co-interventions. The
combination of other chemotherapeutic agents and
treatment modalities such as cyclophosphamide, taxanes,
trastuzumab, and radiation were commonly used with
anthracyclines and were themselves cardiotoxic.17 Most of
the studies accounted for these except the study of Dessi
and collaborators.31 In three of the four studies the effect of
these factors was non-significant but for Bosch, radiotherapy
was more often given to the treatment group. Despite this
the result was still favorable for the treatment arm versus the
placebo, suggesting a greater effect with the addition of
Enalapril and Carvedilol.
F o urth w as th a t t h e t i m i n g of a d m i n i st r a t io n o f
prophylaxis varied between studies. In Georgakopoulos et
al. it was concomitant to administration of anthracycline.29
In Cardinale et al. it was given one month after the last
cycle of high dose chemotherapy.27 In Dessi et al. it was
started one week before the beginning of treatment and
up to six months after discontinuation; for Gulati et al. prior
to initiating with titration up to maximum dose, in Bosch
et. al it was started simultaneously at least 24 hours before
the first cycle of chemotherapy.28,30,31 This difference may
significantly alter the dose response and subsequently
the expected treatment effect, this in itself may account
for the significant heterogeneity in the outcomes even
with same cardioprotective agent. However as there is
no acceptable consensus as to the optimal timing and
definition of prophylaxis except that it should be given prior
to an objective evidence of cardiac dysfunction then all
the studies fulfilled the criteria as prophylactic agents. In
the sensitivity analysis conducted removing the study done
by Cardinale et al, to account for the striking difference in
terms of provision of prophylaxis
In the study of Cardinale et al., the participants included
in the study were those who had a significant troponin I
elevation prior to the initiation of RAS inhibitor.27 Troponin I
was considered to be predictive of the cardiotoxic effect
of anthracycline, hence this was the study’s prerequisite
criterion prior to inclusion of the participant in the study.
This may have significantly affected the outcome leading
to a more effective prevention of anthracycline-induced
cardiotoxicity, when compared to the other studies, which
did not have the same protocol. Determination of troponin I
levels prior to prophylaxis treatment may potentially identify
high-risk population among the cancer patients who are
more predisposed to developing cardiotoxicity after being
Mondragon KAM, et al.
given an anthracycline regimen. Further studies may be
conducted to compare high-risk from low-risk populations
to determine if prophylactic treatment with RAS inhibitors to
limit development of anthracycline-induced heart failure will
be most beneficial among the high-risk population
Lastly, there was variability in the length of follow-up
performed. The average follow up in the study was 15.2
months, which would be acceptable in assessing the acute
cardiotoxicity associated with anthracyclines. However, a
longer follow-up would be necessary in order to fully assess
the incidence of chronic cardiotoxicity which would take
as long as ten years to develop. In fact, ESMO guidelines
would recommend assessment of cardiac function four and
ten years after anthracycline treatment in individuals who
received a cumulative dose of >240 mg/m2 of doxorubicin
and >360 mg/m 2 of epirubicin as was the case in most
patients studied here.31 As such, adequate surveillance and
monitoring of anthracycline toxicity would need to be long
and drawn out in order to more accurately determine the
incidence of anthracycline-induced cardiotoxicity.
These potential causes of heterogeneity provide
significant implications for future research. It warrants
also a look into concerns regarding future trial protocols
outcome measures (i.e. cardiac biomarkers vis-à-vis clinical
endpoints), appropriate prophylaxis duration, timing of
prophylaxis to initiation of treatment, consensus on schedule
of surveillance and adequate length of follow-up. Each of
these topics presents possible directions for research into this
relevant area of survivorship, particularly in light of improving
outcomes among patients being treated for cancer.
Anthracycline-induced cardiotoxicity is a known barrier
in the improvement of cancer survivorship and strategies to
mitigate its effect have been the subject of recent studies
in the field of cardio-oncology.32 The potential utility of renin
angiotensin system inhibitors as possible cardioprotective
agent is particularly promising, especially when combined
with beta-blocker.
C onclusion
This systematic review and previous published studies
have highlighted the potential role of RASi as cardioprotective
agents. Both in reduction of EF and prevention of cardiac
events, the studies included were able to show benefit in
using RASi as prophylaxis to prevent anthracycline-induced
cardiotoxicity. However, a significant benefit was noted more
in the combination of RAS inhibitor with beta-blocker. This
was supportive of the conclusion of Yun et al, which showed
benefit in giving ACE inhibitor and/or beta-blocker.30
Cardinale et al. was identified to have affected the
heterogeneity of the study. On further review, the study was
Volume 55 Number 3 July-Sept., 2017 7
 Mondragon KAM, et al.
also different in the methodology; wherein the participants
included in the study all had a baseline significant cardiac
troponin I. This study may have potentially selected the
population who may benefit more from RAS inhibitors as
cardioprotective agents against anthracycline-induced
cardiotoxicity.
The researchers recommend further randomized con-
trolled trials be done on this topic. A comparison between
those with significant Troponin I versus those without may
possibly demonstrate the significance of identifying the
population that may benefit more from RAS inhibitors as
prophylaxis. Inclusion of more studies with similar methodolo-
gies may also decrease the heterogeneity, giving a more
robust conclusion on the benefits of RAS inhibitors.
R eferences
1. Carver JR, Shapiro CL, Ng A, et al. American Society of Clinical
Oncology clinical evidence review on the ongoing care of adult
cancer survivors: cardiac and pulmonary late effects. J Clin Oncol
Off J Am Soc Clin Oncol. 2007;25(25):3991-4008. doi:10.1200/
JCO.2007.10.9777.
2. Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L.
Anthracyclines: molecular advances and pharmacologic
developments in antitumor activity and cardiotoxicity. Pharmacol
Rev. 2004;56(2):185-229. doi:10.1124/pr.56.2.6.
3. Sawyer DB, Peng X, Chen B, Pentassuglia L, Lim CC. Mechanisms
of anthracycline cardiac injury: can we identify strategies for
cardioprotection? Prog Cardiovasc Dis. 2010;53(2):105-113.
doi:10.1016/j.pcad.2010.06.007.
4. Pai VB, Nahata MC. Cardiotoxicity of chemotherapeutic agents:
incidence, treatment and prevention. Drug Saf. 2000;22(4):263-
302.
5. Billingham ME, Mason JW, Bristow MR, Daniels JR.
Anthracycline cardiomyopathy monitored by morphologic changes.
Cancer Treat Rep. 1978;62(6):865-872.
6. Mackay B, Ewer MS, Carrasco CH, Benjamin RS. Assessment
of anthracycline cardiomyopathy by endomyocardial biopsy.
Ultrastruct Pathol. 1994;18(1-2):203-211.
7. Curigliano G, Cardinale D, Suter T, et al. Cardiovascular toxicity
induced by chemotherapy, targeted agents and radiotherapy: ESMO
Clinical Practice Guidelines. Ann Oncol Off J Eur Soc Med Oncol.
2012;23 Suppl 7:vii155-166. doi:10.1093/annonc/mds293.
8. Mann DL, Zipes DP, Libby P, Bonow RO, Braunwald E,
eds. Braunwald’s Heart Disease : A Textbook of Cardiovascular
Medicine. Philadelphia, PA: Elsevier/Saunders; 2015.
9. Bovelli D, Plataniotis G, Roila F, ESMO Guidelines Working
Group. Cardiotoxicity of chemotherapeutic agents and
radiotherapy-related heart disease: ESMO Clinical Practice
Guidelines. Ann Oncol Off J Eur Soc Med Oncol. 2010;21 Suppl
5:v277-282. doi:10.1093/annonc/mdq200.
10. Eschenhagen T, Force T, Ewer MS, et al. Cardiovascular side
effects of cancer therapies: a position statement from the Heart
Failure Association of the European Society of Cardiology. Eur J
8 Volume 55 Number 3 July - Sept., 2017
The Role of Prophylactic Renin-angiotensin System Inhibitors
Heart Fail. 2011;13(1):1-10. doi:10.1093/eurjhf/hfq213.
11. Ky B, Vejpongsa P, Yeh ETH, Force T, Moslehi JJ. Emerging
paradigms in cardiomyopathies associated with cancer
therapies. Circ Res. 2013;113(6):754-764. doi:10.1161/
CIRCRESAHA.113.300218.
12. Denlinger CS, Sanft T, Baker KS, et al. Survivorship, Version
2.2017, NCCN Clinical Practice Guidelines in Oncology. J Natl
Compr Cancer Netw JNCCN. 2017;15(9):1140-1163. doi:10.6004/
jnccn.2017.0146.
13. Spagnuolo RD, Recalcati S, Tacchini L, Cairo G. Role
of hypoxia-inducible factors in the dexrazoxane-mediated
protection of cardiomyocytes from doxorubicin-induced toxicity.
Br J Pharmacol. 2011;163(2):299-312. doi:10.1111/j.1476-
5381.2011.01208.x.
14. Hiona A, Lee AS, Nagendran J, et al. Pretreatment with
angiotensin-converting enzyme inhibitor improves doxorubicin-
induced cardiomyopathy via preservation of mitochondrial
function. J Thorac Cardiovasc Surg. 2011;142(2):396-403.e3.
doi:10.1016/j.jtcvs.2010.07.097.
15. Abd El-Aziz MA, Othman AI, Amer M, El-Missiry MA.
Potential protective role of angiotensin-converting enzyme
inhibitors captopril and enalapril against adriamycin-induced
acute cardiac and hepatic toxicity in rats. J Appl Toxicol JAT.
2001;21(6):469-473.
16. Richard C, Lauzier B, Delemasure S, et al. Effects of
angiotensin-1 converting enzyme inhibition on oxidative stress
and bradykinin receptor expression during doxorubicin-induced
cardiomyopathy in rats. J Cardiovasc Pharmacol. 2008;52(3):278-
285. doi:10.1097/FJC.0b013e3181865f28.
17. van Dalen EC, Caron HN, Dickinson HO, Kremer LC.
Cardioprotective interventions for cancer patients receiving
anthracyclines. Cochrane Database Syst Rev. 2011;(6):CD003917.
doi:10.1002/14651858.CD003917.pub4.
18. Kalam K, Marwick TH. Role of cardioprotective therapy for
prevention of cardiotoxicity with chemotherapy: a systematic
review and meta-analysis. Eur J Cancer Oxf Engl 1990.
2013;49(13):2900-2909. doi:10.1016/j.ejca.2013.04.030.
19. Smith LA, Cornelius VR, Plummer CJ, et al. Cardiotoxicity of
anthracycline agents for the treatment of cancer: systematic review
and meta-analysis of randomised controlled trials. BMC Cancer.
2010;10:337. doi:10.1186/1471-2407-10-337.
20. Yun S, Vincelette N, Abraham I. Cardioprotective role of beta-
blockers and angiotensin antagonists in early-onset anthracyclines-
induced cardiotoxicity in adult patients: a systematic review and
meta-analysis. Postgrad Med J. 2015;(0):1-7.
21. Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group.
Preferred reporting items for systematic reviews and meta-analyses:
the PRISMA statement. Int J Surg Lond Engl. 2010;8(5):336-341.
doi:10.1016/j.ijsu.2010.02.007.
22. Higgins J, Green S, eds. Cochrane Handbook for Systematic
Reviews of Interventions Version 5.1.0 [updated March 2011].
2011. http://handbook.cochrane.org.
23. Cadeddu C, Piras A, Mantovani G, et al. Protective effects of the
angiotensin II receptor blocker telmisartan on epirubicin-induced
inflammation, oxidative stress, and early ventricular impairment.
Am Heart J. 2010;160(3):487.e1-7. doi:10.1016/j.ahj.2010.05.037.
 The Role of Prophylactic Renin-angiotensin System Inhibitors Mondragon KAM, et al.

24. Dessì M, Piras A, Madeddu C, et al. Long-term protective effects

of the angiotensin receptor blocker telmisartan on epirubicin-
induced inflammation, oxidative stress and myocardial dysfunction.
Exp Ther Med. 2011;2(5):1003-1009. doi:10.3892/etm.2011.305.
25. Blaes A, Duprez D, Defor T, et al. Angiotensin Converting
Enzyme Inhibitors (ACEI) and doxorubicin pharmacokinetics in
women receiving adjuvant breast cancer treatment. SpringerPlus.
2015;4:32. doi:10.1186/s40064-015-0802-4.
26. Nakamae H, Tsumura K, Terada Y, et al. Notable effects of
angiotensin II receptor blocker, valsartan, on acute cardiotoxic
changes after standard chemotherapy with cyclophosphamide,
d o x o r u b i c i n , v i n c r i s t i n e , a n d p r e d n i s o l o n e . C a n c e r.
2005;104(11):2492-2498. doi:10.1002/cncr.21478.
27. Cardinale D, Colombo A, Sandri MT, et al. Prevention
of high-dose chemotherapy-induced cardiotoxicity in high-
risk patients by angiotensin-converting enzyme inhibition.
C i r c u l a t i o n . 2 0 0 6 ; 11 4 ( 2 3 ) : 2 4 7 4 - 2 4 8 1 . d o i : 1 0 . 11 6 1 /
CIRCULATIONAHA.106.635144.
28. Bosch X, Rovira M, Sitges M, et al. Enalapril and carvedilol
for preventing chemotherapy-induced left ventricular systolic
dysfunction in patients with malignant hemopathies: the
OVERCOME trial (preventiOn of left Ventricular dysfunction
with Enalapril and caRvedilol in patients submitted to intensive
ChemOtherapy for the treatment of Malignant hEmopathies).
J Am Coll Cardiol. 2013;61(23):2355-2362. doi:10.1016/j.
jacc.2013.02.072.
29. Georgakopoulos P, Roussou P, Matsakas E, et al. Cardioprotective
effect of metoprolol and enalapril in doxorubicin-treated lymphoma
patients: a prospective, parallel-group, randomized, controlled
study with 36-month follow-up. Am J Hematol. 2010;85(11):894–
896.
30. Gulati G, Heck SL, Ree AH, et al. Prevention of cardiac
dysfunction during adjuvant breast cancer therapy (PRADA): a 2
× 2 factorial, randomized, placebo-controlled, double-blind clinical
trial of candesartan and metoprolol. Eur Heart J. 2016;37(21):1671-
1680. doi:10.1093/eurheartj/ehw022.
31. Dessì M, Madeddu C, Piras A, et al. Long-term, up to 18 months,
protective effects of the angiotensin II receptor blocker telmisartan
on Epirubin-induced inflammation and oxidative stress assessed by
serial strain rate. SpringerPlus. 2013;2(1):198. doi:10.1186/2193-
1801-2-198.
32. Groarke JD, Nohria A. Anthracycline cardiotoxicity: a new
paradigm for an old classic. Circulation. 2015;131(22):1946-1949.
doi:10.1161/CIRCULATIONAHA.115.016704.

Volume 55 Number 3 July-Sept., 2017 9

 Philippine Journal of Internal Medicine
Four-year Clinical Outcomes of Filipino Patients with or at Risk
for Atherothrombotic Events from the REACH Registry
Maria Teresa B. Abola, M.D.*; Felix Eduardo R. Punzalan, M.D.*
Abstract
Introduction: Patients with established atherothrombotic
disease (EAD) or those with only atherothrombotic risk
factors are at high risk for cardiovascular events and
death. There are scant data on the clinical profile of stable
Filipino patients with or at risk for atherothrombosis and their
long-term outcomes. The authors'objective is to present
the baseline clinical profile and four-year cardiovascular
outcomes in Filipino outpatients with EAD and those with
multiple atherothrombotic risk factors in comparison to the
Asian and Global populations
Methods: The Reduction of Atherothrombosis for Continued
Health (REACH) registry is an international, prospective
cohort of 68,236 patients aged at least 45 years old with
either EAD or at least three atherothrombotic risk factors
enrolled from 44 countries in 2003-2004. The Philippine cohort
consists of 1040 outpatients with EAD (N=913) or at least
three atherothrombotic risk factors (N=127) consecutively
enrolled and followed up for at least one to four years for
the occurrence of cardiovascular death (CVD), myocardial
infarction (MI) and stroke.
Results: Nine hundred fifty-five Filipino outpatients (96)%
completed the four-year follow-up. Mean age is 65.5 years
Introduction
Atherothrombosis results from atherosclerosis
complicated by platelet-rich thrombus formation involving
multiple vascular beds. This may present as coronary
artery disease (CAD), cerebrovascular disease (CVD)
and peripheral arterial disease (PAD) and its life- and
limb-threatening complications of acute coronary
syndrome, acute ischemic stroke and acute limb ischemia.
Atherothrombosis remains as a leading cause of death
globally and across different ethnic groups. In 2012, the
World Health Organization (WHO) reported ischemic heart
*Consultant, Section of Cardiology, Department of Medicine, University of
the Philippines-Philippine General Hospital; Clinical Associate Professor,
College of Medicine, University of the Philippines-Philippine General
Hospital
Corresponding author: Maria Teresa Abola, M.D., University of the
Philippines – Philippine General Hospital, Manila, Philippines; Philippine
Heart Center, Quezon City
Email: mtbabola@yahoo.com
The PHILIPPINE JOURNAL OF INTERNAL MEDICINE is a peer reviewed journal and a copyrighted publication of the Philippine College of Physicians
Original Article
with similar sex distribution. Common risk factors included
diabetes (46%), hypertension (87.4%), hypercholesterolemia
(62.9%), and smoking history (29.7%). Ninety-two percent
had EAD-- 43% with coronary artery disease, 45% with
cerebrovascular disease (CVD) and four percent with
peripheral artery disease (PAD). The combined primary
endpoint of CVD/MI/stroke was 14.7%, but higher (19.8%)
among those with polyvascular disease. Cerebrovascular
disease (CVD) patients had the highest CVD/MI/stroke
rates (17.6%); PAD patients had the highest CVD/MI/stroke
and hospitalization rate (33.2%). Baseline medication usage
is 81.1% for antiplatelet agents, 62.6% for statins and 69%
for angiotensin-converting enzyme inhibitor/angiotensin
receptor blocker but four-year follow-up medication usage
rates were lower.
Conclusion: Filipino outpatients with or at risk for athero-
thrombosis experienced high long-term rates of CV events.
This is the first report of long-term cardiovascular outcomes
of stable Filipino outpatients with this high-risk profile.
Keywords: atherothrombotic disease, atherothrombosis,
REACH Registry,
disease (IHD) and stroke to be the overall top two leading
causes of death globally (13.2% and 11.9%, respectively)
and among the lower-middle to high income countries;
lower-respiratory infections, human immunodeficiency
virus/acquired immunodeficiency syndrome (HIV/AIDS) and
diarrheal diseases top the list of causes of mortality in the
low-income countries, but still followed by IHD and stroke.1
The large multinational Reduction of Atherothrombosis
for Continued Health (REACH) registry documented high
rates of recurrent vascular events at three years in patients
with symptomatic vascular disease. 2 For the composite
endpoint of nonfatal myocardial Infacrtion (MI), nonfatal
stroke or vascular death, the one-year and three-year event
rates were 4.7 and 12.0%, respectively, while for patients
enrolled with atherosclerosis risk factors only, the one and
three-year event rates for MI/stroke/vascular death were 2.3
and 6.0%, respectively.2 A four-year analysis of REACH registry
patients showed that among patients with atherothrombosis,
Volume 55 Number 3 July-Sept., 2017 1
 Abola MTB, et al.
those with a prior history of ischemic events at baseline
had the highest rate of subsequent ischemic events (18.3%;
95%confidence interval [CI], 17.4%-19.1%). 3
Ethnicity has been shown to be an independent
predictor of various major adverse cardiovascular events.4
In a substudy analysis of the REACH registry, this time on
patients recruited from the Asian region ( N = 10,692), there
is a higher prevalence of CVD and diabetes mellitus with
lower body mass index compared to those from non-Asian
regions. The one-year cardiovascular event rates were
similar in patients from Asian and non-Asian regions but
significantly lower in patients recruited from Japan.5 At two-
year follow-up of REACH registry patients of various ethnic
groups, cardiovascular death rate was significantly higher in
Black patients compared with all other ethnic groups while
cardiovascular death rates were significantly lower in all
three Asian ethnic subgroups (East Asian, South Asian and
other Asian subgroups which included Filipino patients).6
The Philippines is classified as one of the lower-middle
income countries by the WHO and, as of their 2012 survey,
IHD is the leading cause of death (15.4%) followed by stroke
(11.1%), while diabetes mellitus (5.9%) and hypertensive
heart disease (3.7%) are ranked fourth and fifth. Compared
to 2000 data, these figures have remained the same for
IHD but increased in the last decade for stroke, diabetes
and hypertensive heart disease.1 (WHO) The first Philippine
National Nutritional Health Survey (NNHeS I, N = 4753) done
in 2003 reported that the national prevalence rates of CAD
based on previous diagnosis and angina questionnaire
were 1.8% and 12.5%, respectively, prevalence rates of CVD
based on previous diagnosis and stroke questionnaire as
1.4% and 1.9% respectively, and prevalence of peripheral
artery disease based on previous diagnosis, claudication
questionnaire and ankle-brachial index (ABI) as 0.4%, 4.2%
ad 5%, respectively. 7 The second National Nutritional Health
Survey (NNHeS II, N = 7700) done in 2008 reported that the
overall age-adjusted prevalence rates of CAD, CVD, and
PAD based on previous diagnosis indicated in interview
questionnaires performed by medical personnel in 2003 were
1.1%, 1.4%, and 0.6% respectively and 1.1%, 0.9%, and 1.1%
respectively. 8
To date, there is no large prospective study of Filipino
patients with or at risk for atherothrombosis that has been
reported in Philippine literature. Knowing the natural history,
risk factors and treatment of people with atherosclerosis
risk factors and atherothrombotic events is of paramount
importance to help determine measures to reduce mortality
due to IHD and stroke and other vascular diseases. Our
study aims to report the demographic and risk factor profile
and four-year cardiovascular outcomes of stable Filipino
outpatients with established atherothrombosis or only
atherosclerosis risk factors enrolled in the REACH registry.
2 Volume 55 Number 3 July - Sept., 2017
Four-year Clinical Outcomes of Filipino Patients with or at Risk for
M ethods
The REACH registry is an international, prospective,
observational registry which enrolled 68,375 patients at
baseline of which 45,227 patients had four-year outcomes.
The Philippines was one of the countries where 1,040 patients
were initially enrolled and 995 had four-year follow-up data.
The design, including the strategy for selecting physicians,
follow-up, ensuring data quality, and the baseline description
of the REACH registry has been previously published. 9-11
This protocol was submitted to institutional review boards
in each country according to the local requirements and
signed informed consent was required for all patients.
Consecutive outpatients aged ≥45 years with established
CAD, CVD and/or PAD, or ≥ three atherothrombotic risk
factors (“multiple risk factors only”) were enrolled by their
physicians over an initial seventh-month recruitment period
on a worldwide basis between December 2003 and June
2004. Due to regulatory requirements in Japan, enrollment
in that country was delayed and occurred between August
2004 and December 2004. The multiple risk factors category
consisted of diabetes, diabetic nephropathy, ABI less than
0.9, asymptomatic carotid stenosis of 70% or more, carotid
intima media thickness at least two times that at adjacent
sites, systolic blood pressure of 150 mm Hg or higher despite
treatment, hypercholesterolemia treated with medication,
current smoking of 15 or more cigarettes per day, and
age 65 years and older for men or 70 years and older for
women. Documented CAD consisted of one or more of the
following: stable angina, history of unstable angina, history
of percutaneous coronary intervention, history of CABG, or
previous MI. Documented CVD consisted of a neurologist
report or hospital report with the diagnosis of ischemic stroke
or transient ischemic attack (TIA). Documented peripheral
artery disease consisted of current intermittent claudication
with ABI of less than 0.9 and/or a history of intermittent
claudication together with a previous intervention, such
as angioplasty, stenting, atherectomy, peripheral arterial
bypass grafting, or other vascular interventions, including
amputations. Diabetes was defined as any history of
diabetes or current diabetes (diagnosed by at least two
fasting blood glucose measures >126mg/dL treated with
medication, lifestyle, or both.
Follow-up
Detailed information was collected at baseline, with
subsequent annual follow-up at one, two, three, and four
years. Patients were enrolled between 2003 and 2004
and followed up until 2008. Final database lock was in
April 2009. The initial follow-up was planned for up to two
years and shortly before that point, an additional two-year
extension was proposed. Not all countries and sites that
were in the two-year follow-up cohort chose to continue
participation in the registry, largely for financial reasons,
 Four-year Clinical Outcomes of Filipino Patients with or at Risk for
although the majority did decide to continue. Countries
and sites that decided not to participate in the four-year
follow-up were excluded from the results. Event rates of
cardio- vascular death, MI, stroke, and cardiovascular
hospitalization were calculated. The primary endpoint
was the cardiovascular death/MI/stroke while secondary
endpoints included the individual endpoints of all-cause
mortality, cardiovascular death, nonfatal MI, nonfatal
stroke, and the combined endpoint of the cardiovascular
death/MI/stroke plus hospitalization for atherothrombotic
events. Endpoints were not adjudicated. Cardiovascular
death included fatal stroke, fatal MI, or other cardiovascular
death. Other cardiovascular death included other deaths
of cardiac origin; pulmonary embolism; any sudden death
including unobserved and unexpected death (eg, death
while sleeping) unless proven otherwise by autopsy; death
following a vascular operation, vascular procedure, or
amputation; death attributed to heart failure; death
following a visceral or limb infarction; and any other death
that could not be definitely attributed to a nonvascular
cause or hemorrhage. Any MI or stroke followed by a death
whatever the cause in the next 28 days was considered to
be a fatal MI or fatal stroke. Cardiovascular hospitalization
consisted of hospitalization for unstable angina, transient
ischemic attack, worsening of claudication related to
peripheral artery disease, other ischemic arterial event,
CABG, coronary angioplasty/stenting, carotid surgery,
carotid angioplasty/stenting, amputation affecting lower
limbs, peripheral bypass graft, or angioplasty/stenting for
peripheral artery disease. Groups based on the enrollment
criteria of multiple atherosclerosis risk factors only (ROF) and
stable established atherothrombotic disease (EAD) were
compared. Polyvascular disease was defined as having
atherothrombosis in two or three arterial beds (coronary,
peripheral, cerebrovascular) at baseline.
Our study reports on the demographics, risk factor
profile, and preventive medications taken by 995 Filipino
patients enrolled in the REACH registry at baseline and the
major cardiovascular outcomes at four-year follow-up.
Baseline Demographic Characteristics and Risk Factors
Data were collected centrally with the use of a
standardized international case report form, completed at
the study visit. Baseline seated systolic and diastolic blood
pressure, and available fasting glucose and cholesterol
levels were obtained. Subjects were considered to be
“overweight” if their BMI was 25-29 kg/m2 or “obese” if their
BMI was ≥ 30 kg/m 2. Current smoking was defined as ≥15
cigarettes per day on average within the past month before
enrollment; former smoking was defined as stopping smoking
less than a month before enrollment. Weight, current smoking
status, and chronic medications used at baseline were
recorded. Employment status was described by whether
Abola MTB, et al.
patients were still employed, or already unemployed,
retired or incapacitated for work. Key outcome events as
described above were likewise centrally recorded but were
not adjudicated.
Statistical Analysis
Continuous variables are expressed as mean (standard
deviation), and categorical variables are expressed as
frequencies and percentages. Event rates are reported
as annualized event rates. Cumulative incidence rates
are reported after adjustment for age and sex using the
corrected group prognosis method in the Cox proportional
hazards model. Only patients with complete outcome and
covariate information for a given end point were included
in calculating the rates for that end point. Statistical
significance was considered as a two-sided probability of
less than .05. Statistical analyses were performed using SAS
version 9 (SAS Institute, Cary, North Carolina).
R esults
There were 1040 patients enrolled at baseline from
outpatient clinics of 91 participating investigators--49
internists (53.9%), 26 neurologists (28.6%), eight cardiologists
(8.8%), seven endocrinologists (7.7%) and one general
surgeon (1.1%). Geographical representation of the patient
population was determined by the practice base location of
their physicians-- 79% from Luzon region, eighteen percent
from Visayas region, and the remaining three percent from
the Mindanao region. There were 913 patients with EAD or
the symptomatic group (87.8%) and 127 with risk factors
only (12.2%). Table I shows the distribution of patients to the
different subgroups. Sixty-one percent of Filipino patients
presented with any CVD, 48.7% with any CAD and 7.1% with
any PAD. Forty-one percent of Filipino patients had CVD only,
31% with CAD only, and 1.8% with PAD only. Polyvascular
disease was reported in 12.4% of the total population.
Mean age was 65.5 years (SD = 10.37), with virtually equal
distribution to both genders. There were 46.2% with diabetes,
87.4% with hypertension, 62% with hypercholesterolemia, 7.4%
with BMI > 30, 30.4% who are former or current smokers. There
were 43.4% with documented CAD, 15.5% with a prior MI and
11.4% with prior coronary revascularization-- percutaneous
coronary intervention (PCI) or coronary artery bypass graft
(CABG), 53.2% had documented stroke and/or transient
ischemic attack, and four percent with documented PAD,
0.7% with prior peripheral angioplasty/stenting/surgery
(Table II). Majority of the patients at baseline were on at
least one antiplatelet agent (81.1%), statin therapy (62.6%)
and an angiotensin converting enzyme (ACE) inhibitor or
angiotensin receptor blocker (69.2%) (Table III). However,
at four-year follow-up, there were lower usage rates of at
least one antiplatelet therapy (72.6%) and an ACE inhibitor
Volume 55 Number 3 July-Sept., 2017 3
 Abola MTB, et al. Four-year Clinical Outcomes of Filipino Patients with or at Risk for

Table I. Distribution of filipino patients in the reach registry to subgroup Table II. Baseline profile of filipino patients in the REACH registry
according to atherothrombotic risk or vascular bed involvement with four-year follow-up (N = 995)

Population N (%) Variable Patients

Global 1040 (100%) (Mean) SD (%)
Demographics
Risk factors only 127 (12.2%)
Age 65.46 (10.37)
Symptomatic 913 (87.8%)
Men 492 (49.45 )
CAD only 322 (31.0%)
Diabetes 460 (46.23%)
CVD only 431 (41.4%)
Hypertension 870 (87.44%)
PAD only 19 (1.8%)
Hypercholesterolemia 616 (61.91%)
CAD+CVD 95 (9.1%)
Obesity (BMI>30) 72 (7.44%)
CAD+PAD 16 (1.5%)
Former smoker 227 (23.28%)
CVD+PAD 18 (1.7%) Current smoker 69 (7.08%)
CAD+CVD+PAD 12 (1.2%) Never smoker 679 (69.64%)
CAD * among symptomatic 445 (48.7%) Previous history of atherosclerotic disease
CVD * among symptomatic 556 (60.9%) Any history of symptomatic atherothrombosis 874 (87.8%)
PAD * among symptomatic 65 (7.1%) History of CAD 432 (43.42%)
* Patients can present more than one location of the disease
Stable angina with documented CAD 260 (26.34%)
Unstable angina with documented CAD 95 (9.71%)
or Angiotensin receptor blocker (37.2%), with similar usage
History of MI 153 (15.50%)
rate of statins (62.3%).
History of PCI 44 (4.46%)

For four-year follow-up analysis, there were 995 patients History of CABG 69 (6.98%)
who had at least one follow-up visit; 874 had EAD (87.8%) History of CVD 529 (53.17%)
and 121 (12.2%) with risk factors only. During the follow-up History of TIA 156 (15.95%)
interval, the primary endpoint of CVD/MI/stroke occurred in History of Stroke 445 (45.13%)
14.7% in the total population, with an almost two-fold higher
History of PAD 40 (4.02%)
rate among patients with EAD (21%, CI 95% 16.19%–25.6%)
compared to those with multiple risk factors only (12.7%, CI Claudication and ABI <0.9 35 (4.48%)
95% 5.4-19.4%), p value = 0.02 (Table IV). Patients with CVD History of peripheral angioplasty/stenting/
had the highest rates of CVD/MI/stroke (17.6%, CI 95% 12.1%- surgery 7 (0.70%)
22.7%) compared to that of CAD patients (14.5%, CI 95% Claudication and history of amputation 7 (0.70%)
9.4%-19.4%) and PAD patients (12.6%, CI 95% 1.3%-22.5%).
(Table IV) The latter also had the highest rates of CVD/MI/
stroke/ hospitalization for an atherothrombotic event (33.2%, Table III. Usage rate of preventive medications in filipino patients

CI 95%14.5%-47.7%) followed by CAD patients (22.5%, CI 95% in the REACH registry at baseline and at four-year follow-up

16.6%-28%) and patients with CVD (20.8%, CI 95% 15.4%- 4-year

25.8%). All-cause mortality rate was 13.9% (CI 095% 9.8%- Baseline
Medication Use Follow-up
N (%)
17.8%), 78.4% of which were cardiovascular deaths (10.9%, N (%)
CI 95% 7%-14.4%); these rates were similar between EAD and At least one antiplatelet 807 (81.1%) 464 (72.61%)
risk factors only groups. CAD patients had higher rates of
Aspirin 524 (52.7%) 289 (45.23%)
nonfatal MI and those with CVD had higher rates of nonfatal
stroke. Patients with polyvascular disease (12.4% of the total Other antiplatelet agent 400 (40.2%) 210 (32.86%)
population) had higher rates of the primary endpoint CVD/ At least one lipid lowering agent 671 (67.4%) 422 (65.94%)
MI/stroke (19.8%, CI 95% 11– 27.7%), p-value = 0.00098, and Statins 623 (62.6%) 398 (62.28%)
of all secondary endpoints. (Table V)
Other lipid lowering agents 64 (6.4%) 37 (5.83%)
ACE inhibitors 341 (34.3%) 142 (22.29%)
Table VI shows the cardiovascular outcome rates from
the first year to fourth year of follow-up. All event rates Angiotensin II receptor blockers 347 (34.98%) 228 (35.68%)
linearly increased throughout the four years of follow-up. ACE inhibitor or Angiotensin II
689 (69.2%) 370 (37.18%)
Table VII reveals a comparison of major cardiovascular receptor blockers
outcomes in the different geographical regions compared

4 Volume 55 Number 3 July - Sept., 2017

 Four-year Clinical Outcomes of Filipino Patients with or at Risk for Abola MTB, et al.

Table IV. Four-year cardiovascular event rates for the total population and main subsets of Filipino patients in the REACH registry with four-year
follow-up

Multiple
Event Total Total EAD** CAD CVD PAD Risk Factor p-value***
Only
n 995 874 432 529 40 121
0.03
CV death/MI/ stroke 14.66 15.43 14.52 17.61 12.65 8.97

CI 95% 10.39;18.69 10.91; 19.69 9.35; 19.36 12.10; 22.70 1.29; 22.54 1.99; 15.38
0.15
All cause mortality 13.92 14.32 14.82 14.48 19.3 10.81

CI 95% 9.77; 17.82 9.98; 18.37 9.46; 19.77 9.64; 19.00 4.46; 31.36 3.31; 17.58
CV death 10.88 11.06 11.95 11.61 13.04 9.23 0.29
CI 95% 7.09; 14.45 7.15; 14.74 6.92; 16.61 7.16; 15.76 1.15; 21.11 1.92; 15.83
Non-fatal MI 1.08 1.22 2.21 NE NE NE 0.99
CI 95% 0.02; 2.28 0.03; 2.58 0.03; 4.68
Non-fatal stroke 5.01 5.61 2.97 8.53 NE NE 0.08
CI 95% 2.36; 7.58 2.64; 8.48 0.93; 4.96 3.99; 12.84
CV death/MI/stroke or hospitaliza-
20.02 21.05 22.54 20.81 33.19 12.68 0.02
tion for atherothrombotic event(s)
CI 95% 15.43; 24.35 16.19; 25.60 16.57; 28.05 15.40; 25.85 14.47; 47.70 5.41; 19.36
*Calculated on the basis of the population of patients with non-missing outcomes and non-missing co-variates
** EAD: Established Atherothrombotic Disease
***p-value comparing Total EAD and Multiple Risk Factor Only
NE°:Event rates are non estimable (Number of event<5)
Adjusted on gender and age (using Cox model)

Table V. Major adverse cardiovascular events in Filipino patients in the REACH registry according to number of vascular disease bed location

Multiple Risk Established Atherothrombotic Disease

Event Total p-value
Factor Only 1 location 2 locations 3 locations
N 995 121 751 119 4
CV death/MI/stroke 14.66 8.97 14.59 19.81 NE 0.00098
CI 95% 10.39-18.69 1.99-15.38 10.03-18.89 11.00-27.66
All-cause mortality 13.92 10.81 13.76 16.84 NE 0.03145
CI 95% 9.77-17.82 3.31-17.58 9.35-17.89 8.67-24.11
CV death 10.88 9.23 10.24 14.96 NE 0.01571
CI 95% 7.09-14.45 1.92-15.83 6.35-13.91 7.08-21.99
Non-fatal MI 1.08 NE 0.94 NE NE 0.00418
CI 95% 0.02-2.28 0.00-2.12
Non-fatal stroke 5.01 NE 5.3 6.62 NE 0.00592
CI 95% 2.36-7.58 2.30-8.20
CV death/MI/stroke or hospitaliza-
20.02 12.68 19.88 27.25 NE 0.00058
tion for atherothrombotic event(s)
CI 95% 15.43-24.35 5.41-19.36 15.00-24.45 17.28-35.99
*Calculated on the basis of the population of patients with non-missing outcomes and non-missing co-variates
NE°:Event rates are non estimable (Number of event<5)
Adjusted to gender and age (using Cox model)

Volume 55 Number 3 July-Sept., 2017 5

 Abola MTB, et al. Four-year Clinical Outcomes of Filipino Patients with or at Risk for

to the Philippine cohort and that of the global population. to that of the global population with 63.7% male and that
The Eastern European population had the highest adverse of the Asian subgroup with 67% male distribution. 5,10 The
cardiovascular event rates compared to the rest of the Filipino cohort is also slightly younger (mean age of 65.5
region, with CV death rates similar to that of the Philippine years) compared to 68.5 years in the global cohort and
cohort. When compared to the overall Asian population, the 67.5 years in the Asian cohort. There is a higher prevalence
Philippine population had higher CV death rates but similar of diabetes (46.2%) and hypertension (87.4%) in the Filipino
cluster outcome rates. cohort compared to that of the global cohort (44.3% and
81.8% respectively) and the Asian cohort with a lower rate
D iscussion of hypertension (75.2%). 10 There are fewer Filipino patients
with hypercholesterolemia (61.9%) compared to the global
This global REACH registry population is a multinational cohort (72.4%) but higher than that of the Asian cohort
diverse group of patients belonging to the wide spectrum (54.2%). There are fewer Filipino patients who are current
of atherothrombotic risk and atherothrombotic disease that smokers (7.1%) compared to the global and Asian cohorts
was prospectively followed up for at most four years. The Table VI. Annual rates of major adverse cardiovascular events
Filipino cohort like the global population has approximately in Filipino patients in the REACH registry
90% with symptomatic or established atherothrombotic
disease and the rest with multiple risk factors only. Sixty-one Outcome one-year two-year three-year four-year
follow-up follow-up follow-up follow-up
percent of Filipino patients presented with any CVD, 48.7%
with any CAD and 7.1% with any PAD. The global REACH N 804 859 869 874
population, on the other hand, had 27.8% CVDs, 59.3% All cause mortality 4.72 6.95 11.87 14.3
(CAD) and 12.2% (PAD), respectively. 5 The Asian subgroup CI 95% 4.01-9.78 7.93-15.58 9.9–18.4
had 41% with CVD, 48.6% with CAD, and 8.5% with PAD.10 The
Major CV event
higher prevalence of CVD as index event of Filipino patients
CV death 3.15 5 9.27 11.06
in the REACH registry and the higher occurrence rate of
nonfatal strokes among patients with CVD are consistent CI 95% 2.46-7.45 5.69-12.66 7.15-14.74
with observed higher rates of CVD, mainly strokes, in Asians, Non-fatal MI 0.12 0.7 1.43 1.22
particularly those living perhaps in rural areas. Nonfatal CI 95% 0.00 -1.73 0.02-3.02 0.03-2.58
stroke rates were more than two-fold greater among Chinese Non-fatal stroke 3.95 4.26 4.55 5.61
residing in mainland China compared to East Asians living
CI 95% 1.86 - 6.61 2.09-6.94 2.64-8.48
in North America enrolled in the REACH registry, presumably
related to the higher salt intake in mainland China. 12 CV death/MI/ 7 9.63 13.27 15.43
stroke
Hypertension has been reported to be the strongest risk
factor for both primary and recurrent stroke.12 CI 95% 6.12-12.99 9.09-17.21 10.91-19.69
CV death/MI/stroke 11.68 14.19 19 21.05
or hospitalization
Of note in the demographic and risk factor profile is for atherothrombotic
the virtually equal distribution of patients to both sexes event(s)
(49.4% males), with unexpectedly more females compared CI 95% 10.30-17.90 14.36-23.38 16.19-25.60

Table VII. Three-year outcomes of patients from the different geographical regions compared to the Philippine and global populations*

Outcome North Latin Western Eastern Middle Australia Asia Japan Philippines Global
America America Europe Europe East (including
Philippines)
N 11604 1206 12218 4326 392 2551 3144 4234 869 39675
CV death 6.02 7.61 5.79 9.03 5.61 2.70 5.61 2.42 9.27 5.57
8.97- 9.47- 8.53- 10.36- 5.08- 5.80- 8.51- 4.47- 5.69- 5.15-
95% CI
10.61 13.47 9.96 12.97 10.53 7.90 11.16 5.94 12.66 5.99
CV death/MI/ stroke 11.99 13.65 11.85 17.99 13.25 7.57 13.13 8.63 13.27 11.96
11.08- 11.46- 11.06- 16.47- 9.70- 6.44- 11.68- 7.67- 9.09- 11.37-
95% CI
12.90 15.77 12.64 19.47 16.44 8.69 14.56 9.58 17.21 12.54
CV death/MI/ stroke or
hospitalization for athero- 29.27 25.83 30.69 39.58 30.45 23.51 23.03 17.34 19 28.39
thrombotic event(s)
28.09- 23.24- 29.62- 37.90- 25.85- 21.68- 21.38- 16.10- 14.36- 27.62-
95% CI
30.43 28.32 31.75 41.21 34.77 25.29 26.44 18.56 23.38 29.16
*Adapted from Alberts, et.al.2

6 Volume 55 Number 3 July - Sept., 2017

 Four-year Clinical Outcomes of Filipino Patients with or at Risk for
(15.3% and 14.7%, respectively). 5,10
On follow-up, approximately one in seven patients (14.7%)
in the stable population with established atherothrombotic
disease had a major event (CV death, MI, stroke). There
was an almost two-fold increase in major cardiac events
(CVD/MI/stroke) suffered by patients with established disease
compared to those with risk factors only. Cerebrovascular
disease (CVD) patients had a higher rate of CVD/MI/stroke
(17.6%) and incident recurrent nonfatal strokes compared to
CAD and PAD patients. This is most likely related to the higher
prevalence of hypertension in the Filipino cohort. Compared
to the global and Asian cohorts, there were much higher rates
of CVD in the Filipino cohort.5,10 This should alert the local health
officials to not only monitor the higher rates of CVD but the
increasing rates of adverse cardiovascular outcomes of
CVD/MI/stroke among patients with CVD, especially, with the
observed increasing prevalence of hypertension reported
in the National Nutritional Health Surveys of 2003, 2008, and
2013. 7,8,13
However, one in three PAD patients (33.2%) had a
major event or was hospitalized in this period of observation,
yielding the highest rates of CVD/MI/stroke or hospitalization
compared to those with CAD or CVD probably due to higher
rates of hospitalization for an atherothrombotic event. Our
findings are consistent with the reported event rates in the
overall global REACH registry population. 2-6,11-12 Although
there is a low prevalence of PAD in the REACH registry global,
Asian and Filipino cohorts, there were higher rates of adverse
outcomes among PAD patients with polyvascular disease.
PAD patients are underrecognized and undertreated
and efforts to achieve early recognition and appropriate
treatment of these PAD patients will contribute to the
reduction of adverse cardiovascular outcomes.14
There was a linear increase in event rates throughout
the four-year follow-up period. (Table V) This may be
related to the lower usage rates of preventive medications
like antiplatelet therapy, statins and ACE inhibitors/
angiotensin II receptor blockers at four-year follow-up
which was reported in the Filipino cohort. However, when
compared to the Japanese cohort which had lower rates of
antiplatelet therapy and statins but lower prevalence rates
of hypertension, diabetes and hypercholesterolemia, their
adverse event rates are also much lower than the other
Asians enrolled in the REACH registry. 3 Although reasons
for this lower usage rate of preventive therapy were not
determined, it is interesting to note that over 70% of these
Filipino patients are being managed by internists, and the
rest by neurologists. This lower usage rate may also result
from lower treatment compliance rates due to financial
constraints but this health information was not collected in
this study.
When compared to the different geographical regions,
Abola MTB, et al.
the Eastern European population had the highest adverse
cardiovascular event rates compared to the rest of the
regions; this could only be partially explained by higher
prevalence rate of risk factors, i.e. 85% of symptomatic
patients had hypertension, but >97% of these hypertensive
patients were on at least one antihypertensive therapy. 2
The Philippine cohort had cardiovascular death rates similar
to that of the Eastern European population but had much
lower rates of the cluster outcomes of CV death/MI/stroke
or hospitalization for atherothrombotic events. Compared
to the overall Asian population and to the Japanese cohort,
CV death rates in the Filipino cohort were higher while
cluster outcome rates of CV death/MI/stroke, and that
which included hospitalization for atherothrombotic events
were similar, most probably reflecting the contribution of
recurrent stroke events among patients with index stroke
events and attendant rehospitalization. This could also be
related to the higher prevalence rates of hypertension in the
Filipino population compared to their Asian neighbors. This
observation underscores the need for the National Health
Agenda to prioritize measures addressing the early diagnosis,
optimal treatment and effective control of hypertension and
other atherothrombotic risk factors.
Limitations
Inherent to nonpopulation-based registry studies is
the potential patient recruitment bias and the lack of
adjudication of endpoints which may affect estimates of
prevalence and incidence rates. Investigators were asked to
recruit consecutively patients from their outpatient clinics but
there was no systematic enlistment of patients. Reasons for
medication use or non-use were not recorded systematically.
There was an effort to enlist use of herbal medications
and other supplements which may have replaced the
appropriate medications to be taken but the reported
numbers were low. There were also more investigators and
hence, patients, recruited from the Luzon island compared
to the other regions as a function of accessibility to study
follow-up provided by the sponsor. There was an attempt to
reduce recruitment bias by inviting physicians from various
clinical specialties.
C onclusion
Data from this multiregional cohort of Filipino patients
with or at risk for atherothrombosis confirm the high risk for
developing adverse cardiovascular outcomes as early as
one to four years of follow-up. Compared to the global
population and even to other Asian countries, the Filipino
cohort had higher prevalence rates of diabetes and
hypertension and more patients with baseline CVD who,
in turn, developed higher rates of adverse cardiovascular
outcomes. Moreover, usage rate of optimal medical therapy
to prevent adverse outcomes were comparatively lower
Volume 55 Number 3 July-Sept., 2017 7
 Abola MTB, et al. Four-year Clinical Outcomes of Filipino Patients with or at Risk for

than those patients from other Asian countries and the rest
of the global population. Efforts at controlling risk factors,
especially hypertension, may contribute to the reduction
of adverse events and deaths. More attention directed to
early detection and more effective control of diabetes and
hypertension, and use of secondary prevention measures
of patients with CVD and peripheral artery disease by their
physicians may also improve cardiovascular prognosis
in these subgroups. To our knowledge, this is the first
prospective study on the demographics, risk factor profile
and adverse outcomes of a large number of Filipino patients
with or at high risk for atherothrombosis.
Acknowledgements
The REACH registry was supported by Sanofi-aventis,
Bristol-Myers Squibb and the Waksman Foundation (Tokyo,
Japan). The REACH registry is endorsed by the World Heart
Federation.
lan FE, Sy RAG, Paz-Pacheco E, Amarillo L and Villaruz MV.
National Nutrition and Health Survey (NNHeS): Atherosclerosis-related
Diseases and Risk Factors; Phil J. Internal Medicine, 43:103-115, 2005
8. Sy RG, Morales, DD, Dans, AL, Paz-Pacheco, E, Punzalan FE,
Abelardo NS and Duante CA; Prevalence of Atherosclerosis-related
risk factors and diseases in the Philippines; J Epidemiol., 22(5):4 40-7.
Epub Jul 14, 2012.
9. Ohman EM, Bhatt DL, Steg PG, Goto S, Hirsch AT, Liau CS, Mas JL,
Richard AJ, Rother J and Wilson PWF; The Reduction of Athero-
thrombosis for Continued Health (REACH) Registry: an international,
prospective, observational investigation in subjects at risk for athero-
thrombotic events: study design. Am Heart J., 151(4):786, e1-e10, 2006.
10. Bhatt DL, Steg PG, Ohman EM, Hirsch AT, Ikeda Y, Mas JL, Goto
S, Liau CS, Richard AJ, Rother J, Wilson PW, REACH Registry
Investigators; International prevalence, recognition, and treatment of
cardiovascular risk factors in outpatients with atherothrombosis. JAMA,
295 (2):180-189, 2006.
11. Steg PG, Bhatt DL, Wilson PW, D’ Agostino R Sr., Ohman EM,
Rother J, Liau CS, Hirsch AT, Mas JL, Ikeda Y, Pencina MJ, Goto
S; REACH Registry Investigators. One-year cardiovascular event rates
in outpatients with atherothrombosis. JAMA, 297(11):1197-1206, 2007.

R eferences 12. Chiu JF, Bell, AD, Herman RJ, Hill MD, Steward JA, Cohen EA, Liau
CS, Steg PG, Bhatt DL; REACH Registry Investigators; Cardiovas-
cular risk profiles and outcomes of Chinese living inside and outside
1. World Health Organization. http://www.who.int/countries/phl/en
China. Eur J of Cardiovacular Prev and Rehab., 17:668-675, 2010.
and http://www.who.int/mediacentre/factsheets/fs310/en/index1.html
13. Food and Nutrition Research Institute and Department of Science
2. Alberts MJ, Bhatt DL, Mas JL, Ohman, EM, Hirsch AT, Rother J,
and Technology. Burden of Selected Risk Factors to Non-commu-
Salette G, Goto S, Smith Jr. SC, Liau CS, Wilson, PWF, and Steg
nicable diseases among Filipino Adults (8th National Nutritional
PG; Three-year follow-up and event rates in the international REduc-
Survey). 2015.
tion of Atherothrombosis for Continued Health Registry. Eur Heart J.,
14. Cacoub PP, Abola MT, Baumgartner I, Bhatt, DL, Creager MA, Liau
30(19):2318-2326, 2009.
CS, Goto S, Rother J, Steg PG, Hirsch AT; REACH Registry Inves-
3. Bhatt DL, Eagle KA, Ohman EM, Hirsch AT, Goto S, Mahoney
tigators. Cardiovascular risk factor control and outcomes in peripheral
EM, Wilson PWF, Alberts MJ, D’Agostino R, Liau CS, Mas JL,
artery disease patients in the Reduction of Atherothrombosis for Contin-
Rother J, Smith Jr. SC, Salette G, Contant CF, Massaro JM and
ued Health (REACH) Registry. Atherosclerosis, 204(2):e86-92, 2009.
Steg PG; Comparative Determinants of 4-year cardiovascular event
rates in stable outpatients at risk of or with atherothrombosis. JAMA,
304(12): 1350-7, 2010.
4. Ducrocq G, Bhatt DL, Labreuche J, Corbalan R, Porath A, Gao R,
Panchenko E, Liau CS, Ikeda Y, Goto S, Amarenco P and Steg PG;
Geographic differences in outcomes in outpatients with established
atherothrombotic disease: results from the REACH Registry. Eur J
Prev Cardiology, 21(12):1509-1516, 2014.
5. Goto S, Ikeda Y, Chan JCN, Wilson PWF, Yeo TC, Liau CS, Abola
MT, Salette G, Steg PG and Bhatt DL; Risk-factor profile, drug
usage and cardiovascular events within a year in patients with and at
high risk of atherothrombosis recruited from Asia as compared with
those recruited from non-Asian regions: a substudy of the Reduction
of Atherothrombosis for Continued Health (REACH) registry. Heart
Asia, 93-98, 2011.
6. Meadows TA, Bhatt DL, Hirsch AT, Creager MA, Califf RM, Ohman
EM, Cannon CP, Eagle KA, Alberts MJ. Ethnic differences in the
prevalence and treatment of cardiovascular risk factors in US outpa-
tients with peripheral arterial disease: Insights from the Reduction of
Atherothrombosis for Continued Health (REACH) Registry. Amer
Heart J, 158(6):1038-45, 2009.
7. Dans, AL, Morales, DD, Velandria, F, Abola TB, Roxas Jr. A, Punza-

8 Volume 55 Number 3 July - Sept., 2017

 Philippine Journal of Internal Medicine
Barriers to Hand Hygiene Compliance in the Medicine Wards
and Intensive Care Unit of a Tertiary Teaching Hospital in the
Philippines
Anna Flor G. Malundo, M.D.*; Regina P. Berba, M.D.**
Abstract
Introduction: Healthcare associated infections (HCAI)
continue to be major problems in our institution. Studies
have shown that hand hygiene remain to be the primary
measure that prevents HCAI. This study aimed to measure
hand hygiene compliance rate and determine factors
affecting compliance.
Methods: Healthcare workers in the medicine wards
and intesive care units (ICU) were directly observed for
compliance to the World Health Organization hand hygiene
guidelines. In a month period, subjects were selected by
convenience sampling. Factors affecting hand hygiene
compliance was investigated. Survey of infrastructure and
hand hygiene products was concurrently done. Thereafter,
self-administered survey was distributed to assess knowledge,
attitudes and perceptions toward hand hygiene.
Results: Overall hand hygiene compliance was 11%.
Compliance was less likely for doctors, in the ward, and
before patient contact. On the other hand, compliance
was likely among nurses, in the ICU, before aseptic
procedure, after exposure to body fluid, and after patient
contact. Demand for hand hygiene was high with mean of
Introduction
Health-care associated infections (HCAI) remain to be
a major problem in most clinical institutions. It affects five
to15% of hospitalized patients in developed countries, with
an annual economic impact of approximately six and a half
billion in the US and €13-24 billion in Europe.1 Data on HCAI are
limited in developing countries, particularly in the Philippines
where data varies among community, city, government and
university hospitals. A 1999 study in the Philippine General
Hospital (PGH) showed that hospital acquired pneumonia
occurs among 28% of patients admitted in the intensive care
unit (ICU) resulting to increased mortality rates (from 12.3% to
*Department of Medicine, University of the Philippines-Philippine General
Hospital
**Section of Infectious Diseases; Hospital Infection Control Unit, Department
of Medicine, University of the Philippines-Philippine General Hospital
Corresponding author: Anna Flor G. Malundo, M.D., University of the
Philippines – Philippine General Hospital, Manila, Philippines
Email: annaflormalundo@gmail.com
The PHILIPPINE JOURNAL OF INTERNAL MEDICINE is a peer reviewed journal and a copyrighted publication of the Philippine College of Physicians
Original Article
35 (SD=nine) opportunities per hour of patient care. Hand
hygiene products are less available in the wards than in the
ICU. Sinks are not in convenient locations. Hand hygiene
posters were either not visible or lacking. Majority of the
survey respondents know at most only two of the five hand
hygiene indications.
Discussion: Access to hand hygiene products, training and
education, and reminders in the workplace are among the
basic requirements in the implementation of hand hygiene
programs. With problems related to these three components,
hand hygiene compliance is expected to be low.
Conclusion: Low compliance to hand hygiene was associated
with professional status, location and indication. Barriers to
hand hygiene include inadequate and inaccessible sinks
and hand hygiene products in the ward, high demand for
hand hygiene, poor knowledge of hand hygiene, and lack
of reminders in the workplace.
Keywords: hand hygiene compliance, healthcare associated
infections
42.4%) and prolonged hospitalization (from 15.1±12.5 days to
29.7±23.9 days).2 A more recent but unpublished surveillance
data from the PGH hospital infection control unit (HICU) in
2016 reported HCAI incidence of six and a half percent to
23% per 1,000 patient days in the ICU.
Multiple studies have shown evidence of association
between HCAI and infections with drug resistant pathogens.
A systematic review by Cardoso et a.l in 2015 showed
that the odds of getting an infection with potentially drug
resistant organisms is four times higher in patients with
HCAI compared to those who have community acquired
infections. 3 Local studies, including that from PGH and
University of Santo Tomas Hospital, likewise showed that most
cases of multi-drug resistant Acinetobacter infections are
indeed nosocomial.4,5 But apart from this, the rates of multi-
drug resistant organisms have been increasing for the past
years. Philippine surveillance of antimicrobial resistance from
2015 to 2016 showed increasing rates of extended spectrum
beta lactamase-producing Enterobacteriaceae, multidrug-
Volume 55 Number 3 July-Sept., 2017 1
 Malundo AFG, et al.
resistant and extensively drug resistant Pseudomonas
aeruginosa and Acinetobacter species. 6,7
At least 20% of HCAI are preventable by appropriate
infection control measures.8 And among these strategies,
hand hygiene is considered to be the primary measure
n e c e s s a r y t o r e d u c e H C A I . 1,9 S u b s t a n t i a l e v i d e n c e
demonstrated the efficacy of hand hygiene in preventing
the spread of infection not only in the hospital but also
in the community.1 Although randomized controlled trials
are lacking, several studies have shown reduction in HCAI
rates10-12 and cross transmission of drug resistant pathogens
particularly methicillin-resistant Staphylococcus aureus. 13-15
Between handwashing and handrubbing with alcohol
solutions, the latter showed greater efficacy in reducing
transient 16 and drug resistant organisms. 17,18 The Centers
for Disease Control and Prevention and the World Health
Organization (WHO) recommends handrubbing with alcohol-
based solution for routine hand antisepsis except when
hands are visibly soiled or possibly exposed to spore-forming
organisms which necessitates handwashing with soap and
water.1,19
Although the value of hand hygiene is universally known
and the practice simple, overall compliance is unacceptably
low among health care workers (HCW). WHO reviewed
studies from 1981 to 2008 showing baseline hand hygiene
adherence of five percent to 89% with an overall average
of 38.7%. 1 The wide range of values could have resulted
from differences in definition of adherence and as well as
observation. This was addressed in 2009 when WHO published
guidelines which standardized definitions and methods for
observation.
Factors contributing to hand hygiene noncompliance
have been extensively studied. Identified factors include:
skin irritation by hand hygiene agents, inaccessible supplies,
interference with patient –HCW relationship, patient needs
perceived as priority over hand hygiene, wearing of gloves,
forgetfulness, lack of knowledge of guidelines, insufficient
time for hand hygiene, high workload and understaffing.20-24
Conversely, there were also factors identified to improve
adherence such as: introduction of accessible alcohol-
based handrub, sink automation, years of practice, training,
incentives, recognition, penalty, administrative support,
prioritization and active participation at institutional
level. 10,12,25,26
In our institution, hand hygiene is being promoted
for years. Strategies were mainly focused on information
dissemination through lectures, posters, and training
workshops conducted annually. Hand hygiene surveillance
was only done in high risk areas (ICU), showing a very dismal
three percent compliance rate recorded in the medical ICU
for the year of 2011 (unpublished). However, this data was
from random observation in the ICU, consisting only of 70
2 Volume 55 Number 3 July - Sept., 2017
Barriers to Hand Hygiene Compliance
opportunities observed in nine sessions of 120-minute each.
Apart from that, observations were not yet standardized in
accordance to the 2009 WHO guidelines. There have been
efforts to provide hand hygiene products at point of care
but a lot of the products went missing. Also, reasons as to
why wall-mounted hand hygiene products are rarely used
remains to be investigated.
Thus, this study was conducted in 2012 to establish
baseline data on hand hygiene compliance in accordance
to the 2009 WHO guidelines. It also probed into the factors
that affected compliance and whether results were similar
to existing studies. Study results led to a multifaceted
intervention to improve hand hygiene in 2014..
M ethodology
The study was conducted in PGH, a tertiary referral
center and teaching hospital administered by the University
of the Philippines (UP). It is the largest government training
hospital in the Philippines with about 1,500 bed capacity,
annual average of 600,000 patients, and over 800 trainees,
600 medical students, and 4,000 employees. 27 Observations
were limited to the Medicine female ward (48 beds), male
ward (50 beds) and ICU (12 beds).
The wards are open with patient beds that are
arranged in four rows and are approximately three feet
apart. Rows are lined opposite each other and separated
by a discontinuous cement wall. All of the beds are visible
from the center aisle. In each ward, there is one isolation
room for immunocompromised patients consisting of five
patient beds. All patients are visible from the center of
the rooms. In the ICU, beds are lined in two opposite rows
with bed distances of about four to five feet. These beds
can be separated by curtain dividers, but nonetheless are
visible from the center aisle. For both the wards and ICU,
there is at least one isolation room for patients with highly
communicable diseases. These rooms have large glass
windows or walls which allow monitoring of general patient
status and all patient care activities from outside the rooms.
Direct observation of hand hygiene practices over a
one-month period was done at different times of the day
and days of the week to ensure that differences in the density
of opportunities were accounted. Eligible subjects include
doctors, nurses and students who entered the patient zone,
defined as the area which includes the patient and surfaces
or items that are temporarily or exclusively dedicated to him
or her.28 Subjects were selected by convenience sampling.
The primary investigator trained in accordance with the
WHO hand hygiene guidelines and recorded observations on
their prescribed form.28 Observations were done discreetly,
as far as possible from the subjects yet making sure that
 Barriers to Hand Hygiene Compliance Malundo AFG, et al.

patient care activities were still visible. At most two persons
were observed at a time. Subjects were observed up to a
maximum of 20 minutes or until completion of patient care
episode, whichever comes first, before moving on to another
subject. The availability and accessibility of hand hygiene
products and posters were concurrently evaluated.
Self-administered questionnaires evaluating knowledge,
perceptions and attitudes toward hand hygiene were
distributed (Appendix A). Questions were patterned from
existing studies, 29,30 and modified specifically for the PGH
setting. Survey items assessed different cognitive aspects
toward hand hygiene. Submission of accomplished forms
implied consent.
Microsoft Excel and GraphPad software were used for
statistical analyses.
The UP Manila Research Ethics Board approved the
protocol as a researcher-initiated study on quality of care.
The Department of Medicine and HICU were notified of the
conduct of the study; but schedule of observations were
withheld. Anonymity was maintained by omitting names from
the data record. After completion of the study, results were
reported in department conferences, lectures and meetings
with the hospital staff.
R esults

A total of 394 patient care episodes which provided

Opportunities for hand hygiene and compliance were
1,176 opportunities for hand hygiene were observed over
assessed based on the 2009 WHO hand hygiene guidelines.
36 hours of observation. Overall hand hygiene compliance
An opportunity for hand hygiene was identified whenever
was 11% (n=125). Handwashing (8%) was preferred over
an indication exists, whether single or multiple. Hand hygiene
handrubbing with alcohol-based solution (3%). Majority
between a contaminated site to another site in the same
performed handwashing for most indications except before
patient was also considered as an opportunity for hand
doing aseptic procedures when handrubbing with alcohol-
hygiene. The main outcome was hand hygiene compliance,
based solution was preferred. Table I shows the distribution
either by handwashing with soap and water, or handrubbing
of opportunities over different study variables.
with an alcohol-based solution for every opportunity for hand
hygiene. Inability to perform hand hygiene when indicated
Compliance differed significantly by professional status,
corresponds to noncompliance. Failure to remove gloves
location and hand hygiene indication. The likelihood of hand
after patient contact or between a contaminated and
hygiene compliance was higher for nurses, in the ICU, before
clean body site on the same patient was also considered
aseptic procedure, after body fluid exposure risk and after
noncompliance.
patient contact. On the other hand, adherence was less
likely for doctors, in the wards and before patient contact.
Study variables included: professional status, sex,
location, time of day, day of the week, glove use, and
Glove use contributed to about 14% (n=143) of missed
activity index. Activity index represents hand hygiene
opportunities for hand hygiene. Moreover, gloves were not
demand (number of opportunities per hour of patient care). 28
changed as often as needed especially in between patient
contact except when exposed to body fluids.
Knowledge of hand hygiene was measured by the
number of hand hygiene indications that survey participants
The average activity index was 35 (SD=nine) opportunities
were able to enumerate (refer to Appendix A). These
per hour of patient care. Figure 1 shows a trend toward
five moments of hand hygiene include (1) before patient
decreased compliance with increased activity index,
contact, (2) before clean or aseptic procedures, (3) after
however was not statistically significant.
body fluid exposure risk, (4) after patient contact, and (5)
after contact with patient’s surroundings.
In the ICU, hand hygiene solutions at the entrance and
at the nurses’ station were supplemented by alcohol-based
Sample size was calculated using the expected
solutions at point of care. However, supplies of soap and
correlation coefficient of 0.39 based on similar existing
hand towels in sink areas were not maintained. Sinks are only
studies. With a level of significance of five percent, margin
present at the nurses’ station.
of error of 0.2, and alpha = 0.1, at least 366 opportunities for
hand hygiene must be observed to estimate hand hygiene
In the wards, alcohol-based solutions at point of care
compliance rate.
were lacking and alcohol placeholders were not being
utilized. This was partially compensated by patients and HCW
Association with hand hygiene compliance were
who provide their own handrub solutions. And just like in the
investigated using chi square for categorical variables and
ICU, supplies of soap and hand towels in sink areas were not
logistic regression for correlation with activity index. The
maintained. Sinks are present at the nurses’ station and at
magnitude of association was measured by odds ratio with
far corners of the wards.
95% confidence intervals. All tests were two-tailed, and a p
value less than 0.05 was considered statistically significant.
Only posters on proper handwashing were visible in the

Volume 55 Number 3 July-Sept., 2017 3

 Malundo AFG, et al. Barriers to Hand Hygiene Compliance

Table I. Distribution of 1,176 hand hygiene opportunities observed within 36 hours of observation and factors associated with hand hygiene
compliance in PGH medicine wards and ICU

Variables Opportunities Compliance Chi square Odds ratio (95% CI)

n (%) % p value
Professional status
Doctor 248 (21) 6 18.9 0.44 (0.25 – 0.78)
Nurse 424 (36) 16 p<.001 2.17 (1.49 – 3.15)
Student 504 (43) 9 0.73 (0.49 – 1.07)
Sex
Male 451 (38) 11 0.48 1.16 (0.80 – 1.70)
Female 725 (62) 10 p=0.49 0.86 (0.59 – 1.25)
Location
Female ward 414 (35) 11 14.66 1.00 (0.68 – 1.47)
Male ward 425 (36) 7 p<.001 0.50 (0.32 – 0.77)
ICU 337 (29) 15 1.91 (1.31 – 2.80)
Time of day
Morning (6am-12nn) 418 (36) 10 1.99 0.87 (0.59 – 1.29)
Afternoon (12nn-6pm) 413 (35) 12 p=0.37 1.31 (0.90 – 1.92)
Night (6pm-6am) 345 (29) 10 0.85 (0.56 – 1.29)
Day of the week
Weekdays 653 (56) 12 3 1.43 (0.97 – 2.09)
Weekends 523 (44) 9 p=0.08 0.70 (0.48 – 1.03)
Use of gloves
Yes 165 (14) 13 0.05 1.64 (1.00 – 2.70)
No 1011 (86) 12 p=0.82 0.61 (0.37 – 1.00)
Indication*
Before patient contact 760 (46) 5 54.37 0.32 (0.22 – 0.48)
Before aseptic procedure 76 (5) 17 p<.001 2.11 (1.13 – 3.93)
After body fluid exposure risk 44 (3) 30 4.38 ( 2.24 – 8.57)
After patient contact 740 (45) 12 1.86 (1.32 – 2.61)
After contact with patient’s surroundings 15 (1) 0 0.00 (0.00 – 2.16)

* Total number of indications: 1,635

p value = 0.1768
Odds ratio = 0.98 (95% CI 0.96 – 1.01)

Activity Index (Opportunities for hand hygiene per hour of patient care)
Figure 1. Scatter plot of activity index – related hand hygiene compliance among PGH health care workers in the medicine ward
and ICU (Logistic regression analysis). Infrastructure survey

4 Volume 55 Number 3 July - Sept., 2017

 Barriers to Hand Hygiene Compliance Malundo AFG, et al.

Table II. Survey of knowledge and preference for hand hygiene of

124 healthcare workers in the PGH medicine wards and ICU
D iscussion
Survey Items Doctors Nurses Students Overall Compliance to hand hygiene was low. Identified barriers
n = 50 n = 32 n = 42 N (%) to compliance include lack of hand hygiene products,
inadequate knowledge of hand hygiene indications, and
Hand Hygiene training 46 31 41 118 (95)
lack of reminders in the workplace. These three factors are
Knowledge of hospital 48 33 40 121 (98) among the five basic requirements in the implementation
policy on hand hygiene of hand hygiene programs as recommended by the WHO.1
Knowledge of five moments Indeed, without these basic requirements compliance is
of hand hygiene * expected to be low.
0 19 16 2 37 (30)
1 6 2 2 10 (8) Another barrier to compliance was the high demand
2 5 5 11 21 (17) for hand hygiene in our setting. With this, the WHO
3 8 5 8 21 (17) recommendation of handrubbing with alcohol-based
4 9 0 10 19 (15) solution for routine antisepsis1 cannot be overemphasized.
5 2 5 9 16 (13) This is very important given that most HCW preferred
Preference for hand hygiene† handwashing with soap and water over the use of handrub
Soap and water 27 17 22 66 (53) solutions. Then again, the problem on understaffing should
Alcohol-based solution 5 0 4 9 (7) also be addressed, as it also contributes to the high workload
Either 17 15 16 48 (39) among the hospital staff.
* Knowledge was measured by the number of hand hygiene indications
(WHO five moments of hand hygiene) correctly enumerated Other important issues that should be addressed in
† One respondent did not give an answer devising a strategy to improve hand hygiene compliance
include: appropriate glove use and acceptability of hand
wards and ICU. Reminders on the five moments of hand hygiene products to HCW. Education and training should
hygiene and the use of alcohol-based solution were lacking. focus on correcting the practice that gloves can be used
in place of hand hygiene. Again, gloves are intended to
About 124 HCW submitted accomplished survey forms. complement and not replace hand hygiene. Handrub
Table II shows the result of different parameters assessing solutions should be of acceptable quality to encourage
knowledge of hand hygiene. Majority reported knowledge HCW to do hand hygiene.
of hand hygiene and had also attended training. However,
further testing revealed that most participants have Compliance was lowest even with commonly cited hand
knowledge of at most only two hand hygiene indications. hygiene indication – that is, before patient contact. Students
Most commonly cited indications were after patient contact who demonstrated better knowledge of these indications
(n=72), before patient contact (n=68), and before aseptic were outperformed by nurses in practice. Indeed, hand
technique (n=53). Average self-reported compliance was hygiene practice is complex and other factors such as years
7 (SD=2) in a 10-point scale. of clinical practice, type of patient care activities performed
and working condition could have affected the result.
The reported reasons for noncompliance were lack
of hand hygiene products (n=73), busy schedule (n=70), As in our study, self-report overestimated true compliance.
forgetfulness (n=49), inaccessible hand hygiene products Hence, we should utilize other methods of monitoring
(n=43), and lack of prioritization for hand hygiene over other compliance such as direct observation, monitoring of
tasks (n=27). Other reasons include: skin irritation, unsure of hygiene product consumption, and automated monitoring
need, and unpleasant odor of available hand sanitizer. systems. 1

Health care workers have a general positive response on
time-related (86%), ethical and accountability-related (99%),
and usefulness-related (98%) questions on hand hygiene
(Appendix B). Majority (95%) were motivated to improve
compliance with provision of more hand hygiene products.
The overwhelming response was for the hospital to provide
adequate, accessible and acceptable hand hygiene
products. Other suggestions include: frequent reminder in
the workplace, adequate staffing, performance feedback,
and administrative commitment to implement hand hygiene.
The problem on hand hygiene encompasses resources,
working condition, cognition and behavior. Therefore,
hand hygiene interventions should be multifaceted, as
recommended by the WHO. A systematic review in 2016
showed that a multimodal approach resulted to moderate
improvement in hand hygiene compliance.31 In our setting,
administrative commitment, funding, staffing, education and
training, regular surveillance, and performance feedback are
necessary to improve hand hygiene compliance.

Volume 55 Number 3 July-Sept., 2017 5

 Malundo AFG, et al.
Biases and Limitations
1. Study findings may not be similar to other areas in the
hospital.
2. The quality of handwashing or handrubbing was not
assessed.
3. Some health care workers might have noticed being
observed and performed better than usual.
4. Since only one of the researchers did the observations,
observation bias may exist. This was minimized by strictly
adhering to the WHO guidelines.
C onclusion
Hand hygiene compliance was low (11%). Location,
professional status and hand hygiene indications
significantly affected compliance. Barriers to hand hygiene
compliance include: inadequate and inaccessible hand
hygiene products, poor knowledge of hand hygiene
indications, lack of reminders in the workplace, and high
workload. A multifaceted approach to improve hand
hygiene compliance should be devised.
Conflicts of interest. R.P.B. is the head of the PGH Hospital
Infecti o n Co ntrol Un i t . H ow e v e r , ob se r v a t i o n s we r e
performed solely by A.G.M. Hence, authors report no
conflicts of interest relevant to this article.
R eferences
1. World Health Organization. WHO Guidelines on Hand Hygiene
in Health Care 2009. Geneva, Switzerland: WHO Press; 2009.
2. Berba R, Alejandria M, Rosaros J, Reside I, Ang C, Cordero C,
et al. Incidence, Risk Factors, and Outcome of Hospital-Acquired
Pneumonia in Critically-Ill Patients at the Philippine General
Hospital. Phil J Microbiol Infect Dis , 28 (2), 29-38, 1999.
3. Cardoso T, Almeida M, Carratala J, Aragao I, Costa-Pereira
A, Sarmento AE, and Azevedo L. Microbiology of heathcare-
associated infections and the definition accuracy to predict infection
by potentially drug resistant pathogens: a systematic review. BMC
Infectious Diseases, 15: 565, 2015.
4. C h u a M M , a n d A l e j a n d r i a M M . T h e e p i d e m i o l o g y o f
Acinetobacter infections among critically-ill adult patients admitted
at the University of the Philippines - Philippine General Hospital.
Phil J Microbiol Infect Dis , 37 (1), 38-53, 2008.
5. Ranola JMT, Panaligan MM, and Coronel RF. Acinetobacter
baumannii: an Emerging Nosocomial Infection Pathogen. Phil J
Microbiol Infect Dis, 39 (1), 66-70, 2010.
6. Antimicrobial Resistance Surveillance Reference Laboratory,
Research Institute of Tropical Medicine, Department of Health.
Antimicrobial Resistance Surveillance Program: 2015 Data
Summary Report. 2015. Available: http://arsp.com.ph/arsp-data-
summary-report-2015/ [2017, August 30].
7. Antimicrobial Resistance Surveillance Reference Laboratory,
Research Institute of Tropical Medicine, Department of Health.
6 Volume 55 Number 3 July - Sept., 2017
Barriers to Hand Hygiene Compliance
Antimicrobial Resistance Surveillance Program: 2016 Data
Summary Report. 2016. Available: http://arsp.com.ph/arsp-data-
summary-report-2016/ [2017, August 30].
8. Harbarth S, Sax H, and Gastmeier P. The preventable proportion
of nosocomial infections: An overview of published reports. J Hosp
Infect. 54: 258-266, 2003.
9. Weinstein RA. Chapter 131: Health Care-Associated Infections.
In Longo, DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, and
Loscalzo, J. Harrison’s Principles of Internal Medicine (18th ed.)
New York, McGraw-Hill; 2012. P 1114.
10. Rosenthal VD, Guzman S, and Safdar N. Reduction in nosocomial
infection with improved hand hygiene in intensive care units of a
tertiary care hospital in Argentina. American Journal of Infection
Control. 33:392-397, 2005.
11. Zerr DM, Allpress AL, Heath J, Bornemann R, and Bennett
E. Decreasing hospital-associated rotavirus infection: A
multidisciplinary hand hygiene campaign in a children’s hospital.
Pediatric Infectious Diseases Journal, 24:397-403, 2005.
12. Won SP, Chou HC, Hsieh WS, Chen CY, Huang SM, Tsou KI, and
Tsao PN. Handwashing program for the prevention of nosocomial
infections in a neonatal intensive care unit. Infection Control and
Hospital Epidemiology, 25:742-746, 2004.
13. Huang Y, Oie S, and Kamiya A. Comparative effectiveness of hand-
cleansing agents for removing methicillin-resistant Staphylococcus
aureus from experimentally contaminated fingertips. American
Journal of Infection Control, 22:224-227, 1994.
14. Wade JJ, Desai N, and Casewell MW. Hygienic hand disinfection
for the removal of epidemic vancomycin resistant Enterococcus
faecium and gentamicin-resistant Enterobacter cloacae. Journal of
Hospital Infection, 18:211-218, 1991.
15. Grayson ML,  Jarvie LJ,  Martin R,  Johnson PD,  Jodoin
ME,  McMullan C,  Gregory RH,  Bellis K,  Cunnington K,  Wilson
FL,  Quin D,  and Kelly AM. Significant reductions in methicillin
resistant Staphylococcus aureus bacteremia and clinical isolates
associated with multisite, hand hygiene culture change program
and subsequent successful statewide roll-out. Medical Journal of
Australia, 188:633-640, 2008.
16. Kac G, Podglajen I,  Gueneret M,  Vaupré S,  Bissery A,  and Meyer
G. Microbiological evaluation of hand hygiene procedures achieved
by healthcare workers during routine patient care: a randomized
study. Journal of Hospital Infection, 60:32-39, 2005.
17. Johnson PD,  Martin R,  Burrell LJ,  Grabsch EA,  Kirsa
SW, O’Keeffe J, Mayall BC, Edmonds D, Barr W, Bolger
C,  Naidoo H,  and Grayson ML. Efficacy of an alcohol/
chlorhexidine hand hygiene program in a hospital with high rates of
nosocomial methicillin-resistant Staphylococcus aureus (MRSA)
infection. Medical Journal of Australia, 183:509-514, 2005.
18. MacDonal A, Dinah F,  MacKenzie D,  and Wilson A. Performance
feedback of hand hygiene, using alcohol gel as the skin decontaminant,
reduces the number of inpatients newly affected by MRSA and
antibiotic costs. Journal of Hospital Infection, 56:56-63, 2004.
19. Centers for Disease Control and Prevention. Guideline for
Hand Hygiene in Health-Care Setting. Recommendations of the
Healthcare Infection Control Practices Advisory Committee and
the HICPAC/SHEA/APIC/IDSA Hand Hygiene Task Force. CDC
MMWR, 51, 2002.
 Barriers to Hand Hygiene Compliance Malundo AFG, et al.

20. Pittet D. Improving compliance with hand hygiene in hospitals.

Infection Control and Hospital Epidemiology, 21:381-386, 2000.
21. Pittet D,  Hugonnet S,  Harbarth S,  Mourouga P,  Sauvan
V,  Touveneau S, and  Perneger TV. Effectiveness of a hospital-
wide programme to improve compliance with hand hygiene. Lancet,
356:1307-1302, 2000.
22. Pittet D, and Perneger TV. Compliance with handwashing. Annals
of Internal Medicine, 131:310, 1999.
23. Harbarth S, Pittet D,  Grady L,  and Goldmann DA. Compliance
with hand hygiene practice in pediatric intensive care. Pediatric
Critical Care Medicine, 2:311-314, 2001.
24. Harbarth S,  Sudre P,  Dharan S,  Cadenas M,  and Pittet
D. Outbreak of Enterobacter cloacae related to understaffing,
overcrowding, and poor hygiene practices. Infection Control and
Hospital Epidemiology, 20:598-603, 1999.
25. Ciofi degli Atti ML,  Tozzi AE,  Ciliento G,  Pomponi M,  Rinaldi
S,  and Raponi M. Healthcare workers’ and parents’ perceptions of
measures for improving adherence to hand-hygiene. BMC Public
Health. 11:466, 2011.
26. Rosenthal VD,  McCormick RD,  Guzman S,  Villamayor C,  and
Orellano PW. Effect of education and performance feedback on
handwashing: The benefit of administrative support in Argentinean
hospitals. American Journal of Infection Control, 31:85-92, 2003.
27. Philippine General Hospital. Available: http://www.pgh.gov.ph/
en/about-us-1/ [2017, August 30]
28. World Health Organization. WHO Hand Hygiene Technical
Reference Manual 2009. Geneva, Switzerland: WHO Press; 2009
29. Pittet D, Simon A, Hugonnet S, Pessoa-Silva CL, Sauvan V,
and Perneger TV. Hand hygiene among physicians:performance,
beliefs, and perceptions. Ann Intern Med , 141(1), 1-8, 2004.
30. De Wandel D, Maes L, Labeau S, Vereecken C, and Blot S.
Behavioral determinants of hand hygiene compliance in intensive
care units. Am J Crit Care , 19 (3), 230-239, 2010.
31. Kingston L, O’Connell NH, and Dunne CP. Hand hygiene-related
clinical trials reported since 2010: a systematic review. Journal of
Hospital Infection, 92(4):309-20, 2016.

Volume 55 Number 3 July-Sept., 2017 7

Malundo AFG, et al. Barriers to Hand Hygiene Compliance

APPENDIX A.
Self-administered Survey Questionnaire

Sex: o Male o Female

Profession: o Doctor o Nurse o Student

1. Is there a hand hygiene policy in the hospital that you are aware of?
Yes No Don’t Know

2. Did you receive any lecture or training regarding proper hand hygiene?
Yes No Cannot recall

3. Do you know the WHO recommended indications for hand hygiene?

Yes No Not entirely

4. Please list down the WHO 5 moments of hand hygiene that you are aware of.
(1)_________________________________________________________________
(2)_________________________________________________________________
(3)_________________________________________________________________
(4)_________________________________________________________________
(5)_________________________________________________________________

5. In a scale of 1 to 10, rate your hand hygiene compliance based on the WHO recommendations. Encircle your answer.
Never Sometimes Always
1 2 3 4 5 6 7 8 9 10

6. Which products do you prefer to disinfect your hands? Check one.

o soap and water
o alcohol-based solution
o either soap and water, or alcohol-based solution
o other disinfectant (please specify) _________________________

7. When you DO NOT disinfect your hands when you should, what is the reason? You can check more than one.
o Too busy
o Forget
o Unsure of need
o There are more important things to do
o Out of products (soap, water, alcohol, etc.)
o Products not in convenient location
o Skin irritation
o Other reasons (please specify) _______________________________

8. Washing hands whenever recommended would mean loss of precious time.

Yes No

9. Washing hands saves lives.

Yes No

10. Do you feel bad when you are not able to wash your hands sufficiently?
Yes No Sometimes

11. Are you completely convinced of the usefulness and importance of hand hygiene?
Yes No

12. Would you perform hand hygiene more often if more sinks and alcohol dispensers are available?
Yes No Not sure

13. If the hospital could do one thing to help you practice hand hygiene, what would it be?
____________________________________________________________________________________________________________________
__________________________________

8 Volume 55 Number 3 July - Sept., 2017

Barriers to Hand Hygiene Compliance Malundo AFG, et al.

APPENDIX B
Assessment of individual cognitive factors related to hand hygiene

Variable Item #
Knowledge of hospital policy 1
Perception of knowledge of hand hygiene 3
indications
Actual knowledge of hand hygiene 4
indications
Perception of hand hygiene compliance 5
Perception of factors contributing to 7
noncompliance
Perception of being able to behave as 12
desired (self-efficacy)
Time-related attitude 8
Ethical and accountability-related attitude 9, 10
Usefulness-related attitude 11

Volume 55 Number 3 July-Sept., 2017 9

 Philippine Journal of Internal Medicine
Clinico-pathologic Profile and Clinical Outcomes of Patients
with Indolent Lymphoma at the Cancer Institute of the
Philippine General Hospital: A Seven-year Experience
Paolo R. dela Rosa, M.D.*; Charles Vincent O. Uy, M.D.*; John Anthony D. Tindoc, M.D.**; Corazon A. Ngelangel M.D.**
Abstract
Introduction: Indolent lymphoma (IL) is a slowly growing
lymphoma, generally refractory to conventional
chemotherapy. There are several types of IL, which
includes follicular lymphoma (FL), marginal zone lymphoma
(MZL), small lymphocytic lymphoma (SLL), mantle cell
lymphoma (MCL), and waldenstrom macroglobulinemia/
lymphoplasmacytic lymphoma (WM/LPL). Presently, there
are no known data in the Philippines on IL. This study is done
to determine the clinico-pathologic profile and outcomes
of Filipino patients with IL.
Methods: This study is a retrospective chart review of
outpatient department cases of IL seen at the Philippine
General Hospital-Cancer Institute from January 2009 to
January 2016. The following were documented: age; gender;
primary location; presence or absence of B symptoms; type
of IL; Ann-arbor stage; prognostic indices for FL and MCL;
and staging with bone marrow aspiration and whole body
CT scan. Treatment intervention and clinical outcomes were
documented.
Introduction
Indolent non-hodgkin’s lymphomas (NHL) were made up
of mature B cells with a long median survival and generally
poor response to conventional chemotherapy. 1 Some
reports included T-cell large granular lymphocyte leukemia. 2
Because of its chronic course and mostly asymptomatic
nature, prognosis was relatively good.3
Bone marrow involvement was common. As a result,
guidelines included bone marrow aspiration (BMA) as
an essential or useful component in diagnosing and
staging indolent lymphoma (IL). Presently, there is no
established treatment of choice for IL. Most guidelines
recommends observation for asymptomatic patients.
Treatment may be given once the patient becomes
symptomatic. The goal for treatment was to maintain the
*Section of Medical Oncology, Department of Medicine, University of the
Philippines-Philippine General Hospital
**Department of Pathology and Laboratories, University of the Philippines-
Philippine General Hospital
Corresponding author: Paolo R. dela Rosa, M.D., University of the
Philippines – Philippine General Hospital, Manila, Philippines
Email: paolo98ph@gmail.com
The PHILIPPINE JOURNAL OF INTERNAL MEDICINE is a peer reviewed journal and a copyrighted publication of the Philippine College of Physicians
Original Article
Results: This study showed that SLL was the most common IL.
Most were elderly (>40 years old); male; lacked B symptoms;
limited disease; and primary location at or near the orbital
area. MCL were seen in all risk groups. Follicular lymphoma
(FL) were mostly low risk and had grade one histology.
Majority had disease control regardless of treatment
intervention. Most patients with recurrence/progression after
initial treatment had limited disease but were understaged.
Most of the patients were not staged with bone marrow
aspiration or whole body computed tomography.
Conclusion: The results of this study are mostly consistent with
known literature on IL. Absence of B symptoms and limited
disease may indicate a low-grade histology. Observation
was the most common option for asymptomatic patients.
Keywords: indolent, lymphoma, Philippines
best quality of life. Alteration of this approach needed
evidence of survival benefit with early therapy. Options for
management depended on whether the lymphoma was
advanced or localized. Generally, management options
included the “watch and wait approach”, radiotherapy,
chemoimmunotherapy, autologous/allogenic stem cell
transplantation, radioimmunotherapy and monotherapy
with monoclonal antibodies.4­
Several classification schemes had been developed
for NHL. The initial classification scheme by the International
Panel Working Formulation of the National Cancer Institute
included three morphologically different groups. Eventually,
various molecular and immunohistochemistry tests were
discovered, which further improved the classification of
NHL. The present staging for NHL was an amalgamation of
these advances in technology - the 2008 REAL/WHO 2008
Classification. In the present classification scheme, IL was
not considered a unique group; it was divided based on its
morphology, phenotype, genotype and clinical findings.5
Histologically, IL was made up of small to medium-sized cell,
however further characterization with immunohistochemistry
and/or chromosomal analysis was required.3
Volume 55 Number 3 July-Sept., 2017 1
 Dela Rosa PR, et al.
Among IL, follicular lymphoma (FL) was the most
common subtype and the second most common NHL after
diffuse large B cell lymphoma (DLBCL) in America and
Europe.5 FL was composed of malignant germinal center-
derived B-cells that exhibited follicular growth pattern.
The genetic hallmark was t(14;18), which led to ectopic
expression of the Bcl2, an anti-apoptotic protein. 6 WHO
divided FL into three grades based on the presence of
centroblasts and/or centrocytes. Grade one and two were
managed similarly while grade three was managed like
DLBCL. 7,8 The immunophenotype of FL was usually positive
for pan-B cell markers (CD20), specific germinal center B-cell
markers (Bcl6 and CD10) and Bcl2. Occasional cases may
be negative for CD10 or Bcl2. There were conflicting reports
on the prognostic significance of Bcl2.9
Small lymphocytic lymphoma (SLL) consisted of
abnormal lymphocytes found primarily in the lymph nodes
and bone marrow. Typical immunophenotype included
CD23 positive, CD5 positive, and cyclin D1 negative tumor.
A diagnosis of SLL should only be made when effacement of
lymph node architecture was seen. Additional diagnostics
included determination of the certain deletions (del13q,
del11q, del17p) that were important prognostic and/or
predictive factors. In contrast, chronic lymphocytic leukemia
(CLL) consisted of abnormal lymphocytes in the bone
marrow and blood.5
Mantle cell lymphoma (MCL) had the characteristics of
an indolent disease and an aggressive lymphoma. Similar
to an indolent disease, it generally didn’t respond well to
conventional chemotherapy. It was associated with t(11;14).
Most MCL were positive for the cyclin D1 protein, however
some cases were negative for cyclin D1. Clinically, there
was no difference between a cyclin D1-positive and a
cyclin D1-negative MCL. 10 However, cyclin D1 status was
an independent factor for survival.11 Since this lymphoma
could occur in the gastro-intestinal (GI) tract, EGD and
colonoscopy should be done to confirm Ann-arbor stage.8
Marginal zone lymphoma (MZL) based on the REAL/
WHO 2008 classification was divided into nodal, extranodal
and splenic subtypes. The marginal zone corresponded
to the outer part of secondary follicles. It was well formed
in the spleen, intra-abdominal lymph nodes and musoca-
associated lymphoid tissue (MALT). The most common
location of extranodal MZL was the stomach, associated with
t(11;18). The presence of this translocation was predictive of
poor response to anti-Helicobacter pylori regimen. MZL was
strongly positive for IgM, IgG or IgA.5
Waldenstrom’s macroglobulinemia(WM) was nor-
mally characterized by bone marrow infiltration of
lymphoplasmacytic cells and IgM monoclonal gammopathy
in the serum. It was both a pathologic and a clinical
diagnosis. Lymphoplasmacytic differentiation was not
2 Volume 55 Number 3 July - Sept., 2017
Clinico-pathologic Profile and Clinical Outcomes
pathognomonic for WM, because it could also be seen
in splenic MZL. Clinically, it may present with symptoms of
hyperviscosity. Morphologically, intranuclear (Dutcher
bodies) and intracytoplasmic (Russell bodies) inclusions were
usually noted.12
Presently, there were no known local studies on IL. For
this reason, the purpose of this study was to determine the
baseline clinical and pathologic characteristics of patients
with IL seen at the Philippine General Hospital-Cancer
Institute (PGH-CI). Obtaining real-world data in the Philippines
was important because it could be used to plan future
health-care services and monitor the impact of therapeutic
changes.13
M ethods
A retrospective review of the out-patient department
(OPD) charts of patients with IL seen at the PGH-CI was done.
It only included patients diagnosed with B-cell Non-Hodgkin’s
lymphoma. This included FL, MCL, MZL (gastric MALtoma,
non-gastric MALtoma,nodal,splenic), SLL and WM/LPL. The
presence of lymphoplasmacytic differentiation on bone
marrow and serum IgM monoclonal gammopathy was
used to diagnose WM. On the other hand, this study did not
include patients at the charity ward, pay ward or intensive
care unit. It also did not include patients diagnosed purely
with leukemia.
This study included patients diagnosed as IL
morphologically and confirmed through immunohistochemistry
seen at the PGH-CI from January 2009 to January 2016.
Data was collected using an encoded data collection
form. Histopathologic records of cases of IL were retrieved
and reviewed from the PGH Department of Laboratories.
The following data were documented from review of hospital
charts as part of the clinical and pathologic profile:
• Age
• Gender
• Presence or absence of B symptoms
• Primary site of lymphoma
• Staging with BMA or whole body CT scan
• Type of IL
• Ann-arbor stage
• Prognostic indices (MIPI for MCL and FLIPI for FL)
• Grading for FL (grade one, two, or three)
The type of treatment intervention was also documented,
which included surgery, radiotherapy, chemotherapy with
or without immunotherapy, or combined modality therapy.
Patients who did not follow-up after the planned treatment
intervention were also documented. For the patients who
underwent chemotherapy with or without immunotherapy,
the type of regimen, number of cycles, and clinical
 Clinico-pathologic Profile and Clinical Outcomes Dela Rosa PR, et al.

outcomes (complete response, partial response, stable Table I. Frequency of indolent lymphoma based on age
disease, progression, recurrence) after treatment were
documented. For the patients who underwent radiotherapy, Age Range Mantle Marginal Small Follicular Total
they were stratified into three different dose range based on Frequency Cell Zone Lymphocytic
the most commonly used radiotherapy dose for IL - <24 Gy, (%)
24-30 Gy, and >30 Gy. Clinical outcomes after radiotherapy 20-29 0 0 1 0 1
were documented. For those who underwent surgery, (0) (0) (8.3) (0) (3.1)
outcomes were classified as complete or partial resection. 30-39 0 1 2 1 4
After the surgery, the patients were followed-up and were (0) (10) (16.7) (14.3) (12.5)
noted if it the disease progressed, recurred, or remained 40-49 1 3 3 1 8
stable. The month when the clinical outcome occurred (33.3) (30) (25) (14.3) (25)
was documented. For the patients who did not receive
50-59 0 3 3 3 9
any intervention, the disease was observed if it progressed,
(0) (30) (25) (42.8) (28.1)
recurred or remained stable. The month when the clinical
outcome occurred was documented. For the patients who 60-69 1 3 3 0 7
underwent combined modality therapy, they were classified (33.3) (30) (25) (0) (21.9)
if they received surgery then chemotherapy; chemotherapy ≥70 1 0 0 2 3
then surgery; or chemotherapy then radiotherapy. Clinical (33.3) (0) (0) (28.6) (9.4)
outcomes and the month when this occurred were Total 3 10 12 7 32
documented. (100) (100) (100) (100) (100)

Table II. Frequency of indolent lymphoma based on gender

Descriptive statistics was used to summarize the clinical
profile, pathologic profile, and treatment outcomes. Gender Mantle Marginal Small Follicular Total
Definition of the clinical outcomes was based on the original Frequency Cell Zone Lymphocytic
International Working Group criteria5 for response assessment (%)
for NHL.
Male 1 6 8 3 18
(33.3) (60) (66.7) (42.9) (56.3)
The protocol was submitted for review to the Technical
Female 2 4 4 4 14
Review Board (TRB). After it was approved by the TRB, it was
(66.7) (40) (33.3) (57.1) (43.7)
passed to the University of the Philippines Manila Research
and Ethics Board (UPMREB). The study was conducted with Total 3 10 12 7 32
the approval of the UPMREB. Since this was a retrospective (100) (100) (100) (100) (100)
review, there was no direct contact between the investigator Table III. Frequency of indolent lymphoma based on B symptoms
and the patient. Confidentiality was ensured by assigning
a patient a code number associated with his/her case B Symptoms Mantle Marginal Small Follicular Total
number to preserve anonymity. The study was funded by Frequency Cell Zone Lymphocytic
the investigators. There were no conflicts of interest. (%)
Present 2 0 4 3 9
(66.7) (0) (33.3) (42.9) (28.1)
R esults Absent 1 10 8 4 23
(33.3) (100) (66.7) (57.1) (71.9)
A total of 32 patients were included in this study. Of
the 32 patients, three had MCL; ten had MZL; 12 had SLL; Total 3 10 12 7 32
and seven had FL. No patient with WM/LPL was included in (100) (100 (100) (100) (100)
the study. There were two cases of thyroid lymphoma both cervical and inguinal area (Table IV). Most were not staged
with a MZL subtype. There were five cases of GI lymphoma with BMA, except for some patients with SLL (Table V). CT
(three MZL and two SLL). Treatment interventions were any scan of the primary site was done for all patients but most
of the following: chemotherapy, surgery, combined modality were staged with chest xray and/or with holoabdominal
therapy or no active intervention. ultrasound only. (Table VI). Majority had limited stage except
for MCL (Table VII).
More than eighty percent (>80%) of patients with IL
were above 40 years old (Table I). The eldest patient was There were three patients with MCL. One had low,
74 years old, diagnosed with FL; the youngest 27 years old, intermediate, and high risk MIPI. Most patients with FL had low
diagnosed with SLL. Majority were male with predominantly or intermediate risk FLIPI and grade one histology (Table
SLL and MZL histology (Table II). Most presented with B VIII).
symptoms (Table III). Most were located in the orbital,

Volume 55 Number 3 July-Sept., 2017 3

Dela Rosa PR, et al. Clinico-pathologic Profile and Clinical Outcomes

Table IV. Frequency of indolent lymphoma based on location Table VI. Frequency of indolent lymphoma based on staging
with CT scan
Primary Mantle Marginal Small Follicular Total
Location Cell Zone Lymphocytic Whole Body Mantle Marginal Small Follicular Total
Frequency CT Scan Cell Zone Lymphocytic
(%) Frequency
Eye/Orbit/ 1 5 1 0 7 (%)
Conjunctivae (33.3) (50) (8.3) (0) (21.9) Yes 2 1 5 2 10
Tonsillar 0 0 0 1 1 (66.7) (10) (41.7) (28.6) (31.2)
(0) (0) (0) (14.3) (3.1) No 1 9 7 5 22
Sub- 2 0 0 0 2 (33.3) (90) (58.3) (71.4) (68.8)
mandibular (66.7) (0) (0) (0) (6.3) Total 3 10 12 7 32
Maxillary 0 0 1 0 1 (100) (100) (100) (100) (100)
(0) (0) (8.3) (0) (3.1)
Cervical 0 0 4 2 6 Table VII. Frequency of indolent lymphoma based on Ann-
(0) (0) (33.4) (28.6) (18.8) arbor stage

Thyroid 0 2 0 0 2 Ann-arbor Mantle Marginal Small Follicular Total

(0) (20) (0) (0) (6.3) Stage Cell Zone Lymphocytic
Axillary 0 0 2 0 2 Frequency
(0) (0) (16.8) (0) (6.3) (%)
Gastric 0 1 0 0 1 Limited I 0 9 6 2 17
(0) (10) (0) (0) (3.1) (0) (90) (50) (28.6) (53.1)
Pancreas 0 0 0 1 1 II 1 1 2 2 6
(0) (0) (0) (14.3) (3.1) (33.3) (10) (16.7) (28.6) (18.8)
Colon 0 2 1 0 3 Advanced III 2 0 3 2 7
(0) (20) (8.3) (0) (9.4) (66.7) (0) (25) (28.6) (21.9)
Ileocecal 0 0 1 0 1 IV 0 0 1 1 2
(0) (0) (8.3) (0) (3.1) (0) (0) (8.3) (14.2) (6.2)
Abdominal 0 0 1 0 1
Total 3 10 12 7 32
area (0) (0) (8.3) (0) (3.1)
(100) (100) (100) (100) (100)
Inguinal 0 0 1 3 4
(0) (0) (8.3) (42.8) (12.4)
Table VIII. Frequency of follicular lymphoma based on flipi
Total 3 10 12 7 32 and grade
(100) (100) (100) (100) (100)
Pathologic Characteristic Category Frequency
(%)
Table V. Frequency of indolent lymphoma based on staging
with BMA Follicular Lymphoma Low risk 3
International Prognostic (42.9)
BMA Done Mantle Marginal Small Follicular Total Index (FLIPI) Intermediate risk 3
Frequency Cell Zone Lymphocytic
(42.9)
(%)
High risk 1
Yes 0 0 3 0 3
(14.2)
(0) (0) (25) (0) (9.4)
No 3 10 9 7 29 Grade one 3
(100) (100) (75) (100) (90.6) (42.8)

Total 3 10 12 7 32 Grade two 2

(100) (100) (100) (100) (100) (28.6)
Grade three 2
(28.6)
FLIPI 0-1: Low risk FLIPI 2: Intermediate risk FLIPI 3-4: High risk

4 Volume 55 Number 3 July - Sept., 2017

Clinico-pathologic Profile and Clinical Outcomes Dela Rosa PR, et al.

Table IX. Outcomes of indolent lymphoma after chemotherapy Chemotherapy with or without targeted therapy was the
± targeted therapy most common management. Most of the patients had partial
response to chemotherapy. Regimens used were CHOP or
Chemotherapy ± Mantle Marginal Small Follicular Total R-CHOP (four to eight cycles). All patients who completed
Targeted Therapy Cell Zone Lymphocytic chemotherapy had disease control, although a substantial
Frequency number did not follow up (Table IX).
(%)
Complete 0 1 1 0 2 Some patients did not receive any active intervention.
Response (0) CHOPx6 CHOPx6
(0) CHOPx6 These patients were observed clinically and through imaging.
(50) (16.7) (15.3) Majority were lost to follow-up. For patients who followed up,
Partial 2 1 2 1 6 two had stable disease and one progressed 24 months after
Response CHOPx8 CHOPx6 CHOPx6
CHOPx5
CHOPx4, initial diagnosis (Table X). On the other hand, most patients
R-CHOPx8 CHOPx4 CHOPx5,
(50) (33.3) CHOPx6, who had surgery had complete resection, especially for GI
(100) (33.3) CHOPx8,
R-CHOPx8 lymphoma. For those who followed up after resection, half
(46.2) had disease control (Table XI).
Stable Disease 0 0 1 0 1
(0) (0) CHOPx6
(0) CHOPx6 Half of the patients who had combined modality therapy
(16.7) (7.7) (chemotherapy and radiotherapy) were diagnosed with FL
Progression 0 0 0 0 0 had complete response (Table XII).
(0) (0) (0) (0) (0)
Did not follow- 0 0 2 2 4 D iscussion
up (0) (0) (33.3) (66.7) (30.8)
Total 2 2 6 3 13 Clinical Profile
(100) (100) (100) (100) (100)
Indolent lymphoma (IL) belonged to a heterogenous
Table X. Outcomes of indolent lymphoma with no active
group of low-grade B cell Non-hodgkin’s lymphoma.1 This
intervention
study showed that the most common IL in the PGH-CI
Observation Mantle Marginal Small Follicular Total was SLL followed by MZL, FL, and MCL. SLL and CLL were
Cell Zone Lymphocytic manifestations of the same disease but the former should
have a tissue diagnosis. The frequency of SLL may be
Stable 1 0 0 1 2
(100) (0) (0) (50) (25) underestimated in this study because CLL, the leukemic
8 mos. 24 mos. 8 mos. variant, was not included. Compared to other countries, FL
24 mos. was the most common histology.14
Progression 0 1 0 0 1
(0) (50) (0) (0) (12.5) In this study, majority of MZL were non-gastric, mostly in
24 mos. 24 mos.
the eyelid. There was one case of gastric MZL. Gastric MZL
Did not 0 1 3 1 5 should ideally be tested for t(11;18) and Helicobacter pylori.
follow-up (0) (50) (100) (50) (62.5)
These tests were not done. After one consult, the patient was
Total 1 2 3 2 8 lost to follow-up. Hepatitis C should ideally be tested for all
(100) (100) (100) (100) (100) patients with MZL, also not done.8

Table XI. Outcomes of indolent lymphoma based on resection status

Surgery Marginal Zone Lymphoma (Total number=5) Small Lymphocytic Lymphoma (Total number=2) Total (n=7)
Recurrence Progression Stable Did not Recurrence Progression Stable Did not Recurrence = R
Disease follow-up Disease follow-up Progression = P
Stable Disease = SD
Did not ff-up = DNF
Complete 1 (7 mos) 0 1 (2 mos) 2 0 0 0 1 MZL, R=1 (7 mos)
Resection MZL, SD=1 (2 mos)
DNF=3
Partial 0 0 1 (6 mos) 0 0 1 (9 mos) 0 0 MZL, SD=1 (6 mos)
Resection SLL, P=1 (9 mos)
Total 1 0 2 2 0 1 0 1 R=1 (7 mos)
SD=2 (2 mos, 9 mos)
P=1 (9 mos)
DNF=3

Volume 55 Number 3 July-Sept., 2017 5

 Dela Rosa PR, et al.
Table XII. Outcomes of indolent lymphoma after combined modality therapy
Combined Modality Marginal Zone Lymphoma
Surgery  chemotherapy 1 0
(Partial response after chemotherapy)
Chemotherapy  surgery 0 1
Chemotherapy  RT 0 0
(R-CHOPx8 then LINAC 30Gy
R-CHOPx3 then LINAC 30.6 Gy)
Only a handful of cases were included in this study.
Possible reasons may be due to misdiagnosis or poor
health seeking behavior. Misdiagnosis may be due to poor
specimen handling; poor tissue processing; and lack of a
more comprehensive training in hematopathology.14 Possible
reasons for poor health seeking behavior especially for
developing countries included low educational attainment;
lower priority on health policies by the government; and
certain Filipino traits such as procrastination.15,16
Diffuse large B cell lymphoma (DLBL) was the most
common NHL in adults. It could also co-exist with IL. DLBCL
could also arise from IL in a process called histologic
transformation. Histologic transformation could be monitored
by checking for presence of rapidly growing masses,
extranodal disease, new-onset B symptoms, hypercalcemia,
and elevated LDH.5 Patients with mixed IL and DLBCL should
be managed aggressively with chemotherapy.8 One case
with FL in histologic transformation received chemotherapy.
Indolent lymphoma (IL) was mostly seen in elderly
males, as shown in this study. In developed countries, most
IL occurred in the elderly, usually those in their 60’s or 70’s.14
The predominance of male diagnosed with lymphoma
may be due to less access to medical care for women in
developing countries.14 Indolent lymphoma (IL) was usually
asymptomatic, in contrast to DLBCL.17 This may suggest that
patients with B symptoms have a more aggressive histology.
The most common location of the mass in the study was
at or near the orbital area. Most orbital mass in the study
were MZL similar to a study done in Germany. 18 A study
done in the United States several decades before showed
most presented with lymphadenopathy and fever. 20 The
difference observed may be due to change in the disease
landscape over the years.
Most IL in this study had Ann-arbor stage I and II. A study
in Pakistan of extranodal DLBCL mostly presented with
advanced stage. 17 Most IL with a limited stage may be due
to a slow glowing biology. In contrast to other IL, MCL could
be indolent or aggressive. A study in Europe showed that
majority of patients with MCL had advanced stage.20 This
may be due to a more aggressive bone marrow invasion.
6 Volume 55 Number 3 July - Sept., 2017
Clinico-pathologic Profile and Clinical Outcomes
Small Lymphocytic Lymphoma Follicular Lymphoma
0
0
(Partial response after chemotherapy)
2
(Complete response after RT)
Staging for IL included BMA and whole body CT scan
recommended as standard of care.8 Most of the cases in this
study were understaged. Staging would affect treatment
and prognosis, hence it should be always be accurate. The
authors hypothesized that understaging may be due to lack
of knowledge on the need for BMA for accurate staging;
lack of skilled doctors to perform BMA; and lack of money
by the patient for BMA (including immunophenotyping) and
whole body CT scan. However, these were only assumptions
and would need further validation.
In 2014, PET-CT scan was included in staging and
response assessment of NHL referred to as Lugano criteria.8
PET scan was based on the idea that metabolically active
cells take up the labeled glucose (FDG) to be used for
its various cellular processes. 5 Cells who took the labeled
glucose were then detected. However, the Lugano criteria
was limited only to cells with active FDG uptake or aggressive
lymphomas. In addition, this criteria was only validated for
DLBCL and Hodgkin’s lymphoma 8 The original International
Working Group criteria (IWG 1999) could be used for IL
which used CT scan only. 8 In addition, PET-CT scan was not
typically done on patients of PGH diagnosed with IL during
the study period due to economic constraints. In this study,
one case of FL grade three was staged with whole body
PET/CT scan. Studies showed that FL grade three behaved
similarly to aggressive lymphomas. 5,8 Guidelines indicated
that FL grade three­should be treated similarly to DLBCL.
Pathologic Profile
Prognostic indices were developed to guide patient
counseling and treatment decisions. 5 Several prognostic
indices were validated for NHL. The International Prognostic
Index (IPI) was used for DLBCL consisting of age, stage,
performance status, extranodal involvement and LDH.
For IL, FL Internal Prognostic Index (FLIPI) and Mantle cell
International Prognostic Index (MIPI) were used.
MIPI consisted of age, performance status, LDH and WBC.
It was divided into three risk groups - low risk (44% patients,
median overall survival (OS) not reached); intermediate risk
(35% of patients, median OS at 51 months); and high risk (21%
patients, median OS at 29 months).20 A study done in Europe
showed that majority of patients with MCL had intermediate
 Clinico-pathologic Profile and Clinical Outcomes
or high risk. In contrast, this study showed all of the three MCL
were equally distributed in the three risk groups.
Follicular Lymphoma Internal Prognostic Index (FLIPI)
consisted of age, Ann-arbor stage, hemoglobin level, LDH,
and number of nodal sites. It was divided into three risk groups
- low risk (five and ten-year OS of 91% and 71%, respectively);
intermediate risk (five and ten-year OS of 78% and 51%,
respectively); and high risk (five and ten-year OS of 53% and
36%, respectively). 21,22 In this study, majority of the cases were
low or intermediate risk.
The clinical aggressiveness of a FL was correlated with
the number of centroblasts. 5 The number of centroblasts
formed the basis of classifying FL into three major grades –
grade one (less than six centroblasts/hpf), grade two ( six -15
centroblasts/hpf), and grade three ( >15 centroblasts/hpf).
In this study, majority of the FL had grade one histology.
Both the FLIPI and grade may predict risk of histologic
transformation. FL with high risk FLIPI and grade were at
greater risk of histologic transformation.5,8,22 In this study, one
case documented in the process of histologic transformation
had a high risk FLIPI and grade three histology.
Treatment Outcomes Profile
In this study, those who had chemotherapy were treated
with CHOP or R-CHOP. A study showed that bendamustine
plus rituximab had higher PFS and fewer adverse events than
R-CHOP.23 In the Philippines, due to financial constraints, most
with NHL were treated with CHOP with or without rituximab,
because it was relatively cheaper; it could also be covered
by the national health insurance program of the Philippines
– the Philhealth.
In this study, those who had surgery were mostly GI and
thyroid MZL consistent with the standard of care. The present
guidelines for extranodal MZL recommended surgery for
resectable masses located in the thyroid, colon, small bowel,
lung and breast.7
In this study, those who had no active intervention
generally had disease control lasting up to two years. Indolent
lymhoma (IL) had a slow growing biology and generally
incurable with conventional chemotherapy.2,5,8 Weighing the
risk of possible adverse event or complications, observations
could be the more prudent choice if asymptomatic.
In this study, those who had combined modality therapy
were mostly FL. Post-chemotherapy radiation was given
if with residual disease as in this case, consistent with the
standard of care.8,23
Most of the patients in this study did not follow-up which
may affect the results.
Dela Rosa PR, et al.
Lymphoma by Location
Thyroid Lymphoma
In this study, both cases of thyroid lymphoma were
MZL. One was male in his fourth decade, pre-operative
biochemically euthyroid; the other was female in her fifth
decade, pre-operative hypothyroid on levothyroxine, with
a history of Hashimoto’s thyroiditis.
Thyroid lymphoma was a rare malignancy of the thyroid
gland usually comprising one to five percent and one
to seven percent of all thyroid cancers and lymphomas,
respectively. It could be seen in elderly (>60 years old)
females primarily presenting with an anterior neck mass.
Histology was primarily MZL and DLBCL. Clinical features
that would favor thyroid lymphoma would be a history
of Hashimoto’s thyroiditis, tumor size less than seven
cm, obstructive symptoms and a rapid growth of a firm,
diffuse thyroid mass. A retrospective study done in Filipino
patients showed that thyroid lymphomas occurred at a
lower mean age (<60 years old) with more presenting with
a MZL histology. In this study, both cases did not present
with symptoms of obstruction but one had a histologically
confirmed Hashimoto’s thyroiditis.24 Both cases with thyroid
lymphoma underwent surgery, consistent with the standard
of care.
Gastro-intestinal (GI) Lymphoma
The most common location of extranodal NHL was the
GI tract, usually in the stomach. Although the most common
histology for GI lymphoma was DLBCL, MZL and FL were also
observed.25 In this study, majority of the cases were located
in the colon, limited stage, with MZL or SLL histology. Primary
colorectal lymphoma was a rare disease with most cases
usually presenting as an extension of a more wide spread
disease.
In this study, most cases presented with abdominal pain
as the chief complaint, consistent with the reported literature.
Other symptoms, reported in some studies included weight
loss, and GI bleeding. Obstruction and perforation, both rare
in GI lymphoma, were not observed for the cases included
in this study.5,25
Management of GI lymphoma (indolent and aggressive)
depended on the histology of the malignancy. Low-grade
lymphomas could be managed several ways depending
on the location, presence of symptoms, and presence of
co-morbidities.7 For non-gastric MALToma, radiotherapy was
the preferred diagnostic modality provided that the patient
had good performance status.
However, guidelines also recommended surgery as an
alternative to radiotherapy for MZL located in the lung, breast,
Volume 55 Number 3 July-Sept., 2017 7
 Dela Rosa PR, et al.
thyroid, colon, and small bowel. In this study, most cases had
surgery usually hemicolectomy, as treatment intervention.
Other options were targeted therapy or observation.26
C onclusion
Small lymphocytic lymphoma (SLL) was the predominant
type of IL at the PGH-CI. Most cases seen were elderly, usually
aged 40 years old and above, except for FL mostly seen
for those aged 50 years old and above. Low sample size
was attributed to various factors such as the inherent rarity
of IL; certain Filipino traits and values; relatively imperfect
procedure in specimen handling; and relatively lack of
expertise in hematopathology.
Indolent lymphoma (IL) was more common in males,
especially for MZL and SLL. It also showed that most had
B symptoms and limited disease, in contrast to aggressive
lymphomas such as DLBCL. It demonstrated that majority
presented with an orbital mass, mostly with MZL histology. FL
had mostly low-risk FLIPI and low grade histology.
Indolent lymphoma (IL) which received chemotherapy
had disease control with at least four cycles of CHOP.
Those who had surgery had a MZL histology; about half had
disease control for up to nine months only. Those who did
not undergo any active intervention had disease control for
up to two years. Due to the long duration of disease control,
observation as intervention for asymptomatic patients with
IL remained a viable option.
The clinico-pathologic profile presented in the study
may be limited by the fact that certain work-ups such BMA
and whole body CT scan recommended as standard of care
were not always done.
Recommendations
The authors recommend biopsy of solid tissues even
in patients confirmed to have CLL in order to document
SLL. They recommend further study of factors influencing
understaging as this will affect prognosis and treatment.
Glossary
1. Indolent Lymphoma – malignancies of predominantly
small lymphocytes with monoclonal proliferation of
mature B-cells expressing surface immunoglobulin in
a light- and heavy-chain restricted manner with low
proliferative rate explaining its long median survival
and general incurability of disease with conventional
chemotherapy. It consists of FL, MCL, MZL, SLL and WM/
LPL (Grogan, 1996).
2. Limited-stage IL – includes stage I and II lymphoma.
3. Advanced-stage IL – includes stage III and IV lymphoma.
8 Volume 55 Number 3 July - Sept., 2017
Clinico-pathologic Profile and Clinical Outcomes
4. Disease outcomes – includes any of the following:
complete response, stable disease, partial response,
progressive disease or recurrence.
5. Complete response (CR) – complete disappearance
of detectable disease; nodes >1.5 cm before therapy
regress to <1.5cm; nodes 1.1 to 1.5 cm in long axis and
>1.0 cm in short axis shrink to ≤1.0 cm in short axis.
6. Partial response (PR) - greater than 50% decrease in in
the sum of the diameters in up to six nodal masses or in
hepatic or splenic nodules.
7. Stable disease (SD) – neither PR nor relapse/progression
8. Relapse or Progression - new or increase in size of mass
or lymph node
9. Disease control – CR, PR and SD
R eferences
1. Grogan T. New classification of low-grade lymphoma. Annals of On-
cology. 1996; 7(suppl 6):S3-S12. doi:10.1093/annonc/7.suppl_6.S3
2. Pileri SA, Zinzani PL, Went P, Pilera A Jr, Bendandi M. Indolent
lymphoma: the pathologist’s viewpoint. Annals of Oncology. 2004;
15(1):12-15.
3. Sakata S, Tsuyama N, Takeuchi K. Pathology of Indolent B-cell
Neoplasms Other than Follicular Lymphoma. Journal of Clinical and
Experimental Hematopathology. 2014; 54(1): 11-12.
4. Gribben JG. How I treat indolent lymphoma. Blood. 2007; 109(11):
4617-25. doi: 10.1182/blood-2006-10-041863
5. DeVita VT, Lawrence TS, Rosenberg SA. Cancer: Principles and
Practice of Oncology. 10th ed. Philadelphia: Wolters Kluwer Health
6. Li Y, Hu S, Zuo Z, et. al. CD5-positive follicular lymphoma: clinico-
pathologic correlations and outcome in 88 cases. Modern Pathology.
2015; 28(6):787-98. doi: 10.1038/modpathol.2015.42.
7. Casulo C, Day B, Dawson KL, Zhou X, et. al. Disease character-
istics, treatment patterns and outcomes of follicular lymphoma in
patients 40 years of age and younger: an analysis from the National
Lymphocare Study . Annals of Oncology. 2015; 26(11):2311-7. doi:
10.1093/annonc/mdv375.
8. Non-Hodgkin’s Lymphoma. [Electronic version]. NCCN Guidelines
version 2.2015. Retrieved April 10, 2016, from https://www.nccn.
org/professionals/physician_gls/f_guidelines.asp/
9. Pezzella F, Jones M, Ralfkiaer E, Ersboll J, Gatter KC, Mason
DY. Evaluation of Bcl-2 protein expression and 14;18 translocation
as prognostic markers in follicular lymphoma. British Journal of
Cancer. 1992; 65(1): 87-89.
10. Fu K, Weisenburger DD, Greiner TC, et. al. Cyclin D1-negative
mantle cell lymphoma: a clinicopathologic study based on gene
expression profilling. Blood. 2005; 106(13):2311-7. doi: 10.1182/
blood-2005-04-1753.
11. Yatabe Y, Suzuki R, Tobinai K, et. al. Significance of cyclin D1
overexpression for the diagnosis of mantle cell lymphoma: a
clinicopathologic comparsion of cyclin D1-positive MCL and cyclin
D1-negative MCL-like B-cell lymphoma. Blood. 2000; 95(7):2253-
61. doi: dx.doi.org.
12. Vijay A, Gertz M. Waldenstrom macroglobulinemia. Blood. 2007;
109(12): doi:10.1182/blood-2006-11-055012.
Clinico-pathologic Profile and Clinical Outcomes Dela Rosa PR, et al.

13. Smith A, Crouch S, Lax S, et. al. Lymphoma incidence, survival and
prevalence 2004-2014: sub-type analysis from the UK’s Haemato-
logical Malignancy Research Network. British Journal of Cancer.
2015; 112(9): 1575–1584. doi:  10.1038/bjc.2015.94
14. Perry A, Diebold J, Nathwani BH, et. al. Non-Hodgkin lymphoma
in the developing world: a review cases from the International Non-
Hodgkin Lymphoma Classification Project. Journal of the European
Hematology Association. 2016; __ (__): 1-37. doi:10.3324/haema-
tol.2016.148809.
15. Dy M. Values in Philippine Culture and Education. Washington: The
Council of Research.
16. Dupas P. Health Behavior in Developing Countries. [Electronic ver-
sion]. Annual Review of Economics. 2011;3:2-29, from http://web.
stanford.edu/~pdupas/AR_health_behavior.pdf/
17. Lal A, Bhurgri Y, Vaziri I, et. al. Extranodal Non-Hodgkin’s Lym-
phomas-A Retrospective Review of Clinico-Pathologic Features and
Outcomes in Comparison with Nodal Non-Hodgkin’s Lymphomas.
Asian Pacific Journal Cancer Prev. 2008; 9(3): 453-458.
18. Schack I, Grossniklaus HE, Hartmann S. Lymphoma of Ocular and
Periocular Tissues - Clinico-pathological Correlation. Klin Monbl
Augenheilkd. 2016; 233(7): 824-846. doi: 10.1055/s-0042-110574
19. Gall EA, Mallory TB. Malignant Lymphoma. [Electronic ver-
sion]. American Journal of Pathology. 1941; 18: 381-429 from
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2032954/pdf/amj-
pathol00685-0020.pdf/
20. Hoster E, Dreyling M, Klapper W, et. al. A new prognostic index
(MIPI) for patients with advanced-stage mantle cell. Blood. 2008;
111(12): 558-565. doi:10.1182/blood-2007-06-095331
21. Gine E, Montoto S. Bosch F, et. al. (2006). The Follicular Lympho-
ma International Prognostic Index (FLIPI) and the histological sub-
type are the most. Annals of Oncology. 2006; 17(10): 1539-1545.
22. Olteanu H, Fenske TS, Harrington AM, Szabo A, He P, Kroft
SH. CD23 Expression in Follicular Lymphoma Clinicopathologic
Correlations. Hematopathology. 2011; 135(1):46-53. doi: 10.1309/
AJCP27YWLIQRAJPW.
23. Rummel MJ, Niederle N, Maschmeyer G, et. al. Bendamustine plus
rituximab versus CHOP plus rituximab as first-line treatment for
patients with indolent and mantle-cell lymphomas: an open-label,
multicentre, randomised, phase 3 non-inferiority trial. Lancet. 2013;
381(9873):1203-10. doi: 10.1016/S0140-6736(12)61763-2.
24. Musngi-Paras C, Salpin A, Veloso J. Primary Thyroid Lymphoma.
Philippine Journal of Otorhynolaryngology-Head and Neck Surgery.
2012; 27(1): 38-40.
25. Ghimire P, Wu GY, Wu L. Primary gastrointestinal lymphoma.
World J Gastroenterology. 2011; 17(6): 697-707. doi:  10.3748/wjg.
v17.i6.697.

Volume 55 Number 3 July-Sept., 2017 9

 Philippine Journal of Internal Medicine
Blood Eosinophilia as Predictor for Patient Outcomes in Chronic
Obstructive Pulmonary Disease (COPD) Exacerbations
Ralph Elvi M. Villalobos, M.D.*; Aileen D. Wang, M.D.*
Abstract
Introduction: The eosinophilic phenotype of chronic ob-
structive pulmonary disease (COPD) has been demonstrated
to respond better to corticosteroids and associated with
better outcomes. This review aims to clarify the correlation
of blood eosinophilia and outcomes patients with COPD
exacerbations.
Methods: This is a review of cohorts and case-control
studies that looked into eosinophilia and outcomes in
exacerbations using the meta-analysis of observational
studies in epidemiology (MOOSE) guidelines. The primary
study outcome was length of hospitalization; other outcomes
include readmission and mortality rate within one year,
in-patient mortality, and need for mechanical ventilation.
Results: Six studies were included in the review. Patients with
blood eosinophilia had significantly shorter hospital stay
compared to non-eosinophilic patients (mean difference
Introduction
The natural course of chronic obstructive pulmonary
disease (COPD) is characterized by a steady decline in lung
function characterized by periods of exacerbations.1,2 In the
Philippines, COPD is the seventh cause of death over-all, 3
and fifth worldwide. Nonetheless, it is expected to steadily
climb up in the succeeding years to become one of the top
causes of mortality and morbidity.
Exacerbations of COPD pose a significant burden in
health care cost and spending and is also associated with
increased complications and mortality, particularly the
hospitalized patients with moderate to severe exacerbations.
Different treatment recommendations exist for the
management of exacerbations, depending on the general
level of severity and presence of comorbidities. Current
Global Initiative for Obstructive Lung Disease (GOLD) 4
and National Institute for Health and Care Excellence
(NICE) 5 guidelines reserve the use of corticosteroids in the
management of COPD, particularly for those with severe
COPD and frequent exacerbations (GOLD Class C and D),
*Section of Pulmonary Medicine, Department of Medicine,
University of the Philippines-Philippine General Hospital, Manila, Philippines
Corresponding author: Ralph Elvi M. Villalobos, M.D., University of the
Philippines - Philippine General Hospital, Manila, Philippines
Email: ralphvillalobos@yahoo.com
The PHILIPPINE JOURNAL OF INTERNAL MEDICINE is a peer reviewed journal and a copyrighted publication of the Philippine College of Physicians
Meta-Analysis
0.68 days [95% CI 1.09,0.27]). Eosinophilic patients had
significantly less frequent readmissions (OR 0.69 [95%
CI 0.55,0.87]) but there was no statistically significant
difference in the one-year mortality rate (OR 0.88 [95% CI
0.73, .06]). Analysis showed a trend toward lower in-patient
mortality among eosinophilic patients (OR 0.53 [95% CI
0.27,1.05]). Furthermore, COPD patients with eosinophilia
had significantly less need for mechanical ventilation during
an exacerbation (OR 0.56 [95% CI 0.35,0.89]).
Conclusion: COPD patients with blood eosinophilia had
significantly shorter hospital stay, less frequent readmissions,
and are less likely to require mechanical ventilation
compared to the non-eosinophilic phenotype.
Keywords: COPD, eosinophilia, chronic obstructive
pulmonary disease
as these are also associated with significant adverse events.6
COPD is both a complex and heterogenous disease,
characterized by varying pathophysiologic mechanisms,
different prognosis and response to treatment. This concept
lead to research advances that characterize the phenotypes
of COPD and the differences in response to various
available therapy. 7 One commonly studied and described
phenotype is the inflammatory phenotype characterized
by sputum and/or blood eosinophilia. Sputum eosinophilia
has been consistently shown in randomized controlled trials
to benefit from corticosteroid therapy, compared to the
non-eosinophilic counterpart.8,9 Blood eosinophilia (defined
as peripheral eosinophils >2% or >200 cells/μL) has also
been shown to be a reliable surrogate marker for increased
systemic inflammation and is currently the focus of a number
of studies that look at the response of these patients to anti-
inflammatory therapy and possibly better clinical outcomes
versus the non-eosinophilic phenotype.10
It is therefore important to characterize this specific
phenotype of COPD with regards to the factors that affect
patient outcome and severity in exacerbations to guide
decisions in therapy and prognosis.
This review aims to identify the correlation between
blood eosinophilia and patient outcomes in hospitalized
patients with COPD exacerbations and differences between
Volume 55 Number 3 July-Sept., 2017 1
 Villalobos REM, et al.
eosinophilic and non-eosinophilic exacerbations. The primary
outcome is the correlation between blood eosinophilia
and length of hospital admission for an exacerbation. Other
outcomes include readmission rate and mortality within one
year, in-patient mortality during admission including mortality
in the intensive care unit (ICU), and need for mechanical
ventilation.
M ethods
This review was performed in accordance with the meta-
analysis of observational studies in epidemiology (MOOSE)
guidelines 11 and was approved by a technical review board
prior to commencement. An extensive literature search
(current search as of June 25, 2016) in various databases
including PubMed, MESH, EMBASE, Cochrane Database
and GoogleScholar was conducted to search for studies
that fulfil the inclusion criteria. Key terms for the search were
“COPD”, “chronic obstructive pulmonary disease”,
“eosinophilia”,and “exacerbations”. Unpublished studies
were also extensively searched and individual authors were
contacted for discrepancies and queries regarding their
respective studies. Likewise, references of articles and their
individual authors were also contacted via email for potential
inclusion of their studies. No language nor time barriers were
imposed during the search.
All studies including cohort (prospective or retrospective),
case-control studies, and randomized controlled trials
that looked into the association of blood eosinophilia
and outcomes in hospitalized COPD exacerbations were
included in the study. Studies were included for the review
if they performed an analysis correlating eosinophilia with
at least one of the study outcomes, and not necessarily of
the primary outcome alone.
Analysis was performed using the most current version
of Revman (5.3). Two study authors independently assessed
all relevant studies for potential inclusion, and also assessed
methodological quality of each of the studies. A dedicated
data collection form for eligibility and a methodological
a ssessment form - i nc l ud i ng ri sk of b i a s a ss es s ment
that prescribes to the standards set by the Cochrane
collaboration were used throughout the study. (Appendix A)
A standardized data extraction form for the measures
of treatment effect was also used during the entire study
and used the length of hospital stay, one-year readmission
rate, one-year mortality, in-patient mortality and need for
mechanical ventilation as the treatment effects.
Data were analyzed either as mean differences for
continuous outcomes and odds ratio for dichotomous
outcomes, all using 95% confidence interval for analysis.
Random effects model was used throughout the analysis. to homogeneity of the population and methodology.
2 Volume 55 Number 3 July - Sept., 2017
Blood Eosinophilia as Predictor for Patient Outcomes
Data are also presented visually as forest plots. Study outcomes
were reported by different studies as different values (i.e.
mean with standard deviation or median with interquartile
range). For purposes of standardization and reporting of data,
we used the equation published by Hozo et al.12 to estimate
the mean and standard deviation from the median and
interquartile range. Heterogeneity was tested in all treatment
effects via the I 2 and chi-squared statistic, with significant
heterogeneity defined as I2>50% or chi-square p<0.1.
R esults
Eighteen studies met the inclusion criteria for the
preliminary search. Twelve studies were excluded because
either the studies did not meet the methodological criteria
either analysed in relation to a treatment drug or were
methodologically not fit for inclusion, or analyzed COPD
patients with sputum rather than blood eosinophilia.
(Appendix B)
A total of six studies13,14,15,16,17,18 with a total population
of 7,293 patients (1,562 in the eosinophilic group and 5,731
in the non-eosinophilic group) were included in this review
(Appendix C). Four of the studies 14-17 were retrospective
cohorts that compared outcomes between eosinophilic
and non-eosinophilic COPD exacerbations, and included
one or more of outcomes that are described in this review.
One study 13 is a retrospective post-hoc analysis from a
multi-centre randomized controlled trial that recruited
patients admitted for a COPD exacerbation and involved
a rehabilitation program; and one study18 is a three-year
prospective cohort that analysed differences in outcome
among persistently eosinophilic versus non-eosinophilic
patients. All studies analyzed the patients regardless of
the treatment given during the exacerbation, particularly
whether they were given corticosteroids or not. Furthermore,
all studies admitted only patients with COPD exacerbations
and excluded patients with other concomitant pulmonary
diseases (e.g. pneumonia, lung cancer, or asthma). One
study16 included admissions of exacerbations in the intensive
care unit, and analyzed general outcomes in the ICU.
Study outcomes
Length of hospital stay:
Four studies included the primary outcome in their
analysis. Patients with blood eosinophilia had a significantly
shorter hospital stay compared to the non-eosinophilic
patients, mean difference 0.68 days less in the eosinophilic
group versus the non-eosinophilic group (95% CI -1.09,
-0.27days) [Figure 1]. This treatment effect was significantly
heterogenous (I 2=98%, chi-squared p<0.01) but sensitivity
analysis nor subgroup analysis could not be performed due
 Blood Eosinophilia as Predictor for Patient Outcomes Villalobos REM, et al.

Figure 1. Hospital length of stay comparing eosinophilic and non-eosinophilic patients

Figure 2. One-year readmission rate between eosinophilic and non-eosinophilic patients.

Figure 3. Difference in one-year mortality between the eosinophilic and non-eosinophilic group patients

Figure 4. Comparison of In-patient mortality between eosinophilic and non-eosinophilic patients

Figure 5. Need for mechanical ventilation between eosinophilic and non-eosinophilic patients

Volume 55 Number 3 July-Sept., 2017 3

 Villalobos REM, et al. Blood Eosinophilia as Predictor for Patient Outcomes

Re-admission in one year: explored as an established factor for patient outcomes in

Three studies included readmission rate in their COPD, the studies showed a mix of results and outcomes
outcomes. Eosinophilic patients had 31% less frequent were not consistently the same across studies.
readmissions versus the non-eosinophilic patients, OR 0.69
(95% CI 0.55, 0.87), and this result is statistically significant Over-all, as the trend toward “personalized” COPD
(Figure 2). There is no significant heterogeneity across the management is being explored, more and more studies
studies (I 2=0%, chi-squared p=0.88). are expected to be done, focusing on specific disease
phenotypes and response to various therapies.
One-year mortality:
Three studies reported one-year mortality in the study
outcomes. There was no statistically significant differences
C onclusions
in the one-year mortality rate among eosinophilic versus
Patients with eosinophilic COPD exacerbations
non-eosinophilic patients, OR 0.88 (95% CI 0.73, 1.06) [Figure
have better clinical outcomes in terms of length of
3]. There was also no significant heterogeneity among the
hospitalization, readmission and need for mechanical
studies (I 2=0%, chi-squared p=0.71).
ventilation compared to the non-eosinophilic patients.
There is also a trend toward lower short- and long-term
Mortality during admission:
mortality among these eosinophilic patients.
Three studies had in-patient mortality included in their
analysis of outcomes. Analysis showed a trend toward lower
in-patient mortality among patients with eosinophilia versus
no eosinophilia, although this difference is not statistically
R eferences
significant, OR 0.53 (95% CI 0.27, 1.05) (Figure 4).
1. Kasper D, Fauci A, Hauser S, Longo D, Jameson J, Loscalzo
J. Harrison’s Principles of Internal Medicine, 19th edition.
Need for mechanical ventilation:
McGraw-Hill, 2015.
Only two studies involved mechanical ventilation as
2. Broaddus V, Mason R, Ernst J, King T, Lazarus S, Murray
end-point. COPD patients with eosinophilia had significantly
J. Murray and Nadel’s Textbook of Respiratory Medicine, 6th
less need for mechanical ventilation during admission for an
edition. Elsevier, 2015.
exacerbation compared with patients with no eosinophilia,
3. Department of Health of the Philippines National Epidemiology
OR 0.56 (95% CI 0.35, 0.89). However, this has a significantly
Center, January 2009). “Leading causes of Mortality”. www.doh.
heterogenous result (Figure 5).
gov.ph/node/198.html. Accessed 10 July 2016.
4. Global Initiative for Chronic Obstructive Lung Disease, 2015
Update.
D iscussion 5. National Institute for Health and Care Excellence for Chronic

Obstructive Pulmonary Diseases, 2010 Update.
This review summarized the current available evidence
6. Walters JA, Gibson PG, Wood-Baker R, et al. Systemic
on the correlation of blood eosinophilia and patient
corticosteroids for acute exacerbations of chronic obstructive
outcomes in COPD exacerbations. Significant improvements
pulmonary disease. Coch Dat Syst Rev 2009; 1: CD001288.
were observed in the length of hospital stay, one-year
7. Vestbo J, Anderson W, Coxson HO, Crim C, Dawber F, Edwards
readmission rate and use of mechanical ventilation favouring
L, Hagan G, Knobil K, Lomas DA, Maknee W, Silverman
eosinophilic over the non-eosinophilic patients. Although
E. Evaluation of COPD Longitudinally to Identify Predictive
there were no statistically significant differences in more
Surrogate End-points (ECLIPSE). Eur Respir J  2008;31:869-873
important outcomes, i.e. mortality both in-patient and one
8. Brightling CE, Monteiro W, Ward R, Parker D, Morgan
year mortality, the data show trends toward benefit, again,
MD, Wardlaw AJ, Pavord ID. Sputum eosinophilia and short-
favouring the eosinophilic phenotype. These findings could
term response to prednisolone in chronic obstructive pulmonary
be partially explained by the fact that most moderate/severe
disease: a randomised controlled trial. Lancet. 2000 Oct 28;
COPD patients and patients in exacerbation tend to be given
356(9240):1480-5
corticosteroid therapy as part of the treatment regimen.
9. Brightling CE, McKenna S, Hargadon B, Birring S, Green R,
Siva R, Berry M, Parker D, Monteiro W, Pavord ID, Bradding
The findings of this review generally follow the current
P. Sputum eosinophilia and the short term response to inhaled
concept that eosinophilia is indeed a predictor for better
mometasone in chronic obstructive pulmonary disease. Thorax.
patient outcomes in COPD because of response to available
2005 Mar; 60(3):193-8.
anti-inflammatory therapy.
10. Mona Bafadhel, Susan McKenna, Sarah Terry, Vijay Mistry,
Mitesh Pancholi, Per Venge, David A. Lomas. Blood Eosinophils
The studies reviewed were good quality retrospective or
to Direct Corticosteroid Treatment of Exacerbations of Chronic
prospective cohorts, which is apt for the specific outcomes.
Obstructive Pulmonary Disease: A Randomized Placebo-Controlled
However, as blood eosinophilia is still continued to be

4 Volume 55 Number 3 July - Sept., 2017

 Blood Eosinophilia as Predictor for Patient Outcomes
Trial. Am J Respir Crit Care Med. 2012. Vol 186, Iss. 1, pp 48–55
11. Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD,
Rennie D. Meta-analysis of observational studies in epidemiology:
a proposal for reporting. Meta-analysis Of Observational Studies
in Epidemiology (MOOSE) group. JAMA 2000;283:2008–12.
12. Hozo S, Djulbegovic B, Hozo I. Estimating the mean and variance
from the median, range and the size of the sample. BMC Medical
Research Methodology. 2005, 5:13.
13. Bafadhel M, Greening N, Harvey-Dunstan T, Williams J,
Morgan M, Brightling C, Hussain S MD. Blood eosinophils and
outcomes in severe hospitalised exacerbations of COPD. CHEST
(2016), doi: 10.1016/j.chest.2016.01.026
14. Serafino-Argrusa L, Scichilone N, Spatafora M, Battaglia
S. Blood eosinophils and treatment response in hospitalized
exacerbations of chronic obstructive pulmonary disease: A case
APPENDICES
Appendix A1. Risk of bias summary for the studies
Appendix A2. Individual risk of bias summary
Villalobos REM, et al.
control study. J Pulm Pharm Ther. 2016, 89e94.
15. Hasegawa K, Camargo C. Prevalence of blood eosinophilia
in hospitalized patients with acute exacerbation of COPD.
Respirology. 2015 doi: 10.1111/resp.12724.
16. Salturk C, Kurakurt Z, Adiguzel N, Kargin F, Saria R, Celik
M, Takir H. Does Eosinophilic COPD exacerbation have a better
patient outcome than non-eosinophilic in the intensive care unit?
Int J of Chron Obstruct Pulmon Dis 2015:10 1837–1846.
17. Duman D, Aksoy E, Agca MC, Kocak ND, Ozmen I,
Akturk UA, Gungor S. The utility of inflammatory markers
to predict readmissions and mortality in COPD cases with or
without eosinophilia. Int J Chron Obstruct Pulmon Dis. 2015
Nov 11;10:2469-78.
18. Singh D, Kolsum U, Brightling CE, Locantore N, Agusti A, Tal-
Singer R. Eosinophilic inflammation in COPD: prevalence and
clinical characteristics. Eur Respir J. 2014 Dec; 44(6):1697-700.
Volume 55 Number 3 July-Sept., 2017 5
 Villalobos REM, et al. Blood Eosinophilia as Predictor for Patient Outcomes

Records identified through Additional records identified

Identification

database searching through other sources

(n = 18) (n = 0)

Records after duplicates removed

(n = 18)
Screening

Records screened Records excluded

(n = 8) (n = 10)

Full-text articles assessed Full-text articles excluded, with

reasons: analyzed using a study
for eligibility
Eligibility

drug, sputum eosinophilia

(n = 8 ) (n = 2 )

Studies included in
qualitative synthesis
(n = 6 )
Included

Studies included in
quantitative synthesis
(meta-analysis)
(n = 6)

Appendix B. Flowchart of study selection process

6 Volume 55 Number 3 July - Sept., 2017

Blood Eosinophilia as Predictor for Patient Outcomes Villalobos REM, et al.

Author
Title Design Duration Outcomes Comparison
(Year)
Eosinophilic inflammation Hospitalization, rate of exacer-
Singh three-year follow-up Persistently no
in COPD: prevalence and Prospective Cohort bation, admissions in one year,
(2014) period eosinophilia
clinical characteristics. pulmonary function
Primary outcome: length of
Blood eosinophils and treatment
Serafino- hospitalization
response in hospitalized exac- Retrospective analy-
Argrusa Non-eosinophilic
erbations of chronic obstructive Case-control study sis of a two-year
(2015) Other outcomes: comorbidities, patient
pulmonary disease: A case control period
steroid dose, duration of IV
study
steroid treatment
Retrospective
Prevalence of blood eosinophilia Hospital length of stay, intuba-
Hasegawa cohort and analysis Non-eosinophilic
in hospitalized patients with acute Retrospective cohort tion and mechanical ventilation
(2015) over a ten-year patients
exacerbation of COPD rates, mortality
period
Retrospective co-
Does Eosinophilic COPD exac-
hort over two years,
Salturk erbation have a better patient Intubation and NIV rates, ICU Non-eosinophilic
Retrospective Cohort analysing severe
(2015) outcome than non-eosinophilic in mortality patients
exacerbations ad-
the intensive care unit?
mitted in the ICU
The utility of inflammatory mark-
Hospital length of stay, one-year
Duman ers to predict readmissions and Retrospective Non-eosinophilic
Retrospective Cohort mortality, one year readmission
(2015) mortality in COPD cases with or cohort patients
rate
without eosinophilia.
Retrospective post-hoc
analysis of a random- Hospital length of stay, mortality
Blood eosinophils and outcomes
Bafadhel ized controlled trial 12 month follow-up during admission and within one Non-eosinophilic
in severe hospitalised exacerba-
(2016) involving pulmonary period year, readmission rate within patients
tions of COPD
rehabilitation in COPD one year
exacerbation patients
Appendix C. Characteristics of included studies

Appendix D. Search strategy used for Pubmed

Volume 55 Number 3 July-Sept., 2017 7

 Philippine Journal of Internal Medicine
Non-invasive Ventilation Versus Conventional Oxygen Therapy
in Immunocompromised Patients: A Meta-analysis
Ulysses King Gopez, M.D.*; Karen Flores, M.D.*; Ralph Elvi Villalobos, M.D.**; Norman Maghuyop, M.D.***
Abstract
Introduction: Respiratory failure is common in immuno-
compromised patients. Intubation and mechanical
ventilation (MV) is the mainstay of treatment but is associated
with increased risk of pneumonia and other complications.
Non-invasive ventilation (NIV) is an alternative to MV in a
select group of patients and aims to avoid the complications
of MV. In these patients, we performed a meta-analysis on the
effect of NIV versus conventional oxygen therapy in reducing
intubation rates and other important clinical outcomes.
Methods: We performed an extensive online and unpublished
data search for relevant studies that met the inclusion
criteria. Randomized controlled trials that used NIV versus
conventional oxygen therapy in immunocompromised
patients with respiratory failure were included in the meta-
analysis. Eligbility and risk of bias assessments were performed
independently by three authors. The primary outcome of
interest was intubation and mechanical ventilation rate.
The secondary outcomes were intensive care unit (ICU)
and all-cause mortality, ICU length of stay and duration of
mechanical ventilation.
Results: Out of the twenty initially screened studies, four
studies with a total of 553 patients met the criteria for inclusion
and were included in the analysis. Patients given NIV were
38% less likely to be intubated vs. those given oxygen, RR 0.62
(95%CI 0.42,0.93); however, this analysis result is significantly
Introduction
Immunocompromised patients are a special group of
patients due to their high propensity to develop infectious
complications.1 These patients include those with underlying
solid organ/hematologic malignancies, those on chronic
steroids and other immunosuppressive drugs for various
condi ti ons, pati ents w i th huma n i mm unod eficiency
virus/acquired immune deficiency syndrome (HIV/
*Department of Medicine, University of the Philippines-Philippine General
Hospital
**Section of Pulmonary Medicine, Department of Medicine, University of
the Philippines-Philippine General Hospital
**Section of Adult Medicine, Department of Medicine, University of the
Philippines-Philippine General Hospital
Corresponding author: Ulysses King, Gopez, M.D., University of the
Philippines – Philippine General Hospital, Manila, Philippines
Email: ukggopez@gmail.com
The PHILIPPINE JOURNAL OF INTERNAL MEDICINE is a peer reviewed journal and a copyrighted publication of the Philippine College of Physicians
Meta-Analysis
heterogenous. After sensitivity analysis, results showed 48%
less likelihood of intubation and mechanical ventilation in
the group treated with NIV, RR 0.52 [95% confidence interval
(CI) 0.35,0.77]. Patients on NIV had 1.18 days less stay in the
ICU vs. oxygen group (95%CI -1.84,-0.52 days ).
Three studies included ICU mortality in their outcomes
and showed a 54% decrease in ICU mortality among
patients given NIV, RR 0.46 (95% CI 0.17, 1.29), however this
result is non-significant and heterogenous I 2=58%. There was
no statistically significant decrease in all-cause mortality
between the two groups, RR 0.77 (95% CI 0.53,1.11). After a
sensitivity analysis performed specifically for this outcome,
results showed a 32% reduction in all cause mortality in
patients given NIV vs. oxygen therapy, however was not
statistically significant RR 0.68 (95% CI 0.53-1.11) and was
heterogenous I2=50%. There is no difference in the duration
of mechanical ventilation between groups.
Conclusion: In immunocompromised patients with respiratory
failure, NIV reduced intubation rates, and length of ICU stay,
compared to standard oxygen therapy. This intervention also
showed trend toward ICU and all-cause mortality reduction.
Keywords: non-invasive ventilation, conventional oxygen
therapy
AIDS), neutropenia, uncontrolled diabetes, and other
underlying conditions that have an effect on suppressing
any component of the immune system. 2 Oftentimes,
these patients are admitted to the hospital for infectious
diseases, and are at an increased risk for developing in-
patient infectious complications such as hospital-acquired
pneumonia and diarrhea. 1,2,5 These patients frequently
require more intensive monitoring and aggressive treatment
because mortality and morbidity rates are high.3
The lungs are the most common site of infection in
immunocompromised patients,2,3 and some of the commonly
afflicting organisms are unusual microorganisms that rarely
affect immunocompetent individuals. These infections are
also often severe enough to cause respiratory failure and
warrant intensive care unit (ICU) admission and mechanical
ventilation.
Volume 55 Number 3 July-Sept., 2017 1
 Gopez UK, et al.
Invasive mechanical ventilation through endotracheal
or nasotracheal ventilation is often employed in critically ill
patients with respiratory failure to augment the increased
oxygen demands. The usual indications for invasive ventilation
are severe pneumonia, aspiration, chronic obstructive
pulmonary disease (COPD) exacerbations, acute respiratory
distress syndrome (ARDS), etc. Although life-saving, it is
especially associated with a high complication and morbidity
rates, with ventilator-associated pneumonia being one of
the most common complications noted. This is indeed very
worrisome for immunocompromised patients since they
have higher propensity to develop infectious complications
associated with invasive mechanical ventilation.
Non-invasive ventilation (NIV) using a tight-fitting face
mask and employed through Bi-level positive airway pressure
ventilation (BIPAP) or continuous positive airway pressure
ventilation (CPAP) is subtype of mechanical ventilation that
was developed to avoid the serious morbidity and mortality
rates associated with invasive mechanical ventilation. It is
associated with lower infection rates, lower rates of airway
injuries and allows earlier return to normal level of activity and
earlier hospital discharge. It is widely employed in a variety of
patients in respiratory failure; unfortunately, this mechanical
ventilation strategy is highly selective and is also associated
with high failure rates if patient selection is not done properly.
Some of the contraindications to non-invasive ventilation
include severe respiratory distress, encephalopathy,
facial trauma or burns, inability to effectively clear airway
secretions and cardiopulmonary arrest—all of which, if
present, are managed by invasive mechanical ventilation.
Non-invasive ventilation (NIV) is an alternative to inva-
sive ventilation in highly select patients with respiratory
failure and is also hypothesized to be effective as tide-over
for patients with respiratory failure and thus avoid invasive
ventilation. However, the only proven indication for NIV
that showed convincing results are patients suffering from
acute hypercapnia and respiratory acidosis in patients with
respiratory failure from exacerbations of COPD.1 Because
it is safer and avoids the usual complications from invasive
mechanical ventilation, it is imperative to explore other
patient subgroups where NIV may have benefits. Immuno-
compromised patients with respiratory failure are one group
wherein it is postulated that may benefit from NIV because
of the great benefit of avoiding an invasive device, thus
reducing the risk of potential infections. In one retrospective
study by, first line NIV markedly improved survival by a 25%
reduction in mortality among patients with acute respiratory
failure. Two more studies, a prospective case-control trial8
supported noninvasive positive-pressure ventilation (NPPV)
use in acute respiratory failure (ARF) from pneumocystis jir-
oveci pneumonia (PCP) in patients with AIDS demonstrating
33% reduction in invasive mechanical ventilation (IMV) and
better survival, and the other, a multicenter, prospective,
randomized trial 14 showed significant reduction in intuba-
2 Volume 55 Number 3 July - Sept., 2017
Non-invasive Ventilation Versus Conventional Oxygen Therapy
tion and length of ICU stay in NIV in patients with severe
community-acquired pneumonia (CAP). Studies involving
immunocompromised patients however are still lacking, and
are also conflicting. One retrospective review9 on patients
with hematologic malignancies did not show a difference
in the mortality rates between patients treated with NIV
compared to those who were intubated. These conflicting
evidences prompted studies on NIV in immunocompromised
patients with more robust methodologies to be done.1,2,3,4
Therefore, NIV is purported to be of benefit in immuno-
compromised patients with respiratory failure since it may
avoid invasive ventilation and the complications associated
with it. It is important to ascertain the benefit of NIV in these
subgroup of patients, because if proven beneficial, it will
potentially decrease mortality and complication rates
associated with invasive ventilation.
This review is aimed primarily to determine the efficacy
of NIV versus conventional oxygen therapy in reducing
intubation and mechanical ventilation rates among
immunocompromised patients with respiratory failure.
Secondary outcome measures are the efficacy of NIV versus
conventional oxygen therapy in reducing ICU length of
stay, ICU mortality rate, all-cause mortality and duration of
mechanical ventilation.
Methods
We included randomized controlled trials (RCT) that
employed non-invasive ventilation versus conventional therapy
with oxygen via face mask in adult immunocompromised
patients with acute respiratory failure in our meta-analysis.
Studies that included immunocompromised patients aged
18 and above (from neutropenia, hematologic malignancy,
post solid organ or bone marrow transplantation, solid
organ malignancies, chronic steroid use or HIV infection/
AIDS) with respiratory failure were included in the review.
Acute respiratory failure (ARF) is defined as PaO2<60 mmHg
on room air, tachypnea >30/min, or labored breathing or
respiratory distress or dyspnea at rest.
The intervention used in this study involved non-invasive
ventilation employing various commercial ventilators versus
conventional oxygenation via face mask or nasal cannula,
adjusting flow rates to maintain O2 Saturation > 90%. Studies
excluded would be studies apart from randomized control
trials, and those who did not meet the above criteria.
The primary outcome of interest in this review is
intubation and mechanical ventilation rates between
those treated with NIV versus those placed on conventional
oxygen therapy. Other outcomes that were also measured
were the ICU length of stay, ICU mortality rate, all-cause
mortality, duration of mechanical ventilation, and length
of hospital stay between the two groups.
 Non-invasive Ventilation Versus Conventional Oxygen Therapy
A computerized search using the standard PUBMED
free text search and MeSH terms “Non invasive ventilation”,
“immunocompromised host”, “hematologic malignancy”,
“solid tumors”, “solid organ transplant”, “immunosuppresive
drug use”, “HIV” were using the following databases:
PubMed, Medline, Embase and CENTRAL, Cochrane
Database, and Google Scholar. Unpublished researches
thru conference book of abstracts and pharmaceutical
companies were also sought. Three authors independently
assessed studies for inclusion into the meta-analysis.
Uncertainties and discrepancies were settled by votation
and consensus.
Results
Twenty studies were initially screened for inclusion,
however 16 studies failed the inclusion because they were
either case reports, or cohorts and did not meet the criteria
for inclusion. Studies were included if it included at least one
of our study outcomes in their analysis and not necessarily of
the primary outcome alone (see Appendix A).
Four studies met the eligibility criteria and were
10,11,12,13
included in the final analysis with a total population of 553
patients (280 in the NIV group and 273 in the oxygen therapy
group). All four studies were prospective, randomized trials
that dealt with immunocompromised patients with respiratory
failure. However, the reason for the immunocompromised
states differ from study to study. Antonelli et al. performed
this trial in patients who were immunosuppressed after solid
organ transplantation, and Wermke et al had a population
of patients who underwent allogeneic hematopoietic stem
cell transplantation. Furthermore, Hilbert et al. and Lemiale
et. al had a mix of immunodeficient patients enrolled in their
trials (chemotherapy-induced neutropenia, AIDS, prolonged
steroid use and hematologic malignancies). Despite this
differences in the population subgroup, all studies were
uniform in the definition of respiratory failure.
All four studies compared standard oxygenation methods
(via cannula or face mask) versus NIV (via full face mask),
using different commercial machines available. All the studies
employed intermittent NIV or oxygen therapy adjusted to
achieve adequate oxygen saturations. These studies also
employed intubation and mechanical ventilation in patients
who were not able to tolerate either conventional oxygen or
NIV and were recorded in the study as an outcome; and all
but one study had intubation and mechanical ventilation as
the primary outcome (Table I and II).
Eligible Studies
1. Antonelli, et al. Noninvasive ventilation for treatment
of acute respiratory failure in patients undergoing solid
organ transplantation (2000)
Gopez UK, et al.
2. Hilbert, et al. Noninvasive ventilation in immunosuppressed
patients with pulmonary infiltrates, fever, and acute
respiratory failure. (2001)
3. Wermke, et al. Respiratory failure in patients undergoing
allogeneic hematopoietic SCT – a randomized trial on
early non-invasive ventilation based on standard care
hematology wards. (2011)
4. Lemiale et al. Effect of noninvasive ventilation vs oxygen
therapy on mortality among immunocompromised
patients with acute respiratory failure: A randomized
clinical trial (2015)
Three authors extracted data independently from
eligible studies using a standard data extraction form
(Appendix B). The following outcomes will be evaluated:
rates of intubation and mechanical ventilation as primary
outcome; ICU mortality rate, ICU length of stay, all-cause
mortality, duration of mechanical ventilation, incidence of
infectious complications and total hospital length of stay as
secondary outcomes.
The authors also assessed the risk of bias in terms of
sequence generation, allocation concealment, blinding,
incomplete outcome data, selective outcome reporting
independently. Discrepancies and issues were resolved
by consensus. All parameters were low risk for each of the
study except blinding which is attributed to the nature of
the intervention. (Table III)
Study Outcomes
Intubation and Mechanical Ventilation Rates
All included studies had failure of oxygenation or NIV
included in their outcomes. Analysis showed that patients
who were given NIV had a significant 38% reduction in
intubation compared to those given conventional oxygen
therapy, relative risk (RR) 0.62 (95% [confidence interval (CI)
0.42, 0.93]. This outcome was significantly heterogenous,
I 2=54% (Figure 1).
We performed a sensitivity analysis and excluded the
study by Lemiale due to a heterogenous population, and
no difference was noted in outcome - showing a statistically
significant 48% less likelihood of intubation in the group
treated with NIV, RR 0.52 (95% CI 0.35, 0.77), except for the
marked reduction in heterogeneity, I2=6% (Figure 2).
Length of ICU Stay
Three studies included ICU length of stay in their
outcomes. Our analysis shows that patients given NIV had
significantly shorter stays in the ICU, with 1.18 days less in
the NIV group (95% CI 1.54 to 0.52 days less) compared to
those given conventional oxygen therapy. The results of this
analysis is homogenous, I2=10% (Figure 3).
Volume 55 Number 3 July-Sept., 2017 3
Gopez UK, et al. Non-invasive Ventilation Versus Conventional Oxygen Therapy

Table I. Baseline characteristics of studies included

Patients
Study Gender (M/F) Mean age (years) Outcomes
NIV/ Conventional O2
NIV Conventional O2 NIV Conventional O2
Antonelli 20/20 13/7 12/8 45 44 Intubation rates, development of complica-
2000 (0.65/0.35) (0.60/0.40) tion, duration of stay in the ICU, duration of
ventilator assistance, death in the ICU
Hilbert 26/26 18/8 19/7 48 50 Intubation rates, development of complica-
2001 (0.69/0.30) (0.73/0.26) tions, length of stay in the ICU, duration of
ventilator assistance, death in the ICU, death
in the hospital
Lemiale 191/183 117/74 105/78 64 61 28 day mortality, intubation rates, sequential
2015 (0.61/0.40) (0.54/0.42) organ failure assessment scre on day three,
ICU acquired infections, duration of mechani-
cal ventilation, ICU length of stay
Wermke 42/44 32/10 37/7 42 44 Intubation rate, ICU admission rate, 100 day
2012 (0.76/0.22) (0.88/0.15) mortality, long term survival

Table II. Baseline characteristics of studies included

Characteristics of included studies

Conventional
Domain Population Inclusion Exclusion NIV
O2 Therapy
MV Requirement
CP Arrest
Full face mask with
Hemodynamic instability
RR > 35 an inflatable soft
Status Asthmaticus Venturi Mask
Study 1 Solid Organ transplant PaO2/FiO2 < 200 cushion seal.
Neurologic cause with FiO2 > 0.4
Antonelli 2000 patients with respiratory *accessory musle use Goal ETV of 8mL/kg
Tracheostomy to achieve PaO2
N: 40 failure *paradoxical abdomi- PEEP 2-3cm until
Facial deformities of 90%
nal breathing 10cmH2O, FiO2 0.6
Recent oral, esophageal, gas-
and less
tric surgery
2 or more organ failures
MV Requirement
CP Arrest, GCS < 8
Face mask in
SBP < 80mmHg
Pressure-Support
Immunosuppressed MI or Ventricular Arrhythmias,
RR > 30, Fever > mode. Venturi Mask ad-
Study 2 patients with fever, RF of cardiac origin, COPD
38.3C, Pulmonary Goal ETV of justed to achieve
Hilbert 2001 pulmonary infiltrates Recent 2 or more organ failures
infiltrates 7-10mL/kg peripheral satura-
N: 52 and early hypoxemic Facial deformities
PaO2/FiO2 < 200 PEEP 2-3cm until tions >90%
respiratory failure Recent oral, esophageal, gas-
10cmH2O, FiO2
tric surgery
0.65 and less
PCO2 > 55, pH < 7.35
Uncorrected bleeding
Immune deficiency Goal ETV of 8mL/kg
Age > 18 Acute hypoxemic MV requirement PEEP between
Hematologic or solid failure (RR>30, PaO2 Cardiogenic Edema 2-10cmH2O
Study 3 Oxygen modality
organ malignancy < 60mmHg, labored MI, GCS < 13, pressor support PEEP and FiO2
Lemiale 2015 at the discretion
Solid organ transplant breathing, respiratory Pregnancy, MI or ACS adjusted to maintain
N: 375 of the physician
Long term immunosup- distress, dyspnea at Pneumothorax, vomiting, inabil- 92% SpO2
presive drug or steroid rest) less than 72hrs ity to protect airway, PCO2 > 50 60minute sessions
use Q4h
MV Requirement Full-face mask with
Cardiac origin for RF cushion
Patients who underwent
Study 4 RR > 25 Hemodynamic Instability requir- PEEP 7mbar, PS Nasal insufflation
hematopoietic stem cell
Wermke 2012 O2 Saturation < 92% ing pressor support 15mbar or full face mask
transplant with respira-
N: 86 PaO2/FiO2 < 300 LF failure with pulmonary Administered starting at 3L/min
tory failure
edema intermittently 30mins
GCS < 8 Q3h

4 Volume 55 Number 3 July - Sept., 2017

 Non-invasive Ventilation Versus Conventional Oxygen Therapy Gopez UK, et al.

Figure 1. Forrest plot of pooled analysis comparing intubation rates between NIV and conventional therapy

Figure 2. Forrest plot of sensitivity analysis comparing intubation rates between NIV and conventional therapy

Figure 3. Forrest plot of pooled analysis comparing length of icu stay between NIV and conventional therapy

Figure 4. Forrest Plot of pooled analysis comparing ICU Mortality between NIV and conventional therapy.

Figure 5. Forrest Plot of pooled analysis comparing all-cause mortality between NIV and conventional therapy.

Volume 55 Number 3 July-Sept., 2017 5

 Gopez UK, et al. Non-invasive Ventilation Versus Conventional Oxygen Therapy

Table III. Assessment of risk of bias in included studies

Concealment

Outcome
Generation

Incomplete

Selective

Over-all risk
reporting
Sequence

Allocation

Outcome
DOMAIN

Blinding

of bias
Participants
Personnel

Assessor
Outcome
Study 1
A A B B B N/A A A
Antonelli 2000
Study 2
A A B B B N/A A A
Hilbert 2001
Study 3
A A B B B N/A A A
Lemiale 2015
Study 4
A A B B B N/A A A
Wermke 2012
Legend: A – Low Risk, B – Unclear Risk, C – High Risk Figure 6. Funnel plot of studies included

ICU Mortality with respiratory failure, while the other studies10,11 concluded
benefit in clinical outcomes. Additionally, with the varying
Three studies, which included a total of 180 patients, population per study included, there was an expected sub-
analysed mortality in the ICU as an outcome. There was a stantial heterogeniety. Despite this, our results were consis-
54% decrease in ICU mortality among patients given NIV, tent and has shown that the use of NIV significantly reduced
RR 0.46 (95% CI 0.17, 1.29), this result was however non- the rate of intubation, length of stay in the ICU. Furthermore,
significant and heterogenous I2=58% (Figure 4). though outcome in ICU mortality and all-cause mortality was
non-significant, and despite the heterogeneity, the trend
All-cause mortality remained toward mortality reduction. This meta-analysis has
now given important clinical outcomes with NIV use, and its
All four included studies included mortality from all future interventional application.
causes in their outcome. There was no significant difference
in the mortality from all causes in the analysis performed, RR The studies covered patients with hematologic or solid
of death is 0.77 (95% CI 0.53,1.11), and was not heterogenous cancers, immune deficiency, immunosuppresive drug use,
I 2=49%. Sensitivity analysis for this outcome was performed, hematopoietic stem cell transplant, which was a well repre-
and we removed the study of Wermke because it analysed sentation of the immunocompromised population. Looking
only patients admitted in the wards, and not in the ICU. Post at NIV related complications, reports included only facial
sensitivity analysis, there is an observed 32% less chance necrosis 10, facial abrasions 11, while all fatal complications
of dying from all-causes in the NIV group versus the group were from organ dysfunction and none was directly associ-
treated with conventional oxygen therapy, however it was ated with its use.
not statistically significant, RR 0.68 (95% CI 0.53-1.11) and
heterogenous I2=50% [Figure 5]. Given the significant clinical outcomes - preventing
mechanical intubation, and its associated complications,
Publication Bias trend toward mortality reduction – and the limited non-fatal
complications of NIV, we conclude that NIV is now an option
A funnel plot comparing all-cause mortality between for immunocompromised patients with respiratory failure.
NIV and the conventional oxygen therapy group was made
to check for publication bias. The scatter plot showed an
assymetrical distribution suggesting publication bias.
C onclusion
Among immunocompromised patients with respiratory
D iscussion failure, NIV compared with standard oxygen support sig-
nificanlty reduced intubation, and ICU length of stay. This
Of the four studies included, RCTs 12,13 showed no sig- intervention also showed trend toward ICU and all-cause
nificant benefit with NIV in immunocompromised patients mortality reduction.

6 Volume 55 Number 3 July - Sept., 2017

 Non-invasive Ventilation Versus Conventional Oxygen Therapy Gopez UK, et al.

Limitations Cohen Y, Schwebel C, Soufir L, Jamali S, Souweine B, Azoulay

E. Non-invasive mechanical ventilation in acute respiratory failure:
The main limitations were the limited number of studies trends in use and outcomes. Int Care Med, 40(4):582-91, 2014.
that met the criteria for inclusion, and the different subpopu- 8. Confalioneri M, Calderini E, Terraciano S, Chidini G, Celeste
lations within each study. The funnel plot (Figure 6) was as- E, Puccio G, Gregoretti C, Meduri G. Noninvasive ventilation
symetric suggesting publication bias, most likely due to the for treating acute respiratory failure in AIDS patients with
limited number, and heterogeneity of the studies, but does pneumocystis carinii pneumonia. Int Care Med, 28:1233-1238,
not exclude the limitations within the studies. 2002.
9. Depuydt P, Benoit D, Vandewoude K, Decruyenaere J, Colardy
Recommendations F. Outcome in Noninvasively and invasively ventilated hematologic
patients with acute respiratory failure. Chest, 126:1299-1306, 2004
More studies with equally distributed subpopulations of 10. Antonelli M, Conti G, Bufi M, Costa M, Lappa A, Rocco M,
immunocompromised hosts are needed to further strengthen Gasparetto A, Meduri G. Noninvasive ventilation for treatment
the results made in this meta-analysis, specifically mortal- of acute respiratory failure in patients undergoing solid organ
ity benefits. Further studies can also incorporate subgroup transplantation: a randomized trial. JAMA, 283:235-241, 2000.
analyses to compare outcomes. Additionally, the definition 11. Hilbert G, Gruson D, Vargas F, Valentino R, Benissan G,
of immunocompromised patient remains to be broad, and Dupon M, Reiffers, Cardinaud J. Noninvasive ventilation in
this makes way for identifying similar populations who may immunosuppressed patients with pulmonary infiltrates, fever, and
benefit from the intervention. The studies included gave clear acute respiratory failure. N Engl J Med, 344: 481-7, 2001.
clinical criteria for inclusion, and this may be consolidated 12. Wermke M, Schiemanck S, Hoffken G, Ehninger G, Bornhauser
to formulate an approach or a guideline for patients with M, Illmer T. Respiratory failure in patients undergoing allogeneic
similar conditions. hematopoietic SCT—a randomized trial on early non-invasive
ventilation based on standard care hematology wards. Bone Mar
Funding Transpl, 47:574-580, 2012.
13. Lemiale V, Mokart D, Rigon M, Pene F, Mayaux J, Faucher
This study was not funded by any institution, and solely E, Nyunga M, Girault C, Perez P, Guitton C, Ekpe K,
funded by the authors. Kouatchet A, Theodose I, Benoit D, Canet E, Barbier F.
Effect of noninvasive ventilation vs oxygen therapy on mortality
among immunocompromised patients with respiratory failure: a
R eferences randomized clinical trial. JAMA 314(16), 1711-1719, 2015.
14. Confalioneri M. et al., Acute Respiratory Failure in Patients
1. Kasper D, Fauci A, Hauser S, Longo D, Jameson J, Loscalzo
with Severe Community Acquired Pneumonia: A Prospective
J.; Harrison’s Principles of Internal Medicine, 19th edition.
Randomized Evaluation of Non-Invasive Ventilation. Am J Respir
McGraw-Hill, 2015.
Crit Care Med Vol 160, 1585–1591, 1999.
2. Mandell G, Bennett J, Dolin R.; Mandell, Douglas and Bennett’s
Principles of Infectious Diseases, Seventh edition. Elsevier, 2010.
3. Yu M, Villalobos R, Juan-Bartolome M, Berba R.; Predictors
of outcome and severity in adult Filipino patients with febrile
neutropenia, Intensive Care Medicine Experimental, 3(Suppl
1):A253, 2015.
4. Keenan SP, Sinuff T, Burns K, Muscedere J, Kustogiannis J,
Mehta S, Cook DJ, Ayas N, Adhikari N, Hand L, Scales D,
Pagnotta R, Lazosky L, Rocker G, Laupland K, Sanders K,
Dodek P.; Clinical practice guidelines for the use of noninvasive
positive-pressure ventilation and noninvasive continuous positive
airway pressure in the acute care setting. Can Med Assoc J.
183(3):E195-214, 2011.
5. Bott J, Carroll MP, Conway JH. Randomized controlled trial
of nasal ventilation in acute ventilatory failure due to chronic
obstructive airways disease. Lancet, 341:1555–7, 1993.
6. Lightlower JV, Wedzicha JA, Elliott MW. Non-invasive positive
pressure ventilation to treat respiratory failure resulting from
exacerbation of chronic obstructive pulmonary disease: Cochrane
systematic review and meta-analysis. BMJ 326:185–90, 2003.
7. Schnell D, Timsit J, Darmon M, Vesin A, Goldgran-Toledano
D, Dumenil A, Orgeas M, Adrie C, Bouadma L, Planquette B,

Volume 55 Number 3 July-Sept., 2017 7

Gopez UK, et al. Non-invasive Ventilation Versus Conventional Oxygen Therapy

Appendix A. PRISMA Chart of studies identified, screened, reviewed for eligibility and included.

8 Volume 55 Number 3 July - Sept., 2017

Non-invasive Ventilation Versus Conventional Oxygen Therapy Gopez UK, et al.

Appendix B. Sample Data Extraction Template

Trial ID Extractor: Year of publication:

Title
Authors

Participants
Inclusion criteria:
Exclusion criteria:

Experiment group:
Control group:

Risk of Bias Table

Domain Judgement Support for Judgement/
Low Risk/ High Risk/ Unclear Description
Method of Random sequence
Generation (Selection Bias)
Method of allocation
Concealment (Selection Bias)
Incomplete Outcome Data/Loss of
participants to follow up (Attrition Bias)
Blinding of Participants and Personnel
(Performance Bias)
Blinding of Outcome Assessment
(Detection Bias)
Selective Reporting/ Intention to treat
analysis (Reporting Bias)
Other Bias
Additional information requested
Notes

Outcomes
Total women =
Outcome Measures (Dichotomous)
Intervention group Control group
n= n=
events total events total
Primary:
1
Secondary:

2
3

----------------------------------END OF SAMPLE DATA EXTRACTION------------------------------------

Volume 55 Number 3 July-Sept., 2017 9

 Gopez UK, et al. Non-invasive Ventilation Versus Conventional Oxygen Therapy

Sample search strategy:

PubMed Google Scholar

Cochrane Database

Cochrane Database

8 Volume 55 Number 3 July - Sept., 2017

 Philippine Journal of Internal Medicine Meta-Analysis

The Efficacy of Oral Trimetazidine in Preventing Contrast-

Induced Nephropathy Among Patients Undergoing Elective
Coronary Procedures: A Meta-analysis of Randomized
Controlled Trials

Roland Reuben B. Angeles, M.D.*; Rich Ericson C. King, M.D.*; John D. Anonuevo, M.D.***; Elaine B. Alajar, M.D.***; Jose Eduardo D. Duya, M.D.**

Abstract
Introduction: Contrast-induced nephropathy (CIN) is
a serious but preventable complication of coronary
procedures. Trimetazidine (TMZ) has recently been explored
for use in preventing post-procedural CIN due to its cellular
anti-ischemic and antioxidant properties. The objective is to
assess the efficacy of oral TMZ in the prevention of contrast
induced nephropathy during elective coronary angiography
and PCI among patients with renal impairment.
Results: A total of four studies comprising 714 patients
(TMZ group=352, Control group=362) were included in
the final analysis. Pooled results revealed the TMZ group
was associated with significantly fewer incidences of CIN
compared to control (RR 0.33, 95% confidence interval [CI],
0.20, 0.53; P<.00001), with a relative risk reduction of 67%
and an absolute risk reduction of 11.04% (NNT=nine). No
dialysis-requiring CIN was observed in the included studies.

Methods: We conducted a systematic search of the
Cochrane Central Register of Controlled Trials, Pubmed/
MEDLINE, EMBASE, clinicaltrials.gov for articles published until
June 2016 for randomized controlled trials examining the
effects of adding oral TMZ to standard therapy in preventing
CIN. Outcome measures were incidence of CIN, defined
as a 0.5 mg/dl or ≥25% increase in serum creatinine 48-72
hours after contrast exposure, and incidence of dialysis-
requiring CIN. Validity of studies was assessed through a
risk assessment tool available from Cochrane. Treatment
effect was estimated by calculating the Mantel-Haenszel-
weighted risk ratio (RR) using a fixed-effects model available
from RevMan 5.3.
Conclusion: The addition of oral TMZ to standard hydration
confers a significant benefit in preventing CIN after coronary
procedures among patients with mild to moderate renal
impairment. We recommend the addition of TMZ to standard
prevention strategies. However, a large well-designed
trial should be conducted to determine its effect on other
outcomes such as prevention of dialysis-requiring CIN and
mortality.
Keywords: oral trimetazine, contrast-induced nephropathy,
elective coronary procedures

Introduction 15% of patients with CIN required short-term hemodialysis,10

Freeman et al., reported a low incidence of dialysis requiring
Contrast-induced nephropathy (CIN), defined as an
CIN (<0.5%). 9 Nevertheless, in their cohort, patients who
increase in the baseline serum creatinine concentration (SCr)
required dialysis had a significantly greater mortality rate
by ≥25% or 0.5 mg/dl 48-72 hours after contrast exposure,1
than those who did not (39% vs. 1.4%, p<0.001). Patients with
is a serious but preventable complication of coronary
pre-existing renal impairment and significant comorbidities
angiogram and percutaneous coronary interventions
are at higher risk for CIN, with prevalence rising to as high as
(PCI), occurring in as many as three to 24% who undergo
50% in patients with pre-existing renal disease or diabetes.10,11
such procedures despite existing methods of prevention.2–4
Several authors have found that even transient elevations of
The mechanism of injury is not yet fully understood but
serum creatinine is associated with increased morbidity and
is theorized to be due to either renal medullary hypoxia or
mortality, longer hospital stays, greater health expenditures
direct cellular toxicity from cytokine-mediated release of
and increased incidence of chronic renal failure. 5–9 While
free radicals and oxidative stress . 7,12,13 The role of volume
Manske, Sprafka, Strony and Wang found that as much
depletion and the resulting depressed activity of anti-
* Resident-in-training, Department of Internal Medicine, University of the oxidants and renal medullary ischemic injury have been
Philippines-Philippine General Hospital implicated. 14
**Cardiology fellow, Section of Cardiology, Department of Medicine,
Philippine General Hospital
***Consultant, Section of Cardiology, Department of Medicine, University Trimetazidine (TMZ) is a widely used anti-anginal agent
of the Philippines-Philippine General Hospital
that has anti-oxidant properties lending a protective effect
Corresponding author: Roland Reuben B. Angeles, M.D., University against free-radical damage. On the postulation that the
of the Philippines – Philippine General Hospital, Manila, Philippines pathogenesis of CIN can be attributed to medullary ischemia
Email: roland.angelesmd@gmail.com

The PHILIPPINE JOURNAL OF INTERNAL MEDICINE is a peer reviewed journal and a copyrighted publication of the Philippine College of Physicians Volume 55 Number 3 July-Sept., 2017 1
 Alajar EB, et al.
and generation of reactive oxygen species, TMZ has thus
been explored as a possible preventive strategy. 15 Such
a benefit was demonstrated in one animal study in which
fewer signs of glomerular and kidney damage were found
rats treated with TMZ prior to contrast exposure.16
Standard practice in the prevention of contrast-induced
nephropathy involves volume expansion with crystalloids
beginning three to 12 hours prior and up to six to 12 hours
after contrast exposure.17,18 Other interventions used for the
prevention of CIN include reduction of contrast volume and
use of non-ionic hypo-osmolar contrast agents. Administration
of medications such as statins, N-acetylcysteine (NAC),
ascorbic acid and sodium bicarbonate have been explored
as well, however the strength and quality of evidence for
many of these interventions are lacking.3,17–20 Trimetazidine
(TMZ) is another widely accessible intervention that has been
shown to have an added benefit in several small randomized
controlled trials.21–23 This is an update of a previous meta-
analysis published in 2015 by Nadkarni et al. 24, which had
inconclusive results due to the small number of studies
and small sample size involved. Since then, an additional
study has been conducted by Liu et al.25 which could add
robustness to currently available data.
Research question
Among adult patients with renal impairment undergoing
elective percutaneous coronary procedures, how effective
is oral trimetazidine compared to placebo, in addition
to standard therapy, in preventing contrast-induced
nephropathy?
Specific objectives
To determine the efficacy of oral trimetazidine
compared to placebo in reducing renal morbidity among
patients with renal impairment undergoing elective coronary
procedures in terms of:
a. incidence of CIN, defined as an increase in serum
creatinine (SCr) by ≥25% or 0.5 mg/dl from baseline
48-72 hours after contrast exposure
b. incidence of dialysis-requiring CIN
M ethods
Criteria for considering studies for this review
1. Types of studies - We included randomized controlled
trials that compared the effects of adding TMZ vs.
placebo to standard treatment in preventing CIN in a
population of patients with renal impairment undergoing
either coronary angiography +/- PCI. We included all
studies with original data on at least our target primary
outcome. No language constraints were applied.
2 Volume 55 Number 3 July - Sept., 2017
The Efficacy of Oral Trimetazidine in Preventing Contrast-induced Nephropathy
2. Types of participants - Study participants included adult
patients with renal impairment who underwent elective
coronary angiography and/or PCI.
3. Types of interventions - We included trials that compared
the effect of the addition of oral TMZ versus placebo
on top of standard therapy, which involved volume
expansion with 1.0 – 1.5 mL/kg/hr of isotonic crystalloid
for three to 12 hours prior to until six to 12 hours after
contrast exposure.
4. Types of outcome measures
• Primary outcomes - We included studies with outcome
measures of incidence of CIN, defined as either an
increase in serum creatinine by 0.5 mg/dL or 25% from
baseline values 48-72 hours post-procedure.
• Secondary outcomes - We searched for studies with
data on the incidence of dialysis-requiring CIN.
Search methods for identification of studies
The two authors independently searched the Cochrane
Central Register of Controlled Trials, Pubmed/MEDLINE,
EMBASE, clinicaltrials.gov for articles published until June
2016 for randomized controlled trials examining the effects of
adding oral TMZ to standard therapy in preventing CIN. We
employed a strategy of using three comprehensive search
themes combined with the boolean operator “OR”. For the
theme “coronary angiography”, we used combination of
MeSH, entry terms and text words for “coronary angiogra*”,
“coronary angiography” & “percutaneous coronary
intervention”. For the theme “acute kidney injury”, we used
renal failure, contrast nephropathy, acute kidney injury &
kidney. For the theme “contrast media”, we used contrast
& contrast media. The search result was then combined with
the term “Trimetazidine” using the boolean operator “AND”.
No language restrictions were imposed. The investigators
reviewed all relevant articles, with any discrepancies
resolved by consensus.
Searching other resources
The reference lists of relevant articles were perused
to search for any studies we might have missed. Studies
citing the RCTs and the meta-analysis were also sought.
Pharmaceutical companies involved in manufacturing
TMZ were contacted to request for any unpublished trials.
Unfortunately, the authors were not able identify or contact
any local authority who is currently conducting research on
the topic.
Data collection and analysis
Collected articles were independently screened and
evaluated by two authors (AR & KR) and differences in
judgment were settled by consensus. Data was extracted
using a data collection form. Analysis was performed in
accordance with the Cochrane Collaboration guidelines.26
 The Efficacy of Oral Trimetazidine in Preventing Contrast-induced Nephropathy Alajar EB, et al.

Data obtained was transcribed onto data collection forms R esults

and analyzed using Revman 5.3.
The initial search strategy yielded a total of 135 articles
Selection of studies
until June 2016. Ten studies were deemed relevant to our
research question, of which five are RCTs. We excluded one
Studies included all prospective, randomized controlled
study because it did not use the universal definition of CIN
trials investigating the efficacy of peri-procedural
(observed for up to seven days post-exposure, no data on
administration of oral TMZ in preventing CIN, compared to
Scr at 48-72 hours) (Figure 1).
standard treatment involving hydration with isotonic fluids.
We included only studies with available data on the baseline
and post-procedural (48-72 hours post-procedure) serum
creatinine values.

Data extraction and management

The two authors independently extracted the data

of included studies using a data extraction sheet, which
included publication year, details on trial participants
(number per treatment group, mean age, baseline
creatinine and presence of diabetes), description of the
intervention including trimetazidine dose, interval between
administration and coronary procedure, primary outcome
(creatinine clearance) including timing of measurement,
secondary outcomes, and study results.

Assessment of risk of bias in included studies

A risk assessment tool available from Cochrane was
used to assess for the validity and risk of bias of included
studies. Differences in assessment were settled by consensus.

Measures of treatment effect

We calculated the risk ratio to compare the benefit of
Figure 1. Preferred reporting items for systematic reviews and meta-analysis
adding TMZ vs. placebo to standard therapy in preventing flow chart of the included studies.
CIN.

Dealing with missing data Included studies

We attempted to contact the authors of the RCTs with
missing data.
Assessment of heterogeneity
The I 2 statistic was used to estimate heterogeneity
between trials.
Assessment of reporting biases
Screened articles were assessed using a risk assessment
tool available from the Cochrane library. Both authors
performed quality assessment independently. Disagreements
were resolved by consensus.
Data synthesis
We estimated treatment effects by calculating the
Mantel-Haenszel-weighted risk ratio (RR) using a fixed-
effects model of data analysis available with RevMan 5.3.
This was deemed ideal as the rates of CIN were low and the
collective sample size of included studies was low.
Four RCTs were included in the final analysis. Risk of bias
assessment of individual studies are summarized in Figure 2.
The characteristics of included studies are illustrated Table
I. The overall analysis included 714 patients (352 for TMZ plus
standard therapy and 362 for placebo). All participants
had mild to moderate CKD (serum creatinine of 1.2-2.5 mg/
dL or eGFR 30-90). The control group of all studies received
standard hydration defined as one ml/kg/hr of isotonic saline
solution 12 hours prior until 12-24 hours after the procedure.
One study included only patients undergoing angiography,
while another study only involved patients undergoing
PCI. The two others included those undergoing either
angiography or PCI. Patients with diabetes were included
in all studies except one. All studies excluded patients with
acute renal failure, end stage renal disease, shock, heart
failure and use of nephrotoxic agents. One study excluded
patients who were given N-acetylcysteine within the previous
48 hours. All studies utilized hypo-/iso-osmolar, non-ionic
contrast media.

Volume 55 Number 3 July-Sept., 2017 3

 Alajar EB, et al. The Efficacy of Oral Trimetazidine in Preventing

Table I. Characteristics of included RCTs

Study No. Control/ Age Diabetic Baseline SCr NAC Contrast Hydration TMZ Timing of Timing of SCr
(Year) No. Intervention (years ±SD) (%) (mmol/L ± given volume & timing dose TMZ determination
SD) (mL ± SD) (hrs. post-CA/PCI)

1cc/kg/hr 48 hrs.
Onbasili
60.49 113.41 12 hrs. prior 20mg PO prior until
et al. 42/40 56.1 No 232.68 24, 48
± 10.51 ± 18.01 until 12 hrs. 3x/day 24 hrs.
(2007)
after CA after CA

1cc/kg/hr 48 hrs.
Rahman
56.51 123.18 96.40 12 hrs. prior 35mg PO prior until
et al. 200/200 0 No 24, 48
± 10.36 ± 20.75 ± 4.94 until 12 hrs. 2x/day 48 hrs.
(2012)
after CA after CA
1-1.5cc/kg/hr 48 hrs.
Liu et al. 58.63 105.43 122.16 3-12 hrs. prior 20mg PO prior until
70/62 60.6 No 48, 72
(2015) ± 10.93 ± 21.59 ± 33.06 until 12 hrs. 3x/day 24 hrs.
after CA after CA
1cc/kg/hr 48 hrs.
Shehata
58.5 176.60 275 12 hrs. prior 35mg PO prior until
et al. 50/50 100 Yes 72
± 5.5 ± 39.74 ± 12.5 until 24 hrs. 2x/day 24 hrs.
(2014)
after PCI after PCI
*CA, coronary angiography; NAC, N-acetylcysteine; PCI, percutaneous coronary intervention; RCT, randomized controlled trial; SCr, serum creatinine; TMZ, trimetazidine

out of 362 (17%) who received standard therapy. The TMZ

group was significantly less associated with CIN compared
to control (RR: 0.33, 95% confidence interval [CI]: 020-0.53;
p<.00001). The absolute risk reduction was 11.4%, with a
computed NNT of nine in order to prevent one episode of
CIN.

Secondary outcome

The original protocol aimed to synthesize data on

dialysis-requiring CIN; however, no incidence of such was
reported in any of the studies.

Post-hoc analyses

The authors conducted sensitivity analyses to determine

if the pooled estimate of treatment effect would differ if we
excluded 1) the subgroup with more severe renal dysfunction
at baseline 2) the studies which did not complete 72 hours
of monitoring of SCr.

The study by Shehata et al. 23 included patients with

relatively more severe renal dysfunction at baseline
compared to the other three studies. As demonstrated in
Figure 4, there was still a significant difference between
treatment groups, favoring the addition of TMZ (RR: 0.30;
95% CI: 0.17-0.53, p<0.0001). The magnitude of effect for the
Figure 2. Summary of risk of bias assessment of included RCTs subgroup is slightly greater than the pooled estimate, and
even more so when compared to the findings of Shehata
Primary outcome et al. with a RR of 0.43.

Pooled results for incidence of CIN are illustrated in Liu et al. 25 and Shehata 23 observed for CIN up to 72
Figure 3. In the TMZ plus standard therapy group, 20 of the hours after exposure to contrast, noting the risk ratio for
352 (5.6%) participants developed CIN compared to 63 these studies (RR: 0.42, 95% CI 0.22-0.90, p = 0.008) is slightly
higher than the overall pooled estimate (Figure 5).

4 Volume 55 Number 3 July - Sept., 2017

 The Efficacy of Oral Trimetazidine in Preventing Contrast-induced Nephropathy Alajar EB, et al.

Figure 3. Forest plot showing the risk ratio for contrast-induced nephropathy (CIN) in patients given trimetazidine plus standard therapy versus standard therapy alone.
TMZ, Trimetazidine; ST, Standard therapy (Hydration +/- NAC); CI, confidence interval.

Figure 4. Forest plot showing risk ratio for contrast-induced nephropathy (CIN) in patients given trimetazidine plus standard therapy versus standard therapy alone after
excluding the subgroup with more severe renal impairment at baseline. TMZ, Trimetazidine; ST, Standard therapy (Hydration +/- NAC); CI, confidence interval.

Figure 5. Forest plot showing the risk ratio for contrast-induced nephropathy (CIN) in patients given trimetazidine plus standard therapy versus standard therapy alone
after only including studies which observed up to 72 hours after contrast exposure. TMZ, Trimetazidine; ST, Standard therapy (Hydration +/- NAC); CI, confidence interval.

D iscussion As of this writing, volume expansion by hydration is the

only pharmacological intervention recommended with a
high quality of evidence for the prevention of CIN.3,27,28 The
Contrast-induced nephropathy (CIN) is a serious
evidence for N-acetylcysteine, on the other hand, is so far
complication which needs to be addressed, especially since
inconclusive due conflicting results from various studies29 With
dialysis requiring CIN confers a very poor prognosis.9 Even
the collective evidence from the RCTs we have obtained,
without needing dialysis, occurrence of CIN is still associated
we found that TMZ, an oral anti-ischemic medication with
with significant morbidity and mortality 6,8 The results of our
a favorable safety profile, is efficacious in preventing CIN
meta-analysis show that compared to standard hydration
after coronary angiography.
± NAC alone, addition of oral TMZ is associated with a
significant decrease in the incidence of CIN after coronary
The RCTs included in this analysis enrolled patients
angiography among at-risk patients. The number needed to
with increased risk of CIN due to mild to moderate renal
treat was notably low, with only nine patients needed to be
dysfunction with or without diabetes mellitus, but all similarly
treated with TMZ to prevent the incidence of CIN. However,
employed guideline-based volume expansion and used
we were not able to assess its effects in preventing dialysis-
nonionic hypo- to iso-osmolar contrast media. TMZ was
requiring CIN because no data were available in the studies.
administered orally, with a dose of either 20 mg three times
a day 21,25 or 35 mg twice a day 22,23, given peri-procedurally
Our findings affirm the result of the meta-analysis by
for three days. Despite some methodological differences
Nadkarni which showed a similar magnitude of risk reduction
in the included studies, individual study results consistently
of 11%.24 Inclusion of the study by Liu, which included 132
favor the TMZ group (I2 = 0%).
patients, into the analysis further provided consistency to the
evidence for the benefit of trimetazidine in the prevention
Total contrast volume use varied from study to study,
of CIN.25
with the group of Shehata et al.23 in particular employing

Volume 55 Number 3 July-Sept., 2017 5

 Alajar EB, et al.
the highest volume (275 mL) of contrast per procedure, since
patients from that group underwent percutaneous coronary
intervention together with angiography.
Of note, patients included in the study of Shehata et
al. were patients at higher risk of CIN (all diabetic, higher
baseline SCr, higher volume of contrast used). We performed
a post-hoc analysis to compare the risk ratio of the patients
with lower baseline SCr to those with higher baseline SCR
and found a slightly lower renoprotective of TMZ for the
former. This may or may not imply that TMZ may be less
beneficial for those with higher baseline Scr due to the
presence of confounding factors. These findings should be
further investigated in future studies to better ascertain this
effect.
In addition, while an increase in SCr by >0.5mg/dL or
>25% from baseline was uniformly used as the definition
of CIN, two RCTs measured only up to 48 hours after
angiography21,22, potentially missing a subset of patients that
may present with CIN by the 72nd hour. Thus, the incidence
of CIN and in turn the effect of TMZ might be under or
overestimated. Indeed, the incidence of CIN was lower in
the group in which observation was done only for 48 hours
(eight percent) compared to those who observed for up to
72 hours (16%), which might explain the lower risk ratio for the
former (RR: 0.26, 95% CI: 0.13-0.53) compared to the latter
(RR: 0.42; 95% CI: 0.22-0.80).
Dropouts occurred in only one study 25, on which we
performed a sensitivity analysis that revealed the results to be
robust. While most of the RCTs showed only a trend favoring
TMZ (Figure 3), the pooled effect showed a significant
decrease in CIN with a relative risk of 0.33 (95% CI 0.20 –
0.53). The particularly wide confidence interval in the study
of Onbasili et al.21 may be due to its small sample size and
low incidence of observed outcome. While we also aimed
to investigate for the incidence of dialysis-requiring CIN with
and without TMZ, none of the included RCTs reported such
outcome. This may be due to both the small sample size of
the RCTs and the low incidence of dialysis-requiring CIN,
showing that a much larger population must be investigated
to observe such outcome.
Only one study added another intervention-
N-acetylcysteine on top of standard hydration23 Although this
might be seen as a potential confounder, both the treatment
group and control group received NAC. Whether or not there
was a synergistic effect between NAC and TMZ remains to
be seen; a study comparing TMZ alone and TMZ combined
with NAC may be necessary. No data was available whether
patients were receiving statins, but patients taking any
nephrotoxic medications were excluded.
The positive findings we have obtained for TMZ in
the prevention of CIN are particularly encouraging given
6 Volume 55 Number 3 July - Sept., 2017
The Efficacy of Oral Trimetazidine in Preventing Contrast-induced Nephropathy
its widespread availability, ease in administration, and
safety profile. Many patients who are to undergo coronary
procedures might in fact be already on TMZ due to its
anti-anginal properties. For the rest of patients, evidence
from this review shows that only a short treatment duration
is necessary (three to four days) for CIN prevention. Its
relatively low cost and oral route of administration make it
an acceptable intervention to many patients. Use of TMZ
was found to be safe across all studies included, with no
attributable adverse events noted.
There are some limitations in our meta-analysis that
should be considered. We were unable to analyze and
compare CIN risk among non-diabetic versus diabetic
patients because separate data on each group was not
available in two studies 21,25 Our study population included
only patients with a serum creatinine between 83.84-216.34;
thus, we were unable to analyze data for those with more
severe reductions in creatinine clearance. The current
available data is also still insufficient to draw conclusions as
to which populations of patients draw the greatest benefit
from administration of TMZ in terms of CIN prevention.
C onclusion
Our meta-analysis affirms the findings of previous studies
and strengthens the conclusion that TMZ is a safe and
effective addition to the strategies employed to prevent
CIN. Larger trials may be needed to assess for side-effects
and its effect on outcomes such as dialysis-requiring CIN and
mortality. We recommend for physicians to consider adding
oral TMZ as part of the therapeutic strategy to prevent CIN
after coronary angiography or percutaneous coronary
intervention among at-risk patients.
R eferences
1. Mehran R, Nikolsky E. Contrast-induced nephropathy: Definition,
epidemiology, and patients at risk. Kidney Int. 2006 Apr;69:S11–5.
2. Tsai TT, Patel UD, Chang TI, Kennedy KF, Masoudi FA,
Matheny ME, et al. Contemporary Incidence, Predictors,
and Outcomes of Acute Kidney Injury in Patients Undergoing
Percutaneous Coronary Interventions. JACC Cardiovasc Interv.
2014 Jan;7(1):1–9.
3. Subramaniam RM, Suarez-Cuervo C, Wilson RF, Turban S,
Zhang A, Sherrod C, et al. Effectiveness of Prevention Strategies
for Contrast-Induced Nephropathy: A Systematic Review and
Meta-analysis. Ann Intern Med. 2016 Mar 15;164(6):406.
4. Nikolsky E, Sudarsky D. Contrast-induced nephropathy in
interventional cardiology. Int J Nephrol Renov Dis. 2011 Jul;85.
5. Bartholomew BA, Harjai KJ, Dukkipati S, Boura JA, Yerkey
MW, Glazier S, et al. Impact of nephropathy after percutaneous
coronary intervention and a method for risk stratification. Am J
Cardiol. 2004 Jun;93(12):1515–9.
6. Finn WF. The clinical and renal consequences of contrast-induced
 The Efficacy of Oral Trimetazidine in Preventing Contrast-induced Nephropathy
nephropathy. Nephrol Dial Transplant. 2006 Jun 1;21(Supplement
1):i2–10.
7. Mohammed NM, Mahfouz A, Achkar K, Rafie IM, Hajar R,
others. Contrast-induced nephropathy. Heart Views. 2013;14(3):106.
8. James MT, Samuel SM, Manning MA, Tonelli M, Ghali WA,
Faris P, et al. Contrast-induced acute kidney injury and risk of
adverse clinical outcomes after coronary angiography a systematic
review and meta-analysis. Circ Cardiovasc Interv. 2013;6(1):37–43.
9. Freeman RV, O’Donnell M, Share D, Meengs WL, Kline-
Rogers E, Clark VL, et al. Nephropathy requiring dialysis after
percutaneous coronary intervention and the critical role of an
adjusted contrast dose. Am J Cardiol. 2002 Nov;90(10):1068–73.
10. Manske CL, Sprafka M, Strony JT, Wang Y. Nephropathy in
Azotemic Diabetic Patients Undergoing Coronary Angiography.
The American Journal of Medicine; 1990.
11. Thomsen HS, Morcos SK, Barrett BJ. Contrast-Induced
Nephropathy: The Wheel Has Turned 360 Degrees. Acta Radiol.
2008 Jan;49(6):646–57.
12. Geenen RWF, Kingma HJ, van der Molen AJ. Contrast-induced
nephropathy: pharmacology, pathophysiology and prevention.
Insights Imaging. 2013 Dec;4(6):811–20.
13. Andreucci M, Faga T, Pisani A, Sabbatini M, Russo D,
Michael A. Prevention of Contrast-Induced Nephropathy through
a Knowledge of Its Pathogenesis and Risk Factors. Sci World J.
2014;2014:1–16.
14. Yoshioka T, Fogo A, Beckman JK. Reduced activity of antioxidant
enzymes underlies contrast media-induced renal injury in volume
depletion. Kidney Int. 1992;41(4):1008–15.
15. McCarthy CP, Mullins KV, Kerins DM. The role of trimetazidine
in cardiovascular disease: beyond an anti-anginal agent. Eur Heart
J - Cardiovasc Pharmacother. 2016 Oct;2(4):266–72.
16. Akgüllü Ç, Saruhan T, Eryilmaz U, Boyacıoğlu M, Onbaşılı
OA, Meteoğlu İ, et al. The first histopathological evidence of
trimetazidine for the prevention of contrast-induced nephropathy.
Ren Fail. 2014 May;36(4):575–80.
17. Gupta R, Bang T. Prevention of Contrast-Induced Nephropathy
(CIN) in Interventional Radiology Practice. Semin Interv Radiol.
2010 Dec;27(4):348–59.
18. Owen RJ, Hiremath S, Myers A, Fraser-Hill M, Barrett BJ.
Canadian Association of Radiologists Consensus Guidelines for
the Prevention of Contrast-Induced Nephropathy: Update 2012.
Can Assoc Radiol J. 2014;65(2):96–105.
19. Owens DK, Lohr KN, Atkins D, Treadwell JR, Reston JT,
Bass EB, et al. AHRQ series paper 5: grading the strength of a
body of evidence when comparing medical interventions--agency
for healthcare research and quality and the effective health-care
program. J Clin Epidemiol. 2010 May;63(5):513–23.
20. Singh N, Lee JZ, Huang JJ, Low SW, Howe C, Pandit A, et al.
Benefit of statin pretreatment in prevention of contrast-induced
nephropathy in different adult patient population: systematic review
and meta-analysis. Open Heart. 2014;1(1):e000127.
21. Onbasili AO, Yeniceriglu Y, Agaoglu P, Karul A, Tekten T,
Akar H, et al. Trimetazidine in the prevention of contrast-
induced nephropathy after coronary procedures. Heart. 2007 Jun
1;93(6):698–702.
22. Rahman MM, Haque SS, Rokeya B, Siddique MA, Banerjee
Alajar EB, et al.
SK, Ahsan SA, et al. Trimetazidine in the prevention of contrast
induced nephropathy after coronary angiogram. Mymensingh Med
J MMJ. 2012 Apr;21(2):292–9.
23. Shehata M. Impact of Trimetazidine on Incidence of Myocardial
Injury and Contrast-Induced Nephropathy in Diabetic Patients With
Renal Dysfunction Undergoing Elective Percutaneous Coronary
Intervention. Am J Cardiol. 2014 Aug;114(3):389–94.
24. Nadkarni GN, Konstantinidis I, Patel A, Yacoub R, Kumbala
D, Patel RAG, et al. Trimetazidine Decreases Risk of Contrast-
Induced Nephropathy in Patients With Chronic Kidney Disease:
A Meta-Analysis of Randomized Controlled Trials. J Cardiovasc
Pharmacol Ther. 2015 Nov 1;20(6):539–46.
25. Liu W, Ming Q, Shen J, Wei Y, Li W, Chen W, et al. Trimetazidine
Prevention of Contrast-Induced Nephropathy in Coronary
Angiography. Am J Med Sci. 2015;350(5):398–402.
26. Moher D. Preferred Reporting Items for Systematic Reviews and
Meta-Analyses: The PRISMA Statement. Ann Intern Med. 2009
Aug 18;151(4):264.
27. Zhang B, Liang L, Chen W, Liang C, Zhang S. The efficacy of
sodium bicarbonate in preventing contrast-induced nephropathy
in patients with pre-existing renal insufficiency: a meta-analysis.
BMJ Open. 2015 Mar 17;5(3):e006989–e006989.
28. Ali-Hassan-Sayegh S, Mirhosseini SJ, Ghodratipour
Z, Sarrafan-Chaharsoughi Z, Rahimizadeh E, Karimi-
Bondarabadi AA, et al. Strategies Preventing Contrast-Induced
Nephropathy After Coronary Angiography: A Comprehensive
Meta-Analysis and Systematic Review of 125 Randomized
Controlled Trials. Angiology [Internet]. 2016 Aug 1 [cited
2016 Sep 27]; Available from: http://ang.sagepub.com/cgi/
doi/10.1177/0003319716661445
29. Sun Z, Fu Q, Cao L, Jin W, Cheng L, Li Z. Intravenous
N-Acetylcysteine for Prevention of Contrast-Induced Nephropathy:
A Meta-Analysis of Randomized, Controlled Trials. Lipinski M,
editor. PLoS ONE. 2013 Jan 30;8(1):e55124.
Volume 55 Number 3 July-Sept., 2017 7
Alajar EB, et al.
Liu et al. (2015)
Bias
Random sequence generation
(selection bias)
Allocation concealment
(selection bias)
Blinding of participants and
personnel (performance bias)
Blinding of outcome assess-
ment (detection bias)
Incomplete outcome data
(attrition bias)
Selective reporting
(reporting bias)
Other bias
Onbasili et al. (2007)
Bias
Random sequence generation
(selection bias)
Allocation concealment
(selection bias)
Blinding of participants and
personnel (performance bias)
Blinding of outcome assess-
ment (detection bias)
Incomplete outcome data
(attrition bias)
Selective reporting
(reporting bias)
Other bias
Rahman et al. (2012)
Bias
Random sequence generation
(selection bias)
Allocation concealment
(selection bias)
Blinding of participants and
personnel (performance bias)
Blinding of outcome assess-
ment (detection bias)
Incomplete outcome data
(attrition bias)
Selective reporting
(reporting bias)
Other bias
8 Volume 55 Number 3 July - Sept., 2017
The Efficacy of Oral Trimetazidine in Preventing Contrast-induced Nephropathy
Appendix 1. Risk of bias assessment for individual studies
Authors’
Support for judgement
judgement
Low risk This study was a prospective, randomized and controlled clinical trial. Patients were ran-
domly allocated into control group (n=75) and TMZ group (n=75).
Unclear risk
No mention
Unclear risk No mention of blinding
(but outcome not affected)
Low risk Clinicians who were responsible for collecting information during follow-up were blind to
grouping in this study.
Low risk Complete laboratory tests were not available in 8 patients (control group: n=3, TMZ group:
n=5)
Results robust with sensitivity analysis.
Low risk There were another 4 patients of TMZ group withdrawing from this study for refusing to use
TMZ before PCI; and one patient in TMZ group without receiving coronary angiography due
to other reasons. The 18 patients mentioned above were excluded from the final analysis.
However, due to nature of intervention (simple to follow and supervised in a hospital set-
ting), virtually very low risk of problems with compliance
Low risk
Authors’
Support for judgment
judgment
Low risk
Patients were randomly assigned to two groups: TMZ (n=40) and control (n=42).
Unclear risk
No mention
Low risk This study was a prospective double-blind, randomized, controlled trial.
Low risk
This study was a prospective double-blind, randomized, controlled trial.
Low risk
No dropouts in the study
Low risk
All patients at the start of the trial were accounted for in the results.
Low risk
Authors’
Support for judgment
judgment
Low risk The patients were randomly assigned to receive either trimetazidine and hydration with
normal saline (treated group) or hydration with normal saline only (control group).
Unclear risk
No mention of allocation concealment
Unclear risk
No mention of blinding
Low risk No mention of blinding
Although nature of treatment outcome unlikely to be affected by lack of blinding
Low risk
No missing outcome data
Low risk
All subjects analyzed in the group to which they were randomized
Low risk
 The Efficacy of Oral Trimetazidine in Preventing Contrast-induced Nephropathy Alajar EB, et al.

Shehata et al. (2014)

Authors’
Bias Support for judgment
judgment
Random sequence generation Low risk After enrollment and before PCI, patients were randomly assigned in 1:1 fashion to either
(selection bias) the trimetazidine group or the control group according to a computer-generated random
series of numbers. Randomization was performed by block randomization (blocks of 10
patients).
Allocation concealment Unclear risk
No mention of allocation concealment
(selection bias)
Blinding of participants and Low risk
Physicians participating in the PCI procedures were unaware of block randomization
personnel (performance bias)
Blinding of outcome assess- Low risk
No mention (although will not affect outcome)
ment (detection bias)
Incomplete outcome data Low risk
No missing outcome data
(attrition bias)
Selective reporting Low risk
All subjects analyzed in the group to which they were randomized
(reporting bias)

Volume 55 Number 3 July-Sept., 2017 9

 Philippine Journal of Internal Medicine
Association of the Platelet–Lymphocyte Ratio (PLR) with
Outcomes in Patients Admitted for Acute Coronary Syndrome:
The PLACS Study
Lauro L. Abrahan IV, M.D.*; Jaime Alfonso M. Aherrera, M.D.*; John Daniel A. Ramos, M.D.*; Paul Ferdinand Reganit, M.D.**; Felix Eduardo Punzalan, M.D.**
Abstract
Introduction: Patients with acute coronary syndrome (ACS)
exhibit a wide spectrum of early risk of death (one to 10
percent). High platelet counts may indicate a propensity
for platelet-rich thrombi. Lymphocyte counts drop during
ACS due to stress-induced cortisol release. Combining these
two markers, recent studies have found that the platelet-to-
lymphocyte ratio (PLR) is associated with adverse cardiac
events among patients with ACS, but local data is limited.
The objective of this study is to determine if an elevated
PLR taken on admission is associated with higher rates of
adverse cardiac events.
Methods: A retrospective cohort of adult patients with
ACS admitted at the UP-Philippine General Hospital was
analyzed. Leukocyte and platelet counts were measured
by an automated hematology analyzer. The PLR values of
these patients were computed, and they were stratified
into two groups after determining the optimal cut-off
from the receiver operating characteristic curve (ROC)
curve. The primary outcome was in-hospital mortality.
Secondary outcomes included development of heart failure,
cardiogenic shock, reinfarction, and significant arrhythmias.
Introduction
Inflammation plays a central role in the atherosclerotic
process that underlies coronary artery disease (CAD). 1
Platelets, in particular, have a crucial part in the pathogenesis
of atherosclerosis. They interact with endothelial cells and
white blood cells (WBCs), releasing chemoattractant
substances that facilitate monocyte transmigration through
the vessel wall. 2,3 Low-grade inflammation, through a variety
of mediators, also induces thrombocytosis.4 Several studies
have demonstrated the association of thrombocytosis with
decreased survival and poor clinical outcomes following an
acute coronary event.5,6,7,8
Lymphocytes, on the other hand, have been implicated
in regulating the inflammatory response during the
*Fellow in training, Section of Cardiology, Department of Medicine,
University of the Philippines-Philippine General Hospital
**Consultant, Section of Cardiology, Department of Medicine, University
of the Philippines-Philippine General Hospital
Corresponding author: Lauro L. Abrahan IV, M.D., University of the
Philippines – Philippine General Hospital, Manila, Philippines
Email: s.abrahan@gmail.com
The PHILIPPINE JOURNAL OF INTERNAL MEDICINE is a peer reviewed journal and a copyrighted publication of the Philippine College of Physicians
Original Paper
Results: A total of 174 Filipinos with ACS were included.
In-hospital mortality occurred in 30 patients (17%). These
patients had a higher PLR compared to those who were
discharged alive (p-value <0.0001). The optimal cutoff value
of PLR to predict in-hospital mortality is 165, with a sensitivity
of 77% and specificity of 70% (area under the ROC curve of
0.766). On multiple logistic regression analysis, a high PLR was
an independent predictor of in-hospital mortality (RR 8.52; p
0.003) after controlling for the effect of other variables. The
development of the predetermined secondary outcomes
did not correlate with PLR on multivariate analysis.
Conclusion: Among Filipino patients with ACS, an elevated
PLR taken within 24 hours of admission is a useful marker to
predict in-hospital mortality, thus providing vital information
for risk stratification and more aggressive management
strategies.
Keywords: platelet-lymphocyte ratio, acute coronary
syndrome
development of atherosclerotic lesions,9 and low lymphocyte
counts have been correlated with higher mortality and
low ejection fraction (EF) in patients with acute coronary
syndrome (ACS).10,11 It is theorized that high cortisol levels from
the stress of ACS leads to lymphopenia via apoptosis. 12,13
Combining platelet count with the lymphocyte
count yields the platelet-lymphocyte ratio (PLR), and
several foreign studies have already substantiated the
use of PLR as a prognostic marker (Appendix A, Table I).
Given the generally limited resources in our healthcare
system, the PLR may be a useful but inexpensive tool for risk
stratification in Filipino patients with ACS, and may have
improved discriminative capability compared to either
platelet or lymphocyte count alone. Prognostication is
a vital element in the ACS treatment pathway, since
patients known to have high risk features and increased
mortality rates will likely benefit from more aggressive
and/or invasive strategies such as early percutaneous
coronary intervention. To our knowledge, this is the first
study examining this simple but reliable tool in our local
setting.
Volume 55 Number 3 July-Sept., 2017 1
 Abrahan LL, et al.
Research Question:
Among patients diagnosed with ACS in the Philippine
General Hospital (PGH), is an elevated PLR taken within
24 hours of admission associated with higher rates of
cardiovascular mortality and morbidity?
Objectives
General Objective
1. To determine if PLR taken within 24 hours of hospital
admission is associated with adverse outcomes in
patients diagnosed with ACS
Specific Objectives
1. To describe the clinical and laboratory profile of patients
admitted for ACS
2. To determine the optimal cut-off value of PLR for
predicting in-hospital mortality in patients diagnosed
with ACS
3. To determine if there is a correlation between a high PLR
on admission and the occurrence of adverse outcomes
a. Primary outcome: in-hospital mortality
b. Secondary outcomes: development of heart considered. A p-value < 0.25 was considered as a statistically
failure (or worsening of chronic compensated heart
failure), reinfarction, arrhythmias, cardiogenic
shock
4. To enumerate other predictors of adverse cardiovascular
outcomes in ACS
M ethods
This study is a single-center, retrospective cohort study
conducted at the UP-PGH. All admitted adult patients with
a diagnosis of ACS (UA, NSTEMI, STEMI) at UP-PGH within
a span of seven months were screened. The diagnosis of
ACS was independently verified by two of the investigators
using the universal definition of ACS (Appendix B). Patients
who met any of the following exclusion criteria were not
included in the study: any form of infection on admission,
any acute inflammatory/autoimmune condition (including,
but not limited to, acute renal failure, gout in flare, lupus in
flare, etc.), active tuberculosis, any hematologic disease,
bleeding of any form, managed at a different facility prior
to UP-PGH, and onset of symptoms more than 24 hours prior
to admission.
The complete blood count on admission (sent to our
centralized laboratory utilizing the automated Beckman
Coulter® UniCel DxH 800 Cellular Analysis System) of
these patients was recorded in the standardized data
sheet (Appendix C). The PLR values of these patients
were computed: platelet count divided by lymphocyte
count. Their in-hospital course was then monitored for the
development of the predetermined outcomes. The primary
outcome for this study was in-hospital death (cardiac or
2 Volume 55 Number 3 July - Sept., 2017
Association of the Platelet–Lymphocyte Ratio (PLR)
non-cardiac). Secondary outcomes were the following:
development or worsening of heart failure, reinfarction,
significant arrhythmias (excluding premature atrial or
ventricular complexes), and cardiogenic shock.
Descriptive analysis was done by obtaining the mean
and standard deviation of quantitative variables. Proportions
and frequencies were reported for qualitative variables. For
quantitative variables, T-test of two independent samples
was used to determine if there was a statistically significant
difference. For categorical variables, the Z-test was used.
The optimal cut-off for the PLR to predict adverse outcomes
(in-hospital mortality) was determined using the receiver
operating characteristic (ROC) curve. After determining the
optimal cut-off, the population was divided into those with
a high PLR versus a low PLR.
Logistic regression analysis was used to find correlation
between a high PLR and the subsequent development
of cardiovascular events with or without adjustments for
potentially confounding baseline variables. Age, male sex,
obesity (BMI >25 kg/m2), high risk TIMI scores, elevated WBC,
and occurrence of adverse cardiovascular events were also
significant association in univariate analysis. All significant
variables were included in the final model of multivariate
analysis to determine the association with the predetermined
outcomes.
The protocol was submitted for ethical review to the
University of the Philippines Manila Research Ethics Board
(UPMREB) prior to data collection, and the study was carried
out only upon ethical approval of the protocol. There is no
conflict of interest in this study which may arise from financial,
familial, or proprietary considerations of the primary and co-
investigators or the study site. The investigators shouldered
the cost of this research.
R esults
Clinical Profile of Patients with ACS
In total, 174 patients recruited over a span of seven
months were included in the analysis. The mean age was
59 ± 12 years, and 72% of the sample population was male.
The baseline characteristics of these patients are summarized
in Table I, classified according to the primary outcome of
in-hospital mortality, which occurred in 30 patients (17.2%).
Patients who died were older (p=0.001), predominantly male
(p=0.034), and had a higher proportion of chronic kidney
disease (CKD) as a co-morbidity (p=0.011). There were no
significant differences in terms of other individual risk factors
for ACS. Diagnosis on admission was unstable angina (26%),
NSTEMI (34%), and STEMI (40%). Mortalities had higher TIMI
risk scores and faster heart rates on admission.
 Association of the Platelet–Lymphocyte Ratio (PLR) Abrahan LL, et al.

Table I. Baseline clinical characteristics

Variables Total Mortalities Survivors p-value

(n=174) (n=30) (n=144)
Age (mean ± SD) 59.05 ± 12.59 65.87 ± 13.01 57.63 ± 12.07 0.0010
Sex
Male 48 (27.59) 13 (43.33) 35 (24.31)
Female 126 (72.41) 17 (56.67) 109 (75.69) 0.0339
BMI (mean ± SD) 24.94 ± 3.34 25.25 ± 4.18 24.87 ± 3.15 0.5754
Co-Morbidities and Risks
Diabetes 54 (31.03) 7 (23.33) 47 (32.64) 0.3162
Hypertension 127 (72.99) 24 (80.00) 103 (71.53) 0.3417
Dyslipidemia 67 (38.51) 12 (40.00) 55 (38.19) 0.8533
Smoker 71 (40.80) 11 (36.67) 60 (41.67) 0.6122
Chronic Kidney Disease 22 (12.64) 8 (26.67) 14 (9.72) 0.0111
Prior Angina 65 (37.36) 12 (40.00) 53 (36.81) 0.7421
Prior MI 49 (28.16) 10 (33.33) 39 (27.08) 0.4887
New York Functional Class
I or II 172 (98.85) 29 (96.67) 143 (99.31)
III or IV 2 (1.15) 1 (3.33) 1 (0.69) 0.2174
Prior Revascularization 12 (6.90) 3 (10.00) 9 (6.25) 0.4609
Documented CAD 19 (10.92) 3 (10.00) 16 (11.11) 0.8591
Diagnosis
UA 45 (25.86) 3 (10.00) 42 (29.17)
NSTEMI 59 (33.91) 16 (53.33) 43 (29.86) 0.0220
STEMI 70 (40.23) 11 (36.67) 59 (40.97)
% Risk of Mortality Based on TIMI
13.95 ± 10.44 24.63 ± 10.43 11.72 ± 8.99 <0.0001
(mean ± SD)
High Risk TIMI Score * 65 (37.36) 21 (70.00) 44 (30.56) <0.0001
Heart Rate (mean ± SD) 81.26 ± 20.22 101.13 ± 22.40 77.12 ± 17.11 <0.0001
Admission Heart Rate >100 bpm 27 (15.52) 16 (53.33) 11 (7.64) <0.0001
*TIMI Score: A high risk TIMI score was >3 points for UA/NSTEMI and >5 points for STEMI. Components of the score include age, diabetes/hypertension/angina, systolic BP ≥100, heart rate > 100, Killip class, weight,
anterior ST elevation or LBBB on ECG, and time to treatment for STEMI; and age ≥65, ≥3 traditional risk factors for vascular disease, known coronary stenosis ≥50%, presence of >0.5 mm ST segment deviation on
admission ECG, angina episodes within the last 24 hours, positive biomarkers, and use of ASA in the last 7 days for UA/NSTEMI.

Table II. Patient laboratory findings

Variables Total Mortalities Survivors p-value

(n=174) (n=30) (n=144)
Hemoglobin (mean ± SD) 130.22 ± 22.36 123.40 ± 21.93 131.65 ± 22.26 0.0660
WBC (mean ± SD) 11.73 ± 9.00 15.28 ± 16.47 10.99 ± 6.31 0.0170
Platelet (mean ± SD) 253.27 ± 82.73 265.93 ± 99.09 250.63 ± 79.04 0.3583
Lymphocyte (mean ± SD) 20.13 ± 10.71 12.03 ± 6.91 21.82 ± 10.61 <0.0001
PLR (mean ± SD) 160.05 ± 102.91 242.10 ± 128.78 142.96 ± 87.99 <0.0001
Trop I (n=129, mean ± SD) 18.19 ± 27.08 10.22 ± 17.18 20.10 ± 28.70 0.1014
CKMB (n=53, mean ± SD) 72.09 ± 106.69 39.10 ± 31.34 79.76 ± 116.46 0.2819
Creatinine (n=169, mean ± SD) 149.84 ± 160.83 239.52 ± 263.45 131.26 ± 123.52 0.0008

Volume 55 Number 3 July-Sept., 2017 3

 Abrahan LL, et al. Association of the Platelet–Lymphocyte Ratio (PLR)

Table III. In-hospital adverse cardiovascular events

Variables Total Mortalities Survivors p-value

(n=174) (n=30) (n=144)
Reinfarction 26 (14.94) 11 (36.67) 15 (10.43) 0.0002
Severe CHF 61 (35.06) 28 (93.33) 33 (22.92) <0.0001
Arrhythmia 31 (17.82) 12 (40.00) 19 (13.19) 0.0005
Cardiogenic Shock 54 (31.03) 21 (70.00) 33 (22.92) <0.0001

Laboratory Profile of Patients with ACS Table IV. Univariate analysis: predictors of in-hospital mortality

Table II describes the laboratory parameters for the Variables Relative Risk p-value
patients in this study. PLR was demonstrated to be significantly Age > 50 years 2.41 (0.79 – 7.36) 0.121
higher for patients in the mortality group (p< 0.0001). The
Male Sex 0.42 (0.19 – 0.95) 0.037
mean PLR of patients who died was 242.10, while the mean
BMI > 25 kg/m2 1.60 (0.73 – 3.53) 0.244
PLR of patients who survived was 142.96. Of note, there
was no significant statistical difference between mean High Risk TIMI Score 5.30 (2.25 – 12.50) <0.001
platelet counts of non-survivors and survivors (265.93 vs. PLR > 165.35 7.72 (3.08 – 19.33) <0.001
250.63, p=0.358). There was also no significant difference WBC > 12 x 109/L 1.04 (1.00 – 1.08) 0.072
between the two groups in terms of levels of cardiac Occurrence of Complications
enzymes (whether troponin I or CKMB). Creatinine levels Reinfarction 4.98 (1.99 – 12.43) 0.001
were higher in patients who expired. Severe CHF 47.09 (10.65 – 208.16) <0.001
Arrhythmia 4.39 (1.83 – 10.53) 0.001
Outcomes Cardiogenic Shock 7.85 (3.28 – 18.78) <0.001

Thirty patients (17%) experienced the primary outcome Table V. Multivariate analysis: independent predictors of in-hospital
of mortality. Table III shows that the occurrence of the mortality
other secondary adverse cardiovascular events was all
Variables Relative Risk p-value
significantly higher for the patients who expired.
Severe CHF 28.12 (5.40 – 146.31) <0.001
Optimal Cut-Off of PLR to Predict In-Hospital Mortality High PLR > 165.35 8.52 (2.06 – 35.21) 0.003
High Risk TIMI Score 4.81 (1.29 – 17.93) 0.019
In the ROC analysis (Figure 1), a PLR >165 had 76.7%
BMI > 25 kg/m2 4.09 (1.06 – 15.74) 0.040
sensitivity and 70.1% specificity to predict death, with an area
under the curve or C-statistic of 0.766. A cut-off PLR of >165 is
Predictors of In-Hospital Mortality (Primary Outcome)
therefore associated with higher risk for mortality.

Univariate logistic regression analysis determined the

FIGURE 1. ROC curve for PLR to predict in-hospital mortality in ACS.
association of certain variables with in-hospital mortality:
age >50 years, male sex, obesity (BMI >25 kg/m2), high risk
TIMI scores, high PLR (>165), elevated WBC (>12 x 109),
and occurrence of adverse cardiovascular events. Table
IV shows the results of univariate analysis. On multivariate
analysis (Table V), a high PLR value of > 165 was demonstrated
as an independent predictor of in-hospital mortality (RR 8.52;
p= 0.003), after adjusting for other factors. Other significant
predictors include HR >100 beats/min. (RR 10.46; p=0.001),
severe CHF (RR 28.12; p < 0.001), high risk TIMI score (RR 4.81;
p = 0.019) and obesity (RR 4.09; p=0.04). The relative risk
of mortality in patients with an elevated PLR (>165) is 8.52
times higher than those with lower PLR values (CI 2.06 – 35.21,
p=0.003), thus supporting our hypothesis that there is indeed
a statistically significant correlation between a high PLR and
mortality in ACS patients.

4 Volume 55 Number 3 July - Sept., 2017

 Association of the Platelet–Lymphocyte Ratio (PLR)
Table VI. Multivariate analysis: independent predictors of secondary
outcomes
Outcome Independent Predictors
Heart Failure Shock, reinfarction, age > 50, male sex
Cardiogenic Shock Severe CHF, high risk TIMI score, age > 50
Reinfarction Severe CHF
Arrhythmia Shock, male sex
Predictors of Secondary Outcomes
The secondary outcomes (development of heart
failure, cardiogenic shock, reinfarction, and significant
arrhythmias) did not correlate with PLR on multivariate
analysis. Other variables such as male sex and age >50
were more prominent as independent predictors for these
complications of ACS (Table VI).
D iscussion
Our present study examined the relationship between
PLR on admission and in-hospital mortality in ACS patients.
Baseline clinical characteristics between mortalities and
survivors were mostly similar, with the exception of age,
sex, and presence of CKD. The higher TIMI risk scores in
patients who died is supported by previous studies that
examined the use of the TIMI score as a prognostic tool for
patients with ACS.14,15,16 A notable finding is that the level of
cardiac enzymes (troponin, CKMB) did not differ significantly
between the two groups, which can be partly explained by
incomplete sampling and non-standardized timing of serum
collection (ranging from one hour to three days). Faster heart
rates on admission were also seen in the mortality group,
which highlights the importance of adequate heart rate
control in the early post-MI period.
In our multivariate logistic regression analysis, we
demonstrated that high PLR is a statistically significant and
independent predictor of in-hospital mortality in patients
with ACS. Interestingly though, mean platelet count was
not significantly different between mortalities and survivors
(265.9 x 10 9/L vs. 250.6 x 10 9/L, p=0.338), implying that PLR
may actually be a more reliable marker for prognosis than
platelet count alone. From the ROC analysis of our data
set, we have determined a PLR >165 as the optimal cut-off
value for predicting in-hospital mortality in ACS (sensitivity
of 76.70% and specificity of 70.10%, area under the curve
0.766). The mechanism behind this association of elevated
PLR with increased mortality may be explained by a higher
degree of antiplatelet drug resistance and/or more platelet-
rich thrombi in atherosclerotic plaques.17
Our findings are consistent with other studies in foreign
literature that have reviewed the relationship of PLR with
various cardiovascular surrogate and clinical outcomes. The
Abrahan LL, et al.
most similar to our study was that of Oylumlu et al.17, albeit
with a slightly lower optimal PLR cut-off value of 142. Azab
et al.18 found PLR to be an independent predictor of four-
year mortality in NSTEMI patients. Also examining NSTE-ACS
patients, Bekler et al.13 showed that PLR correlated well with
poor LV systolic function on echocardiography. The studies
by Hudzik et al. 19, Temiz et al. 20, and Ugur et al. 21 focused on
STEMI patients, and they all successfully demonstrated high
PLR to be a predictor of mortality for this subset of ACS. In
terms of angiographic grading for CAD, Kurtul et al.22 and
Yüksel et al. 23 showed that higher PLR correlated with higher
SYNTAX and Gensini scores, respectively. Finally, Gary et al. 24
found high PLR to be an independent marker for critical limb
ischemia in patients with PAD. The major findings of these
studies are summarized in Appendix A.
There is a mild degree of variation in the optimal PLR
value used as a cut-off for the aforementioned publications
as well as our own study, ranging from 111 to 176. These
may be accounted for by racial differences in the study
populations, together with some permutations as to the
exact subset of ischemic heart disease included for the
studies (NSTE-ACS vs. STEMI vs. stable CAD). In addition,
some studies examined surrogate outcomes such as left
ventricular ejection fraction on echocardiography and
lesion severity on coronary angiography instead of patient
mortality. Nevertheless, these studies all generally agree that
high PLR values portend a poorer prognosis for patients with
atherosclerotic disease.
In terms of the secondary outcomes, PLR failed to
significantly correlate with any of the adverse cardiovascular
morbidities that were monitored for this study (reinfarction,
severe HF, significant arrhythmias, and cardiogenic shock).
This seeming disparity may be explained by limitations in the
study design, particularly the short follow-up duration. Patients
were only monitored during their hospital confinement, and
major adverse CV events may have occurred after hospital
discharge.
Limitations and Recommendation
This study represented a single-center experience
and only examined in-hospital mortality and outcomes.
Recommendations for future studies include involvement of
other major health centers to enlarge the sample size, as well
as long-term follow-up that extends even beyond hospital
discharge.
C onclusion
Among patients with ACS, a high PLR >165 taken within 24
hours of presentation is a useful and readily available marker
to predict in-hospital mortality. The PLR values of ACS patients
who died (PLR 242.10) were significantly higher compared to
Volume 55 Number 3 July-Sept., 2017 5
 Abrahan LL, et al. Association of the Platelet–Lymphocyte Ratio (PLR)

the survivors (PLR 142.96). For this cohort, however, PLR did
not correlate with the development of other major adverse
cardiovascular outcomes, such as worsening heart failure,
reinfarction, arrhythmias, and cardiogenic shock. Other
independent predictors of mortality among ACS patients
included the development of severe heart failure, high risk
TIMI scores, and BMI > 25 kg/m 2. Used in conjunction with
clinical judgment and other risk scoring systems, a high PLR
in ACS patients may reflect the need for more aggressive
therapeutic interventions. This paper represents the first
endeavor to investigate the utility of PLR in Filipino ACS
patients, and can pave the way for future studies.
J 1994;127:1226-30.
12. Gupta S, Agrawal A, Agrawal S, Su H, Gollapudi S. A paradox
of immunodeficiency and inflammation in human aging: lessons
learned from apoptosis. Immun Ageing 2006; 3: 5.
13. Bekler A, Gazi E, Yılmaz M, et al. Could elevated platelet-
lymphocyte ratio predict left ventricular systolic dysfunction in
patients with non-ST elevated acute coronary syndrome? Anadolu
Kardiyol Derg. 2014 Apr 16.
14. Antman EM, Cohen M, Bernink PJ, et al. The TIMI risk
score for unstable angina/non-ST elevation MI: A method for
prognostication and therapeutic decision making. JAMA. 2000
Aug 16;284(7):835-42.
15. Hess EP, Agarwal D, Chandra S, et al. Diagnostic accuracy of

R eferences the TIMI risk score in patients with chest pain in the emergency
department: a meta-analysis. CMAJ. 2010 Jul 13;182(10):1039-44.
16. Morrow DA, Antman EM, Charlesworth A, et al. TIMI risk score
1. Hansson GK. Inflammation, atherosclerosis, and coronary artery
for ST-elevation myocardial infarction: A convenient, bedside,
disease. N Engl J Med 2005; 352: 1685-95.
clinical score for risk assessmentat presentation: An intravenous
2. Gawaz M, Langer H, May AE. Platelets in inflammation and
nPA for treatment of infarcting myocardium early II trial substudy.
atherogenesis. J Clin Invest 2005; 115: 3378-84.
Circulation. 2000 Oct 24;102(17):2031-7.
3. Lindemann S, Kramer B, Seizer P, Gawaz M. Platelets,
17. Oylumlu M, Yıldız A, Oylumlu M, et al. Platelet-to-lymphocyte
inflammation and atherosclerosis. J Thromb Haemost 2007; 5:
ratio is a predictor of in-hospital mortality patients with acute
203-11.
coronary syndrome. Anadolu Kardiyol Derg. 2014 Apr 8.
4. A l e x a n d r a k i s M G , P a s s a m F H , M o s c h a n d r e a I A ,
18. Azab B, Shah N, Akerman M, et al. Value of platelet/
Christophoridou AV, Pappa CA, Coulocheri SA, et al. Levels
lymphocyte ratio as a predictor of all-cause mortality after non-
of serum cytokines and acute phase proteins in patients with
ST-elevation myocardial infarction. J Thromb Thrombolysis. 2012
essential and cancer-related thrombocytosis. Am J Clin Oncol
Oct;34(3):326-34.
2003; 26: 135-40.
19. Hudzik B, Szkodzinski J, Gorol J, et al. Platelet-to-lymphocyte
5. Iijima R, Ndrepepa G, Mehilli J, Bruskina O, Schulz S, Schomig
ratio is a marker of poor prognosis in patients with diabetes
A, et al. Relationship between platelet count and 30 day clinical
mellitus and ST-elevation myocardial infarction. Biomark Med.
outcomes after percutaneous coronary interventions. Pooled
2015 Mar;9(3): 199-207.
analysis of four ISAR trials. Thromb Haemost 2007; 98: 852-7.
20. Temiz A, Gazi E, Güngör Ö, et al. Platelet/lymphocyte ratio
6. Nikolsky E, Grines CL, Cox DA, Garcia E, Tcheng JE, Sadeghi
and risk of in-hospital mortality in patients with ST-elevated
M, et al. Impact of baseline platelet count in patients undergoing
myocardial infarction. Med Sci Monit. 2014 Apr 22;20:660-5.
primary percutaneous coronary intervention in acute myocardial
21. Ugur M, Gul M, Bozbay M, et al. The relationship between
infarction (from the CADILLAC trial). Am J Cardiol 2007; 99:
platelet to lymphocyte ratio and the clinical outcomes in ST
1055-61.
elevation myocardial infarction underwent primary coronary
7. Jakl M, Sevcik R, Ceral J, Fatorova I, Horacek JM, Vojacek
intervention. Blood Coagul Fibrinolysis. 2014 Dec;25(8):806-11.
J. Mean platelet volume and platelet count: overlooked markers
22. Kurtul A, Murat SN, Yarlioglues M, et al. Association of platelet-
of high on-treatment platelet reactivity and worse outcome in
to-lymphocyte ratio with severity and complexity of coronary
patients with acute coronary syndrome. Anadolu Kardiyol Derg
artery disease in patients with acute coronary syndromes. Am J
2014; 14: 85-6.
Cardiol. 2014 Oct 1;114(7):972-8.
8. Ly HQ, Kirtane AJ, Murphy SA et al: Association of platelet
23. Yüksel M, Yıldız A, Oylumlu M, et al. The association between
counts on presentation and clinical outcomes in ST-elevation
platelet/lymphocyte ratio and coronary artery disease severity.
myocardial infarction (from the TIMI Trials). Am J Cardiol,
Anadolu Kardiyol Derg. 2014 Jul 11.
2006; 98: 1–5.
24. Gary T, Pichler M, Belaj K, et al. Platelet-to-lymphocyte ratio:
9. Mallat Z, Tedgui A. Immunomodulation to combat atherosclerosis:
a novel marker for critical limb ischemia in peripheral arterial
The potential role of immune regulatory cells. Expert Opin Biol
occlusive disease patients. PLoS One. 2013 Jul 2;8(7):e67688.
Ther. 2004 Sep;4(9):1387-93.
25. Cannon CP, Battler A, Brindis RG, et al. American College of
10. Nuñez, J, Sanchiz J, Bodí V, et al. Relationship between low
Cardiology key data elements and definitions for measuring the
lymphocyte count and major cardiac events in patients with acute
clinical management and outcomes of patients with acute coronary
chest pain, a non-diagnostic electrocardiogram and normal troponin
syndromes: a report of the American College of Cardiology Task
levels. Atherosclerosis. 2009 Sep;206(1):251-7.
Force on Clinical Data Standards (Acute Coronary Syndromes
11. Blum A, Sclarovsky S, Rehavia E, Shohat B. Levels of
Writing Committee). J Am Coll Cardiol 2001;38:2114-30.
T-lymphocyte sub-populations, interleukin-1 beta, and soluble
interleukin-2 receptor in acute myocardial infarction. Am Heart

6 Volume 55 Number 3 July - Sept., 2017

Association of the Platelet–Lymphocyte Ratio (PLR) Abrahan LL, et al.

APPENDIX A

Summary of published literature involving PLR in atherosclerotic disease

Author Population Outcome Results

Oylumlu et al. 587 ACS patients In-hospital mortality High PLR is an independent predictor of mortality in ACS patients
(2014) OR = 1.012 (1.005-1.087, p = 0.027)
ROC: PLR > 142 had 69% sensitivity, 63% specificity
Azab et al. (2012) 619 NSTEMI four-year all-cause High PLR is an independent predictor of 4-year mortality in NSTEMI patients
patients mortality For patients with PLR > 176, those on dual antiplatelets had lower mortality than single
antiplatelet (p = 0.0018).
Bekler et al. (2014) 220 NSTE-ACS LV systolic High PLR is an independent predictor of LV systolic dysfunction in NSTE-ACS patients
patients dysfunction(EF ≤ 40%) OR = 2.88 (1.39-5.95, p = 0.004)
Hudzik et al. (2015) 523 STEMI In-hospital & one-year High PLR is an independent predictor for in-hospital and 1-year mortality in STEMI
patients with DM mortality patients with DM
ROC: optimal cut-off value for predicting early mortality was higher than that for late
mortality (PLR > 155 vs. 146)
Temiz et al. (2014) 636 STEMI In-hospital mortality High PLR is an independent predictor of mortality in STEMI
patients HR = 2.16 (1.16-4.0, p = 0.014)
ROC: PLR > 144 had 51% sensitivity, 69% specificity
Ugur et al. (2014) 639 STEMI six-month all-cause High PLR is an independent predictor of 6-month mortality in STEMI patients who
patients (s/p PCI) mortality undergo PCI
OR = 2.51 (1.058-5.95, p = 0.03)
Kurtul et al. (2014) 1016 ACS SYNTAX score High PLR is an independent predictor of higher SYNTAX score in ACS patients who
patients (s/p CA) undergo urgent CA
OR = 1.018 (1.013-1.023, p < 0.001)
ROC: PLR ≥ 116 had 71% sensitivity and 66% sensitivity
Yüksel et al. (2014) 388 CAD patients Severity of High PLR is an independent predictor of severe atherosclerosis
atherosclerosis ß = 0.141 (p = 0.004)
(Gensini score) ROC: PLR > 111 had 61% sensitivity, 59% specificity
Gary et al. (2013) 2121 PAD Critical limb ischemia High PLR is an independent predictor of CLI in PAD patients
patients (CLI) OR = 1.9 (1.7-2.1, p < 0.001)
ROC: PLR > 150 optimal cut-off value

APPENDIX B
Operational Definitions

Myocardial Infarction Defined by the presence of symptoms suggestive of ischemia or infarction, with either electrocardiographic evidence (new Q waves
in two or more leads) or cardiac-marker evidence of infarction, according to the standard Thrombolysis in Myocardial Infarction
(TIMI) and American College of Cardiology definition25
Unstable Angina Defined as ischemic discomfort at rest for at least 10 minutes prompting rehospitalization, combined with one of the following: ST-
segment or T-wave changes, cardiac-marker elevations that were above the upper limit of normal but did not meet the criteria for
myocardial infarction, or a second episode of ischemic chest discomfort lasting more than 10 minutes and that was distinct from
the episode that had prompted hospitalization25
Cardiogenic Shock Defined as a systolic arterial pressure of less than 80 mm Hg for a duration of at least 30 minutes with evidence of organ hypoperfusion
(clouded sensorium, cold extremities, oliguria, acidosis) and/or low urine output (<0.5ml/kg/hr) and with a pulse rate >60 beats per
minute with or without evidence of pulmonary congestion
Heart Failure (HF) Defined as development of signs/symptoms of systolic dysfunction such as dyspnea, orthopnea, neck vein engorgement, rales/
crackles, edema, pulmonary congestion on chest X-ray, or ejection fraction < 50% on echocardiography
• Mild HF: Rales in 50% or less of the lung fields
• Severe HF: Rales in more than 50% of the lung fields / evidence of pulmonary edema
D e c o m p e n s a t i o n o f Defined as development of worsening signs/symptoms of systolic dysfunction (as above) from a patient with a known diagnosis of
Chronic Heart Failure congestive heart failure prior to present admission
Reinfarction Defined by development of recurrence of symptoms during the admission after initial management. It may be an ST elevation or
non-ST elevation myocardial infarction

Volume 55 Number 3 July-Sept., 2017 7

Abrahan LL, et al. Association of the Platelet–Lymphocyte Ratio (PLR)

APPENDIX C
DATA COLLECTION SHEET

GENERAL DATA
Number

Location Age / Sex Weight / Height BMI

Diabetes Prior Angina Beta Blocker

Hypertension Prior MI P Antiplatelets

R
Dyslipidemia Prior CHF Anticoagulants
I
R R
PAD Previous PCI / CABG O ARB/ACEi
I I
R
S Former Smoking S Documented CAD Calcium Ch Block
K Current Smoker K History of CVD/TIA Statins
M
S S
CKD Others: E Nitrates
D
Family History: CAD S Digoxin

Others: Non Compliant

Others:

Date of Admission Date Discharged

Admission Diagnosis STEMI NSTEMI Unstable Angina

p Symptoms p Cardiac Enzymes p ECG

Basis of Diagnosis
Time from Symptom
Onset
Other Diagnosis
Rate: aVR Elevation? QT / QTc: EF (2.264 avr) + (age x 0.645):

ECG Reading
Final Reading:

Hemoglobin Neutrophils

Complete Blood Count WBC Count Lymphocytes

Platelet Count Monocytes

Trop I: CKMB
Laboratory Work Up on
EF Teicholz EF Simpsons
Admission
LVEDD Creatinine

Cholesterol HDL

LDL TG

Medical Reperfusion
Beta Blocker Calcium Ch Blck PCI

Management Antiplatelets Statins CABG

Anticoagulants Nitrates Thrombolysis

ARB/ACEi Digoxin

8 Volume 55 Number 3 July - Sept., 2017

Association of the Platelet–Lymphocyte Ratio (PLR) Abrahan LL, et al.

OUTCOMES (If No Complications occurred, may Disregard this part)

Death from Cardiac Cause
Date of Death:
Cause of Death:
Death from Non-Cardiac Cause
Date of Death:
Cause of Death:
Heart Failure
Complications Mild
During Present Severe
Admission
Shock

Re-Infarction
NSTEMI
STEMI
Development of High Risk Pneumonia
Development of Dialysis requiring renal failure

CP arrest, but survived

Arrhythmia (Bradyarrhythmia, Tachyarrhythmia): ____________

Death from Cardiac Cause

Date of Death:
Cause of Death:
Death from Non-Cardiac Cause
Complications
Date of Death:
After Discharge
Cause of Death:
Heart Failure
(within 30 day
period) Re-Hospitalization – Indicate Reason:

Others (enumerate):

Volume 55 Number 3 July-Sept., 2017 9

 Legal Prescription
Off-label Drug Use
Atty. Rodel V. Capule M.D.*
Off-label drug use is the practice of prescribing drugs
outside the scope of the drug’s approved label—this
could be prescribing drugs beyond their intended use,
duration, population or dosage.” 1 “A physician prescribing
a drug exactly as approved by FDA [Food and Drug
Administration] is doing so on-label. When a physician
veers from that path, he or she is prescribing a drug off-
label.” 2
Take note that [FDA] approval “doesn’t play a
part in defining the drug’s standard of care or how it is
prescribed” 3 and FDA even conceded that some use of
off-label drugs does not fall within the current standards
of medical care or treatment. 4 Furthermore, when the
FDA approves a drug or device for sale and marketing,
it does so only with respect to the indicated uses. 5 This is
not to say that other FDA labeling must be ignored. “The
FDA-approved label may also include ‘contraindications’
and ‘warnings and precautions.’ A ‘contraindication’
is a ‘situation[] in which the drug should not be used
because the risk of use . . . clearly outweighs any possible
therapeutic benefit.’ ‘Warnings and precautions’ are
descriptions of ‘clinically significant adverse reactions .
. , other potential safety hazards . . . , limitations in use
imposed by them . . . , and steps that should be taken if
they occur,’ as well as any other information regarding
any special care to be exercised by the practitioner for
safe and effective use of the drug…” 6
Notwithstanding, off-label prescribing is common and
in most cases legally and ethically acceptable. In third
world countries, engaging in off-label use of drugs is even
more compelling for economic reasons. There are even
occasions that the first drug of choice is not available in
the local market or prohibitively expensive, prompting
physicians to resort to innovation justifying off-label use
of drugs readily available.
Although the FDA approves drugs for only the uses
indicated in the product labeling, drugs may have other,
off-label uses that are beneficial. 7 However, “The fact that
FDA has not approved labeling of a drug for a particular
use does not necessarily bear on those uses of the drug
that are established within the medical and scientific
community as medically appropriate.” 8 Emphatically,
“the FDA does not regulate the practice of medicine,”
and “the decision whether to use a drug for an off-label
purpose is a matter of medical judgment, not of regulatory
approval.” 9
“It is also important to differentiate between
experimentation and therapy. The difference lies mainly
*Dr. R.V. Capule is an attorney specializing in medical malpractice,
physical injuries and food torts. He is a law professor of Legal Medicine at
Arellano University School of Law and a consultant in Legal Medicine at
Adventist Medical Center-Manila and Makati Medical Center.
V
Philippine Journal of Internal Medicine
in intent. If it benefits the patient the off-label usage of
a drug is deemed therapy, but if the purpose is to gain
general knowledge for a broader population then it is
considered human experimentation. Furthermore, “the
interests of the researcher and the subject may conflict” in
human experimentation. Therapeutic misconception arises
from this conflict when patients believe that the research is
going to benefit them directly, even though the intent and
purpose of the study is to gain general knowledge and not
necessarily benefit the patient. Thus, the ultimate purpose
of research is discovery and knowledge, unlike therapy
which promotes the best interest of the patient. Medical
practice also recognizes “innovative therapy” that
combines “research and practice”; here the “physician
may wish to give a patient the best-known medication
and simultaneously evaluate the medicine’s efficacy.”
However, legally defining innovative therapy comes down
to the physician’s intent.” 10
“Physicians’ freedom to prescribe drugs off-label
carries important advantages. It permits innovation in
clinical practice, particularly when approved treatments
have failed. It offers patients and physicians earlier access
to potentially valuable medications and allows physicians
to adopt new practices based on emerging evidence.
And it can provide the only available treatments for
“orphan” conditions. The spectrum of off-label use includes
guideline-recommended practice, last-resort therapy, and
first-line therapy.” 11 On the flip side, off-label prescribing is
often done in the absence of adequate supporting data.
Off-label uses have not been formally evaluated, and
evidence provided for one clinical situation may not apply
to others. 12 It undercuts expectations that drug safety and
efficacy have been fully evaluated. When newer, more
expensive drugs are used off-label, it increases health
care costs. 13 In other words, “off-label drug use presents a
unique paradox: it can both aid and harm the patient.” 14
Ultimately, off-label use of drugs should be made
known to a patient. The fiduciary nature of a physician-
patient relations demands securing an informed consent
for its use. The information must not be limited to a bare
“off-label” use of the drug, but should also include its
reasonable use within the concept of standard of care
for a particular illness.
References
1. Holley, Danielle; “Balancing on the Edge: the Implications and
Acceptability of Off-label Drug Use”, 638, ALB. L.J. SCI. &
TECH. [Vol. 19.3] 2009
2. “On-Label vs. Off-Label Drug Prescribing” by Heather Claverie,
28 IG Living | December-January 2016 | IGLiving.com
3. “On-Label vs. Off-Label Drug Prescribing” by Heather Claverie,
29 IG Living | December-January 2016 | IGLiving.com
4. FDA Advisory 2013-035, “Consumer Protection Tips when
Availing Treatment Modalities Outside of the Standard of
Care”
 Philippine Journal of Internal Medicine Legal Prescription

5. Mark Herrmann and Pearson Bownas; “Keeping the Label out

of the Case”, 103:477, Northwestern University Law Review
Colloquy 2009
6. Id.
7. Id
8. Weaver v. Reagen, 886 F.2d 194, 198 (8th Cir.1989)
9. Klein v. Biscup, 109 Ohio App.3d 855, 673 N.E.2d 225, 231 (1996)
10. Holley, Danielle; “Balancing on the Edge: the Implications and
Acceptability of Off-label Drug Use”, 638, ALB. L.J. SCI. &
TECH. [Vol. 19.3] 2009
11. Randall S. Stafford, M.D., Ph.D.; “Regulating Off-Label Drug
Use —Rethinking the Role of the FDA” N Engl J Med 358;14
www.nejm.org April 3, 2008
12. Id.
13. Id.
14. Holley, Danielle; “Balancing on the Edge: the Implications and
Acceptability of Off-label Drug Use”, 633, ALB. L.J. SCI. &
TECH. [Vol. 19.3] 2009

VI
 Philippine Journal of Internal Medicine
A Case Report on Cerebrogenic Fatal Cardiac Arrhythmia in a
Patient with Acute Ischemic Stroke
Rainier Mark Alegria, M.D.*; Ethel Deloso-Añonuevo, M.D. **; John Añonuevo, M.D.***
Abstract
Background: Patients with acute ischemic stroke are
susceptible to cardiac arrhythmias however, fatal
arrhythmias are rare in the absence of cardiac disease.
Cardiac arrhythmias can develop in lesions at the right side
of the brain specifically the insular, frontal and parietal area.
Data that show the direct relationship of ischemic stroke and
arrhythmia are scarce but they are indirectly attributed to
an imbalance in the autonomic nervous system. This paper
aims to present a rare case of an association between a
fatal arrhythmia and right thalamic infarct.
Case: Presenting a case of a 39-year-old admitted as a
survivor of sudden cardiac death from ventricular fibrillation.
She presented with a history of left sided weakness a week
prior but no work-up was done. Baseline serum electrolytes
and cardiac markers were all normal. Electrocardiogram
(ECG) post-cardioversion showed sinus tachycardia.
Echocardiogram and cardiac computed tomography (CT)
angiography were normal. Magnetic resonance imaging
(MRI) and angiography (MRA) of the brain showed an acute
infarct at the right thalamus and an absent left internal
I ntroduction
Serious cardiac arrhythmia occurring after an acute
stroke is an under-recognized threat. These may include atrial
fibrillation, ventricular tachyarrhythmia, supraventricular
tachycardia, and atrioventricular blocks. Fatal cardiac
arrhythmias such as ventricular fibrillation may occur but are
rarely documented. Cardiac arrhythmias are noted to be
more common in the first 24 hours after an acute ischemic
stroke and would show a decreasing trend after 72 hours.1
Arrhythmias may still be seen within three weeks post stroke.1,2
These are commonly seen in lesions at the right side of the
cerebrum particularly in the insular cortex, frontal, parietal
cortex, amygdala, basal ganglia and thalamus. 3,4 The
*Resident Physician, Department of Medicine, Asian Hospital and Medical
Center, Muntinlupa City, Philippines
**Pulmonary Medicine Specialist, Department of Medicine, Asian Hospital
and Medical Center, Muntinlupa City, Philippines
***Interventional Cardiology Specialist, Department of Medicine, Asian
Hospital and Medical Center, Muntinlupa City, Philippines
Corresponding author: Rainier Mark Alegria, M.D.
Department of Medicine, Asian Hospital and Medical Center,
Muntinlupa City, Philippines
Email: rainier.alegria@gmail.com
The PHILIPPINE JOURNAL OF INTERNAL MEDICINE is a peer reviewed journal and a copyrighted publication of the Philippine College of Physicians
Case Series
carotid artery (ICA). Electroencephalogram (EEG) was
negative. Bisoprolol was given and an Automatic Implantable
Cardioverter Defibrillator (AICD) was subsequently
placed. No recurrence of cardiac arrhythmia was noted
on continuous cardiac telemetry monitoring during her
hospitalization and on six months of follow-up.
Conclusion: Fatal cardiac arrhythmias, can occur in patients
with acute thalamic infarct even beyond 24 hours in the
presence of other confounding factors despite the absence
of cardiac pathology. This case showed the association of
heightened autonomic imbalance caused by an acute
stroke, decreased cerebral flow, and fatal arrhythmia. This
elucidates the importance of cardiac monitoring in acute
ischemic stroke. With the paucity of information on serious
cardiac arrhythmia and ischemic stroke, a future study on
this correlation will be useful.
Keywords: Cerebrogenic cardiac arrhythmia, post-stroke
arrhythmia, acute ischemic stroke
mechanism of arrhythmia that is proposed in several studies
is the increase in catecholamines brought about by the
disruption in the balance of the autonomic nervous system
(ANS). The sympathetic nerve terminals that are connected to
the heart’s subendocardium release catecholamines directly
into the heart and this affect the cardiac conduction system
and cause the arrhythmia.5
A congenitally absent left internal carotid artery is rare
and only occurs in less than 0.01% of the population. They are
often asymptomatic due to a well-compensated collateral
circulation. Symptoms only occur when atherosclerotic
disease sets in or in conditions causing vascular blood flow
disruption. Often times, the symptoms are neurogenic like a
transient ischemic attack but there was no documentation
of sudden cardiac death nor cardiac arrhythmia.5,6
We are presenting a case of a possible cerebrogenic fatal
cardiac arrhythmia in a patient with an acute right thalamic
infarct. This case validates the importance of cardiac
monitoring in patients with acute stroke.
Volume 55 Number 2 April - June, 2017 1
 Alegria RM, et al. A Case Report on Cerebrogenic Fatal Cardiac Arrhythmia

C ase
A 39-year-old female was brought in the emergency
room (ER) after surviving a sudden cardiac death from
ventricular fibrillation. Seven days prior to admission, she
developed persistent left-sided mild hemiparesis and
hemisensory loss on the face, arm, and leg. Forty minutes prior
to admission, the patient had sudden loss of consciousness
preceded by an emotional outburst. As related by the
relatives, the emergency medical services (EMS) was
called and they documented her to be unresponsive and
with ventricular fibrillation (Vfib) on their monitor. Chest
compressions were done followed by defibrillation which
resulted to a return of spontaneous circulation after three to
four minutes of resuscitation. The post arrest ECG according
to the EMS responders was then normal sinus rhythm and she
was brought to the ER.

The patient had a history of episodic syncopal attacks

since her teenage years, this was investigated extensively Figure 1. Plain Brain MRI (DWI) of patient case with Acute Right
two years prior to admission and was determined to occur Thalamic Infarct (red arrow)
due to a brain blood circulation etiology. Tests revealed a
congenitally absent left internal carotid artery that was well
compensated by collateral blood flow from the anterior
and posterior communicating artery. However, Transcranial
Doppler revealed that hyperventilation maneuver (causing
cerebral artery vasoconstriction) dropped cerebral blood
flow significantly to 43% and caused dizziness that she
experiences prior to subsequent syncopal attacks. Brain
MRI revealed an old lacunar infarct in the right internal
capsule where she was asymptomatic. Extensive work
up for stroke in the young yielded unremarkable findings.
Examinations to rule-out a hypercoagulable syndrome also
were unremarkable. She has no relatives who had a sudden
cardiac death nor any familial heart disease that can cause
syncope.

At the ER, she was drowsy but oriented to three spheres.

Vital signs then showed, heart rate of 106/min with regular
rhythm, blood pressure 120/70mmHg, respiratory rate 19
breaths per min and temperature of 36.8°C. She had an
absent left carotid pulse but had a strong right carotid
pulse. Cardiovascular and pulmonary exams were normal.
Pertinent neurologic exam showed left sided hemiparesis
with a shallow left nasolabial fold and motor strength of 3/5
on the left upper and lower extremities, and an 80% intact
sensation on both the left upper and lower extremities. The
right upper and lower extremities had motor strength of 5/5
with 100% intact sensory perception.
Cardiac diagnostics done to detect a structural
abnormality were all unremarkable. Brain natriuretic peptide
(BNP), D-Dimer, Troponin-I, CK-MB, Sodium, Potassium,
Magnesium, Calcium, Creatinine, thyroid function tests
and lipid profile were all normal. ECG done on admission
showed sinus tachycardia (Figure 3). Chest radiograph was
Figure 2. MRA of patient case with congenitally absent left internal
carotid artery. Right internal carotid artery (red arrow) has normal course
and caliber; basilar artery (green arrow) has normal course and caliber.
unremarkable. Echocardiogram showed an ejection fraction
of 73.2% with normal size and adequate contractility. CT
Angiography revealed unremarkable coronary arteries, no
aortic aneurysm and normal pulmonary vessels.
Cranial MRI (Figure 1) revealed an acute infarct over the
right thalamus and the MRA (Figure 2) showed an absent left
internal carotid artery, with normal caliber of the right internal
carotid artery and its branches. These findings were also
noted in the Carotid Duplex scan. Electroencephalogram

2 Volume 55 Number 2 April - June, 2017

 A Case Report on Cerebrogenic Fatal Cardiac Arrhythmia Alegria RM, et al.

Figure 3. 12-Lead EKG of patient case at ER post Cardioversion (Sinus Tachycardia, Normal Axis)

Figure 4. 12-Lead EKG of patient case seven days post Ventricular Fibrillation Normal Sinus Rhythm, Normal Axis)

was normal. Investigation for cause of stroke in the young
with a hypercoagulability panel (anticardiolipin antibody,
antithrombin III, factor V leiden gene mutation, factor VIII
activity, homocysteine, protein C activity, protein S activity,
prothrombin gene mutation and aPTT-LA) was normal.
She was treated with bisoprolol 2.5mg tablet once a
day and clopidogrel 75mg tablet once a day. Continuous
cardiac telemetry monitoring did not record occurrence
of cardiac arrhythmia. The 12-Lead ECG taken seven days
post ventricular fibrillation (Figure 4) shows normal sinus
rhythm with normal axis. Despite the unremarkable course
in the hospital, the patient and family decided to have
an implantation of an AICD. The patient was discharged
and maintained on bisoprolol and clopidogrel. Six months
post discharge, review of the AICD record did not show
recurrence of any cardiac arrhythmia and the patient
remained asymptomatic.

Volume 55 Number 2 April - June, 2017 3

Alegria RM, et al.
D iscussion
There is correlation between acute ischemic stroke
and cardiac arrhythmia. However, the paucity of cases
precludes predicting patients who will develop serious
cardiac arrhythmia.
Studies have shown that most fatal cardiac arrhythmias
in those with acute ischemic stroke are seen in those
with inherent structural heart disease 1 which our patient
did not have. Fatal cardiac arrhythmia in those with
acute ischemic stroke were also noted to be associated
with myocardial ischemia, ventricular dysfunction, and
electrolyte abnormalities. In our patient, test results were all
unremarkable negating a possible cardiac and electrolyte
cause of the ventricular fibrillation. The question then arises,
what caused the ventricular fibrillation in the absence of a
cardiac pathology?
The interplay between the congenitally absent ICA,
hyperventilation from an emotional outburst, and acute
thalamic infarct may therefore be the key contributors
to the patient’s fatal cardiac arrhythmia. Despite the
documentation of a good collateral circulation, it is a
possibility that intimal changes within the vessels of both
the anterior and posterior circulation maybe present.
These changes coupled with vasoconstriction from
hyperventilation can significantly decrease cerebral
blood flow and predisposed this patient to arrhythmia from
catecholamine surge.8,9 The acute ischemic stroke in the
right thalamus may have also been a result of the diminished
cerebral flow despite this area being supplied by four arterial
systems. 10 Maria del Mar Salez de Ocariz, et al noted in
their study that thalamic stroke commonly occurs in young
adults and that its mechanism is often undetermined of
which majority are ischemic in nature. Smoking was found
to be the main risk factor associated with thalamic infarct,
however, in isolated thalamic infarct, single lesion as in
our case, most of the patients have no predominant risk
factors.10
Among the proposed pathophysiology of
arrhythmogenesis after stroke, autonomic dysfunction is
the most probable for our patient. Despite paucity of data
on fatal arrhythmia in thalamic infarcts, the effect of excess
catecholamine caused by decrease cerebral flow and
infarct can account for the cerebrogenic fatal arrhythmia.
C onclusion
Fatal cardiac arrhythmias can occur in patients with
acute thalamic infarct even beyond 24 hours, especially
in the presence of other confounding factors despite the
absence of cardiac pathology. This paper presented an
unusual case of a patient with a congenitally absent left
4 Volume 55 Number 2 April - June, 2017
A Case Report on Cerebrogenic Fatal Cardiac Arrhythmia
ICA with an acute ischemic stroke at the right thalamus
who survived a sudden cardiac death from ventricular
fibrillation occurring within seven days from the onset of
her neurologic symptoms. The proposed association of
fatal arrhythmia and acute thalamic infarct was shown to
be possible in our patient. The congenitally absent left ICA
and hyperventilation further contributed to arrhythmogenesis
because of the resultant diminished cerebral blood flow. It
is very important to advise the patient to avoid activities
that can trigger hyperventilation such as strenuous physical
and heightened emotional stressors. This paper validates the
need for cardiac monitoring in patients with acute ischemic
stroke. We recommend future studies in acute ischemic
stroke patients to look into the frequency of occurrence of
serious and fatal cardiac arrhythmias and to correlate it with
the location of the lesion.
R eferences
1. Kallmunzer, B. et al. “Serious Cardiac Arrhythmias After
Stroke: Incidence, Time Course, And Predictors--A Systematic,
Prospective Analysis”. Stroke 43(11): 2892-2897, 2012
2. Praveen Kumar, AS, E Babu, and DK Subrahmanyam.
“Cerebrogenic Tachyarrhythmia in Acute Stroke”. Journal of
Neurosciences in Rural Practice 3(2): 204, 2012.
3. Ruthirago, D, Julayanont, P, et.al. “Cardiac Arrhythmias and
Abnormal Electrocardiograms After Acute Stroke”. American
Journal of Medical Sciences 351(1): 112-118, 2016
4. Seifert, F., Kallmunzer, B., Gutjahr, I. et al. “Neuroanatomical
Correlates of Severe Cardiac Arrhythmias in Acute Ischemic
Stroke”. Journal of Neurology 262: 1182-1190, 2015.
5. Samuels, M. A. “The Brain-Heart Connection”. Circulation 116(1):
77-84, 2007.
6. Amer, Syed. “Rare Case of Congenital Absence of Left Internal
Carotid Artery”. Annals of Indian Academy of Neurology 0.0
(2014): 0. Web. 4 Dec. 2016.
7. Patel, Shonak B. et al. “Congenital Absence of The Left Internal
Carotid Artery”. Annals of Vascular Surgery 24.3 (2010): 415.
e9-415.e11. Web. 7 Dec. 2016.
8. Raichle, ME and Plum, F. Hyperventilation and Cerebral Blood
Flow. Stroke 3: September-October, 1972.
9. Reeves, AG and Swenson, RS. Disorders of the Nervous System:
A Primer, 2008. Online version developed by Dartmouth Medical
School. Chapter 27 Cerebrovascular Disease.
10. Salez de Ocariz, M, Nader, JA, et al. Thalamic Vascular Lesion:
Risk Factors and Clinical Course for Infarcts and Hemorrhages.
Stroke 27(9), 1996.
 Philippine Journal of Internal Medicine
Kikuchi Fujimoto Disease: A Series of Three Cases
Rhona L. Recto, M.D.*; Charito Cruz-Bermudez, M.D.*
Abstract
Introduction: Kikuchi-Fujimoto disease (KFD) is a rare
self-limited disorder manifested by painful cervical
lymphadenopathies commonly associated with fever
and night sweats. This is a series of three female patients
presenting with fever and lymphadenopathies diagnosed
with KFD.
Case: The first case is a 34-year-old female admitted due
to fever of 10 days associated with lymphadenopathies
and joint pains. Excision biopsy done showed necrotizing
histiocytic lymphadenitis consistent with KFD. Other
laboratories showed hypocomplementemia, positive ANA
and anti-dsDNA. Patient was discharged improved with
low dose oral corticosteroid and hydroxychloroquine.
The second case is a 53-year-old female with fever,
lymphadenopathies, polyarthritis and morning stiffness.
Biopsy of the cervical lymph node was done showing KFD
and lupus serologies (ANA 1:640 speckled, anti-dsDNA and
anti-Smith) revealed positive results as well. Patient was
I ntroduction
Kikuchi-Fujimoto disease (KFD) is a rare self-limited
disorder manifested by painful cervical lymphadenopathies
commonly associated with fever and night sweats. 1 It is
more common in young adults less than 30 years of age with
female predominance. Kikuchi first described the disease
in 1972 in Japan. Fujimoto and colleagues independently
described KFD in the same year.2
C ase
The first case is a 34-year-old female admitted due to
fever, arthritis, palatal ulcers and palpable masses on her
neck and axilla. Initial laboratories revealed elevated ESR
(47 mm/hr), CRP (12 mg/L) and LDH (405 U/L). Complete
blood count showed normochromic, normocytic anemia
(hemoglobin: 11.1 g/dl) with slightly decreased WBC count
(4990 mm3). Excision biopsy done on the cervical lymph
*Section of Rheumatology, Department of Medicine, St. Luke’s Medical
Center, Quezon City, Philippines
Corresponding author: Rhona L. Recto, M.D., St. Luke’s Medical
Center – Quezon City, Quezon City, Philippines
Email: rhona_recto@yahoo.com
The PHILIPPINE JOURNAL OF INTERNAL MEDICINE is a peer reviewed journal and a copyrighted publication of the Philippine College of Physicians
Case Series
then diagnosed with SLE and was started on low dose oral
corticosteroid and hydroxychloroquine which resulted to
resolution of fever and gradual resolution of lymph nodes on
out-patient follow up. The last case is a 45-year-old female
admitted due to persistent fever, painful lymphadenopathies
and headache. Serological work-up including autoantibody
tests for SLE were all unremarkable but showed associated
iron deficiency anemia. Biopsy of the cervical lymph node
showed Kikuchi’s disease. Patient was discharged with oral
methylprednisolone.
Conclusion: The rarity of KFD makes defining an autoimmune
etiology a challenge to clinicians. Careful disease course
follow up is then recommended for patients who initially lack
parameters for SLE diagnosis.
Keywords:Kikuchi-Fujimoto disease, cervical
lymphadenopahy, SLE
node showing well circumscribed paracortical lesions with
necrotizing changes were all consistent with necrotizing
histiocytic lymphadenitis as seen in KFD (Figure 1).
Laboratories requested showed marked hypo-
complementemia (34 mg/dl), positive ANA (1:160 speckled
pattern) and anti-dsDNA (23.3 U/mL). Having met the
diagnosis for systemic lupus erythematosus (SLE)(arthritis,
mucosal ulcers, positive ANA, positive anti-dsDNA,
hypocomplementemia), patient was started with low dose
oral corticosteroid and hydroxychloroquine.
The second case is a 53-year-old female who consulted
as outpatient due to fever, lymphadenopathies, polyarthritis
and morning stiffness. Patient underwent excision biopsy of
cervical lymph node showing KFD. Patient later developed
fever, alopecia and oral ulcers. Initial laboratories revealed
normochromic, normocytic anemia (hemoglobin: 11.6 g/dl),
elevated ESR (61 mm/hr) and CRP, normal complement levels
and positive lupus serologies (ANA 1:640 speckled, positive
anti-dsDNA and anti-smith). Patient was also diagnosed with
lupus.
The last case is a 45-year-old female admitted due to
persistent fever, painful lymphadenopathies and headache.
Volume 55 Number 2 April-June, 2017 1
 Rerto RL, et al.
Figure 1. A. Microscopically, the affected nodes show focal, well-circumscribed paracortical lesions. B. Higher power view showing the boundary between an area of karyorrhexis/
pyknosis and an area of karyolysis. There are abundant karyorrhectic debris, scattered fibrin deposits, and collections of mononuclear cells (mostly plasmacytoid dendritic cells and
activated T cells). No plasma cells and neutrophils were seen.
There were no o t h e r s y s t e m i c s i g n s a n d s y m p t o m s
consistent with an autoimmune condition. Serologies for
SLE were negative. Biopsy of the cervical lymph node showed
KFD. Patient was discharged with oral methylprednisolone.
D iscussion
In patients presenting with lymphadenopathies, the
primary disease entities that should be considered are
infections and malignancy. Important differentials include
Tuberculosis, considering the endemicity in the country,
and lymphoid malignancy which may present similarly.
Lymphadenopathies seen In SLE show aggregates of
degenerated nuclear debris (hematoxylin bodies) and
aggregates of degenerated nuclear material present in the
walls of blood vessels (Azzopardi phenomenon). There is also
prominent reactive follicular hyperplasia, abundant plasma
cells in SLE lymphadenitis. 3
Laboratory findings seen KFD include anemia, elevated
lactate dehydrogenase levels, liver function tests and
erythrocyte sedimentation rate. Mild leucopenia is present
in 20%- 58% of patients which may be attributed to cytokine
induced mechanisms. Atypical lymphocytes can be seen
in up to 25% of patients with KFD. 1 Hutchinson on his paper
on histopathologic findings of KFD describes three evolving
phases of the disease- proliferative, necrotizing and
xanthomatous phase.3
In the cases cited, two of the patients presenting with
KFD were diagnosed with systemic lupus erythematosus.
Goldblatt in his paper on the discussion of KFD and SLE in
2008, postulated that the association may be supported
by electron microscopic studies showing tubular reticular
structures in the cytoplasm of stimulated lymphocytes and
histiocytes which are also noted with the endothelial cells
and lymphocytes of SLE patients. 4 Having a number of
2 Volume 55 Number 2 April-June 2017
Kikuchi Fujimoto Disease: A Series of 3 Cases
overlapping clinical features, differentiating KFD and lupus
lymphadenitis may be tedious. Clinicians may however be
guided by several key points in the diagnosis of each disease
entity; 1, KFD which is characterized by lymphadenopathies,
fever and other systemic features has less of extra-nodal
involvement upon presentation and 2, Lupus lymphadenitis,
which has been reported in between 12% and 59%of patients
with SLE, in contrast to KFD, is rarely the presenting feature
of Lupus. Still, the most reliable way to differentiate the two
entities is by careful clinical examination and correlation with
lymph node histopathology.4
Kikuchi Fujimoto Disease typically affects women
although it has been described in both genders and a variety
of ethnic backgrounds. Lymphadenopathies, which are
present in 59% of cases, range from 0.5 to 4.0 cm in size are
described as tender and painful. Extranodal involvement
is uncommon but well documented. Skin lesions, more
common in the face or upper body, may be present as
erythematous plaques, papules, indurated lesions and ulcers.
Upper respiratory infections have also been described. Less
common symptoms include fatigue, joint pain, nausea,
vomiting and sore throat.3
A study published in Clinical Rheumatology compared
the clinical and laboratory data of 244 patients reported
in 181 publications. Of the 244 cases, 33% were male and
77% were female, with mean age of 25. Most cases were
reported in Taiwan (36%), USA (6.6%) and Spain (6.3%).
Fever (35%) and lymphadenopathies (100%) were the most
frequent symptom and physical finding. 5 KFD associated
with autoimmune disease was also reported in the case of
a 43 year old with eight-year history of Overlap Syndrome
(Scleroderma and SLE) with features consistent with the
cases in this publication.6 Aside from a presumptive aberrant
autoimmune reaction, an infectious etiology was also
suspected to be a possible inciting event in the pathogenesis
of KFD as supported by the presence of peripheral blood
abnormalities suggestive of mononucleosis-like viral
infection.7

The disease course of KFD is typically self-limited.

Lymphadenopathies run a benign course and appear
to resolve spontaneously one to six months after definite
diagnosis. A recurrence rate of 3-4% has been reported.
A local treatment guideline is lacking. The treatment plan
includes use of analgesics, antipyretics and nonsteroidal anti-
inflammatory drugs to alleviate lymph node tenderness and
fever. The use of corticosteroids has been recommended
in severe extranodal or generalized KFD but is of uncertain
efficacy. 1 In this case series, corticosteroids were used as
first line with good outcomes.

R eferences
1. Bosch X and Guilabert A. Kikuchi-Fujimoto Disease. Orphanet
Journal of Rare Diseases 2006, 1:18.
2. Boone J and Koyamangalath K. Kikuchi Disease. Accessed
in: http://emedicine.medscape.com/article/210752-overview,
August 2016.
3. Hutchinson CB and Wang E. KFD. Arch Pathol Lab Med Vol
134, February 2010.
4. Goldblatt F, Andrews J, Russell A and Isenberg D. Association
of Kikuchi- Fujimoto’s disease with SLE. Rheumatology Oxford
journals 2008; 47:554-555.
5. Kuckurdali Y, Solmazgul E and Kunter E, et al. Kikuchi-
Fujimoto Disease: analysis of 244 cases. Clinical Rheumatology.
January 2007, 26: 50-54.
6. Yung-Hsiang Hsu. Kikuchi-Fujimoto disease. Tzu Chi Medical
Journal 2014; 26: 51.
7. Hudnall DS. Kikuchi-Fujimoto Disease. American Journal of
Clinical Pathology 2000; 113: 761-764.

Volume 55 Number 2 April-June, 2017 3

 Philippine Journal of Internal Medicine
A Case Report on a 29-Year-Old Male with Difficult to Treat
Bronchial Asthma in Exacerbation: Rediscovering Asthma COPD
Overlap Syndrome (ACOS)
Christoper John N. Tibayan, M.D.* Jonathan Arquiza, M.D. , FPCP, FPSCCM**
Abstract
Background: Asthma chornic obstructive pulmonary disorder
(COPD) overlap syndrome (ACOS) was formally described
by the joint project of global initiative for asthma (GINA) and
global Initiative for chronic obstructive lung disease (GOLD)
as persistent airflow limitation with several features usually
associated with both asthma and COPD. ACOS is identified
by the features shared with both asthma and COPD. The
underlying cause though remains unknown, hence the
project did not offer current formal definition.
Case: This is a case of a 29-year-old male, asthmatic with
an eight - pack year smoking history who presented with
chronic obstructive respiratory symptoms with non significant
improvement on control of exacerbation despite standard
maximal therapy. Diagnostic tests such as pulmonary
function Tests, 2D Echo, chest CT scan and even assay for
I ntroduction
Historically, asthma and chornic obstructive pulmonary
disorder (COPD) have been considered as separate and
unique diseases with distinct characteristics. Classically,
asthma has been characterized by reversible airways
obstruction and COPD by fixed, less reversible, or irreversible
airways obstruction. These definitions however have
undergone major revisions recently. Even though asthma
and COPD can be and are often appropriately separated
as clinical entities, there are times when they are clinically
and physiologically indistinguishable.
Clinicians often encounter difficult to treat bronchial
asthma cases despite maximal therapy especially among
smoker patients. These patients often present with less
reversible or even irreversible airflow obstruction often seen in
COPD. Further classification to several phenotypes has been
formulated making asthma and COPD distinction less well
defined. They often share clinical features that showed similar
*Resident-in-Training, Department of Internal Medicine, Ospital ng
Makati
**Pulmonology Consultant, Department of Internal Medicine, Ospital
ng Makati
Corresponding author: Christoper John N. Tibayan, MD
Ospital ng Makati, Makati City, Philippines
Email: cjntibayanmd@gmail.com
The PHILIPPINE JOURNAL OF INTERNAL MEDICINE is a peer reviewed journal and a copyrighted publication of the Philippine College of Physicians
Case Series
alpha 1 anti trypsin were done to rule out for other disease
entities and prognosticate the patient’s condition leading
to the diagnosis of asthma COPD overlap syndrome (ACOS).
Conclusion: ACOS as a disease entity is still under debate and
still has no current formal definition due to lack of specific
biomarkers and lack of defining characteristics. Despite
this, management should not be compromised since these
patients often present with higher rates of exacerbations,
hospitalization, associated co morbid illness and mortality.
Treatment therefore is individualized.
Keywords: asthma, COPD, bronchial asthma, ACOS
responses to the available treatments for asthma to COPD
and vice versa, and these may have prognostic implications.
Clinically, asthma COPD overlap syndrome (ACOS)
usually corresponds to asthmatic smokers who develop
non-fully reversible airway obstruction 1, however, when the
previous history of asthma is unknown, the diagnosis of ACOS
may be difficult due to the lack of specific biomarkers.
The Joint Global Initiative for Asthma (GINA) and
Global Initiative for Chronic Obstructive Lung Disease
(GOLD) Guidelines in 2014 defined ACOS as persistent
airflow limitation with several features usually associated
with asthma and several features usually associated with
COPD 1. The syndrome is identified by the features that it
shares with both asthma and COPD1. The underlying cause
though remains unknown, hence did not offer current formal
definition.
This report then aims to present a case of a young
male patient who manifested with unresponsive asthmatic
symptoms that are not relieved with maximal medications.
On work up, obstructive airway disease was confirmed but
could not be attributed to purely bronchial asthma alone.
The findings also suggest features of a COPD however with
non significant smoking pack years to really conclude COPD,
hence managed as ACOS. Restrictive lung component
Volume 55 Number 2 April - June., 2017
 Tibayan CJN, et al. Difficult to Treat Bronchial Asthma in Exacerbation

though was also noted that could have contributed to the

Table I. Complete blood count with platelet count
patient’s underlying lung condition.
Patient Value Reference Values

C ase Presentation Hemoglobin 15.0 14.0 – 18.0

Hematocrit 48 40 – 54
Patient is a 29-year-old male who came in at the RBC 4.8 5.0 – 6.4
Emergency Department with shortness of breath. Patient was WBC 7.1 4.0 – 11.0
clinically diagnosed case of bronchial asthma for three years
Segmenter 63 50 – 70
that was partly controlled as per GINA Guidelines maintained
on salmeterol + fluticasone 250.0mcg / 25.0mcg metered Lymphocyte 22 20 – 40
dose inhaler (MDI) with poor compliance. The history of Eosinophil 1 2–4
present illness started one month prior to admission when Monocyte 13 2–5
the patient experienced increasing severity of dyspnea Basophi 0 0–1
associated with physical activity relieved by rest and / or
Platelet 211 150 – 450
inhaler. Three days prior to admission had worsening severity
of dyspnea with associated non productive cough. Few Table II. Arterial blood gas (ABG) taken at 10 lpm via face
hours prior to admission, patient had persistent shortness mask. Partly compensated respiratory acidosis with more than
of breath with no relief with salmeterol + fluticasone MDI adequate oxygenation
hence admitted. Pertinent negatives include the absence
of associated fever, diaphoresis, chest pain, weight loss nor Patient Reference Values
orthopnea. pH 7.29 7.35 – 7.45
pCO2 77.4 35 – 45
Patient was previously treated with pulmonary
pO2 159.7 80 – 100
tuberculosis (PTB) in 2012 and was able to complete the
standard six months HRZE/HR regimen. There were no HCO3 36.4 22 – 26
history of allergy to any food and drugs nor eczema. He SaO2 98.8
is a previous eight - pack year smoker who started at 14
years old and stopped at 24 years old and who has been
chronically exposed to a second - hand smoker. Patient also given at 4.0 mg/kg/body weight thru IV, salbutamol +
had history of drug abuse with marijuana with the last intake ipratropium nebulization every hour and as needed for
approximately two months prior to the admission and usual dyspnea and aminophylline drip at dose 0.4/kg given thru IV.
intake approximately twice a year for five years. The family On the initial hospital stay, patient was clinically improving,
members showed no history of asthma, allergy, atopy or any hence, nebulization was decreased and aminophylline
pulmonary and cardiac diseases. was shifted to doxofylline. Hydrocortisone was later shifted
to oral prednisone. The ABGs though showed persistently
He was seen at the Emergency Room conscious compensated to partly compensated respiratory acidosis.
coherent speaks in phrases with vital signs as follows: BP However, during the later part of hospital stay, patient had
130/80; HR 107; RR 24; Temperature 36.9; SaO2 82% taken been noted of intermittent repeated bouts of exacerbation
at room air.Pertinent physical examination showed an apex and consistent respiratory acidosis. Despite of persistent
beat at sixth ICS left anterior axillary line and chest findings hypercarbia, patient was not intubated because patient
of symmetric chest expansion, no retraction, (+) fair air entry is clinically stable and comfortable post-nebulization
(+) wheezes bilateral lung fields. with inhaled short acting beta agonist combined with
anticholinergic agent. Furthermore the patient presents
Chest Xray showed fibrotic densities with cystic with an ABG consistent of a chronic hypercarbia that could
lucencies on bilateral upper lungs that has been stable as be probably due to chronic obstruction (as suggested by
compared from his previous chest xray (the findings signify compensatory increase in HCO3). Compliance and proper
PTB with bullae formation). There was cardiomegaly with technique of the use of medications were regularly checked.
cardiothoracic ratio of 0.6. Pulmonary hyperaeration was Additional medications such as montelukast, budesonide
also noted. nebulization and tiotropium 18 mcg/cap one cap via hand
inhaler were also started however did not offer significant
Results of the electrocardiogrgam (ECG) revealed sinus improvement in the overall control of exacerbation.
tachycardia with right ventricular hypertrophy. Patient was Diagnostic work ups were done to further characterize
admitted with primary working impression of bronchial the patient’s clinically insignificant improvement despite
asthma in exacerbation and PTB treatment completed in maximal therapy for asthma.
2012. Medications were started such as hydrocortisone

2 Volume 55 Number 2 April - June., 2017

 Difficult to Treat Bronchial Asthma in Exacerbation Tibayan CJN, et al.

Table III. Series of ABGs at the ward Table V. Pulmonary fuction test #2

Day 1 Day 2 Day 3 Day 4 Pre Post

Parameter Predicted Broncho- Broncho- Change
pH 7.388 7.35 7.368 7.21 dilator dilator
pCO2 70.7 67.7 59.8 88.6 FEV1/ 80 41 34
FVC (%)
pO2 73.2 106.5 111.6 98.1
FEV1 3.96 0.34 (9%) 0.34 (9%) 1
HCO3 38.7 36.4 33.8 44.7 Liters (%)
SaO2 93.2 97.54 98.3 96.5 FVC 4.90 0.84 (17%) 1.03 (21%) 22
Liters (%)

Table IV. Pulmonary fuction test #1

Diffusion
Pre Post
Parameter Predicted Broncho- Broncho- Change Reference Patient
dilator dilator
DLCO (mmol/Kpa min) 7.6 1.5
FEV1/FVC (%) 79 43 38 VA 6.42 1.79
FEV1 Liters (%) 3.93 0.40 (10%) 0.41 (10%) 2 (2%)
Lung Volume
FVC Liters (%) 4.88 0.93 (19%) 1.09 (22%) 22 (18%)
Reference Patient
Interpretation: Very Severe airflow obstruction with no significant response to post
bronchodilator study Vital Capacity (L) 4.9 1.28
Inspiratory Capacity (L) 3.23 0.84
The findings suggest an irreversibility of airway Expiratory Reserve Volume (L) 1.61 0.43
obstruction as evidenced by FEV1/FVC ratio that was less
Residual Volume (L) 1.59 2.56
than 0.7 (Patients value 0.43) and a non significant post
Total Lung Capacity (L) 6.30 3.84
bronchodilator response with FEV1 that is less than 12% and
/ or 200mL (Patient’s value: 2%). A possible a component of The pulmonary tests were repeated to give a more
restricted airway is also entertained as reflected by decrease complete picture of the lung function. Irreversible airway
in FVC, however this is not very sensitive. obstruction is again noted, now with values of DLCO and
lung volumes. The decrease in DLCO can be significantly
correlated several disease entities in relation to FEV1 and
The 2D Echo findings are suggestive of a right sided heart
FVC values and a decreased value of DLCO is commonly
failure probably due to the underlying pulmonary disease
seen in emphysema. The low lung volumes in particular
that is yet to be investigated. The Chest CT scan findings
the low Total Lung Capacity (TLC) signify a restrictive lung
are consistent with bronchiectatic changes probably from
disease. The elevated Residual Volume (RV) may indicate
the result of previous PTB that could be responsible for the
air trapping, commonly seen in obstructive lung diseases.
restrictive component of the pulmonary disease.

Among young adults who have pulmonary function test

Despite the maximal treatment with long acting inhaled
showing low DLCO in the presence of airway obstruction may
bronchodilator and inhaled corticosteroid along with long
indicate a possibility of cystic fibrosis or alpha1-antitrypsin
acting antimuscarinic agent and a phosphodiesterase
deficiency. The assay test for alpha1-antitrypsin deficiency
inhibitor, patient still experienced repeated bouts of
was tested in this patient and yield negative result.
dyspnea, hypoxemia with associated uncompensated
respiratory acidosis in ABG. Compliance with medications
Given the described clinical presentation of the patient
as well as proper technique of inhaler use were frequently
as well as the series of laboratory and diagnostics done lead
checked and emphasized. Incentive spirometry was also
to the diagnosis of the so-called ACOS.
tried but still of no significant control of the exacerbation.
Additional work up were done as seen in Table V.
D iscussion
Interpretation
Even before the joint project of GINA and GOLD in
1. Very severe airway obstruction.
2. No significant response to post bronchodilator study with defining and characterizing ACOS, the clinical syndrome has
restrictive component been described in several countries both in prospective and
3. Severe decrease in DLCO retrospective studies. A two-stage multi center study in Italy
4. Lung volumes: Low VC, IC, TLC; High RV described physician diagnosed ACOS to be more prevalent
in older age occurring at 1.6% among 20 – 44 years old age

Volume 55 Number 2 April - June., 2017 3

 Tibayan CJN, et al.
class and 4.5% among 65 – 84 years old age class. It also
described that patients with ACOS presented with higher
frequency of respiratory symptoms, functional limitation and
hospitalization2. This may imply significant economic burden
than in cases of asthma or COPD alone.
An epidemiological study in Poland had a study that
involved 384 pulmonary specialists who enrolled a total of
12,103 patients in the period from March 2012 to September
2013 and described ACOS. It emphasized that there is no
universally recognized diagnostic criteria for ACOS and that
profile of patients is markedly different across the studies.
However, patients with ACOS were described to have
more severe course of the disease, with more symptoms,
more exacerbations and more frequent hospitalizations,
and portends a poorer prognosis3. There has been also a
report of more frequent presence of concomitant diseases,
metabolic and circulatory disorder. In particular, eighty five
percent have been diagnosed with concomitant arterial
hypertension (62.9%) and metabolic diseases (46.4%) such
as metabolic syndrome, obesity, type 2 diabetes (Brzostek,
et.al., 2014). The study though was non interventional3.
The usual temporal profile of patients with ACOS was
described in a retrospective study from January 2000 to
March 2012 among 650 patients that were followed up at
Tottori University Hospital in Japan. In this retrospective study,
ACOS patients are commonly older, male, current and past
smoking histories. They usually have low FEV1/FVC values
and low FEV1 % predicted values. Patients also had a higher
percentage of malignant disease and the mortality among
all patients was higher in patients with ACOS than those with
asthma 4.
The Joint GINA and GOLD Project described ACOS
based on the findings among available studies and
characterize the syndrome with a step wise diagnosis and
treatment. Common asthma symptoms of ACOS include
paroxysmal dyspnea with wheezing, and good response to
inhaled steroids and COPD symptoms include long-lasting
reduction in FEV1< 80% after administering a bronchodilator
and chronic productive cough1. These characteristics were
seen in our patient. The physical exam of ACOS patient may
be normal but most patients will present with evidence of
hyperinflation and other features of chronic lung disease or
respiratory insufficiency and abnormal auscultation (wheeze
and/or crackles)1. However, the guideline set by GINA and
GOLD did not provide any specific criteria for diagnosing
the syndrome with the disclaimers such as “final diagnosis is
left to the physicians” and a “similar number” of overlapping
features common to asthma and COPD support the diagnosis
of the syndrome. The GINA and GOLD Project still provided
a step- wise approach in diagnosis and management of
ACOS as follows:
STEPWISE APPROACH TO DIAGNOSIS OF PATIENTS WITH
4 Volume 55 Number 2 April - June., 2017
Difficult to Treat Bronchial Asthma in Exacerbation
RESPIRATORY SYMPTOM1
STEP 1: Does the patient have chronic airway disease?
• CXR or CT scan may be normal especially in
early stages
• Hyperinflation, airway wall thickening, hyper
lucency, bullae
• May identify or suggest an alternative or
additional diagnosis
E.g. bronchiectasis, tuberculosis, interstitial lung
disease, cardiac failure
STEP 2: Syndromic Diagnosis in Adults
• Compare the number of features for diagnosis
of COPD versus asthma
• Several positive features (three or more) for
either asthma and COPD suggest the diagnosis
• If there are “similar” number for both asthma
and COPD, consider the diagnosis of ACOS
STEP 3: : Spirometry
• Essential if chronic airway disease is suspected
• Confirms chronic airflow limitation
• More limited value in distinguishing between
asthma with fixed airflow limitation, COPD and
ACOS
STEP 4: Initial Therapy
• GINA and GOLD failed to set out clear
guidelines for the treatment
• If syndromic assessment suggests ACOS,
start treatment as for asthma pending further
investigation
o First-line treatment: Inhaled Corticosteroids
o Doses adjusted to the severity of the
disease
• COPD component
o Combined individualized bronchodilator
therapy
A case report of ACOS in South Korea by Lee, et.al. 5, 2015
emphasized the statement of Tho, et.al.6, that the definitive
diagnosis of ACOS can often be postponed with follow-up
monitoring. This is because most clinical features favoring
asthma or COPD are based on the patient’s history and present
laboratory findings, but persistent airflow limitation, which is
one of the clinical features favoring COPD, requires time to
confirm7. Thus, as shown in this case, when ACOS is suspected in
patients with asthma and limitation, of follow-up lung function
test after regular inhaled therapy is necessary to confirm the
presence of persistent airflow limitation.
Though the GINA and GOLD Joint Project failed to set
out clear guidelines for the treatment of ACOS, as part
on the stepwise approach the following treatment
recommendations are enumerated for patients with ACOS1.
• If the syndromic assessment suggests asthma or ACOS,
or there is significant uncertainty about the diagnosis
of COPD, it is prudent to start treatment as for asthma
until further investigation has been performed to
Difficult to Treat Bronchial Asthma in Exacerbation Tibayan CJN, et al.

Table VI. Characteristics observed and/or documented in our called LABA monotherapy) if 
there are features
patient 1 of asthma. 


Features • I f t h e s y n d r o m i c a s s e s s m e n t s u g g e s t s C O P D ,
if present Asthma COPD appropriate symptomatic treatment with
suggest: bronchodilators or 
combination therapy should be
Age of onset After age of 40 years commenced, but not ICS alone (as monotherapy)1.
Before age 20 years
Pattern of Variation over minutes, Persistent despite
• Treatment of ACOS should also include advice about
symptoms hours or days treatement
other therapeutic strategies including1: 

Worse during night or Good and bad days
early morning but always daily
o Smoking cessation
Triggered by exercise, symptoms and exertion
o Pulmonary rehabilitation
emotions including dyspnea
o Vaccinations


laughter, dust or exposure Chronic cough and

o Treatment of comorbidities, as advised in the

to allergens sputum preceded onset

respective GINA and GOLD reports
of dyspnea, unrelated to
triggers
The guideline was further supported by the study of
Lung function Record of variable Record of persistent Kostikas, et.al. that recommends the aggressive treatment
airflow limitation(spirometry airflow limitation (FEV1/ of both asthma and COPD. The optimal bronchodilation and
or peak flow) FVC <0.70 post BD) the appropriate dose of ICS must be adjusted for disease
Lung function Normal severity. Most consensus papers recommend the use of long-
Abnormal
between acting beta agonist (LABA)/ ICS combination therapy. The
symptoms term “Triple therapy” (LAMA, LABA, and ICS) can be given
among patients with more severe symptoms and more
Past history or Previous doctor Previous doctor
frequent exacerbations4. Furthermore, reduced response to
family history diagnosis of asthma diagnosis of COPD,
ICS was seen especially patients with COPD who continue
Family history of chronic bronchitis or
to smoke or those who smoke and have asthma, hence the
asthma and other allergic emphysema
importance to advise smoking cessation.
conditions (allergic rhinitis Heavy exposure to
or eczema) risk factors: tobacco,
Prognosis of ACOS is different from asthma or COPD
smoker, biomass fuels
alone, It was described in a retrospectively collected data
Time course No worsening of Symptoms slowly for in patients (age >40 years) with exacerbation of COPD
symptoms over time. worsening over time and/or asthma in 1073 hospitals across Japan between July
Variation in symptoms (progressive course 2010 and May 2013 from national database by Yamauchi,
either seasonally or from over years) et.al8. Patients with COPD alone had higher mortality and
year to year Rapid acting asthma alone had lower mortality than those with ACOS. The
May improve bronchodilator treatment higher mortality with ACOS is associated with high doses of
spontaneously or have an provide only limited corticosteroids requirements, the absence of the asthmatic
immediate response to relief component and presence of the COPD component.
bronchodilators or to ICS
over weeks Clinical Correlation
Chest x-ray Normal Severe
The case presented was diagnosed of Asthma COPD
hyperinflation
Overlap Syndrome (ACOS) on the basis of the above clinical
features checked on Step 2 (Syndromic Diagnosis in Adults)
confirm or refute this initial position
as suggested by the Joint Guidelines of GINA and GOLD
in diagnosis of ACOS. The number smoking pack years is
o Treatments will include an ICS (in a low or
not significant enough to diagnose the patient of COPD.
moderate dose, depending on level of symptoms)
The patient’s use of marijuana did not appear to have
significant effect on patient’s clinical condition, though
o A long-acting beta2-agonist (LABA) should also
the restrictive lung disease as a result of previous PTB could
be continued (if already prescribed), or added
contribute to the patient’s lung function. According to
the Division of Pulmonary and Critical Care Medicine of
o However, it is important that patients should not
UCLA published in 2013 by American Thoracic Society,
be treated with a LABA without an ICS (often
habitual use of marijuana alone does not appear to lead

Volume 55 Number 2 April - June., 2017 5

 Tibayan CJN, et al. Difficult to Treat Bronchial Asthma in Exacerbation

Table VII. Differences between asthma, COPD and ACOS using spirometric variables1

Spirometric variable Asthma COPD ACOS

Normal FEV1/FVC pre- or post-BD
Post-BD FEV1/FVC <0.7
FEV1=80% predicted
FEV1<80% predicted
Post-BD increase in FEV1
>12% and 200 mL from baseline
(reversible airflow limitation)
Post-BD increase in FEV1 >12%
and 400 mL from baseline
Compatible with asthma
Indicates airflow inflammation;
may
Compatible with asthma
(good control, or interval
between symptoms
Compatible with asthma, A
risk factor for exacerbations
Usual at some time in course
of asthma; not always
present
High probability of asthma
Not compatible with diagnosis
(GOLD)
Required for diagnosis by
GOLD criteria
Compatible with GOLD
category A or B if post BD
FEV1/FEV <0.7
Indicate severity of airflow
limitation and risk of
exacerbations and morality
Common in COPD and
more likely when FEV is
low, but consider ACOS
Unusual in COPD.
Consider ACOS
Not compatible unless other evidence
of chronic airflow limitation
Usual in ACOS
Compatible with mild ACOS
Indicates severity of airflow
limitation and risk of
exacerbations and mortality
Common in ACOS , and is more
likely when FEV is low
Compatible with diagnosis of
ACOS

Table VIII. Specialized investigations to determine asthma vs. COPD1

Investigation Asthma COPD

DLCO
Arterial blood gases
Airway hyperresponsive
High resolution CT scan
High resolution CT scan
Tests for atopy (sigE and/or skin prick
tests)
FENO
Blood eosinophilia
Spolum inflammatory cell analysis
Normal or slightly elevated Often reduced
Normal between exacerbations In severe COPD, may be abnormal between
exacerbations
Not useful on its own in distinguishing asthma and COPD
Usually normal; may shoe air trapping Air trapping emphysema; may show
and increased airway wall thickness. bronchial wall thickening and features of
pulmonary hypertension
Usually normal; may shoe air trapping Air trapping emphysema; may show
and increased airway wall thickness. bronchial wall thickening and features of
pulmonary hypertension
Not essential for diagnosis; increases Conforms to background prevalence; does
probability of asthma not rule out COPD
If high (>50ppb) supports eosinophilic Usually normal. Low in current smokers
inflammation
Supports asthma diagnosis May be found during exacerbations
Role in differential diagnosis not established in large populations

to significant abnormalities in lung function when assessed
either cross - sectionally or longitudinally, except for possible
increases in lung volumes and modest increases in airway
resistance of unclear clinical significance and therefore
of no clear link to chronic obstructive pulmonary disease
has been established. Although, the presentation of ACOS
theoretically would be more of an obstructive rather a
restrictive pattern, one cannot undermine the underlying
restrictive arm of the lung disease of the patient as seen in
the Chest CT scan result. Important implication would be a
more aggressive treatment management focused not only
on ACOS but also for the structural lung disease created by
the post TB bronchiectatic changes.
Furthermore, patient presented with pulmonary arterial
hypertension as evidenced by the 2D Echo findings that were
seen as a very common co morbid illness among patients
with ACOS across the studies described previously.3,6 The type
of pulmonary hypertension of our patient can be classified
as WHO Class three (Hypoxia Induced secondary to Lung
Disease). The AHA ACC 2009 recommends that treatment
patients under this classification should have a treatment
that is directed at the underlying lung disease 9 that include
bronchodilator and anti-inflammatory therapy, and most
importantly, oxygen that was provided to the patient
upon discharge. With the primary pulmonary disease that
presented with a difficult to control obstructive symptoms,
patient was given triple therapy (combination long acting
beta agonist + inhaled corticosteriod + long acting

6 Volume 55 Number 2 April - June., 2017

 Difficult to Treat Bronchial Asthma in Exacerbation Tibayan CJN, et al.

muscarinic antagonist) as suggested by the study of Kostikas, 3. De Marco, et.al., The Coexistence of Asthma and Chronic
et.al., 4 and by GINA and GOLD Guideline 1 in the form of Obstructive Pulmonary Disease (COPD): Prevalence and Risk
salmeterol + fluticasone 250.0mcg/25.0mcg MDI at two Factors in Young, Middle-aged and Elderly People from the
puffs twice a day and tiotropium 18.0mcg cap given once General Population, 2013
a day via hand inhaler, respectively. Additional medications 4. FitzGerald, et.al., Global Strategy for Asthma Management and
such as Montelukast, a leukotriene receptor antagonist Prevention 2014 (Revision): Global Initiative for Asthma, 2014
given 10.0mg tab one tab once daily and doxofylline, a 5. Harada, et.al., Causes of death in patients with asthma and
phosphodiesterase inhibitor given 400.0mg tab one tab asthma–chronic obstructive pulmonary disease overlap syndrome,
three times a day were also prescribed on discharge. There 2015
was no particular mention on the guideline on what specific 6. Kostikas, et.al., The asthma–COPD overlap syndrome: do we
bronchodilator or inhaled steroids must be used in patients really need another syndrome in the already complex matrix of
suspected with ACOS, hence the use of such medications airway disease?,2015
above were on the basis of the readily available drugs at the 7. Lee, et.al., A diagnostic approach and natural course of a patient
hospital. Furthermore, patient was also consistently advised with asthma–COPD overlap syndrome, 2015
of compliance and correct use of inhaled medications. 8. McLaughlin, et.al., ACCF/AHA 2009 Expert Consensus
Document on Pulmonary Hypertension: A Report of the American
College of Cardiology Foundation Task Force on Expert Consensus
C onclusion Documents and the American Heart Association, 2009
9. Tho, et.al., Asthma-COPD Overlap Syndrome (ACOS): a
ACOS should be suspected among male patients
diagnostic challenge. Respirology), 2015
with previous or current smoking history that presents with
10. Yamauchi, et.al., Comparison of in-hospital mortality in patients
chronic obstructive symptoms that are difficult to treat,
with COPD, asthma and asthma–COPD overlap exacerbations,
intractable to maximal medications and are characterized
2015 Oct;66(10):889–93.
atypically with both symptoms of COPD and Asthma that
cannot be attributed to a single entity. Series of Pulmonary
Function Tests is recommended if not yet previously done
to further exemplify and prognosticate airway irreversibility
and detect possible concomitant restrictive lung disease
component. Additional diagnostics such as Chest CT scan
and 2D Echo are also recommended to further typify if
patient has structural lung disease and if with concomitant
cardiac comorbid illness and / or complication. Inhaled
corticosteroid remains as first line treatment if still with
pending diagnosis to cover for the asthmatic symptoms. Long
Acting Beta Agonists (LABA) are usually added for the COPD
symptoms and are adjusted depending on clinical response.
Additional medications such as Long Acting Muscarinic
Antagonist (LAMA), phosphodiesterase inhibitor and
leukotriene receptor antagonist can be added as necessary.
Given these, still there is no current recommendation
standard treatment protocol in patients diagnosed with
ACOS, hence relying the addition of medications based
on clinical response thus implying individualized approach.
Close monitoring and follow up are also recommended since
patients with ACOS often have higher rates of exacerbations,
hospitalization, associated co morbid illness and mortality rate.

R eferences
1. Benfante, et.al., The asthma-COPD overlap syndrome (ACOS):
hype or reality? That is, a curiosity for the media or an opportunity
for physicians?, 2014
2. Brzostek, et.al., Asthma-chronic obstructive pulmonary disease
overlap syndrome in Poland. Findings of an epidemiological
study, 2014

Volume 55 Number 2 April - June., 2017 7

 Philippine Journal of Internal Medicine Original Article

Pediatric Endocrinology Transition Clinic Profile at the

University of Santo Tomas Hospital Outpatient Department –
Clinical Division (USTH OPD-CD)

Kristine S. de Luna, M.D.*, and Leilani B. Mercado-Asis, M.D., PhD, MPH**

Abstract
Introducation: Structured and well-coordinated transition
from pediatric to adult medical care is an integral part of
continuous disease management of maturing adolescents.
However, the evaluation of the degree of efficiency of
transition process is usually taken for granted. The objective
of this study is to characterize the pediatric endocrinology
transition clinic profiles at the University of Santo Tomas
Out-patient Department-Clinical Division (USTH OPD-CD).
Methods: A descriptive observational study that reviewed
the pediatric endocrinology database containing the data
of patients who attended the clinic from January 2012 to
July 2014 was conducted along with a month-long immersion
of the investigator. Patients aged 15 to 19 years old who
attended the pediatric endocrinology clinic were included
in the study. Variables of interest included were the patients’
demographic data, clinical information, follow-up care,
physician-patient interaction, and manner of transitioning
patients by their healthcare provider.
Transfer to adult clinic was advised in a 19-year-old patient
with type 1 diabetes mellitus, and the process was merely
verbal. There was no information whether the patient who
was advised this transfer complied. In terms of physician-
patient interaction, it was noted that physician readily
listened to their patients, after which the former was able
to give education and counselling to their patients in order
to empower them to have informed decisions. In general,
the manner of transitioning patients was done in a purely
verbal manner.
Conclusion: There is a need to modify the system of
transitional care at the USTH OPD-CD primarily in terms of
structured and formal collaboration between pediatric
and adult services to ensure the continuity of care, and
adequacy of disease management. Preparing patients prior
to their target age of transition is imperative. Taking measures
to improve the patients’ compliance with their follow-up and
attain the full cooperation of the family is also necessary.
Regular evaluation of the transition program is essential.

Results: Twenty patients were included in the analysis. Keywords: pediatric endocrinology, transition clinic,
Majority of the patients were female (n=17, 85%) while outpatient department
three (15%) were male. Although all patients had controlled
disease, only twenty percent were compliant with follow-up.
The most common condition was Graves’ disease (45%).

Introduction
efficient transition program. These include a policy on timing
of transfer, preparation period and education programme,
coordinated transfer process, interested and capable
There should be a continuity of medical care in
adult service, administrative support, and primary care
patients with childhood-onset chronic disease. In this
involvement.3,4 Coordination of transition process is not only
case, an organized, consistent, and smooth process of
required from health care professionals. There should also be
transition from pediatric to adult medical care must always
collaboration of patients and families with their health care
be ensured. 1,2 Good transition has been defined as the
providers.1,2,5,6 However, obstacles to attaining an effective
purposeful, planned movement of adolescents and young
transition include the dearth of empirical evidence on the
adults with chronic physical and medical conditions from
best approaches to the transition process, fundamental
child-centered to adult-oriented healthcare systems.3,4 Six
differences in health care delivery between pediatric and
factors have been identified to fulfill in order to have an
adult health care providers, lack of well-defined criteria for
determination of transition readiness, the changing social
*Fellow-in-training, Section of Endocrinology, Diabetes, and Metabolism,
Department of Medicine, University of Santo Tomas Hospital and demographic characteristics of young adults that
**Consultant, Section of Endocrinology, Diabetes, and Metabolism, may influence their utilization of health care, differences in
Department of Medicine, University of Santo Tomas Hospital
learning styles between individuals in this transition period
Corresponding author: Kristine S. de Luna, University of Santo Tomas compared with both younger children and adults beyond the
Hospital, Manila, Philippines. period of emerging adulthood and deficiencies in training
Email: adobe0328@yahoo.com
of health care professionals in care delivery for emerging

The PHILIPPINE JOURNAL OF INTERNAL MEDICINE is a peer reviewed journal and a copyrighted publication of the Philippine College of Physicians Volume 55 Number 2 April - June, 2017 1
 de Luna KS, et al.
adults. 7 Aside from these, there are multiple psychosocial
adjustments during the post adolescent period of emerging
adulthood that can be confounded by financial stressors.7
This is particularly true in our setting.
There have been several unexplored questions about
basic mechanisms during transition from child to adult
healthcare systems. 8 The most fundamental question is
how to find effective strategies that can engage the adult
care, so that young people can be successfully integrated
in a coherent care system.8 Failure to transfer to an adult
service may produce a delay in the acquisition of normal
developmental tasks. 9 In addition to this, evaluation
of effectiveness of transition process has received less
attention. Therefore, the general objective of this study is
to characterize the pediatric endocrinology transition clinic
profiles at the USTH OPD-CD. Other objectives to describe
the process of transitioning patients, and formulate a
recommendation to improve the transition program.
M ethods
Study Design and Setting
This is a descriptive observational study that reviewed
the pediatric endocrinology database owned by the
USTH section of endocrinology, diabetes, and metabolism
containing the data of patients who attended the pediatric
endocrinology transition clinic from January 2012 to July
2014. Information recorded in this document included the
following: date of consultation, patients’ name, age, gender,
address, contact number, hospital registration number,
diagnosis, treatment modality, follow-up date, and name
and signature of pediatric resident and endocrine fellow
who saw the patient. Immersion of the investigator in the said
clinic for one month was also done to observe the process
of transition and healthcare provider-patient interaction.
The pediatric endocrinology transition clinic was
established in 2007 and is located in the outpatient
department of USTH clinical division. The clinic is visited by
budget-restricted patients with childhood-onset endocrine
disorders who are to be transitioned to adult care in the
near future. It is attended by a senior pediatric resident
and assigned senior endocrinology fellow-in-training on a
weekly basis for two hours. The patients (old and new) are
seen initially by the senior pediatric resident together with
the senior endocrinology fellow-in-training. Subsequently,
the patient is presented to the pediatric endocrinologist
senior consultant to discuss and provide plans for the patient.
Transitioning patients were done in a verbal manner, with
the physician telling the patient and his/her mother about
transfer to adult care. This transition advise was noted in
the pediatric follow-up form as well as in the pediatric
endocrinology database. No formal transition form to
2 Volume 55 Number 2 April -June, 2017
Pediatric Endocrinology Transition Clinic Profile
contain the details of transition was accomplished. In
addition, no means were available in order to determine
whether the patient complied with transition. Grandrounds of
notable cases are also facilitated. The study was approved
by the Institutional Review Board of the said hospital.
Inclusion Criteria
Patients, aged 15 to 19 years old who attended the
pediatric endocrinology clinic from January 2012 to July
2014 were included in the study.
Exclusion Criteria
Patients with insufficient data for analysis were excluded
in the study.
Study Variables
Variables of interest included the patients’ gender, age,
diagnosis, compliance with follow-up, degree of control of
disease as indicated by its notation in the database and
absence of admission to hospital, whether the patient is
undergoing transition preparation, number and outcome
of transition, healthcare provider-patient interaction and
manner of transitioning patients by their healthcare provider.
Statistical Analysis
Descriptive statistics namely frequency, percentage,
and mean was used to summarize the data. All data were
encoded and analyzed using the Microsoft Excel for Mac
2011 (Version 14.6.5).
R esults
Twenty patients were included in the study. Majority of
the patients seen were female (n=17, 85%) while three (15%)
were male. Figure 1 shows the proportion of patients who
attended the clinic according to age. The mean age of the
study population was 16.7 years old. The age distribution in
descending order of frequency were the following: 18 years
old (n=6, 30%), 15 years old (n=5, 25%), 16 years old (n=4,
20%), 17 years old (n=4, 20%), and 19 years old (n=1, 5%).
Figure 2 shows the proportion of the different conditions
encountered. The most common condition seen is Graves’
disease (n=8, 45%). Other conditions include type 1 DM
(n=3, 15%), multinodular goiter (n=3, 15%), papillary thyroid
cancer (n=1), type 2 DM (n=1), polycystic ovary syndrome
(n=1), Cushing’s disease (n=1), congenital hypothyroidism
(n=1), and pineal gland germinoma (n=1).
Figure 3 shows the consultation outcome of patients
seen in the pediatric endocrinology clinic. A great proportion
of patients are lost to follow-up (n=15, 75%). Four patients
(20%) are not yet transitioned and remains in pediatric care.
 Pediatric Endocrinology Transition Clinic Profile
FIGURE 1. Proportion of patients seen at the clinic from 2012
to 2014 grouped according to age
FIGURE 2. Proportion of the different conditions encountered in the clinic
from 2012 to 2014
x-axis: conditions encountered
y-axis: percentage
FIGURE 3. Consultation outcome of patients seen in the clinic from
2012 to 2014
x-axis: consultation outcome
y-axis: percentage
During this period, one patient who was 19-years old with
type 1 DM was verbally advised transition into adult care
and this was also documented in the database. However
the compliance of this patient to the advise was unknown.
For the other age groups, no data was found whether they
were advised transition into adult care. No data was found
on successfully transitioned patients. In addition, there was
also no evidence regarding the provision of preparation
period for transition for the remaining age groups. Despite
de Luna KS, et al.
these findings, all patients were noted to have controlled
disease as indicated in the database.
There was no information whether the patient who
was advised this transfer complied. In terms of physician-
patient interaction, it was noted that physician readily
listened to their patients, after which the former was able
to give education and counselling to their patients in order
to empower them to have informed decisions. In general,
t h e m a n n e r o f transitioning patients was done in
a p u r e l y v e r b a l manner.
D iscussion
Transfer to adult clinic was advised in one patient
with type 1 diabetes mellitus, and the process was merely
verbal. There was no information whether the patient who
was advised this transfer complied. These results suggest
that modification of transitional care is necessary. This is to
promote efficient transfer and endorsement of the patient
from child to adult medical care.
A well-timed transition from child- to adult-oriented
health care is specific to each person and ideally occurs
between the ages of 18 and 21 years old.6 Setting a target
age of transition for a particular patient is very important
for both patient and health care provider in preparing
for transition.3,4 A target age of 18 years or school-leaving
age is best. 3,4,10 The finding of the study showed that one
19-year-old patient had been advised transition to adult
care. Probably because that particular patient manifested
the capability of being independent when it comes to
taking care of oneself as assessed by the health care
provider. Whether the patient actually went to adult care
must be determined and this must be documented in the
database. This is not only to ensure continuity of care, but
also to assess the effectiveness of transition process. There
was no data showing that 18-year old patients were advised
transition. There is a probability that patients from this age
group were verbally advised but not documented in the
database. Another possibility is that these patients would
be advised transition on the next visit, however they were
lost to follow-up, as shown by the high proportion of patients
who were non-compliant with follow-up. A data on whether
or not the patient is undergoing preparation for transition or
actual transition should be documented in the database.
Some clinics use cut-off varying from 15 to 20 years. 3,4 Earlier,
at 15 or 16 years, many with chronic illness will not have
completed their growth or pubertal development, and
adult service are unlikely to pay attention to growth and
development.3,4 It is appropriate that these remaining age
groups be prepared for transition at a later age by educating
them. Discussion regarding complications and preparations
for transition must take place before the actual transition
to adult care systems. 5 In addition, the timing of transition
Volume 55 Number 2 April - June, 2017 3
 de Luna KS, et al.
should depend on the developmental readiness and health
status of the adolescent.10 Transition should not occur before
the young person is able to manage his or her illness largely
independent of parents and staff, and can function in an
adult clinic. 10 This can be done by educating the patient
and allowing him/her to take responsibility for medication. 10
A structured assessment of their transition readiness must be
assessed. This may take in the form of validated rating scales,
checklists, questionnaires, and parental interview.
The most common condition seen in the clinic was
Graves’ disease. This is in contrast to the finding that type 1
diabetes mellitus as the most common chronic endocrine
disease in children. 11 This finding may be partially due to
the analysis of a particular subset of pediatric population.
Another possible reason is the small sample size of the study.
All patients were documented to have controlled disease,
and this is the reflection of good quality of medical care
provided by the physicians, and compliance of the parents
and patients with treatment. However, the degree of disease
control may wane with non-follow-up of the disease. This also
puts patients at risk for developing complications.
As noted, a great proportion of the patients did not
comply with follow-up. Financial issues might be one of
the underlying reasons for this non-compliance. Other
possibilities include change of residence that is farther from
the clinic, consult with another clinic, decrease of guidance
from the parents, patient demise, non-satisfaction, lack of
time to go to the clinic due to major school events such
as graduation or exams or acquisition of job, absence of
signs and symptoms, lack of understanding of the need to
move from a service that has served them for many years
and simply the lack of desire to comply with follow-up as
a result of psychosocial adjustment typically experienced
by the adolescent. 7 Transitioning older teens and young
adults are at high risk for disengagement from health care
and, in turn, the emergence of complications that may
go undetected without appropriate follow-up.7 Teens and
young adults require assistance with transition because
they are a vulnerable population at risk for loss to follow-up
care and poor health outcomes. 7 Facilitating consistent
follow-up care may be in the form of strictly and accurately
recording the patients’ residential address, email address,
contact numbers, and sending them reminders in the form
of emails, text messages or phone calls. Always emphasizing
to the parents and patients the importance of carefully
monitoring their disease should also be done. With enough
resources, getting a coordinator or care ambassador or
patient navigator is beneficial especially to health care
providers who may be busy enough to remind the patients.7
Another strategy is to assist the young adult with scheduling
the first appointment within three to four months of the final
pediatric visit. 7
4 Volume 55 Number 2 April -June, 2017
Pediatric Endocrinology Transition Clinic Profile
Another finding was the lack of a structured and
coordinated program in terms of the actual process of
transition from pediatric to adult service. A clear-cut
and effective transition program is important because
there are fundamental differences in the approach and
delivery of care between pediatric and adult patients. 7
This also ensures patients’ compliance with regards to
transition advice leading to uninterrupted management
of their chronic disease. In adult care, focus is more on the
autonomously functioning individual patient, who can be
informed or counseled but then is expected to make his or
her own choices about behavior or treatments.7 Professional
meetings appeared to be of vital importance to enable the
building of bridges between pediatric and adult care. 8 The
collaboration between pediatric and adult medical care
in order to create a smooth transition between the links in
the chain of care for adolescents during the vulnerable
phase of life must be emphasized.8 Regular evaluation of
the program’s effectiveness, identifying its strengths and
weaknesses, formulating a model of a more effective
process provide a room for improvement of the program.
Support from peers and family is indispensable as well as
care providers’ attitudes and strategies.8
According to Ishizaki et al, the prevalence of some
kinds of chronic illnesses in childhood is increasing.1 These
adolescent patients are still developing socially, and they
often lack social experiences because of their childhood
disease and have difficulties in adapting to both adult social
life within their community and adult healthcare systems.1
Therefore, programs are really required to ensure a seamless
transition of medical care in childhood and adolescence
to that in adulthood and to help children grow socially and
become independent, working adults.1 Indeed, there is a
need for a proper endorsement of the patients between
the pediatric and adult service. The provision of a transition
form which contains the patient’s medical data is one way
facilitate this kind of endorsement. The prospective adult
medical care provider must have enough interaction with
the patient in transition. This paves the way to familiarity,
comfort, and trust in both parties.
As mentioned above, there are six core elements of
a successful transition program. 3,4 The policy on timing of
transfer involves the determination of a target transfer age
depending on his developmental readiness.3,4 According
to Viner, transition should not occur until young people
have largely completed the developmental tasks of
adolescence. 3,4 A preparation period and education
program involves the identification of a necessary skill set
to enable the young person to function in adult clinic. 3,4
The preferable period is in early adolescence. 3,4 A series of
educational interventions should tackle their understanding
of disease, rationale of therapy, source of symptoms,
recognizing deterioration, seeking help from health
 Pediatric Endocrinology Transition Clinic Profile de Luna KS, et al.

professionals. 3,4 Leaflets and material about the transition endocrine transition clinic, b.) utilisation of basic, follow-up,
program and details of adult service should be provided.3,4 and transition forms, c.) putting up a registry which includes
Making the patient familiar with adult program can be the patients’ complete address, and contact numbers, d.)
facilitated by provision of its outline, and visit to adult clinic quarterly audit, e.) quarterly grand rounds (c/o pediatrics but
a year before the actual transition.3,4 A joint pediatric-adult with participation of adult endocrinology), and f.) evaluation
clinic is useful to introduce adolescents to adult physicians.3,4 of effectivity of revised transition clinic program in the form
A coordinated transfer process requires a coordinator since of another research and assessment of the patients’ health-
pediatricians may rarely have time to undertake this role.3,4 related quality of life in the form of surveys.
An interested and capable adult service is also required for
the success of the program.3,4 The development of a close
and frequent clinical and academic links between the
R eferences
services can ensure that the collaboration is beneficial to
1. Ishizaki Y, Maru M, Higashino H, Katsumoto S, Egawa K,
both services, and that patients are not lost to follow-up.3,4
Yanagimoto Y, Nagahama T: The transition of adult patients with
Institutional and administrative support must be assured at
childhood-onset chronic diseases from pediatric to adult healthcare
both ends of the transfer chain.3,4 This can be in the form
systems: a survey of the perceptions of Japanese pediatrician and
of secretarial support to ensure the efficient organization
child health nurses. Biopsychosoc Med, 6:8, 2012.
of appointments and the transfer of medical records. 3,4
2. Gawlik A,Malecka-Tendera E: Treatment of Turner’s syndrome
Transition planning must involve primary care providers who
during transition. Eur J Endocrinol, 170(2): R57-R74, 2014.
may provide the only medical continuity for young people
3. Viner R: Barriers and good practice in transition from pediatric
and their families during the time of discontinuities.3,4
to adult care. JRSM, 94(Suppl. 40):2-4, 2001.
4. Viner R: Transition from paediatric to adult care. bridging the
Currently, a paucity of data exist on the most effective
gaps or passing the buck? Arch Dis Child, 81:271-275, 1999.
and practical method of transition. 5,7,12 With a relatively
5. Lee Yah: Diabetes care for emerging adults: transition from
few model practices exemplifying high-quality transition
pediatric to adult diabetes care systems. Ann Pediatr Endocrinol
supports, training providers in the principles of health care
Metab, 18:106-110, 2013.
transition remains challenging.6 Further studies are needed
6. American Academy of Pediatrics, American Academy of Family
to provide evidence-based transitional care programs that
Physicians, and American College of Physicians, Transitions
take both medical and psychosocial aspects of care into
Clinical Report Authoring Group: Clinical report-supporting
consideration.5 Randomized control trials evaluating models
the health care transition from adolescence and adulthood in the
of transition from pediatric to adult care may be performed.12
medical home. Pediatrics, 128(1):182-200, 2011.
Due to small sample size, conduction of researches in a
7. Peters A, Laffel L, The American Diabetes Association
multicenter manner is appropriate. Structured interviews
Transitions Working Group: Diabetes care for emerging adults:
and questionnaire surveys among health care providers, and
recommendations for transition from pediatric to adult diabetes
nurses about their perceptions of the transition process are
care systems. Diabetes Care, 34:2477-2485, 2011.
helpful. 1,8 Finally, assessing the health-related quality of life
8. Lundin CS, Danielson E, Ohrn I: Handling the transition of
of the patients in preparation for transition, and in actual
adolescents with diabetes: participant observations and interviews
transition is as beneficial.
with care providers in pediatric and adult diabetes outpatient
clinics. Int J Integr Care, 7:1-10, 2007.
Conclusion 9. Bryon M: Transition from paediatric to adult care: psychological
principles. JRSM, 94(Suppl. 40):5-7, 2001.
This study is able to identify the major problems in the
10. David TJ: Transition from the paediatric clinic to the adult service.
transition clinic. There is a need to modify the system of
JRSM, 94(8):373-374, 2001.
transitional care at the USTH OPD-CD primarily in terms of
11. Perez-Marin M, Gomez-Rico I, Momtoya-Castilla I: Type 1
structured and formal collaboration between pediatric
diabetes mellitus: psychosocial factors and adjustment of the
and adult services to ensure the continuity of care, and
pediatric patient and his/her family. review. Arch Argent Pediatr,
adequacy of disease management. Preparing patients prior
113(2):158-162,2015.
to their target age of transition is imperative. Taking measures
12. Spaic T, Mahon JL, Hramiak I, Byers N, Evans K, Robinson
to improve the patients’ compliance with their follow-up and
T, Lawson ML, Malcolm J, Goldbloom EB, Clarson CL for
attain the full cooperation of the family is also necessary.
the JDRF Canadian Clinical Trial CCTN1102 Study Group:
Once a structured program is adopted, evaluation of its
Multicentre randomized controlled trial of structured transition
effectiveness in a regular manner must be executed.

The authors recommend formulation of structured

and formal endorsement from pediatric to adult care. This
can be done by a.) strengthening the joint pediatric-adult

Volume 55 Number 2 April - June, 2017 5

 Philippine Journal of Internal Medicine
Low-Dose Systemic Retinoids in Preventing Subsequent Non-
Melanoma Skin Cancers (NMSC) in Patients with History of
NMSC: A Systematic Review
Jolene Kristine G. Gatmaitan-Dumlao, M.D.*; Francesca Mari P. Sumilang, M.D.*; Cynthia P. Ciriaco-Tan, M.D.*
Abstract
Background: Non-melanoma skin cancers (NMSC) consists
of basal-cell carcinomas (BCC) and squamous-cell
carcinomas (SCC). Certain populations are predisposed to
develop NMSC, including patients with previous history of
NMSC. Systemic retinoids have shown promising results in
chemoprevention of recurrence of NMSC in other high-risk
populations (xeroderma pigmentosum and renal-transplant
patients). We assessed the efficacy and safety of low-
dose systemic retinoids compared with placebo, as a
chemopreventive agent for NMSC in patients with previous
NMSC.
Methodology: Electronic databases were systematically
searched for this study. Participants in the studies selected
must have had a biopsy-proven NMSC, over 18 years of age,
with no exclusion of other demographic characteristics.
All types of systemic retinoids were included with no
restriction on dosage. Two authors independently performed
standardized eligibility assessment and data-extraction.
Differences in opinion were resolved by consensus with the
third author. Statistical analysis was done using the Review
Manager 5 software.
I ntroduction
Background
Non-melanoma skin cancers (NMSC) are one of the most
common malignancies in the human population. 1 These
consist of basal cell carcinomas (BCC) and squamous cell
carcinoma (SCC). BCC is more common than SCC. In the
United States, latest estimates of NMSC were noted to be
four million cases diagnosed among 2.5 million people.
Exact incidence is difficult to establish because cases are
not commonly reported in registries. There is overlap with
different subspecialties with regards to the management of
these patients. Furthermore, the use of ablative techniques,
which are usually done in the outpatient setting, prevents
histologic confirmation.1
*Section of Dermatology, Department of Medicine, University of the
Philippines – Philippine General Hospital, Ermita, Manila, Philippines
Corresponding author: Jolene Kristine G. Gatmaitan-Dumlao, M.D.,
University of the Philippines – Philippine General Hospital, Manila,
Philippines
Email: jolenegatmaitan@gmail.com
The PHILIPPINE JOURNAL OF INTERNAL MEDICINE is a peer reviewed journal and a copyrighted publication of the Philippine College of Physicians
Meta-Analysis
Results: Eleven full-text studies were assessed for eligibility out
of 178 studies found. Five studies were excluded because of
the different population, while the two articles used topical
retinoids. Four articles were included. The interventions were
10.0 mg isotretinoin, 25,000IU retinol and 25.0 mg acitretin,
compared with placebo. Meta-analysis produced RR of 0.94
(95% CI, 0.89-1.00), with moderate heterogeneity (34%) due
to the difference in interventions used. There are significantly
more adverse events in the retinoids group, especially in
the incidence of mucocutaneous adverse events, and
deranged lipid profile and liver enzymes.
Conclusion: There is insufficient evidence to support the
use of low-dose systemic retinoids as chemoprevention for
patients with previous NMSC. Furthermore, adverse events
may limit their use. Topical preparations with less side-effects
may be investigated.
Keywords: Low-dose systemic retinoids, Non-melanoma skin
cancers, NMSC
NMSC develop due to damage to the skin through
ultraviolet (UV) radiation. The incidence of NMSC is known to
increase as one lives near the equator, because of the direct
exposure to the sun.2 Although NMSCs are more common
in fair-skinned individuals because of their tendency to
burn easily rather than to tan, these types of cancers are
still prevalent even in dark-skinned, pigmented individuals,
including Asians. 3
In the latest available population-based cancer registry
database in the Philippines (Department of Health Rizal
Cancer Registry and the Philippine Cancer Societry Inc.-
Manila Cancer Registry), cancers of the skin were estimated
at 4.2 per 100,000. The type of skin cancer was not specifically
indicated. 4 Among forty patients found to have malignant
skin tumors at a local hospital, 22 patients (55%) had BCC,
17 (27.5%) SCC, and seven patients (17.5%) had malignant
melanoma (MM). This data approximated skin cancer profile
in foreign studies. 5 Furthermore, among 75 patients who
underwent Moh’s Micrographic Surgery (MMS) in a local
hospital, the most common was BCC (76%) followed by SCC
Volume 55 Number 2 April - June, 2017 1
 Gatmaitan-Dumlao JKG, et al.
(14%). Majority of the NMSCs were primary, but 18% of BCC
and seven percent SCC were recurrent types.6
Aside from the fair skin phenotype, other known risk
factors include older age, chronic sun exposure, previous
pre-cancerous lesion such as actinic keratosis, previous
skin cancers, chronic immunosuppression such as organ
transplant patients, infection with the human papilloma
virus, arsenic exposure, and mycosis fungoides. Other high-
risk populations are at higher risk because of UV radiation-
induced mutations including xeroderma pigmentosum
and basal cell nevoid syndrome. In patients with previous
skin cancers, there is a ten-fold increase in incidence
of developing subsequent NMSCs, compared with the
incidence of a first tumor in the general population. 7
Description of the intervention
Retinoids include natural and synthetic derivatives of
retinol (Vitamin A). Retinol is acquired through diet, absorbed
within the intestinal lumen, and stored mainly in the liver. These
are transported through the retinol-binding proteins (RBP),
that are synthesized in the liver. Other tissues including adipose
tissues, kidney, lungs, heart, and skeletal muscles, also express
this protein. 8 Retinol is converted to retinoic acid through
a two-step oxidation process, first reversibly converted to
retinaldehyde, then irreversibly converted to retinoic acid. 9,10
Retinoids have many important functions in the body
including regulation of cell growth and differentiation,
immune defense, and tumor suppression. In malignant
cell lines, retinoids inhibit cell growth and induce normal
differentiation of the cells through their actions in the DNA
nuclear receptors, the retinoid acid receptor (RAR) and
retinoid x receptor (RXR). Most of these receptors are found
in epidermal and hair follicle keratinocytes in the skin. 10,11
Retinoids come in topical and oral preparations. Retinoids
are currently used for acne vulgaris, Kaposi’s sarcoma,
psoriasis, hand eczema, and cutaneous T-cell lymphoma.
However, because of their activity on cell differentiation,
chemopreventive activity of retinoids has been explored.12
Other proposed mechanisms of action include influence
on growth factors and indirect downregulation of proto-
oncogenes.8,9
In recent years, there were clinical studies done on high-
risk groups prone to acquiring NMSC. These patient groups
include xeroderma pigmentosum patients, epidermolysis
bullosa, patients with previous history of NMSC, and patients
who underwent renal transplant. Only the study on renal
transplant patients, comparing acitretin 30.0 mg per day and
placebo, showed 78% reduction in the risk of NMSC noted
within the first year.13
However, the use of retinoids is limited by the known
side effects, which was consistent across these studies.13,14,15
2 Volume 55 Number 2 April - June, 2017
Systemic Retinoids in Preventing Subsequent NMSC
Common side effects of retinoids appear to be dose-related,
and are largely attributed to their actions on the RAR and
RXR receptors. Most common are mucocutaneous reactions
that are due to the decrease in sebum production, reduced
stratum corneum, and altered ceramides in the skin. 10 These
reactions include cheilitis, dry skin, pruritus, hair thinning, eye
irritation, among others. Teratogenicity is also a major concern,
especially with the use of actiretin, requiring a contraceptive
period of at least three years. Furthermore, due the storage of
excess vitamin A in the liver and adipose tissues, elevations in
liver enzymes and serum triglycerides were reported.
To achieve optimal benefits, the recommended doses
of retinoids vary for different disease conditions and different
generation of retinoids. Isotretinoin given for acne is given at
0.5-1mg/kg/day. Acitretin for psoriasis may also be started
at this dose, however, in order to decrease side effects, this is
initiated at a lower therapeutic dose (0.20-0.25 mg/kg/day),
given for at least two to three months. 11 Long-term retinoid
therapy should be monitored especially at high doses, since
there were reports with skeletal toxicity including tendon and
ligament calcifications and hyperostosis of the spine.12 Thus,
long-term follow-up is still needed to reassess benefit and to
monitor side effects. 9 Proper patient selection, adequate
monitoring, and appropriate dose-adjustments are also
emphasized. 10,11
Importance of review
Patients with a previous history of NMSC have a higher
risk of developing another NMSC. Changing lifestyles of
Fitzpatrick type IV-VI patients in tropical countries may
increase the risk for NMSC as well. Although most NMSC are
not considered life-threatening due to low risk of metastasis,
they may still cause significant physical, psychosocial,
emotional and financial burden on the patients. A
chemopreventive agent may be useful in decreasing the
incidence of NMSC and its sequelae.
Several chemopreventive agents for skin cancers have
been explored in clinical studies, which included retinoids,
difluoromethylornithine, T4 endonuclease V, lycopene,
polyphenolic antioxidants such as green tea and grape
seeds, silymarin, curcumin, selenium, beta-carotene,
and non-steroidal anti-inflammatory drugs (NSAIDS). 9 For
interventions with phase III clinical studies, selenium and
beta-carotene were found to be ineffective in decreasing
the risk of skin cancers, based from single studies.16 Retinoids
and NSAIDs showed promising results, but are still under
further investigation in terms of their efficacy and safety. 9,16
To date, several studies have shown that retinoids decrease
the occurrence of new NMSCs in patients with previous
NMSC. Aside from close monitoring of these patients, options
for prevention should be explored.
 Systemic Retinoids in Preventing Subsequent NMSC
Objectives
To assess the efficacy and safety of low-dose systemic
retinoids, compared with placebo, as a chemopreventive
agent for NMSC in patients with previous NMSC.
M ethods
Eligibility Criteria
Types of Studies: The authors included randomized
controlled trials (RCT) comparing oral preparations of
retinoids with placebo, as chemoprevention for subsequent
development of NMSC.
Types of Participants: Participants must have had a
biopsy-proven NMSC (basal cell carcinoma or squamous cell
carcinoma, or both), must be over 18 years of age, whether
male or female, with no exclusion of other demographic
characteristics.
Types of Intervention: The authors included all types of
systemic retinoids, with no restriction on the dosage.
Types of Outcome Measures:
Primary outcome: Percentage of participants who
developed a new biopsy-proven NMSC within the study
duration
Secondary outcome: Percentage of participants who
developed any adverse event (AE), clinically defined as
any new symptoms experienced by the participants during
treatment and results also expressed in NNT, RR, CI, p-values.
Search methods for identification of studies
The authors conducted the electronic literature search
in the following databases: the Cochrane Skin Group’s
Specialized Register, the Cochrane Central Register of
Controlled Trials, MEDLINE (OVID), EMBASE, and Health
Research and Development Information Network (HERDIN)
database. Reference lists of articles were also used in
the search. Search terms used were chemoprevention,
prevention, retinoids, skin cancer, NMSC, BCC, SCC. Other
relevant journals were hand-searched. The authors also
contacted pharmaceutical companies, trial authors, and
organizations for potential articles and unpublished studies.
No language restrictions were imposed.
Selection of studies
Two authors (JKG, FMS) checked the titles and abstracts
identified from the literature search, and independently
assessed the full-text of all the articles that satisfied the
Gatmaitan-Dumlao JKG, et al.
inclusion criteria. A pre-tested eligibility form was used.
Differences in opinion between reviewers were resolved
by consensus with the adviser. Authors of the trials were
contacted where ambiguities were noted. The reasons for
exclusion of studies were listed.
Data extraction and management
Two authors performed the data extraction using a
pre-tested form, and disagreements were resolved with the
adviser. The following details were extracted from each study.
Method: study design and duration
Participants: age range, sex, duration of treatment
Intervention: description of intervention and the
comparator, dosage
Outcome: outcome measures and adverse effects
Assessment of risk of bias in the included studies
The quality of the studies and the risk of bias were
assessed independently by the authors, based on the
cochrane handbook for systematic reviews of interventions.
Random sequence generation, allocation concealment,
blinding of participants and personnel, blinding of outcome
assessment, incomplete outcome data, and selective
reporting were checked for each study. Based on how the
criteria were met, the methodological quality was classified
into high (all criteria with low risk of bias), moderate (with
one or more than one criteria with unclear risk of bias), and
low (with one or more criteria with high risk of bias).
Data analysis
Results were expressed as risk ratio (RR) with 95%
confidence intervals (CI). Statistical analysis was carried
out using the Review Manager 5 software. Heterogeneity
was tested via I² statistics, and was interpreted as no
heterogeneity (I² = 0%), low heterogeneity (I² = 25%),
moderate heterogeneity (I² = 50%), and high heterogeneity.17
Where subgroup analysis was possible, a calculated
treatment effect was calculated using the fixed effects
model. Descriptive analysis was performed where meta-
analysis was not possible.
R esults
Results of the search
A total of 169 studies were identified through database
search (Figure 1). The search process using reference lists
yielded six articles. Excluding duplicates and non-human
clinical trials, 11 articles were assessed for eligibility. Five
studies were excluded because of the different population
- three studies were on renal transplant patients, one on
recessive dystrophic epidermolysis bullosa (RDEB), and one
Volume 55 Number 2 April - June, 2017 3
 Gatmaitan-Dumlao JKG, et al. Systemic Retinoids in Preventing Subsequent NMSC

Table I. Risk Bias Assessment in the Included Studies

Tangrea Moon Levine Kadakia

1992 1997 1997 2012
Selection Bias: Unclear Unclear Low Low
Random sequence generation

Selection Bias: Unclear Low Low Unclear

Allocation Concealment
Performance Bias: Low Low Low Low

Blinding of patients and

personnel
Detection Bias: Unclear Low Unclear Low
Blinding of assessor outcome
Attrition Bias: Unclear Low Unclear Low
Incomplete outcome data
Reporting Bias Unclear Unclear Low Low

Overall Moderate Moderate Moderate Moderate

were significantly more mucocutaneous reactions (RR = 0.19,

[95% CI, 0.24-1.50], p = 0.005), elevations in triglycerides and/
or liver function tests (RR = 3.39, [CI 95%, 1.99-5.80], p = 0.001),
and musculoskeletal pain (RR = 1.73, [95% CI, 1.18-2.55], p
= 0.005). Dizziness, anxiety, and fatigue were also reported
in the isotretinoin group (RR = 1.76, [CI 95%, 1.11-2.18], p =
0.02). Reporting of adverse events were self-reports, and the
severity was not detailed.

The study by Moon et al 20 utilized retinol 25,000 IU daily

Figure 1. The preferred reporting items for systematic reviews and
meta–analyses (PRISMA) diagram
on xeroderma pigmentosum (XP). Two studies were excluded
because the interventions used were topical retinoids. At
the end of the literature search using the strategy indicated
above, a total of four studies were included in this review.
Risk of bias in the included studies
for fivw years for SCC and BCC. A total of 2297 participants
were randomized. Follow-up data was complete, and
emphasized in the study, with most of the dropout occurring
in the fourth and fifth year of the study. There was no
statistical difference in the development of subsequent
NMSC (RR = 0.83, [CI 95%, 0.66-1.06]). Adverse events were
classified as mild, moderate and severe. For this study,
there were noted significant differences on the incidence
of adverse events.

All of the studies had moderate methodological quality
( Table I). Blinding and patients and personnel were reported
in all of the trials.
Results of Individual Studies
In the study by Tangrea et al18, 10.0 mg isotretinoin (~0.14
mg/kg/day) was used as chemoprevention for BCC. Nine-
hundred eighty one (981) participants were randomized to
receive isotretinoin or placebo daily for three years. About
eight percent of this population were lost to follow-up, and
was not detailed in the study. Participants were monitored
initially at two weeks, then three months, six months,
and every six months thereafter. There was no significant
difference in the development of at least one NMSC for both
groups (RR = 1.00, [95% CI, 0.89-1.13]). For this study, there
There are two interventions in the study by Levine et al. 19,
which compared isotretinoin 10.0 mg daily and retinol 25,000
IU daily with placebo for prevention of NMSC. A total of 790
participants were randomized to receive isotretinoin, retinol,
or placebo. There was no significant difference in decreasing
the number of new NMSC compared with placebo, for both
isotretinoin and retinol. Moderate to severe mucocutaneous
adverse events were noted both in the retinol (RR = 3.55, [CI
95%, 1.20-10.5], p = 0.02) and isotretinoin group (RR = 6.96, [CI
95%, 2.51-19.3], p = 0.002). Abnormalities in blood chemistry
parameters (cholesterol, triglyceride, hemoglobin, liver
function tests) were highest in the isotretinoin group (RR = 10.2,
[95% CI, 1.33-78.1], p = 0.02).
In the study by Kadakia et al. 21, 73 participants were
enrolled but only 53 participants completed the study

4 Volume 55 Number 2 April - June, 2017

 Systemic Retinoids in Preventing Subsequent NMSC
Figure 2. Forest plot of primary outcome of development of at least 1 NMSC (SCC/BCC), and subgroup analysis for develop-
ment of SCC and BCC
according to the protocol. High attrition rate was similar
in both groups. There was no significant difference in the
development of subsequent NMSC (RR = 0.83, [CI 95%,
0.52-1.31]). Incidence of mucocutaneous adverse events
was significantly higher in the treatment group (RR = 2.69
[CI 95%, 1.34-5.24], p = 0.004). On further analysis, among all
the studies, this study showed the least number of patients
to treat. From the findings in the study, it may be deduced
that for every 13 patients given the intervention, one patient
will not develop a new NMSC. Summary table of incidence
of adverse events may be found in Appendix C.
In summary, all four studies did not show statistical
difference in preventing the occurrence of subsequent
development of NMSC. However, adverse events were noted
to be higher in the retinoid group.
Synthesis of results
Pooling of data was done for studies in which results
can be grouped and combined. Meta-analysis on all studies
(3,873 participants) produced a risk ratio of 0.94 (95% CI,
0.89-1.00) with noted moderate heterogeneity at 34%.
Heterogeneity may be attributed to the difference in the
interventions used (Figure 2). Further subdividing studies
with available data for SCC, similar trends favoring retinoids
was noted (RR = 0.88, [CI 95%, 0.74-1.05]) but not statistically
significant. For BCC, similar trends were also noted although
Gatmaitan-Dumlao JKG, et al.
not statistically significant (RR = 0.98, [CI 95%, 0.91-1.05]).
There was no evidence of heterogeneity for both subgroup
(Figure 2).
Incidence of adverse events
Meta-analysis was done on all the studies to check
the incidence of adverse events (Figure 3). Incidence of
mucocutaneous adverse events was noted to be statistically
significant in the retinoid group (RR 2.11, 95% CI, 1.86-2.39).
There was high heterogeneity in the studies, which may be
attributed to the differences in reporting of adverse events.
Meta-analysis in the incidence of the musculoskeletal
adverse events was not statistically significant (RR=1.18 [CI
95%, 0.87-1.59]), with low heterogeneity. There is a trend
favoring the control group in the incidence of abnormalities
in blood chemistry (RR = 1.52, [CI 95%, 1.26-1.83]), with noted
moderate heterogeneity. Meta-analysis on the incidence of
CNS adverse events showed no statistical difference (RR =
1.08, [CI 95%, 0.77-1.51]) with moderate heterogeneity.
D iscussion
The studies on the use of retinoids for chemoprevention
in patients with previous history of NMSC, when assessed
individually, did not show statistically significant results.
However, this meta-analysis highlighted positive trends,
favoring the use of retinoids in chemoprevention of
Volume 55 Number 2 April - June, 2017 5
 Gatmaitan-Dumlao JKG, et al.
Figure 3. Forest plot of incidence of adverse events
subsequent NMSC in patients with a prior history of BCC
and SCC. The studies included in this review have well-
executed methodology. Based from the studies, the
selected interventions were relatively well-tolerated, and
showed dose-related and reversible toxicities.
Retinoids are usually given at a high dose (0.5-1mg/kg/
day) to achieve the optimal effects on the skin. However,
low-dose systemic retinoids (0.20-0.25mg/kg/day) are
recommended for disorders needing lifelong maintenance
such as in keratinizing disorders.22 Adverse events have been
observed in the studies of Kadakia et al.21 and Tangrea et
al.,18 despite the use of the lower dose, and were considered
to be the factors that led to the high attrition rate. However,
it is important to note that the participants were informed
of the possible toxicities at the start of the trial, hence the
possible increase in reports of adverse events in both the
treatment and control groups.
In this review, the adverse events were grouped
according to the involvement of mucocutaneous,
musculoskeletal, abnormalities in blood chemistry, and
central nervous system, with the mucocutaneous adverse
events still the most common, especially noted in the
isotretinoin group. Mucocutaneous adverse events included
6 Volume 55 Number 2 April - June, 2017
Systemic Retinoids in Preventing Subsequent NMSC
cheilitis, dry oral mucosa and dry skin not relieved by
emollients. The next common adverse events were the
abnormalities in blood chemistry, particularly elevations
in liver enzymes and lipid profile, which are typically
seen in patients on retinoid therapy. Transient increase in
liver enzymes are seen in approximately 20% of patients
treated with acitretin and less with isotretinoin. These are
usually mild, developing between two to eight weeks
of therapy, and returns to normal even after a month of
continued therapy.10,11 Hypercholesterolemia and elevated
triglycerides, on the other hand, are seen in 50% and 30%,
respectively, of patients on isotretinoin and acitretin therapy.
In this study, elevations in liver enzymes were noted to be
significant with the treatment of isotretinoin in Levine et al.19
and Tangrea et al.18 Other less reported, but still relevant
adverse events include musculoskeletal and symptoms
pertaining to the central nervous system. Musculoskeletal
adverse events included moderate to severe reporting of
myalgias, arthalgias and arthritis, while the central nervous
system adverse events involved intolerable dizziness, nausea,
and headache.
It is important to note that for all studies, except for
the hematologic adverse events, severity of the symptoms
noted was based on the self-reports by the patients. The
 Systemic Retinoids in Preventing Subsequent NMSC
most common side effects remain to be the dryness of
the mucous membranes and the skin, and this is mainly
due to the mechanism of action of the retinoids. Transient
elevations of the liver enzymes and lipid profile are also seen,
hence monitoring of these parameters are recommended
monthly. These are mild, reversible upon dose-adjustment
and cessation of the drug.
Results of this study suggest that there is currently not
enough evidence on the use of low-dose oral retinoids
for patients with prior history of NMSC. Retinol, acitretin
and isotretinoin are all available in the country at less
than 100 pesos (roughly two dollars) per tablet. Risk and
benefit should always be assessed for each patient. Close
monitoring and follow-up are warranted.
C onclusions
Results of this study suggest that there is not enough
evidence on the use of low-dose systemic retinoids as
chemoprevention for patients with prior NMSC. Furthermore,
adverse events, although mild, limit their use. Hence, the
risks and benefits of the retinoid use should be assessed
for each patient. Close monitoring and follow-up are
warranted.
At the time of this study, the study on acitretin as
chemoprevention for non-transplant patients was still
considered as a pilot study, with noted limited sample size.
Additional future studies and systematic review for acitretin
in NMSC may be helpful in strengthening evidence for its
chemopreventive use. Moreover, topical preparations
for retinoids may have less side effects compared with
oral retinoids, and these may be further investigated and
reviewed for preventing NMSC.
R eferences
1. Rogers, HW, Weinstock, MA, et al. Incidence estimate of
nonmelanoma skin cancer (Keratinocyte Carcinomas) in the US
population, 2012. JAMA Dermatol 151(10): 1081-1086, 2015.
2. Auerbach H. Geographic variation in incidence of skin cancer in the
United States. Public Health Rep, 76: 345–8, 1961.
3. Bradford P. Skin cancer in skin of color. Dermatol Nurs, Jul–Aug;
21(4): 170–178, 2009.
4. Ngelangel and Wang. Cancer and Philippine Cancer Control
Program. Jpn J Clin Oncol 32(suppl1): S52-S61, 2002.
5. Adao-Grey A. Profile of malignant skin tutors at UERMMMC. J
Health Sci 1(1): 36-40, 1998.
6. Ciriaco-Tan. Clinicohistopathologic profile of patients who
underwent Mohs Micrographic Surgery at the Dermatology Center
of St. Luke’s Medical Center from 2003-2008. J Phil Derm Soc,
November; Vol 17 (2), 2008.
7. Marcil I, Stern R. Risk of developing a subsequent non- melanoma
skin cancer in patients with a history of non- melanoma skin cancer:
Gatmaitan-Dumlao JKG, et al.
A critical review of the literature and meta analysis. Arch Dermatol,
136:1524, 2000.
8. Bushue N and Wan YY. Retinoid Pathway and Cancer Therapeutics.
Adv Drug Deliv Rev, 62(13): 1285–1298, 2010.
9. Wright TI, Spencer JM, Flowers FP. Chemoprevention of
nonmelanoma skin cancer. J Am Acad Dermatol CME: June 2006.
10. Thielen AM and Saurat JH. Retinoids. Edited by Bolognia JL,
Jorizzo JL, and Schaffer JV. Dermatology 3rd edition, China,
Elsevier, 2012.
11. Vahlquist A and Saurat JH. Retinoids. Edited by Goldsmith
LA, Katz, SI, Gilchrest BA, Paller AS, Leffel DJ and Wolff K.
Fitzpatrick’s Dermatology in General Medicine 8th edition, USA,
McGraw-Hill, 2012.
12. DiGiovanna JJ. Retinoids chemoprevention in the high-risk patient.
J Am Acad Dermatol 39:S82-5, 1998.
13. Bouwes Bavinck JN, Tieben LM, Van Der Woude FJ, Tegzess
AM, Hermans J, Schegget JT, et al. Prevention
of skin cancer and
reduction of keratotic skin lesions during acitretin therapy in renal
transplant recipients: A double-blind , placebo-controlled study. J
Clin Oncol, 13:1933–8, 1995.
14. George R, Weightman W, Russ GR, Bannister KM, Mathew TH.
Acitretin for chemoprevention of non-melanoma skin cancers in renal
transplant recipients. Australas J Dermatol 43:269–73, 2002.
15. Fine J, Johnson LB, Weiner M, Stein A, Suchindran C.
Chemoprevention of squamous cell carcinoma in recessive
dystrophic epidermolysis bullosa: Results of a phase 1 trial of
systemic isotretinoin. J Am Acad Dermatol, 50(4):563–71, 2004.
16. Bath-Hexall FJ, Leonardi-Bee J, Somchand N, Webster AC,
Dellit J, Perkins W. Interventions for preventing non-melanoma
skin cancers in high-risk groups (Review). Cochrane Library, John-
Wiley &Sons Ltd, 2007.
17. Higgins JPT, Thompson SG. Quantifying heterogeneity in a meta-
analysis. Stat Med 21,1539-1558, 2002.
18. Tangrea JA, Edwards BK, Taylor PR et al. Long-term therapy
with low-dose isotretinoin for prevention of basal cell carcinoma: a
multicenter clinical trial.Isotretinoin-Basal Cell Carcinoma Study
Group. J Natl Cancer Inst, Mar 4;84(5):328-32, 1992.
19. Levine N, Moon TE, Cartmel B, Bangert JL. Trial of retinol and
isotretinoin in skin cancer prevention: a randomized, double-blind,
controlled trial. Cancer Epidemiol Biomarkers Prev, 6:957–61, 1997.
20. Moon TE, Levine N, Cartmel B, Bangert JL, Rodney S, Dong Q .
Effect of retinol in preventing squamous cell skin cancer in moderate-
risk subjects: A randomized, double-blind, controlled trial. Cancer
Epidemiol Biomarkers Prev, 6:949-56, 1997.
21. Kadakia KC, Barton DL, Loprinzi CL, Sloan JAet al. Randomized
controlled trial of acitretin versus placebo in patients at high-risk
for basal cell or squamous cell carcinoma of the skin (North
Central Cancer Treatment Group Study 969251). Cancer,
118(8):2128-47, 2012.
22. Elewa RM and Zouboulis CC. Vitamin A and the Skin. Edited
by Pappas A. Nutrition and Skin: Lessons for Anti-Aging, Beauty
and Healthy Skin, New York, Springer-Verlag, 2011.
Volume 55 Number 2 April - June, 2017 7
 Philippine Journal of Internal Medicine
Determination of Nonalcoholic Fatty Liver Disease in Patients
with Pre-Impaired Glucose Tolerance
Valerie Ann U. Valdez, M.D.*; Leilani B. Mercado-Asis, M.D., PhD, MPH*; Amy A. Lopez, M.D.*; Erick S. Mendoza, M.D.*; Katherine Jane G. Barredo, M.D.**;
Jose D. Sollano, M.D.**; Abigail M. Milo, M.D***; Mario T. Milo, M.D.***
Abstract
Introduction: Pre-impaired glucose tolerance (pre-IGT)
or compensated hyperinsulinemia, is defined as normal
glucose, and elevated insulin two hours after a 75-gram
oral glucose load. It is characteristic of the early stages of
diabetes mellitus (DM), where beta cells compensate for
insulin resistance by increasing insulin secretion to maintain
normoglycemia. With continuing beta cell failure, insulin
secretion eventually fails, leading to the progression to
diabetes. Nonalcoholic fatty liver disease (NAFLD), a
common feature of insulin resistance, is found in 50-75% and
42-55% of DM and pre-diabetes patients. We determined if
NAFLD was present in patients with pre-IGT.
Method: A study on the determination of NAFLD – diagnosed
by liver ultrasound in pre-IGT patients at a university hospital.
Descriptive statistics, Chi square test of independence, 2x2
Fischer Exact test, Z test of difference in proportion, were
I ntroduction
Diabetes mellitus (DM) type 2 is a progressive disease
characterized by beta cell dysfunction and decreasing
insulin sensitivity. In its early stages, the beta cell compensates
for insulin resistance by increasing insulin secretion to
maintain blood glucose within normal levels; this has been
labeled as “pre-IGT” (pre-impaired glucose tolerance) or
compensated hyperinsulinemia by Matawaran et al. 1 in
2009. The local study identified the presence of pre-IGT in
42-52% of individuals who were high risk to develop DM. 1,2
Since it was a relatively new concept, research attempts
have been made to explore the different characteristics
of this new metabolic profile. In a manuscript by Nisce and
Mercado-Asis (2011), they attempted to develop a clinical
scoring to identify pre-IGT state, however, it has not shown
to be helpful, signifying that pre-IGT is subclinical in nature.
*Section of Endocrinology, Diabetes & Metabolism, Department of Medicine,
University of Santo Tomas Hospital, Manila
**Section of Gastroenterology, Department of Medicine, University of Santo
Tomas Hospital, Manila
***Ultrasound Section, Department of Radiology, University of Santo Tomas
Hospital, Manila, Philippines
Corresponding author: Valerie Ann U. Valdez, M.D., University of Santo
Tomas Hospital, Manila, Philippines
E-mail: vauvaldez@yahoo.com
The PHILIPPINE JOURNAL OF INTERNAL MEDICINE is a peer reviewed journal and a copyrighted publication of the Philippine College of Physicians
Original Paper
used for statistical analysis with a p-value set at 0.05α.
IBMSPSS ver 21 was used as software.
Results: The mean age of 22 patients was 29.95 years, with
average BMI of 25.73 kg/m2; 77.3% were female. Average
lipid panels were within optimal limits; kidney and liver
functions were normal. The mean insulin level was 58.36 uIU/
mL. NAFLD was identified in eight of the subjects.
Conclusion: Although pre-IGT is a subclinical phase in
the diabetes spectrum, 36% already have NAFLD. This
prevalence was lower compared to diabetics and pre-
diabetics, but higher compared to the general population.
There was a noticeable trend of increasing insulin levels with
increasing severity of fatty liver.
Keywords: pre-IGT; compensatory hyperinsulinism; NAFLD;
With continuing beta cell failure, increasing insulin levels can
no longer compensate for the insulin resistance and insulin
secretion eventually fails, leading to the progression to type
2 DM.
Nonalcoholic fatty liver disease (NAFLD) is a common
feature of insulin resistance, and is characterized
pathologically by a spectrum encompassing simple steatosis,
non-alcoholic steatohepatitis and cirrhosis. The prevalence
of NAFLD has been reported to be in the range of 10-24%3 in
the general population. Among those with type 2 diabetes
mellitus, the prevalence was as high as 50-75%. 4,5,6 Recent
studies have shown that even patients with IGT or pre-
diabetes have high prevalence of NAFLD (42-55%). 5,6 As the
degree of insulin resistance worsens, so does the severity
of fatty liver disease; conversely, insulin resistance predicts
nonalcoholic hepatic steatosis.5
Although the gold standard in the diagnosis and staging
of NAFLD is liver biopsy, ultrasonography is one modality used
to identify fat in the liver in the early, preclinical form of the
disease 7. It has the advantage of being readily available,
noninvasive, requires only a short time to perform and with
immediate results, making it a good screening method
of NAFLD in a general population. A scoring system using
abdominal ultrasonography was developed by Hamaguchi
Volume 55 Number 2 April - June., 2017 1
 Valdez VAU, et al. Determination of Nonalcoholic Fatty Liver Disease

Table I. Hamaguchi scoring system for fatty liver8

Bright liver and hepatorenal echo contrast

0 Bright liver and hepatorenal echo contrast were negative
1 Either bright liver was positive or hepatorenal echo contrast was positive
2 Bright liver was mild, and hepatorenal echo contrast was positive
3 Bright liver was severe, and hepatorenal echo contrast was positive
Deep attenaution
0 Deep attenuation was negative
1 Visualization of the diagphragm was obscure, but an observer could distinguish the diaphragm
2 An observer could not distinguish the diaphragm
Vessel blurring
0 Vessel burning was negative
1 The borders of intrahepatic vessels were unclear and the lumen of intrahepatic vessels was narrowed
Sum score of A, B, and C, if score of A is more than 1; Total score is 0, if score of A is 0

et al.8 in 2007 to diagnose histologically proven NAFLD. It had that may contribute to the development of fatty liver; 3) to
high sensitivity (91.2 - 92.6%) and specificity (100%), which determine if there is a relationship between fatty liver and the
was actually more accurate compared to previous reports. patients’ clinical and metabolic profile; and 4) to determine
The scoring system was noted to have high reliability, with if a relationship exists between fatty liver and post-glucose
within-observer and between-observer reliability of 0.95 (95% load insulin levels.
CI 0.93-0.97, P<0.001); and it utilizes a simple criterion, both
necessary for a screening method (Table I).
M ethods
There is much to be discovered about the unique
This is a single-center study to determine the prevalence
characteristics of pre-IGT. When this group was first
of NAFLD in pre-IGT patients, conducted in a university
identified, it was observed that patients with pre-IGT had
hospital, and duly approved by the local Institutional Review
higher BMI values compared to the normal and pre-diabetic
Board. Purposive, nonprobability sampling was utilized since
group, however statistical significance was not established 1.
the target population was limited, and the disease of interest
The same held true for insulin levels two hours after an oral
is relatively new.
glucose load. In a separate study on pre-IGT patients, they
observed that glycosylated hemoglobin (HbA1c), second
Patient Profile
hour blood glucose and second hour insulin levels were
significantly higher in the pre-IGT group compared to those
A total of 22 patients who were diagnosed with pre-IGT
patients with normal oral glucose tolerance test (OGTT) 2. A
in a private specialty clinic were recruited to participate
positive correlation was demonstrated between the HbA1c
in the study. All participants have read, understood and
and second hour glucose levels but not with the second hour
signed an informed consent prior to study entry, and the
insulin levels. In knowing the characteristics of this earliest
research conducted in accordance to the ethical principles
stage of the diabetes spectrum, multiple approaches may
in the Declaration of Helsinki. A diagnosis of pre-IGT was
be devised to prevent the development of overt diabetes,
established using a 75-gram OGTT, and defined as having
and its long-term complications. Since NAFLD is associated
normal second hour glucose (less than 140 mg/dL), and
with a constellation of clinical problems that arise from insulin
elevated insulin levels (greater than 30 uIU/mL)1. Individuals
resistance, we hypothesize that in the pre-IGT state, which
who underwent testing were those who were high risk to
is a subclinical state of glycemic abnormality, NAFLD may
develop diabetes mellitus: e.g. family history of diabetes in
not be apparent.
first-degree relatives, previous history of gestational diabetes,

polycystic ovary syndrome and obesity.
The general objective of this study is to determine if
nonalcoholic fatty liver disease is present in patients with
Inclusion And Exclusion Criteria
pre-IGT.

Patients eligible to be enrolled in the study may be male
The specific objectives include 1) to describe the
or female, aged 18 years old and above, with a diagnosis of
clinical profile of pre-IGT patients with and without NAFLD;
pre-IGT. Participating patients who had a history of chronic
2) to identify other risk factors present in pre-IGT patients

2 Volume 55 Number 2 April-June 2017

 Determination of Nonalcoholic Fatty Liver Disease Valdez VAU, et al.

glucocorticoid intake or were previously diagnosed to have
dyslipidemia or any known liver disease were automatically
excluded. Likewise, those who had significant alcohol intake
(defined as more than 20 grams/day) or a history of intake
of lipid-lowering agents were also not included.
Data Gathering
Chi square test of independence, 2x2 Fischer Exact
test, and Z test of difference in proportion were used.
Any associated p-values lesser than 0.05 alpha were
considered statistically significant. To ensure accuracy of
computation, IBMSPSS version 21 and SAS 9.1 were used
as aids in processing the data.

An initial interview was conducted to obtain baseline

R esults
patient information. All data were encoded in a data
Clinical Profile
collection sheet. Patient identity was kept confidential,
identified with a code known only to the author. Only the
A total of 22 subjects participated in this study,
researchers had full access to patient information and data.
composed mostly of females (77.3%); mean age was 29.95
Demographic data included age and sex; anthropometric
years, with an age range of 23 to 48 years. Table II shows
measurements done were weight (kg), height (cm), and
the baseline demographic data and anthropometric
waist circumference (cm), with subsequent calculation of
characteristics of subjects. The average body mass index
the body mass index (BMI) in kg/m2. Pertinent laboratory
(BMI) of all patients was 25.73 ± 4.12 kg/m 2, with 77.2%
data included lipid profile (total cholesterol, triglycerides,
of the patients belonging to the overweight and obese
high density lipoprotein [HDL], low density lipoprotein [LDL]),
category. The mean waist circumference of 84.39 ± 8.76
liver enzymes and insulin level on diagnosis.
cm, signified the presence of abdominal obesity (defined
as waist circumference of ≥ 80 cm for women and ≥90
Procedure
cm for men.

Participants were instructed to have an overnight fast of

Table II. Baseline Characteristics Of Patients
four to six hours prior to undergoing a liver ultrasound. The
procedure was done using the Siemens s3000 machine at Patient Descriptive
the Ultrasound Department of the institution where the study Charactersitics
was conducted. To decrease inter-observer variability, the
procedure was done by a single technician and interpreted Demographic
by the same radiologists, all blinded by the characteristics Age (years), mean ± SD 29.95 ±7.29
of the subjects. Sex, f%
Male 5 22.70%
A diagnosis of nonalcoholic fatty liver was made using
Female 17 77.30%
ultrasonographic results and the Hamaguchi Scoring System8.
The imaging parameters utilized were hepatorenal echo Anthropometric
contrast, bright liver, deep attenuation and vessel blurring – BMIa (kg/m2), mean ± SD 25.73 ±4.12
as outlined in Table I. A score of ≥ 2 was needed to fulfill the Normal (18.5-22.9), f% 5 22.70%
diagnosis NAFLD. The presence of fatty liver was then further
Overweight (23-24.9), f% 3 13.60%
classified into mild, moderate and severe. Mild was defined
Obese 1 (25-29.9), f% 12 54.50%
as having mild increase in the fine echoes in the hepatic
parenchyma with normal visualization of the diaphragm Obese 2 (≥ 30), f% 2 9.10%
and intrahepatic vessel borders; moderate as a diffuse Waist (cm), mean ± SD 84.39 ±8.76
increase in fine echoes with mild impaired visualization of Male 90 ±6.74
the intrahepatic vessels and diaphragm; and severe as
Female 82.74 ±16.27
marked increase in fine echoes with non-visualization of the a
BMI- body mass index; World Health Organization-Asia Pacific criteria 11
intrahepatic vessel borders, diaphragm and posterior portion
of the right lobe of the liver.8,9
Metabolic Profile

Statistical Analysis
The average baseline lipid profiles of patients in
Table III were within normal to near optimal levels 11. Liver
All data were encoded in MSEXCEL 2013. Descriptive
function, was likewise normal; with average SGPT of 22.44
statistics was used to determine measures of central
U/L and SGOT of 17.28 U/L. Mean insulin levels, two hours
tendencies such as mean and standard deviations.
after a 75-gram oral glucose load was 58.36 uU/mL.
Categorical data were presented in frequencies and
percentages, while continuous data were indicated
using mean and standard deviations. To compare rates,

Volume 55 Number 2 April - June., 2017 3

 Valdez VAU, et al. Determination of Nonalcoholic Fatty Liver Disease

Ultrasonographic Profile And Correlation With Patient Profile

Table IV. Clinical and Metabolic Profile of Patients With and
Without Fatty Liver
Out of the 22 patients, eight or 36% were found to have
fatty liver based on ultrasonography criteria. Of the eight Fatty Liver
patients, six had mild and two had moderate fatty liver; Negative Positive
but none had severe. Table IV presents a cross tabulation n=14 n=8
of fatty liver against the different clinical and metabolic
Clinical Profiles Mean Mean p-value
profile present in the patient. It is evident that patients who
(Range) (Range)
had fatty liver had a lower mean age. On the average,
patients with and without fatty liver had abdominal obesity Age (Years) 30.77 28.63 0.527
according to sex-specific definitions. Among male patients, (23-48) (23-40)
those who had normal liver were observed to have greater Waist (cm)
waist circumference than those who had fatty liver. This Male 92.67 86.00 0.494
was conversely true among female subjects, wherein those (85.5-97) (81-91)
who had fatty liver had more abdominal adiposity. A similar Female 80.86 86.18 0.060
trend of having higher values for those without fatty liver was (60-95.5) (81.5-94.5)
observed for HDL levels.
BMIa (kg/m2) 25.08 26.87 0.341
(19.3-36.8) (23-31.2)
Table III. Metabolic Profile Of Patients
To t a l c h o l e s t e r o l 181.61 172.16 0.467
Metabolic Profile Mean Standard (mg/dL) (138-237) (160-196)
Deviation Triglyceride (mg/dL) 68.44 84.45 0.265
Lipid profile (mg/dL) (45-149) (43-165)
Total cholesterol 178.17 28.46 HDL b (mg/dL) 66.62 51.72 0.107
(45-139) (45-60)
Triglyceride 74.26 31.72
LDL c (mg/dL) 101.23 103.30 0.857
HDLa 61.2 20.78
(57-148) (86-129)
LDLb 101.98 24.95
SGPTd (U/L) 22.87 21.70 0.812
Liver function test (U/L)
(9-53) (10-39)
SGPTc 22.44 10.66
SGOTe (U/L) 16.30 18.50 0.217
SGOT d
17.28 3.68 (10-21) (11-24)
75-Gram OGTTe Insulin (uU/mL) 52.48 68.65 0.176
2nd hour insulin (uU/mL) 58.36 26.61 (31.4-112.5) (31.2-106.4)
a
HDL-high density lipoprotein; bLDL-low density lipoprotein; cSGPT-serum glutamate-
pyruvate transaminase; dSGOT-serum glutamic oxaloacetic transaminase; eOGTT-oral a
BMI – body mass index; bHDL-high density lipoprotein; cLDL-low density lipoprotein;
glucose tolerance test d
SGPT-serum glutamate-pyruvate transaminase; eSGOT-serum glutamic oxaloacetic
transaminase

The BMI, total cholesterol, LDL, and liver functions were

similar in both groups. Patients with fatty liver were noted to
have higher triglyceride levels compared to those without.
At baseline, pre-IGT patients already have elevated
second hour insulin levels, since it is a requisite for its
diagnosis. It was observed that patients who had fatty
liver had higher insulin levels. On further analysis, there
was a trend of increasing insulin levels as the severity (mild,
moderate, severe) of fatty liver progressed. However,
analysis of the mean values showed that the differences
of values among those patients with and without fatty liver
were not statistically significant.
D iscussion
Hyperinsulinemia
Increasing evidence show that by the time glucose
tolerance or fasting glucose levels become impaired,
pancreatic beta cell destruction may have already
occurred. At the same time, patients who have glucose
tolerance or those with completely normal OGTT findings
may have elevated insulin to maintain glucose levels within
normal levels – a state of compensated hyperinsulinemia
that equates to insulin resistance1. There is a high prevalence
and rapidly increasing trends of hyperinsulinemia from 25%
to 34.8% according to NHANES 12, with the most dramatic
changes occurring in the 20- to 39-year-old group for both
sexes. This finding is consistent with data showing the
greatest increase in obesity prevalence among people aged

4 Volume 55 Number 2 April-June 2017

 Determination of Nonalcoholic Fatty Liver Disease
18-29 years.13 Both statistical data validate hyperinsulinemia
and obesity characterizing the pre-IGT patients of the same
age group.
NAFLD and Insulin Resistance
Fatty acids (FFAs) in the liver come from three different
sources: dietary fat, adipocytes (lipolysis) and de novo
hepatic lipogenesis. Excess caloric intake in the diet can
result in obesity and associated insulin resistance. This
contributes to the development of fatty liver by impairing
the ability of insulin to suppress lipolysis, which leads to
increased delivery of FFAs to the liver. The increased FFAs
may then induce hepatic insulin resistance. As to whether
insulin resistance in NAFLD is the cause or the consequence,
is still not clear.4
NAFLD is strongly associated with reduced whole-
body insulin insensitivity, documented by 45-50% reduction
of glucose disposal; impaired ability of insulin to suppress
endogenous glucose production (hepatic insulin resistance);
and a defect in insulin suppression of free fatty acid (adipose
insulin resistance). All these findings suggest the possibility
of insulin resistance as an intrinsic defect in NAFLD4.
Associations of insulin resistance and NAFLD have
been established in patients with pre-diabetes and type
2 diabetes. NAFLD has a high prevalence among type 2
diabetic patients, while slightly lower in pre-diabetics as
described above. Since pre-IGT precedes the development
of the latter, the presence of NAFLD is expected to be
minimal at this point. In this study, NAFLD was already
present in 36% of individuals with pre-IGT. It is lower than
the prevalence reported in patients with pre-diabetes
and diabetes but higher compared to that of the general
population. The trend of increasing prevalence across
worsening beta-cell function proves that pre-IGT is the first
phase metabolic dysfunction in the spectrum of glucose
homeostasis. At the same time, this data further supports
the important role of insulin resistance in the pathogenesis
of fatty liver.
Among the conditions associated with insulin resistance,
obesity is the most common factor associated with NAFLD4.
Both of these risk factors lead to increased free fatty acid
delivery to the liver or impaired lipolysis, coupled with
increased de novo lipogenesis, leading to the development
of fatty liver disease. 14 As shown in Table II, the BMI of
the subjects are widely distributed across the different
classifications, however more than 60% are clustered under
the obese category. A cross-section of BMI and fatty liver in
Table V illustrates that those with normal BMI did not have
fatty liver. At the same time, being obese, did not necessarily
equate to having NAFLD. All those who were found to
have fatty liver were overweight/obese. However, the
p-value of 0.226 signified that an association of fatty liver
Valdez VAU, et al.
Table V. Body Mass Index Classification of Patients With and
Without Fatty Liver
Fatty Liver
Clinical Profile Negative Positive p-value
n=14 n=8
BMIa (kg/m2) f%
Normal (18.5-22.9) 5 (36%) 0 (0) 0.226
Overweight / Obese (≥23) 9 (64%) 8 (100%)
a
BMI- body mass index; World Health Organization-Asia Pacific criteria 11
with increasing BMI levels in this subset of patients could not
be established.
The lipid profiles of patients in the study are mostly within
optimal levels 11 to eliminate dyslipidemia as a cause of the
development of fatty liver. However, this did not protect
these patients from developing fatty liver, as noted. Due
to the p-value across all lipid panels, there is not enough
statistical evidence to ascertain their relationship.
Focusing on the association of insulin levels with fatty
liver, it is important to bear in mind that pre-IGT patients
already have elevated insulin levels. Although the
calculated p-values did not allow the establishment of a
statistically significant association, those with fatty liver had
higher insulin levels, and there was a trend of increasing
insulin levels with the progression of the severity of fatty liver
disease (e.g. insulin level of 60 uU/mL for mild disease and 88
uU/mL for moderate disease on further analysis). Increasing
sample size in future studies may be able to eventually help
determine if such a relationship exists or if a cut-off value for
insulin level could be identified that would be predictive for
developing mild, moderate and severe fatty liver.
In a study by Viswanathan, the prevalence of obesity,
hypertension and dyslipidemia were significantly higher
in diabetic subjects with NAFLD. 15 Microvascular and
macrovascular complications were also significantly
higher in diabetic subjects with NAFLD. Whether these
complications are already present in pre-IGT with NAFLD
remains to be investigated. What is significant is that
as early as the pre-IGT state, appropriate lifestyle, and
possibly therapeutic inventions, must be given to patients to
prevent the progression of NAFLD as well as prevent other
complications associated with insulin resistance. But despite
the presence of risk factors like hyperinsulinemia and obesity
in patients with pre-IGT, a statistically significant association
could not be established with the development of fatty liver
disease. The plausible reason that it did not reach statistical
level of significance would be the small sample size. Since
this subset of patients has only been recently described,
there is a paucity of such population. And since it is not
a routine practice to check for insulin levels after an oral
glucose load in high-risk individuals, only a limited number
Volume 55 Number 2 April - June., 2017 5
 Valdez VAU, et al.
of patients will be able to undergo screening and eventually
be diagnosed.
It has been shown that pre-IGT or compensated
hyperinsulinemia, represents the earliest stage along the
spectrum of developing diabetes mellitus, thus highlighting
the subclinical nature of this condition. And since they
are more likely to develop cardiovascular disease,
essential hypertension, and nonalcoholic fatty liver
disease 13, preventing the development of these long-term
complications, would also alleviate the great financial
burden – to the individual and the society - that is associated
with it. We recommend early detection of pre-IGT patients
among high-risk individuals. By increasing awareness among
these individuals, this presents an opportunity to delay the
onset of morbidity related to hyperinsulinemia. On a more
practical standpoint, knowing this high prevalence of insulin
resistance among Filipinos may offer a window for health
care practitioners to refine present practice to include the
determination of insulin levels, to be able to identify these
patients early on in the disease process.
C onclusion
In conclusion, the incidence of nonalcoholic fatty
liver disease in patients with pre-IGT is 36%, which is lower
compared to diabetics and pre-diabetics, but higher
compared to the general population. Despite the presence
of hyperinsulinemia and obesity, which are known risk factors
for the development of fatty liver, more sufficient evidence is
needed to support its association with pre-IGT. An important
observation made, however, was that of increasing insulin
levels with increasing disease severity. Perhaps, further
studies with adjusted and larger samples could detect the
differences among the values of insulin level among those
with fatty liver.
Acknowledgements
The authors would like to thank all patients who
consented and participated in this research endeavor. To
Jesse Batara, for his immense contribution in the statistical
analysis of data. And to all colleagues who took part in the
study, thank you.
R eferences
1. Matawaran B, Asis L; Comparison of Pancreatic Insulin Response to
Hyperglycemia Among Filipino Subjects of Various Glycemic Status.
Phil J Int Med, 47: 25, 2009.
2. Torres-Salvador P, Asis L; Glycosylated Hemoglobin and Second
Hour Glucose Level after Oral Glucose Tolerance Test (OGTT) were
Significantly Higher in Individuals in the Pre-Impaired Glucose Tolerance
(Pre-IGT) State versus those with Normal Oral Glucose Tolerance Test
6 Volume 55 Number 2 April-June 2017
Determination of Nonalcoholic Fatty Liver Disease
and Normoinsulinemic. Endocr Rev, 33:3, 2012.
3. Parekh S, Anania F; Abnormal Lipid And Glucose Metabolism
in Obesity: Implications For Nonalcoholic Fatty Liver Disease.
Gastroenterology, 132: 2191, 2007.
4. Utzschneider K, Kahn S; REVIEW: The Role of Insulin Resistance
in Nonalcoholic Fatty Liver Disease. J Clin Endocrinol Metab, 91(12):
4753-61, 2006.
5. Vernon G, Baranova A, Younossi ZM; Systematic Review: The
Epidemiology and Natural History of Non-alcoholic Fatty Liver Disease
and Non-alcoholic steatohepatitis in Adults. Aliment Pharmacol Ther, 34:
274, 2011.
6. Mohan V, Farooq S, Deepa M, Ravikumar R, Pitchumoni C; Prevalence
Of Nonalcoholic Fatty Liver Disease in Urban South Indians in relation
to different grades of Glucose Intolerance and Metabolic Syndrome.
Diabetes Res Clin Pract, 84(1): 94, 2009.
7. Kennedy G; Non-alcoholic Fatty Liver Disease: Can Ultrasound Assist in
Early Diagnosis of Prediabetes and Delay Progression to Type 2 Diabetes
Mellitus. QUT, 2009.
8. Hamaguchi M, Kojima T, Itoh Y, Harano Y, Fujii K, Nakajima T;
The Severity of Ultrasonographic Findings in Nonalcoholic Fatty Liver
Disease Reflects the Metabolic Syndrome and Visceral Fat Accumulation.
Am J Gastroenterol, 102: 2708, 2007.
9. Gerstenmaier J, Gibson R; Ultrasound In Chronic Liver Disease.
Insights Imaging, 5(4): 441, 2014.
10. World Health Organization, Western Pacific Region, International
Association for the Study of Obesity, International Obesity Task Force.
The Asia-Pacific Perspective: Redefining Obesity and its Treatment.
February 2000.
11. Third Report of the National Cholesterol Education Program
(NCEP) Expert Panel on Detection, Evaluation nd Treatment of High
Blood Cholesterol in Adults (Adult Treatment Panel III). Circulation,
106:3143, 2002.
12. National Health and Nutrition Examination Survey (NHANES)
Hepatic Steatosis Ultrasound Images Assessment Procedures Manual.
Massachusetts Medical Society. N Engl J Med, 346:1221, 2002.
13. Li C, Ford E, McGuire L, Mokdad A, Little R, Reaven G; Trends in
Hyperinsulinemia Among Nondiabetic Adults in the U.S.. Diabetes Care,
29(11): 2396, 2006.
14. Salt, W; Nonalcoholic Fatty Liver Disease (NAFLD): A Comprehensive
Review. J Insur Med, 36:27, 2004.
15. Viswanathan V, Kadiri M, Medimpudi S, Kumpatla S; Association
of Non-alcoholic fatty liver disease with diabetic microvascular and
macrovascular complications in South Indian Diabetic Subjects. Int J
Diabetes Dev Ctries, 30(4): 208, 2010.
 Philippine Journal of Internal Medicine
“Somewhere Up There”: A Case Of Pineal Gland Tumor
in a 20-Year-Old Male
Mary Anne C. Dolom-Mundin, M.D.*; Arman Oronce, M.D.*
Abstract
Background: Pineal region tumor is a rare and reportable
case. Incidence rate adults is 0.025 in 10,000 hence there is
no established guidelines among adults for diagnosis and
management of this case.
Case: A case of a 20-year-old male with a two-month history
of intermittent headache, occipital area with VAS 5/10,
increasing in severity. Until two days prior to admission with
severe headache VAS 9-10/10, occipital, and nonradiating.
Patient noted episodes of projectile vomiting hence,
admitted. Patient presented with non-lateralizing symptoms
but noted papilledema and parinaud syndrome. Cranial
MRI with contrast revealed a 2.5cm pineal gland tumor with
obstructive hydrocephalus. Serum AFP (alpha-fetoprotein
) and beta-HCG (beta subunit of human chorionic
gonadotropin) were requested and revealed elevated
levels. The patient
I ntroduction
Pineal region tumor is a rare and reportable case.
These tumors represent three to eight percent of pediatric
intracranial tumors and 0.4-1 % of adult intracranial
neoplasms. Incidence rate of pineal gland tumors in adults
is 0.025 in 100,000. Peak age at diagnosis is at 10-12 years
old. Male to female incidence is 3:1. 1 This is the first case
reported in this institution.
The pineal gland is located between the right and left
cerebral hemisphere, above the superior colliculus and
below the splenium of the corpus callosum and the vein of
Galen. The size of the gland ranges 10-14mm and develops
during the second month of gestation. Manifestations
of pineal gland tumors are due to mass effect. Clinical
phases of pineal region masses include: 1) headaches with
nausea and vomiting; 2) blurred vision, diplopia, drowsiness,
pupillary changes, ataxia, dizziness, paralysis of extraocular
muscles; 3) papilledema, weakness, spasticity.2 Median time
of symptom presentation may be 20-30 months. MRI with
*University of Perpetual Help System- Jonelta, University of Perpetual Help
Medical Center ,Sto Nino, Binan, Laguna
Corresponding author: Mary Anne C. Dolom-Mundin, M.D., University
of Perpetual Help System- Jonelta, University of Perpetual Help
Medical Center, Sto Nino, Binan, Laguna
Email: macdolom@gmail.com
The PHILIPPINE JOURNAL OF INTERNAL MEDICINE is a peer reviewed journal and a copyrighted publication of the Philippine College of Physicians
Case Series
underwent endoscopic third ventriculostomy but no biopsy
was done due to high risk of bleeding. Patient underwent
series of radiotherapy and was advised to undergo
chemotherapy but patient refused. Patient had improved
upward gaze but with residuals, no recurrence of headache
or vomiting, had normalization of the serum tumor markers
but noted increase in size of the tumor despite radiotherapy.
Conclusion: Case reports of pineal region tumors will help
doctors in the primary hospitals diagnose such cases and
differentiate it from benign causes of headache. This will aid
in early referral to specialists and early intervention.
Keywords: pineal region tumor; Parinaud syndrome,
Endoscopic third ventriculostomy
gadolinium contrast is optimum for diagnosing pineal gland
tumors. Tumor markers such as AFP (alpha-fetoprotein ) and
beta-HCG (beta subunit of human chorionic gonadotropin)
should be routinely requested in differentiating types of
pineal gland tumor. Management of pineal gland tumors in
adults is still adopted from the guidelines in the management
of pineal gland tumors in children. Rarity of the disease
condition warrants further studies to come up with an
internationally accepted guideline for the management of
pineal gland tumors in adults.3
This case report will help doctors in the primary hospitals
to diagnose such cases and differentiate it from benign
causes of headache. This will aid in early referral to specialists
and early intervention.
Objectives
• To present a case of pineal gland tumor
in a 20 year old male
• To discuss the diagnosis and management
of the case
Clinical History
This is a case of a 20-year-old male, Filipino, single,
Volume 55 Number 2 April-June, 2017 1
 Dolom-Mundin MAC, et al.
Roman Catholic, presently residing at San Pedro, Laguna,
admitted for the first time in our institution due to headache
and vomiting. Patient had two months on and off headache,
pulsating in the occipital area with VAS 5/10. There was no
identifiable aggravating factor and headache resolves
spontaneously. Two days prior, there was increased severity
of headache with pain scale 9/10 associated with projectile
vomiting approximately two episodes per day hence
admitted.
Patient denied any weight loss, no blurring of vision or
diplopia, no gait disturbances, no weakness or numbness.
There was no history of behavioral changes or changes in
sensorium, no bowel habit or urinary disturbance. Sexual
development was at par with age. Patient has been
diagnosed with psoriasis for five years and has been taking
methotrexate. No history of asthma or any allergies to food
or medications. No previous surgical procedure.
Patient is a student and resides with his family. He is a
non-smoker and non-alcoholic. He denies use of illicit drugs
and denies exposure to chemicals or radiation. There is
history of hypertension in the maternal side, no family history
of diabetes, no history of cancer.
On physical examination, patient had stable vital signs.
Skin was warm to touch with fair skin turgor. Palpebra was
pink with anicteric sclerae, no cervical lymphadenopathies.
Symmetrical chest expansion, no retractions, clear breath
sounds. Adynamic precordium, PMI at fifth ICS LMCL,
normal rate, regular rhythm, no murmur, no heaves, no
thrills. Abdomen was soft, normoactive bowel sounds, non-
tender, liver and spleen not palpable, intact traube’s space.
Pulses are full. Body hair distribution was normal, no areas of
alopecia, Tanner staging was V.
Patient was conscious, coherent, oriented to three
spheres, follows commands. Pupils were 3.0 mm, sluggishly
reactive to light. Lateral and medial eye movement
were intact but noted vertical gaze paralysis, and
convergence palsy. Fundoscopy was done and noted
bilateral papilledema. There was no facial asymmetry,
hearing was intact, intact gag reflex, intact shoulder
shrug, no tongue deviation. There was no dysmmetria, no
motor or sensory deficit. Reflexes were normal, negative
dysdiadochokinesia, finger to nose test was negative,
negative pathologic reflexes.
Course in the Wards
Patient was initially admitted at ICU and cranial MRI
with gadolinium was done. On MRI, there was note of a
2.5cm pineal gland mass with hydrocephalus. Mannitol was
started and patient referred to neurosurgery department.
acetazolamide was started and celecoxib was given
for headache. Patient was advised endoscopic third
2 Volume 55 Number 2 April-June, 2017
A Case of Pineal Gland Tumor
ventriculostomy and transferred to a government hospital
for the procedure. Serum AFP, B-HCG were noted to be
elevated. (Table I) Patient underwent endoscopic third
ventriculostomy but biopsy was not taken due to the depth
of the tumor. Patient was then referred to an Oncologist and
Radio-Oncologist. CSF level of AFP, Beta-HCG was advised
but was not done. For three months, the patient underwent
30 sessions of radiotherapy, maintained on Dexamethasone
and monitored by serial monitoring of AFP and Beta-HCG
and repeat cranial MRI. There was note of normalization of
AFP and beta-HCG levels after three months. however, noted
increased size of the tumor after four months from diagnosis.
Thoracolumbar spine MRI was done and there was no drop
metastasis noted. There was improvement of vertical gaze
but still with residual palsy. At present, patient is undergoing
physical therapy, until the writing of this paper.
Differential Diagnosis
Patient presented with non-lateralizing neurologic
signs and symptoms. Lesion can be localized in the midline
structures. Patient’s symptom of severe headache and
projectile vomiting with papilledema on physical examination
indicates increased intracranial pressure. Patients presenting
with vertical gaze paralysis, convergence palsy and
accommodation palsy, known as parinaud syndrome will
localize the lesion in the quadrigeminal plate, particularly in
the superior colliculus. This results from the compression of the
rostral midbrain, in the superior colliculus due to mass effect.4
Differential diagnoses for a midline tumor that would present
with parinaud syndrome characterized by upward gaze,
accommodation and convergence palsy, include a pineal
gland tumor, a midbrain AV malformation or metastatic
tumors. Other causes such as infectious, demyelinating
and vascular causes can be ruled out because the course
of the disease was chronic and progressive. Stroke in the
midbrain can be ruled out because of its acute presentation
and is common in the elderly population with risk factors
such as hypertension, diabetes mellitus and smoking which
are absent in the patient. Demyelinating diseases such as
multiple sclerosis can be ruled out because it presents with
recurrent episodes of weakness, numbness, diplopia or loss
of vision, months or years apart which was not seen in the
patient.
The pineal gland is located in the epithalamus behind
the third ventricle which can compress the superior colliculus
which is the upward gaze center hence this is highly
considered. AV malformation may present with progressive
headache with or without focal neurologic signs depending
on the size and location of the lesion. However most
commonly at the time of diagnosis the lesion has ruptured.
Metastatic tumors are commonly from the lungs, breast,
melanoma or kidneys. Fifteen percent are solitary commonly
from the breast and kidneys and 85% are multiple brain
tumors. However based on the symptoms of the patient the
 A Case of Pineal Gland Tumor
Table I. Tumor markers
Before Therapy
Reference
Test Result Unit Test
range
Serum AFP 14.07 IU/mL Less than 5.8 Serum AFP
lesion is most probably solitary. If it were a solitary metastatic
tumor, the mass would have been large enough to cause
increased intracranial pressure hence the course would have
been more chronic.
The most common tumor presenting as Parinaud
syndrome is a pineal gland tumor. It is seen in 50% of cases
of pineal gland tumors 5. Obstruction of the CSF leading
to hydrocephalus and direct tumor mass effect causes
impingement of the superior colliculus responsible for the
upward gaze. This is compatible with the case of the patient
because of the chronic, intermittent, progressive headache
and signs of increased intracranial pressure such as severe
headache with projectile vomiting.
Pineal gland tumors can be classified as: 1. Germ Cell
tumors; 2. Pineal Parenchymal Tumors; 3. Pineal cyst. Germ
cell tumors comprise more than 50% of cases of pineal
gland tumor and has a favorable prognosis with good
sensitivity to radiotherapy. Germ cell tumors are classified
as either a Germinoma or a Nongerminomatous Germ cell
tumor which can further be classified as a 1. Teratoma, 2.
Choriocarcinoma, 3. Endodermal sinus tumor, 4. Mixed Germ
Cell Tumor.6
Germinomas account for 50-65% of intracranial
1. intracranial pressure. Notable on physical examination was
germ cell tumors in the pineal region. It has
a good prognosis and highly responsive to
radiotherapy. These tumors show negative tumor
markers but may have mild elevation in Beta-
HCG.
Nongerminomatous germ cell tumors are
2. splenium of the corpus callosum and the vein of Galen. It is
tumor marker-secreting tumors and are seen
more commonly in males with a 3:1 male to
female ratio. Teratomas may show elevated
Alpha Fetoprotein (AFP) levels whereas
Choriocarcinomas will show elevated Beta-
Human Chorionic Gonadotrophin (HCG). Our
patient presented with elevated serum Beta-
HCG and serum AFP hence a Mixed Germ cell
tumor is highly considered. Germ cell tumors
may show nonspecific signs and symptoms and
imaging studies don’t have pathognomonic
features. Presence of tumor markers is an
unequivocal sign of presence of a secreting
Dolom-Mundin MAC, et al.
After Therapy
Reference
Result Unit
range
Less than
1.2 Ng/mL 2.00
germ cell tumor.4
3. Pineal parenchymal tumors comprise one third
of cases of pineal gland tumors. These tumors
arise from pineocytes. Serum tumor markers are
less characteristic of pineal parenchymal cell
tumors. Melatonin can be elevated but are non-
diagnostic.
Pineal cysts are generally asymptomatic and
4.
commonly seen in patients 40-49 years old. These
lesions remain stable in size over time. They have
characteristic finding on MRI showing peripheral
enhancement and central hypointensity 6.
In this case, a pineal gland tumor probably
nongerminomatous germ cell tumor is highly considered
because of the non-lateralizing signs and symptoms,
Parinaud’s syndrome, and elevated serum AFP and beta-
HCG.
D iscussion
The patient presented with nonspecific headache
but increasing in severity and with signs of increased
the presence of parinaud syndrome and work-up showed a
pineal region tumor with elevated tumor markers hence a
nongerminomatous pineal region germ cell tumor was highly
considered. The pineal gland is a pinecone structure that is
8.0 mm long and 4.0 mm wide, located midline. It is situated
above the tentorium and superior colliculus and below the
attached to the superior aspect of posterior border of the third
ventricle.6 The function of the gland has not been previously
understood but is now linked to sex hormone regulation aside
from the sleep-wake cycle through the hormone melatonin.
The pineal gland is composed of photoreceptor cells
resembling cells in the retina which converts light perception
into wavelengths. Animal studies have shown that continuous
environmental illumination for weeks brought a decrease in
the weight of the pineal gland and consequent increase in
weight of the ovaries. Researchers have then identified a
gonad-inhibiting substance in the pineal gland extract. They
noted that melatonin injection in rats starting before puberty
slowed the estrus cycle and caused decrease in size of the
Volume 55 Number 2 April-June, 2017 3
 Dolom-Mundin MAC, et al.
ovaries. Removal of the pineal gland on the other hand
accelerated the estrus cycle.7
The median time to symptom presentation for pineal
region tumors is usually 20-30 months. Symptoms are usually
evident when the cerebral aqueduct is obstructed. 4 By
virtue of the Monroe Kelly hypothesis, intracranial pressure is
constant and is determined by the brain tissue, blood vessels
and the CSF. The normal intracranial pressure is 10-15mmHg.
Treatment should be instituted once ICP in >20-25mmHg.
Measures to reduce intracranial pressure include mannitol
bolus 0.25-1 g/kg then 0.25-0.5g/kg every two to six hours. If
the patient is hypotensive, hypertonic saline solution can be
given. Steroids are given for brain tumors with surrounding
edema. Acetazolamide on the other hand is a carbonic
anhydrase inhibitor that reduces CSF production and is useful
in hydrocephalus.8
Parinaud syndrome also called dorsal midbrain
syndrome is composed of upward gaze palsy, convergence
palsy and accommodation palsy. The vertical gaze center
lies in close vicinity to the superior colliculus, near the pineal
gland. Compression of the structures due to mass effect
leads to symptoms of Parinaud syndrome.6 Our patient was
noted to have vertical gaze palsy, convergence paralysis,
light accommodation palsy and a pineal gland tumor. The
pineal gland tumor compressed the superior colliculus and
cerebral aqueduct significant to cause Parinaud syndrome
and increased intracranial pressure due to obstructive
hydrocephalus.
Neurologic signs and symptoms of pineal region tumors
are non-lateralizing because the gland is a midline structure.
Peripheral neurologic symptoms may be evident for germ
cell tumors and ependymomas with drop metastasis by
spread thru the CSF. 9 Our patient presented with the typical
symptoms of progressive headache and signs of increased
intracranial pressure due to hydrocephalus, and Parinaud
syndrome. However unlike the other case reports of pineal
region tumor, there was no diplopia, no change in the
sleeping pattern and no endocrinologic abnormalities.
Cranial MRI with gadolinium contrast is optimum for
brain tumors. However, literature suggests that common
pineal gland tumors have no pathognomonic imaging
pattern. There was no significant difference in the T1 and
T2 signal intensity values between the pineal parenchymal
tumors and germinomas. Pineal parenchymal tumors
showed isohypointensity on T1 and isohyperintensity on T2.
Germinomas on the other hand showed hypointensity on T1
and isointensity on T2.10
Pineal region tumors are composed of Germ cell tumors,
70% of cases, Pineal parenchymal tumors 15% and other
types such as Papillary tumors, gliomas and meningiomas
comprising 15% of cases.
4 Volume 55 Number 2 April-June, 2017
A Case of Pineal Gland Tumor
Germ cell tumors can be located both in the pineal
region and the suprasellar area. Bifocal tumors comprise
13% of cases of germ cell tumors. Germ cell tumors are
characterized by secreting tumor markers such as AFP and
beta-HCG. Precocious puberty is more evident in pineal
gland tumors secreting beta-HCG such as choriocarcinoma.
Germinomas are extra-gonadal seminomas whose AFP and
beta-HCG levels are not typically elevated. Germinomas
have a better prognosis and good response rate to radiation
compared to nongerminomatous germ cell tumors.9 Tumor
markers for Nongerminomatous germ cell tumors are evident
in the serum and CSF in 80% and 20% of cases, respectively.
Beta HCG for >50 IU/mL and AFP level of >25 IU/mL are
associated with a worse prognosis. Presence of tumor
markers is assumed to be equivocal sign of presence of
secreting germ cell tumor and it is justified to start therapy
without histologic confirmation. Tumor markers are useful
during treatment and follow-up to monitor response to
therapy. 4 The patient did not have any biopsy but had
elevated tumor markers hence radiotherapy was started.
Serum AFP and beta-HCG levels were monitored during the
course of treatment and noted decrease in levels.
The patient presented with signs of increased intracranial
pressure, Parinaud’s syndrome, and a pineal gland mass
on cranial MRI with elevated serum tumor markers. With
the presentation of the patient and laboratory work-
up, the patient has a pineal gland tumor probably
nongerminomatous germ cell tumor. Final diagnosis was
pineal gland tumor probably nongerminomatous germ cell
tumor.
Pineal gland tumors become evident when the tumor
causes mass effect such as increased intracranial pressure.
In cases wherein the patient presents with increased
intracranial pressure, this must be addressed first. Mannitol,
an osmotic diuretic was initially given to the patient to
do medical decompression. Patient was then referred for
Neurosurgical intervention because the pineal region tumor
was causing obstructive hydrocephalus. Surgical intervention
involved in pineal region tumors include Endoscopic
third ventriculostomy and VP shunting. Endoscopic third
ventriculostomy, which was done to our patient, is the
procedure of choice because of its advantages. This
procedure avoids shunt malfunction and infection, avoids
peritoneal seeding of malignant cells and this approach
allows tissue biopsy and CSF collection for tumor markers.
However, this procedure has risk of bleeding for vascular
tumors.11 In cases wherein a biopsy was taken, case should
be reported by an accredited neuropathologist according
to the NICE guidelines.8 However, biopsy was not taken in
this case due to high risk of bleeding. VP shunting is less used
because of increased risk of infection and malfunction. This
should be the option only if endoscopic third ventriculostomy
fails. 6
 A Case of Pineal Gland Tumor Dolom-Mundin MAC, et al.

Management of pineal gland tumors have been

adopted from the Pediatric guidelines due to lack of
prospective studies in adults. Treatment options include
radiotherapy, chemotherapy and surgical resection. There
is no specific staging system uniformly accepted for germ
cell tumors and investigators utilize the TM staging for
medulloblastoma. Mo corresponds to No metastasis, M1
for free floating malignant cells and M2,M3 for presence of
tumor cells in the spinal or subarachnoid space. T staging is
not used in pineal gland tumors since it is located midline.
Radiotherapy is the backbone in management of pineal
gland tumors but dose to be given is not standardized.
Chemotherapy has been standard in the management of
ovarian and testicular germ cell tumors but has not been
routinely used in intracranial germ cell tumors. The value of
total or near total resection of pineal gland tumors still remain
unproven.12

Figure 1. Cranial MRI with contrast

Germinomas have better prognosis than other histologic
There is a soft tissue mass in the posterior aspect of the third ventricle
types. Germinomas have good response rate to radiation measuring 2.5x2.7x2.9cm. Small internal cystic components are noted.
alone with tumor boost total 4500-5000 cGy. Studies have There is homogenous contrast enhancement of solid portions of the mass.
shown poorer survival rate if dose is less than 4000 cGy.
Craniospinal irradiation was instituted and studies showed
tumor marker, whose level indicate response to therapy.
96% in a three-year relapse free for patients with Germinoma.
Normalization of the levels of tumor markers indicate good
Chemotherapy and radiotherapy have been used and
response to therapy. Repeat cranial MRI scan and spinal MRI
favored in United Kingdom but has not been practiced in
should be done to monitor size and rule out drop metastasis.
France.12

Our patient underwent radiotherapy however
Nongerminomatous germ cell tumors have poorer
repeat cranial MRI showed increase in size of the tumor.
prognosis. Management utilizes radiation therapy and
Chemotherapy have been previously advised but was
chemotherapy. These tumors are less radiosensitive. Dose of
undecided. Patient is now undergoing physical therapy
radiation is limited due to neurocognitive and endocrinologic
and has improved upward gaze but with residual palsy. He
sequelae. Endocrine disturbance may manifest even
does not experience headaches, no vomiting. He is able to
10-15 years after therapy. Radiotherapy is essential but
support himself and can do activities of daily living on his
radiotherapy alone is rarely curative as single treatment
own. He is not currently enrolled but plans to come back to
modality with tumors relapsing within 18 months. One study
school next year until writing of this paper.
showed improved survival with gross total resection of pineal
gland tumor but this has not been extensively confirmed.
Chemotherapeutic drugs used for nongerminomatous C onclusion
germ cell tumors are Cisplatin at 20mg/m2/day, Etoposide
at 100mg/m2/day and Ifosfamide1500mg/m2/day in four Pineal gland tumors are rare cases and should be
courses with 21 days interval. Four cycles of chemotherapy reported. Clinical manifestations may be non-specific and
have been instituted followed by irradiation 5400 cGy. Results clinicians should have a high index of suspicion. There is
of studies suggested chemotherapy can improve overall no widely accepted guidelines for pineal gland tumors in
duration and survival rate when used in combination with adults and management is adopted from the guidelines in
radiotherapy. However, reports contain only few patients the management for the pediatric population. Prospective
which further highlight rarity of these tumors and difficulty studies are needed through aggressive case finding since it
designing the best treatment approach. Five patients treated has good cure response rate.
with four cycles chemotherapy then radiotherapy had
median survival rate of 88 months. Future therapeutics with
R eferences
nongerminomatous germ cell tumors will likely include more
aggressive chemotherapy and lower dose of radiation.12 1. Alexiou, A., Varela, M., Prodomou, N. Management of Pineal
Region Tumors in children. Journal of Solid Tumors. Vol. 2, No.
Patients with pineal gland tumor require regular follow- 2. 2012
up during radiotherapy and repeated evaluation of serum

Volume 55 Number 2 April-June, 2017 5

 Dolom-Mundin MAC, et al. A Case of Pineal Gland Tumor

2. Behari S, Garg P, Jaiswal S, Nair A, Naval R, Jaiswal AK. Major

surgical approaches to the posterior third ventricular region: A
pictorial review. J Pediatr Neurosciences;5:97-101). 2010
3. Blanco, C., Guzman de Villoria,J., Madrid, M., Lesions of
the Pineal Region: a Practical Approach. European Society of
Radiology.10.1594/ecr2013/C-0937. 2013
4. Cecchi, P.C., Gilberto, G. Musumeci, A., Schwarz,A. Pineal
Region Tumors. Explicative Cases of Controversial Issues in
Neurosurgery. ISBN 978-953-51-0623-4. 2012
5. Dolecek,T., Propp, J., Stroup, N. Kruchko, C. CBTRUS
Statistical Report: Primary Brain and Central Nervous System
Tumors Diagnosed in US in 2005-2009. Neuro-Oncology. y14:v1–
v49. 2012
6. Dumrongpisutikul, N., Intrapiromkul, J., Yousem, D.
Distinguishing between Germinomas and Pineal Cell Tumors on
MR Imaging. American Journal of Neuroradiology. 33:550 –55.
2012
7. Echievarria, M., Fangusaro, J., Goldman, S. Pediatric Central
Nervous System Germ Cell Tumors: a Review. The Oncologist.
Pediatric Oncology;13:690 – 699. 2008
8. Junior, M.R., de Rocha, A., de Silva, A. Rosenberg, S. Papillary
Tumor of the Pineal Region: MR Signal Intensity Correlated to
Histopathology. Case Reports in Neurological Medicine. Article
ID 315095,4 pages. 2015
9. Minor, M., O’Brien, W. Pineal Region Masses. Journal of the
American Osteopathic College of Raiology. Vol. 4, Issue 1. 2015
10. Ngelangel, A., Wang, E. Cancer and the Philippine Cancer Control
Program. JPN journal of Clinical Oncology; 32 (Supplement 1)
S52-S61. 2002
11. Norden, A., Kesari, S. Cancer Neurology: Primary and Metastatic
Brain Tumors. Neurology Volume 10, Part 3
12. Packer, R., Cohen, B., Cohen, K. Intracranial Germ Cell Tumors.
The Oncologist;5:312-320. 2000
13. Patil, M., Karandikar, M. Pineal Region Tumors. Journal of
Mahatma Gandhi Institute of Medical Sciences. | Vol 20 | Issue 1.
2015
14. Reisch,N. Kuhne-Eversman,L. Franke, D., et.al. Germinoma
as a very rare cause of Hypopituitarism in a 23 year old man. Exp
Clin Endocrinol Diabete.ISSN 0947-7349. 2008
15. Ruchalski, K. Hatout, G. Midbrain Maladies: A Brief Review of
Midbrain Anatomy and Syndromology for Radiology. Radiology
Research and Practice Volume 2012, Article ID 258524,11pages.
doi:10.1155/2012/258524
16. Rare Brain and CNS Tumours Guidelines. Guidelines on the
Diagnosis and Management of Adult Pineal Area Tumours. British
Neuro-Oncology Society. June 20111
17. Steele, G. etal. Germ Cell Tumors. American Cancer Society Atlas
of Clinical Oncology. BC Decker Inc. London. 2003
18. Sankhyan, N.,Raju, K.N., Sharma, S., Gulati, S. Management
of Raised Intracranial Pressure. Indian Journal of Pediatrics.
77:1409–1416, DOI 10.1007/s12098-010-0190-2. 2010
19. Villano, J.L., Propp, J., Porter, K., et.al. Malignant Pineal Germ
Cell Tumors: an Analysis of cases from three tumor registries.
Neuro-Oncology. 2008

6 Volume 55 Number 2 April-June, 2017

 Philippine Journal of Internal Medicine
Prevalence and Risk Factors for Depression Among Filipino
Adults with Diabetes Mellitus Type 2 at the Makati Medical
Center Outpatient Department
Stanlee James Dy Nieva, M.D.*; Maria Leonora D. Capellan, M.D.*; Carolyn N. Montano, M.D.*
Abstract
Objective: To determine the prevalence of depression in
Filipino adult patients with type 2 diabetes mellitus (DM) and
the risk factors associated in its development.
Methods: This is a prospective cross-sectional study. Adult
patients (age 19 and above) with type 2 DM being seen at
the outpatient department of the Makati Medical Center
from January to March 2015 were included, taking into
account the following: age, gender, marital status, body
mass index, waist circumference, blood pressure, duration
of diabetes, presence of other co-morbid illnesses, pill
burden, insulin use, educational attainment, employment
status, family income, and glycemic status. They were
then screened for depression using the standardized PHQ-9
questionnaire. Bivariate analyses through Chi-square Test (for
categorical variables) and Analysis of Variance (for interval/
ratio variables) were used to determine which among the
risk factors are significant for the development of depression.
Significant risk factors were treated for multivariate and
univariate analyses through ordinal logistic regression.
Introduction
Depression is defined by the International Classification
of Diseases, Tenth Revision (ICD-10) as having at least two
of the three symptoms considered typical of depression:
depressive mood, loss of interest and ability to enjoy, and
increase in fatigability for at least two weeks. It is recognized
by the World Health Organization (WHO) as the leading
cause of disability in the world and is the fourth leading
contributor to the global burden of disease. 1,2 It often
coexists with other chronic diseases and can worsen their
associated health outcomes. 3 In a study among Chinese
patients aged 55 and older, the prevalence of depressive
symptoms in patients with chronic illnesses was between
13.2-24.2%, significantly higher compared to those without
co-morbidities (7.5%).4 Local studies done among chronically
*Department of Medicine, Section of Endocrinology, Diabetes, and
Metabolism, Makati Medical Center
There are no conflicts of interests in the pursuit of this study.
Corresponding author: Stanlee James Dy Nieva, M.D., Makati Medical
Center, Makati, Philippines
Email: stanleenievamd@gmail.com
The PHILIPPINE JOURNAL OF INTERNAL MEDICINE is a peer reviewed journal and a copyrighted publication of the Philippine College of Physicians
Original Paper
Results: A total of 110 adult patients with type 2 DM were
enrolled in this study. There were no drop-outs. Sixty-nine
percent of the patients had none to minimal depression,
24% had mild depression, and 7% had moderate depression.
None of the patients had depression that warranted anti-
depressants or psychotherapy. After step-wise analysis,
increased BMI, elevated diastolic blood pressure and
uncontrolled blood sugar were found to be associated with
higher PHQ-9 scores while unemployment was associated
with decreased PHQ-9 score.
Conclusion: The prevalence of depression among Filipino
type 2 diabetic patients is higher than in non-diabetic
patients. Being obese, having an elevated diastolic blood
pressure, and the presence of uncontrolled blood sugar were
significant predictors and were associated with an increased
likelihood of developing major depressive disorder. Being
unemployed appears to have the opposite effect.
Keywords: depression, type 2 diabetes mellitus, PHQ-9
ill patients utilizing different standardized questionnaires
revealed a prevalence of 26.9 to 32%.5,6
Diabetes mellitus (DM) is a chronic disease characterized
by hyperglycemia and its associated complications.
According to the International Diabetes Foundation, the
global prevalence of diabetes is 8.3% and is projected to
rise to 10.1% in 2035.7 In Southeast Asia, 8.2% of the adult
population or 72.1 million people, have diabetes.7 Based
on the Eigth National Nutrition Survey, the prevalence of
diabetes in the Philippines is 5.4%. This number is significantly
higher compared to the same survey conducted in 2008,
with the urban poor having a higher prevalence compared
to their rural counterparts.8 The WHO estimates that by the
year 2030, the prevalence rate in our country will rise to 8.9%
or 6.16 million cases. 7
The prevalence of mood and anxiety disorders is higher
in patients with diabetes compared to those without. 9,10,11
Studies done in India, Sri Lanka, and Bangladesh, which
comprise most of diabetic population in the Southeast
Asian Region, show a prevalence rate of 23-59%.12,13 Risk
factors associated with the development of depression in
patients with type 2 DM include age, female sex, being
Volume 55 Number 2 April-June 2017 1
 Nieva SJD, et al.
single, central obesity, elevated HbA1c, diabetes-specific
complications (neuropathy, nephropathy, peripheral
vascular disease, diabetic foot disease, erectile dysfunction),
physical impairment, pill burden (the number of pills taken
for glycemic control), reliance on insulin, the absence of
adequate social support, lower educational attainment, low
socioeconomic status, elevated systolic and diastolic blood
pressure, and previous history of depression.12,13,14 Variations
were evident, as these different studies utilized different
validated scales to evaluate for depression.
Depressive symptoms appear to be more prevalent in
patients with type 2 DM compared to those with type 1. 12
In a study among 33 Filipino patients with type 2 DM, there
was no significant correlation between the blood sugar
levels and presence of depression, although fasting blood
sugar was higher among depressed patients. Furthermore,
longer duration of diabetes and presence of certain
complications such as hypertension, diabetic retinopathy,
and diabetic neuropathy tend to influence occurrence
of depression. The prevalence of depression in this study
was 85%. 16 Another local study suggested that the physical
limitations that accompany diabetes resulted to emotional
disturbances, such as depression. 18 Younger age, shorter
duration of diabetes, absence of diabetic complications
and better social support from the family of diabetic patients
significantly influenced a better quality of life among
patients.
The available data regarding the prevalence of
depression in type 2 DM patients in our country is limited.
In thi s paper, w e i n v e st i g a t e d t h e p r e v a l e nc e a n d
determinants of depression in patients with type 2 DM being
seen in a tertiary care hospital and its relationship with
glycemic control and diabetic complications. Demographic
and socioeconomic factors were also examined.
Objectives
The objectives of this study is to determine the
prevalence of depression in patients with type 2 DM seen in
the outpatient setting, also to determine the risk factors for
the development of depression in patients with type 2 DM.
M ethodology
STUDY DESIGN
This research is a prospective cross-sectional study,
utilizing a structured questionnaire for data collection.
PARTICIPANTS
Adult patients (age 19 and above) with type 2 DM
who were seen at the outpatient department of the Makati
2 Volume 55 Number 2 April-June, 2017
Prevalence and Risk Factors for Depression Among Filipino Adults
Medical Center from January 2015 to March 2015 were
included in the study after securing their informed consent.
Patients who were unable to comprehend the questionnaire
and those who had hearing impediments were excluded
from the study.
All participants were given a short briefing on the
study objectives. It was considered that the study involves
a vulnerable population, and steps were taken so as not
to cause any harm during their participation. During the
course of the study, the participants were free to withdraw
at anytime with or without any valid reasons. Should they
choose to withdraw, the standard medical care being
provided were to be continued without any consequences
to them. All participants were able to receive available
information during the course of the research relevant to
their participation.
ETHICAL CONSIDERATIONS
This study was adherent with the guidelines for the
ethical conduct of research (Declaration of Helsinki 2008,
WHO Operational Guidelines, ICH-GCP, National Ethics
Guidelines for health Research). The participants’ inclusion
in this study was voluntary and did not include any monetary
or material compensation. Denial of inclusion did not result
to denial of any medical services to the patient. The study
was considered safe and no complications were expected
to arise during the study period.
In case of an unfavorable incident, the participant
was to be given the standard medical care needed.
This included explanation of abnormal results and its
possible course, prescription of medications if needed and
scheduling of follow-up visits. Standard medications for the
illness will be prescribed, but no free medications will be
given since the objectives of this study do not include the
use of medications.
After securing informed consent, the following patient
parameters were elicited:
1. Age
2. Gender
3. Marital status
4. Body mass index
5. Waist circumference
6. Blood pressure
7. Duration of diabetes
8. Presence of other co-morbid illnesses
9. Pill burden (number of oral medications being
taken for diabetes)
10. Use of insulin
11. Educational attainment
12. Employment status
13. Family income
 Prevalence and Risk Factors for Depression Among Filipino Adults
14. Glycemic status - controlled or uncontrolled.
The patients’ latest HbA1c and FBS (within four months of
the last clinic visit) were recorded whichever was available; if
not, a random capillary blood sugar test was taken instead.
The standards set by the 2015 American Diabetes Association
Guidelines were used to classify the patients’ glycemic
status.17 These include an HbA1c of less than 7%, a fasting
blood sugar of 80 to 130 mg/dL, and a peak postprandial
blood sugar of less than 180 mg/dL. Patients exceeding these
cut offs were classified as uncontrolled.
Depression was screened for by administering the nine-
item PHQ-9 (Appendix B and C), a self-report version of
PRIME-MD which assesses the presence of major depressive
disorder using modified Diagnostic and Statistical Manual,
Fourth edition (DSM-IV) criteria.20 It is available in both English
and Filipino. 21,23
The original test from which it was derived, the Primary
Care Evaluation of Mental Disorders (PRIME-MD), was an
instrument developed and validated in the early 1990s to
efficiently diagnose five of the most common types of mental
disorders presenting in medical populations: depressive,
anxiety, somatoform, alcohol, and eating disorders.20
However, the test proved cumbersome in actual general
medicine outpatient practice because it consisted of a two-
stage process that took an average of five to six minutes of
clinician time in patients without a mental disorder diagnosis
and around 11-12 minutes in patients with a diagnosis.
Recognizing this, Spitzer and colleagues summarized
the major components of the original PRIME-MD instrument
into a nine-item questionnaire which the patient could
understand.22 There was good agreement reported between
the PHQ diagnosis and those of independent psychiatry
health professionals (for the diagnosis of any one or more
PHQ disorder, kappa=0.65; overall accuracy, 85%; sensitivity,
75%; specificity, 90%). A validated Filipino version of the
test is available for patients who could not comprehend
instructions in English (Appendix C). 23
The PHQ-9 Depression Severity was calculated by
assigning scores of 0, 1, 2, and 3, to the response categories
of “not at all”, “several days”, “more than half the days”,
and “nearly every day”, respectively. PHQ-9 total score for
the nine items ranges from 0 to 27. Scores of 5, 10, 15, and 20
represent cutpoints for mild, moderate, moderately severe
and severe depression, respectively.
The PHQ-9 questionnaire yielded a two-fold result. First,
it established a provisional diagnosis of depressive disorder.
Second, it provided a symptoms severity score. Similar to
the work done by Raval et al,13 the diagnosis of clinically
significant depression adapted for this study prompting for
a Psychiatry referral was defined as:
Nieva SJD, et al.
1. Score of 8-9: minor depression
2. Score of 10 or greater: moderate depression
3. Score of 15 or more and one of the two cardinal
symptoms (either depressed mood or anhedonia)
as definite major depression.
For patients attaining a score of eight to nine (minor
depression by the PHQ-9 questionnaire), a psychiatry referral
was offered. However, should they opt to defer the referral,
they will be given reassurance and continued medical
management. On the other hand, patients attaining a
score of 10 or greater were to be referred to the Psychiatry
hospital service program (HSP) service for further evaluation
and counseling.
Statistical Analysis
All valid data were included in the analysis. Missing
values were not replaced nor estimated during analysis.
Summary statistics were presented in tables and reported as
mean ± SD, median (IQR) or proportion (%) as appropriate,
for patient characteristics and prevalence of depression and
associated factors. Bivariate analyses through chi-square
test (for categorical variables) and analysis of variance
(for interval/ratio variables) were used to determine which
among the risk factors are significant for the development
of depression in Filipino patients with type 2 DM. After these
were determined, significant risk factors were treated for
multivariate and univariate analyses through Ordinal Logistic
Regression to determine which factors were associated with
depression in Filipino patients with type 2 DM.
Frequency and percentages, median (range), and
mean + SD were used to describe nominal, ordinal, and
interval/ratio variables, respectively. PHQ-9 scores were
calculated based on its standardized and validated scoring
system. STATA 12 was used for data processing and analysis.
R esults
There were a total of 110 adult patients with type 2 DM
enrolled in this study. Average age of 65.10 ± 11.56 years, and
were predominantly females (76 of 110, 69%). More than half
(57%) were married had attained at least college education
(61 of 110, 55%) and were retired from work (67%), and had
a monthly family income of below 10,000 PHP (52%).
The subjects had a mean BMI of 26.02 ± 5.32, and 17%
of the patients were obese. The mean waist circumference
was at 82.78 cm, or 32.28 inches. The average systolic blood
pressure was pre-hypertensive at 127.36 ± 10.89 mmHg, and
65% of the subjects had cardiovascular disease (Table II).
The subjects have been known diabetics for a median of
10 years, with 19% needing three or more pills for the control
Volume 55 Number 2 April-June 2017 3
Nieva SJD, et al. Prevalence and Risk Factors for Depression Among Filipino Adults

Table I. General characteristics of 110 adult type 2 diabetic patients Table III. Diabetes profile of 110 adult diabetic patients at the Makati
at the Makati Medical Center Endocrinology Outpatient Clinic Medical Center Endocrinology Outpatient Clinic

Median (range), frequency (%)

Mean + SD, Frequency (%) Duration of diabetes mellitus 10 (1-26)
Age Pill burden
Age 65.10 ± 11.56 - 0 to 2 89 (80.91)
Gender - 3 or more 21 (19.09)
- Male 34 (30.91) Insulin use 24 (21.82)
- Female 76 (69.09) 24 (21.82)
Marital status Glycemic control
- Single 11 (10.00) - controlled 63 (57.27)
- Married 63 (57.27) - uncontrolled 47 (42.73)
- Annulled/Separated 8 (7.27)
- Widowed 28 (25.45) Table IV. Results of screening for depression among 110 diabetics
according to PHQ-9
Educational attainment
- Elementary School 7 (6.36) PHQ-9 Screening for Depression Frequency (%)
- High School 42 (38.18) None to minimal depression 76 (69.09)
- College 61 (55.45)
Mild depression 26 (23.64)
Employment
Moderate depression 8 (7.27)
- Contractual 2 (1.81)
- Regular 15 (13.64) Moderately severe depression 0
- Unemployed 19 (17.27) Severe depression 0
- Retired 74 (67.27)

“not difficult at all,” 25.5% replied “somewhat difficult,” and

Table II. Clinical profile of110 adult diabetic patients at the Makati
3.64% answered “Very difficult.”
Medical Center Endocrinology Outpatient Clinic

Mean + SD, Frequency (%) In order to determine factors associated with increased
Height in meters 1.57 ± 0.09 or decreased PHQ-9 scores, a multiple linear regression
analysis was performed, taking into account general
Weight in kilograms 63.91 ± 14.09
characteristics as well as clinical profiles. From the initial
Waist circumference in cm 82.78 ± 11.44
analysis, age, income, BMI, diastolic BP and uncontrolled
BMI 26.02 ± 5.32 glycemic status were significantly related to PHQ9 score
BMI Category (Table VII). This model had 33.17% predicting ability to
1 - Underweight 3 (2.73) depression. However, given that there were 19 independent
2- Normal 53 (48.18) variables in the model, the overall results may be spurious.
3- Overweight 37 (33.64) In order to reduce the presence of spurious regression in the
4- Obese 17 (15.45) model, a step-wise regression analysis was done (Table VIII).
Systolic blood pressure 127.36 ± 10.89
After the step-wise analysis, the following variables
Diastolic blood pressure 78.73 ± 8.03
were retained: BMI, diastolic BP, employment status, and
of their diabetes (pill burden). Of the 110 patients, 24 were uncontrolled glycemic status. Increased BMI, increased
insulin requiring. diastolic blood pressure and uncontrolled blood sugar were
found to be associated with higher PHQ-9 scores while
Based on the validated and translated PHQ-9 unemployment was associated with decreased PHQ-9 score.
questionnaire, 69% of the patients had none to minimal

D iscussion
depression, 24% had mild depression, and 7% had
scores suggestive of moderate depression. In the PHQ-9
questionnaire, most of the subjects replied “not at all” to
This is a cross-sectional study conducted in the diabetes
several items. Some items were reported to be more frequent
clinic of the outpatient department of the Makati Medical
than others, particularly sleeping problems and having little
Center. The aim of the study Is to determine the prevalence
energy (Table V).
of depression among adult persons with type 2 DM and to
identify risk factors associated with its development. Adult
When asked regarding the level of difficulty that the
patients (age 19 and above) with type 2 DM who were being
patients encounter in activities of daily living, 70.9% replied

4 Volume 55 Number 2 April-June, 2017

Prevalence and Risk Factors for Depression Among Filipino Adults Nieva SJD, et al.

Table V. Results from PHQ-9 questionnaire among 110 diabetic adults seen at the Makati Medical Center

Over the last 2 weeks, 0 - Not at all 1 - Several days 2- More than half the 3 - Nearly every day
how often have you (%) (%) days (%)
been bothered by any (%)
of the ff problems?
Little interest or 77 (70.00) 20 (18.18) 12 (10.91)
pleasure in doing things
Feeling down, 75 (68.18) 29 (26.36) 5 (4.55) 1 (0.91)
depressed, or hopeless
Trouble falling or staying 56 (50.91) 37 (33.64) 12 (10.91) 5 (4.55)
asleep, or sleeping too
much
Feeling tired or having 64 (58.18) 33 (30.00) 8 (7.27) 5 (4.55)
little energy
Poor appetite or 82 (74.55) 15 (13.64) 8 (7.27) 5 (4.55)
overeating
Feeling bad about 82 (74.55) 22 (20.00) 6 (5.45) 0 (0.00)
yourself, or that you
are a failure or have let
yourself or your family
down
Feeling bad about 82 (74.55) 22 (20.00) 6 (5.45) 0 (0.00)
yourself, or that you
are a failure or have let
yourself or your family
down
Feeling bad about 82 (74.55) 22 (20.00) 6 (5.45) 0 (0.00)
yourself, or that you
are a failure or have let
yourself or your family
down
Feeling bad about 82 (74.55) 22 (20.00) 6 (5.45) 0 (0.00)
yourself, or that you
are a failure or have let
yourself or your family
down

Table VI. Difficulty in activities of daily living reported by the 110 diabetic patients

Not difficult at all Somewhat difficult Very difficult Extremely difficult

(%) (%) (%) (%)

How difficult have these 78 (70.9) 28 (25.5) 4 (3.64) 0

problems made it for
you to do your work,
take care of things at
home, or get along with
other people?

Volume 55 Number 2 April-June 2017 5

 Nieva SJD, et al. Prevalence and Risk Factors for Depression Among Filipino Adults

Among Filipino Adul

Table VII. Results from PHQ-9 questionnaire among 110 diabetic adults seen at the Makati Medical Center

Over the last two 0 - Not at all 1 - Several days 2- More than half the 3 - Nearly every day
weeks, how often have (%) (%) days (%)
you been bothered (%)
by any of the ff
problems?
Little interest or 77 (70.00) 20 (18.18) 12 (10.91)
pleasure in doing things
Feeling down, 75 (68.18) 29 (26.36) 5 (4.55) 1 (0.91)
depressed, or hopeless
Trouble falling or staying 56 (50.91) 37 (33.64) 12 (10.91) 5 (4.55)
asleep, or sleeping too
much
Feeling tired or having 64 (58.18) 33 (30.00) 8 (7.27) 5 (4.55)
little energy
Poor appetite or 82 (74.55) 15 (13.64) 8 (7.27) 5 (4.55)
overeating
Feeling bad about 82 (74.55) 22 (20.00) 6 (5.45) 0 (0.00)
yourself, or that you
are a failure or have let
yourself or your family
down
Feeling bad about 82 (74.55) 22 (20.00) 6 (5.45) 0 (0.00)
yourself, or that you
are a failure or have let
yourself or your family
down
Feeling bad about 82 (74.55) 22 (20.00) 6 (5.45) 0 (0.00)
yourself, or that you
are a failure or have let
yourself or your family
down
Feeling bad about 82 (74.55) 22 (20.00) 6 (5.45) 0 (0.00)
yourself, or that you
are a failure or have let
yourself or your family
down

Table VIII. Final linear regression model of PHQ9 scores

PHQ9 Coef. [95% Conf. Interval] P-value

BMI 0.148 0.040 0.257 0.008

Diastolic 0.084 0.012 0.156 0.022
Employment Status -1.589 -3.107 -0.071 0.040
(Unemployed)
Uncontrolled glycemic 0.771 -0.383 -1.925 0.188
level
Constant -7.055 -13.261 -0.849 0.026

6 Volume 55 Number 2 April-June, 2017

 Prevalence and Risk Factors for Depression Among Filipino Adults
seen at the outpatient department of the Makati Medical
Center from January 2015 to March 2015 were included in
the study. All of the patients who participated in this study
belonged to the elderly population whose ages ranged from
65 to 75 years, and were predominantly females (76 of 110,
69%).
Based on the validated and translated PHQ-9
questionnaire, 69% of the patients had none to minimal
depression, 24% had mild depression, and 7% had scores
suggestive of moderate depression. All patients had
no previous diagnosis of depression. The prevalence of
depression among this population appeared higher in
comparison to a local study done by Oro-Josef et al,
who used the Geriatric Depression Scale Short Form 15 to
evaluate 196 elderly patients in Rizal.26 Their participants were
not necessarily diabetics but rather had other co-morbid
illnesses, such as hypertension, arthritis, and heart disease.
They noted a 6.6% rate of depression, and concluded that
this prevalence rate among the elderly in Rizal, Philippines
showed that depression can be present even in apparently
healthy Filipino communities.
Elevated diastolic blood pressure was found to be
associated with higher PHQ-9 scores, suggestive of higher risk
of depression. This was similar with the study done by Niraula
et al in Nepal,14 although the study they performed utilized a
different scale (Beck Depression Inventory, BDI). Their study
showed that high blood pressure, either systolic or diastolic,
was associated with greater depression severity.
Patients with a higher BMI also tend to have higher
PHQ-9 scores. In the study of Sweileh et al using the Beck
Depression Inventory (BDI), their score was significantly higher
among obese patients. Depression was more common
among diabetic women especially if they were overweight
and that body weight was a predictor of depression more
than diabetes itself. Similarly, recent studies have found
that higher BMI was a predictor of depression in type 2 DM.
Uncontrolled blood sugar, determined by elevated HbA1c,
fasting blood sugar, or by random capillary blood sugar
determination, was also associated with higher PHQ-9 scores.
This was consistently associated with depression in almost all
studies done among type 2 DM patients. HbA1c in particular
was strongly associated with depression in Niraula’s paper.
They hypothesize that HbA1c may be serve as a proxy for
disease severity. 14
Previous studies have shown that type 2 diabetic
patients with lower socioeconomic status have a higher
risk of depression. 15 Depression is greater among low-
income persons with diabetes, likely influenced by both
greater financial stressors and also by impaired access to
diabetes care. In contrast, however, our study showed that
unemployment was associated with decreased PHQ-9 score,
Nieva SJD, et al.
suggestive of a decreased tendency for depression among
patients with type 2 DM. A possible explanation for this is
that since the participants in the study are elderly and are
either retired or unemployed, the economic burden may
have fallen on the relatives taking care of them. In contrast
to other studies, however, marital status, educational
attainment, duration of diabetes, the presence of co-
morbid illnesses, pill burden and the use of insulin were not
associated with higher PHQ-9 scores.12,13,14,15
C onclusion
The prevalence of depression among Filipino type 2
diabetic patients is higher than in non-diabetic communities.
Being obese, having an elevated diastolic blood pressure,
and the presence of uncontrolled blood sugar were
significant predictors and were associated with an
increased likelihood of developing major depressive
disorders. Being unemployed has the opposite relation.
We highly recommend the incorporation of evaluating the
psychological aspect among the standard diabetic health
care plan in order to reduce the number of the depressed
or the unrecognized depressed diabetic patients and
consequently offer them a better quality of life.
R eferences
1. World Health Organization. The World Health Report 2001.
Mental health: new understanding, new hope. Geneva: WHO
Publications; 2001. 178 p.
2. World Health Organization. The ICD-10 Classification of Mental
and Behavioral Disorders - Clinical Descriptions and Diagnostic
Guidelines.
3. Moussavi S, Chetterji S, Verdes E et al. Depression, chronic
diseases, and decrements in health: results from the World
Health Surveys. The Lancet. Volume 370, No. 9590, p851–858, 8
September 2007
4. Niti M, Ng TP, Kua EH, et al. Depression and chronic medical
illnesses in Asian older adults: the role of subjective health and
functional status.Int J Geriatr Psychiatry. 2007 Nov;22(11):1087-
94.
5. Perlas AP, Briones-Querijero MM, Abcede D et al. The
prevalence of psychiatric disorders among the chronically-ill
medical patients in selected tertiary hospitals in the Philippines.
Philippine Journal of Psychiatry, January-June 2004, 28(1):17-24.
6. De Guzman ML. A Validation of the Hospital Anxiety and
Depression Scale (HADS) in the Medically-Ill. Acta Medica
Philippina, Vol. 47, No 3, 2013.
7. International Diabetes Federation. IDF Diabetes Atlas. 6th ed.
Brussels, Belgium: International Diabetes Federation; 2013
8. Food and Nutrition Research Institute, Department of Science
and Technology . 2nd National Nutrition Summit: 8th National
Nutrition Survey, 2013
9. Lin EH, Katon W, Von Korff M, Rutter C, Simon GE, Oliver
M, Ciechanowski P, Ludman EJ, Bush T, Young B: Relationship
Volume 55 Number 2 April-June 2017 7
 Nieva SJD, et al. Prevalence and Risk Factors for Depression Among Filipino Adults

of depression and diabetes self-care, medication adherence and Using the Geriatric Depression Scale. Geneva Health Forum
preventive care. Diabetes Care 2004, 27(9):2154–2160. 2012 [Internet]. Available from: http://ghf.g2hp.net/2011/09/29/
10. Anderson RJ, Freedland KE, Clouse RE, Lustman PJ: The prevalence-of-depression-among-the-elderly-using-the-geriatric-
prevalence of comorbid depression in adults with diabetes: a depression-scale-sf-15-in-rizal-province-philippines/
meta-analysis. Diabetes Care 2001, 24(6):1069–1078.
11. Lin EH, Korff MV, Alonso J, Angermeyer MC, Anthony J,
Bromet E, et al: Mental disorders among persons with diabetes–
results from the World Mental Health Surveys. J Psychosom Res
2008, 65(6):571–580.
12. Das R, Singh O, Thakurta RG, Khandakar MR, Ali SN,
Mallick AK, et al. Prevalence of Depression in Patients with
Type II Diabetes Mellitus and its Impact on Quality of Life.
Indian J Psychol Med. 2013;35(3):284–289. doi:10.4103/0253-
7176.119502.
13. Raval A, Dhanaraj E, Bhansali A, Grover S and Tiwari P.
Prevalence & determinants of depression in type 2 diabetes patients
in a tertiary care centre. Indian J Med Res. 2010;132:195-200.
14. Niraula K, Kohrt BA, Flora Ms, Thapa N, Mumu SJ, Pathak R,
et al. Prevalence of depression and associated risk factors among
persons with type-2 diabetes mellitus without a prior psychiatric
history: a cross-sectional study in clinical settings in urban Nepal.
BMC Psychiatry. 2013;13:309. doi:10.1186/1471-244X-13-309.
15. Andreoulakis E, Hyphantis T, Kandylis D, Iacovides A.
Depression in diabetes mellitus: a comprehensive review.
Hippokratia. 2012;16(3):205-214.
16. Bernardo J, Sy R. Correlation of clinical depression and glycemic
control in adult diabetes mellitus type 2 patients in Ospital ng
Makati.Philippine Journal of Medicine.
17. Standards of Medical Care in Diabetes 2015. Diabetes Care: The
Journal of Clinical and Applied Research and Education. January
2015, Volume 38, Supplement 1.
18. Esguerra MA, Gomez MH. Assessment of the quality of life in
patients with diabetes mellitus at Santo Tomas University Hospital.
Philippine Journal of Internal Medicine. 2000; 38(2): 77-82.
19. Cumings, JL. Depression in vascular dementia. Hillside Journal
of Clinical Psychiatry. 1988;10(2):209-31.
20. Kroenke K, Spitzer RL. The PHQ-9: a new depression diagnostic
and severity measure. Psychiatric Annals. 2002; 32:509-521.
21. Pfizer Inc. Instruction Manual: Instructions for Patient Health
Questionnaire (PHQ) and GAD-7 Measures [Internet]. 2013
[cited 2014 May 29]. Available from: http://www.phqscreeners.
co m/instructions/instructions.pdf
22. Spitzer RL, Kroenke K, Williams JB. Validation and utility of a
self-report version of PRIME-MD: The PHQ primary care study.
JAMA. 1999;282(18):1737-44.
23. Pfizer Inc. Palatanungan tungkol sa kalusugan ng pasyente - 9
(PHQ-9) [Internet]. 2013 [cited 2014 May 29]. Available from:
http://www.phqscreeners.com/pdfs/02_PHQ-9/PHQ9_Filipino%20
for%20the%20Philippines.pdf
24. Egede LE, Zheng D. Independent factors associated with major
depressive disorder in a national sample of individuals with
diabetes. Diabetes Care 2003 26:104–111.
25. Peacock JL, Peacock PJ. Oxford Handbook of Medical Statistics.
2011. New York: Oxford University Press.
26. Oro- Josef C, dela Cruz MC, Salandanan Jr. T. Prevalence
of Depression among the Elderly Population in Rizal Province

8 Volume 55 Number 2 April-June, 2017

Prevalence and Risk Factors for Depression Among Filipino Adults Nieva SJD, et al.

APPENDIX A

Protocol Flow Chart

Patient

Informed Consent

History and Physical Examination

Blood sugar status

Screening for Depression: PHQ-9 Questionnaire

Data Analysis

APPENDIX B

PATIENT HEALTH QUESTIONNAIRE - 9 (PHQ-9)

Over the last 2 weeks, how often have

you been bothered by any of the following
More than half Nearly
problems? Not at all Several days
the days every day
(Use “a ” indicate your answer)
1. Little interest or pleasure in doing things 0 1 2 3
2. Feeling down, depressed, or hopeless 0 1 2 3
3. Trouble falling or staying asleep, or sleeping 0 1 2 3
too much
4. Feeling tired or having little energy 0 1 2 3
5. Poor appetite or overeating 0 1 2 3
6. Feeling bad about yourself - or that you are 0 1 2 3
a failure or have let yourself or your family
down
7. Trouble concentrating on things, such 0 1 2 3
as reading the newspaper or watching
television
8. Moving or speaking so slowly that other 0 1 2 3
people could have noticed? Or the opposite
- being fidgety or restless that you have
been moving around a lot more than usual
9. Thoughts that you would be better off dead 0 1 2 3
or of hurting yourself in some way
FOR OFFICE CODING _____0_____ + __________ + __________ + ___________
=Total Score: __________

Volume 55 Number 2 April-June 2017 9

Nieva SJD, et al. Prevalence and Risk Factors for Depression Among Filipino Adults

APPENDIX C
PALATANUNGAN TUNGKOL SA KALUSUGAN NG PASYENTE - 9 (PHQ-9)

Nitong nakaraang 14 na araw, gaano ka

kadalas binagabag ng alinman sa mga Lagpas sa
sumusunod na mga problema? Hindi Maraming kalahati ng Halos
kailanman Araw bilang ng mga araw-araw
(Lagyan ng “a ” ang iyong sagot) Araw

1. Di gaanong interesado o nasisiyahan sa 0 1 2 3

paggawa ng mga bagay

2. Pakiramdam na nalulungkot, nadidipress 0 1 2 3

o nawawalan ng pag-asa

3. Hirap na makatulog o manatiling tulog, o 0 1 2 3

labis na pagtulog

4. Pagkaramdam ng pagod o walang lakas 0 1 2 3

5. Kawalan ng ganang kumain o labis na 0 1 2 3

pagkain

6. Pagkaramdam ng masama tungkol sa 0 1 2 3

iyong sarili — o na bigo ka o nabigo mo
ang iyong sarili o ang iyong pamilya

7. Hirap magtuon ng pansin sa mga bagay, 0 1 2 3

tulad ng pagbabasa ng dyaryo or pan-
onood ng telebisyon

8. Pagkilos o pagsasalita ng mabagal na

maaring napansin ng ibang tao? O ang
kabaligtaran — pagiging alumpihit o
0 1 2 3
di mapakali kaya ikot nang ikot nang higit
sa karaniwan

9. Nag-iisip na mas mabuting mamatay ka 0 1 2 3

na lang o saktan mo ang iyong sarili sa
ilang paraan

FOR OFFICE CODING _____0_____ + __________ + __________ + ___________

=Total Score: __________

Kung may tsinekan kang anumang mga problema, gaano ka pinahirapan ng mga problemang ito na gawin ang iyong
trabaho, asikasuhin ang mga bagay sa bahay, o makisama sa ibang tao?

Hinding-hindi Medyo Masyadong Labis na

pinahirapan Pinahirapan Pinahirapan Pinahirapan
□ □ □ □

10 Volume 55 Number 2 April-June, 2017

 Philippine Journal of Internal Medicine
Diffuse Cutaneous Systemic Sclerosis: A Case Report
Janice Natasha C. Ng, M.D.*; Sime Raymond B. Fernandez, M.D.**; Victoria P. Guillano, M.D. ***; Bryan Edgar K. Guevara, M.D. ***
Abstract
Background: Systemic sclerosis (SSc) is a rare, connective
tissue disease with multisystem involvement. This is due to
immunological processes, vascular endothelial cell injury
and extensive activation of fibrolast that commonly affects
the skin and other internal organs such as the esophagus,
lungs, heart, and kidneys. SSc has one of the highest mortality
among the autoimmune rheumatic diseases, hence the
emphasis on the early recognition and management to
prevent significant progression of the disease.
Case: A 22-year-old female presented with a one-year
history of multiple hard and hypopigmented patches on the
face, neck, trunk and upper extremities. Further examination
revealed mask-like facies, microstomia, frenulum sclerosis,
Raynaud’s phenomenon, pitted scars on the digital pulp of
hands and sclerodactyly. Baseline blood chemistry, chest
radiograph and electrocardiography were all negative
for systemic involvement. Autoantibodies were positive for
dsDNA, SS-A/Ro and Scl-70. Skin biopsy revealed sclerosing
dermatitis, which was consistent with SSc.
Outcome: The patient was initially started with oral
prednisone 0.5 mg/kg/day and was increased to 0.75 mg/
Introduction
Systemic Sclerosis (SSc) is a rare, multisystem, connective
tissue disorder based on autoimmunity, inflammation,
widespread vasculopathy and progressive interstitial and
perivascular fibrosis. 1 It has a worldwide distribution, more
common in women than men with a female-to-male ratio
between 3:1 up to 14:1.2 The disease onset ranges between
30 and 50 years old. 3 The incidence is between 0.6-20 per
million/year. 3 The Philippine Dermatologic Society (PDS)
central data from 2011-2016, included only 16 diagnosed
*Resident, Department of Dermatology, Southern Philippines Medical Center,
Davao City, Philippines
**Resident, Department of Internal Medicine, Southern Philippines Medical
Center, Davao City, Philippines
***Consultant, Department of Dermatology, Southern Philippines Medical
Center, Davao City, Philippines
Corresponding author: Janice Natasha C. Ng, M.D., Southern
Philippines Medical Center, Davao City, Philippines
Email: janiceng3@yahoo.com
The PHILIPPINE JOURNAL OF INTERNAL MEDICINE is a peer reviewed journal and a copyrighted publication of the Philippine College of Physicians
Case Series
kg/day for eight weeks. Prednisone was slowly tapered to
5.0 mg/day and methotrexate 15.0 mg/week was included
in the management for eight weeks which resulted in
decreased joint pains, halted the progression of skin
induration, decreased in pruritus and palmar edema.
Conclusion: The characteristic dermatological findings of
SSc are not only important signs to dermatologists, but these
serves as diagnostic clues for clinicians from other disciplines
as well. In our case, the presence of the autoantibody Scl-
70 indicated the potential risk of pulmonary fibrosis and
pulmonary arterial hypertension that accounts with high
mortality. Hence, physicians should be aware of the possible
risk of organ damage, even when asymptomatic because
there is a high risk of disease progression. The importance
of early recognition and a multidisciplinary approach lead
to the good outcome in this case.
Keywords: scleroderma, systemic sclerosis, diffuse cutaneous
systemic sclerosis, prednisone, methotrexate
cases of SSc, 10 of which were diffuse cutaneous SSc and
six cases were limited cutaneous SSc.4
C ase
This is a case of a 22-year-old, female who presented
with one-year history of multiple, pruritic, hypopigmented
macules with associated hardening skin initially at the nape
area; subsequently involving the face, trunk and upper
extremities. Consultation was done, and was given tar
ointment which didn’t improve the lesions. Self medication
with traditional oil and herbal capsules were done, which
afforded no relief as well.
Four months prior to consultation, there was persistence of
lesions now associated with bluish discoloration of fingers upon
exposure to cold temperature. Patient continually applied the
traditional herbal oil and continued to take herbal capsules
three times a day, still with no relief of symptoms. Persistence
of symptoms prompted consultation at our institution.
Volume 55 Number 2 April - June, 2017 1
 Ng JNC, et al.
Figure 1. Mask like facies and microstomia Figure 2. Salt and pepper sign
Figure 4. Pitted scars located on the 2nd, 3rd, 4th digital pulp of both
hands with bilateral sclerodactyly on second digits
General physical examination was unremarkable with
normal vital signs. Dermatologic examination showed mask
like facies, microstomia (Figure 1), hypopigmented patches
with sparing of the perifollicular skin “salt and pepper sign”
(Figure 2) with hard overlying skin on the face, neck, trunk
and upper extremities. Pitted scarring was noted on the
second, third and fourth digital pulps of both hands (Figure
4) and bilateral sclerodactyly on the second digits of both
hands. Oral mucosa showed frenulum sclerosis with no
erosions or ulcerations (Figure 3). Scalp hair and nail findings
were unremarkable.
Significant laboratory findings revealed elevated ESR
at 21 mm/hr (normal range: 0 – 20 mm/hr) and positive
antibodies (positive value, ratio > 1.2), such as anti-double
stranded DNA (anti-dsDNA) with ratio of 1.36, anti- Sjögren’s-
syndrome-related antigen A/Ro (anti-SS-A/Ro) with ratio of
2.38 and anti-topoisomerase 1 (anti Scl-70) with ratio of 3.04.
A 4.0-mm skin punch biopsy taken from a hypopigmented
indurated patch located on the chest hyalinized dermis
2 Volume 55 Number 2 April - June, 2017
Diffuse Cutaneous Systemic Sclerosis
Figure 3. Frenulum sclerosis
Figure 5. Skin punch biopsy- Dermal thickening and
hyalinization of collagen bundles (H&E stain, 100x)
with thickening of collagen bundles and associated
with perivascular inflammatory infiltrates composed
predominantly of eosinophils. The histopathologic diagnosis
was consistent with sclerosing dermatitis (Figure 5).
Patient was co-managed with internal medicine-
rheumatology service. Initially, prednisone was started at
20.0 mg/day (0.5 mg/kg/day) for two weeks, however there
was still persistence of bilateral wrist joint pain and pruritus. It
was then increased to 35.0 mg/day (0.75 mg/kg/day) for an
additional six weeks, which showed significant improvement
of the joint and skin manifestations. Prednisone was slowly
tapered to 5.0 mg/day and was started on methotrexate 2.5
mg/tablet, six tablets (15.0 mg/week) divided over a 48-hour
period. In addition, folic acid 5.0 mg/tablet daily was given.
She was also referred to rehabilitation medicine unit for the
management of musculoskeletal impairments.
After eight weeks of methotrexate 15.0 mg/week with
prednisone 5.0 mg/day, patient had no progression of skin
 Diffuse Cutaneous Systemic Sclerosis
induration, joint pain, pruritus, and palmar edema. Patient
was advised to follow-up every month to monitor disease
progression.
D iscussion
The American College of Rheumatology (ACR)
published a preliminary classification criteria to classify
patients with SSc which showed a 97% sensitivity and 98%
specificity. 2 The diagnosis is ascertained, if either one major
criteria (scleroderma proximal to the metacarpophalangeal
or metatarsophalangeal joints) or at least two or more minor
criteria (sclerodactyly, digital ulcerations and/or pitting
digital scars and bibasilar pulmonary fibrosis) are present. 3
In our case, one major criteria and two minor criteria were
fulfilled (sclerodactyly and digital ulcerations). She did not
present with dyspnea and had unremarkable chest findings.
The natural course of the SSc may vary, a few patients
may have spontaneous remission, however majority would
undergo progression of skin and internal organ involvement,
resulting in considerable morbidity and ultimately in death. 5
The diffuse cutaneous form carries the highest risk of fatality
of the connective tissue diseases, with 20–34% survival at
five years and 55% survival at 10 years. 1,6 The survival rate
is negatively impacted by older age of onset, male sex,
scleroderma renal crisis, pulmonary fibrosis, pulmonary
arterial hypertension, cancer, and positive for anti-
topoisomerase and anti-U1 antibodies.7
Our patient presented with a diffuse cutaneous subtype
of SSc, but has a better prognosis, because of her age, sex
and there was no internal organ involvement. Antibodies
tested was positive for Scl-70, which is associated with
pulmonary fibrosis (PF) and pulmonary arterial hypertension
(PAH). The percentage of SSc patients dying from PF and
PAH has increased (from 6% to 33%), which made it the
most common cause of death.8 It is important that we were
able to diagnosed our patient at an early stage while still
being asymptomatic. Further, we can regularly monitor
the progression of the disease with regular follow-ups and
tests such as chest radiography, lung function tests and
electrocardiography.
Dermatologic findings play an important role on early
recognition of SSc, as cutaneous involvement is a cardinal
feature of the disease. The skin usually presents as a tight,
indurated, and firmly bound to the subcutaneous tissue. 9 The
hair follicles and sweat and sebaceous glands atrophy and
the skin over the hands and face is most frequently involved.9
Raynaud’s phenomenon is the second most common
manifestation of SSc and is present in more than 85% of
patients.9,10 It is characterized by recurrent spasms of small
digital arterioles/arteries at fingers and toes, usually triggered
by cold and emotional stress.3 All these dermatologic findings
Ng JNC, et al.
were present in the case, which attributed to the early
diagnosis of our case.
Pulmonary involvement presents with symptoms of
tachypnea and exertional dyspnea that can be secondary
to either pulmonary fibrosis or pulmonary hypertension.9
Gastrointestinal tract is the most frequent internal organ
system involved in scleroderma at 90%, and in 10% of cases
it is the presenting feature of the disease.9,10 The esophageal
symptoms results from reduced lower esophageal sphincter
pressure and dysmotility of the lower two thirds of the
esophagus leading to reflux, heartburn, and dysphagia to
solid foods. 9 Fortunately for our patient, we were able to
diagnose the case at an early stage wherein she didn’t
present with symptoms of internal organ involvement.
Management of diffuse SSc is challenging and the
current treatments are of limited efficacy. 11 Common
treatments for early diffuse systemic sclerosis includes
systemic steroids, immunosuppressive medications such
as methotrexate, mycophenolate, cyclophosphamide,
azathioprine, and also intravenous immunoglobulin. 2,11
Since systemic sclerosis is a multisystem disease, a number
of subspecialties are involved in the management.3
Our patient was successfully controlled with prednisone
and methotrexate for eight weeks. Our plan is to continue
methotrexate 15.0 mg/week for 12 more months and close
monitoring through regular follow-ups and other laboratory
work ups to rule out possible systemic involvement.
C onclusion
We presented a case of diffuse systemic sclerosis that
was diagnosed early that prevented the progression to
more severe presentation, such as the pulmonary fibrosis
and pulmonary arterial hypertension. The cutaneous
manifestations in systemic sclerosis are not only important
among dermatologists, but also serves as diagnostic clues
for internists to prevent complications of the disease and
to achieve effective management. A multidisciplinary
approach is important to give the best management to the
patient. We recommend that frequent follow ups be done,
since diffuse cutaneous systemic sclerosis has a greater risk
for clinically significant major organ dysfunction.
R eferences
1. Varga J, Abraham D. Systemic sclerosis: a prototypic multisystem
fibrotic disorder. The Journal of clinical investigation. 2007 Mar
1;117(3):557-67.
2. Goldsmith L, Katz S, Gilchrest B, Paller A, Lefell D, Wolff L:
Fitzpatrick’s Dermatology in General Medicine 8th ed, New York,
McGraw-hill, 2012. Chapter in Book: Moinzadeh P, Denton C,
Volume 55 Number 2 April - June, 2017 3
 Ng JNC, et al. Diffuse Cutaneous Systemic Sclerosis

Kreig T, Black C. Scleroderma, 2012, P1942-1956.

11. Frech TM, Shanmugam VK, Shah AA, Assassi S, Gordon JK,
3. Hunzelmann N, Genth E, Krieg T, Lehmacher W, Melchers
Hant FN, Hinchcliff ME, Steen V, Khanna D, Kayser C, Domsic
I, Meurer M, Moinzadeh P, Müller-Ladner U, Pfeiffer C,
RT; Treatment of Early Diffuse Systemic Sclerosis Skin Disease.
Riemekasten G, Schulze-Lohoff E. The registry of the German
Clin Exp Rheumatol, 31:1-11, 2013.
Network for Systemic Scleroderma: frequency of disease subsets
and patterns of organ involvement. Rheumatology. 2008 Aug
1;47(8):1185-92.
4. Philippine Dermatological Society Health Information Systems.
Philippine Dermatological Society. c2011 [updated May 5, 2016;
cited May 5, 2016]. Available by request from: pdshis@outlook.
com
3. Lo T, Racaza G, Penserga E. Clinical profile of Filipino patients
with scleroderma (systemic sclerosis): an 11-year retrospective
review of 40 cases. International Journal of Rheumatic Diseases
2012; 15 (Suppl. 1): 111–118.
4. Jimenez SA, Derk CT. Following the molecular pathways toward
an understanding of the pathogenesis of systemic sclerosis. Annals
of internal medicine. 2004 Jan 6;140(1):37-50.
5. Van den Hoogen FH, Boerbooms AM, Swaak AJ, Rasker JJ,
Van Lier HJ, Van De Putte LB. Comparison of methotrexate
with placebo in the treatment of systemic sclerosis: a 24 week
randomized double-blind trial, followed by a 24 week observational
trial. Rheumatology. 1996 Apr 1;35(4):364-72.
6. Pope JE, Bellamy N, Seibold JR, Baron M, Ellman M, Carette
S, Smith CD, Chalmers IM, Hong P, O’Hanlon D, Kaminska
E. A randomized, controlled trial of methotrexate versus placebo
in early diffuse scleroderma. Arthritis & Rheumatism. 2001 Jun
1;44(6):1351-8.
7. Barnes J, Mayes MD. Epidemiology of systemic sclerosis:
incidence, prevalence, survival, risk factors, malignancy, and
environmental triggers. Current opinion in rheumatology. 2012
Mar 1;24(2):165-70.
5. Amjadi S, Maranian P, Furst D, Clements P, Wong WK,
Seibold J, Postlethwaite A, Khanna D. Course of modified
rodnan skin score in systemic sclerosis clinical trials: Analysis
of 3 large multicenter, randomized clinical trials. In Arthritis And
Rheumatism. 2008 Sep 1; 58 (9) S368.
6. Cutolo M, Sulli A, Pizzorni C, Paolino S, Smith V. Systemic
sclerosis: markers and targeted treatments. Acta reumatologica
portuguesa. 2016 Jan 1;41(1).
7. Frech TM, Shanmugam VK, Shah AA, Assassi S, Gordon JK,
Hant FN, Hinchcliff ME, Steen V, Khanna D, Kayser C, Domsic
RT. Treatment of early diffuse systemic sclerosis skin disease.
Clinical and experimental rheumatology. 2013 Mar;31(2 0 76):166.
8. Sweiss NJ, Hushaw L, Thenappan T, Sawaqed R, Machado RF,
Patel AR, Gomberg-Maitland M, Husain AN, Archer SL; Diagnosis
and management of pulmonary hypertension in systemic sclerosis.
Curr Rheumatol Rep, 12: 8-18, 2010.
9. Jimenez SA, Derk CT; Following the Molecular Pathways Toward
an Understanding of the Pathogenesis of Systemic Sclerosis. Ann
Intern Med, 140:37-50, 2004.
10. Cutolo M, Sulli A, Pizzorni C, Paolino S, Smith V; Systemic
Sclerosis: Markers and Targeted Treatments. Acta Reumatol Port,
41:18-25, 2016

4 Volume 55 Number 2 April - June, 2017

 Philippine Journal of Internal Medicine Original Article

The Prevalence of Potentially Inappropriate Medications

Prescribed in Elderly Patients Admitted in a Tertiary Teaching
Hospital: A Retrospective Cross-Sectional Study
Harold P. Iturralde, M.D.*; Rossana M. Cortez, M.D.**

Abstract
Background: The number of elderly people (aged 60 years
or over) is expected to double in the next 35 years as a result
of decreasing mortality and declining fertility worldwide. The
elderly population is at increased risk of being prescribed
potentially inappropriate medications (PIM).
Objectives: To determine the prevalence of PIM prescribed
among the geriatric patients admitted in a tertiary teaching
hospital in Valenzuela City in 2014.
Methods: This is a retrospective cross-sectional study on
patients who are 65 years and older admitted under Internal
Medicine between January 2014 to December 2014. Medical
records were reviewed for PIM prescription according to the
updated 2012 Beers Criteria.
Results: PIMs were noted in 303 out of of 618 patients.
The most common PIMs were insulin sliding scale, digoxin,
orphenadrine, ipratropium, ketorolac, clonazepam,
clonidine, hydroxyzine, amiodarone and spironolactone.
Conclusion: The prevalence of PIM prescription is 49% among
geriatric patients admitted in a tertiary teaching hospital in
Valenzuela City in 2014. It is recommended to determine
prevalence of PIM use in other geriatric care settings, the
predictors for PIM use, and the economic burden of PIM use.
Keywords: potentially inappropriate medications, PIM
prescription, geriatric patients

Introduction as indigents. By 2040 the country’s senior citizen population

is estimated to increase to 19.6 million per National Statistics
Office (NSO), which bring significant concerns about our
Globally, the number of older persons (aged 60 years or
elderly people today.2
over), which at present is predominantly female, is expected
to increase, from 841 million people in 2013 to more than two
Due to the presence of multiple chronic diseases and
billion, in 2050. This population ageing results from decreasing
conditions in the elderly, there is a great risk for medication-
mortality, and, most importantly, declining fertility. Older
related problems as a result of age-related physiological
persons are projected to exceed the number of children
changes and the types and numbers of prescription and non-
for the first time in 2047. Presently, about two thirds of the
prescription medications they consume.3 Likewise, potentially
world’s older persons live in developing countries. Because
inappropriate medications (PIMs) add an economic burden
the older population in less developed regions is growing
to the elderly and their families in the setting of limited
faster than in the more developed regions, the projections
resources in a developing country. With the projected
show that older persons will be increasingly concentrated in
increase in the elderly population, the economic burden
the less developed regions of the world. It is projected that
becomes even more significant on a national level.
by 2050, nearly eight in 10 of the world’s older population

will live in the less developed regions.1
T h e e lde r ly p a t ie n t s c o n s u me me dic at ions at a
comparatively high rate and numerous other factors add
In the Philippines, it is estimated that the elderly comprise
to the increased prevalence of medication-associated
4.3 million of the country’s more than 73 million population in
morbidity and mortality affecting this vulnerable population.
2013, of whom at least more than one million are classified
Contributing to this are the physiologic changes associated
with aging. The Center for Medicare and Medicaid Services in
*Consultant, Department of Internal Medicine Fatima University
Medical Center, Valenzuela City
the US recognized that consumption of multiple medications
**Active Consultant, Department of Internal Medicine Fatima is an expensive practice and costs its nation’s health plans
University Medical Center, Valenzuela City more than US$50 billion annually.4

Corresponding author: Harold P. Iturralde, Fatima University Medical Currently, a PubMed search using the words
Center, Valenzuela City
“prevalence”, “elderly”, “PIMs”, and “Philippines”, found
Email: iturralde.harold@yahoo.com
no matched items, hence, this could be the first prevalence

The PHILIPPINE JOURNAL OF INTERNAL MEDICINE is a peer reviewed journal and a copyrighted publication of the Philippine College of Physicians Volume 55 Number 2 April - June, 2017 1
 Iturralde HP, et al.
study on the use of PIMs locally. Additionally, since there are
plans to put up a geriatrics section in this hospital within the
next two years, this study can increase awareness among
admitting physicians of the internal medicine department
on the prevalence of PIMs prescription and the updated
Beers Criteria.
An increase in inter-individual variability is the
main change in pharmacokinetics with aging. Of the
pharmacokinetic changes seen in normal aging, reduced
hepatic and renal clearance are generally the most
significant, and these affect maintenance dose and dosing
interval. The changes in volume of distribution are smaller,
and affect the half-life of drugs (to a lesser extent than the
changes in clearance do) and the loading dose. The main
changes in bioavailability with aging result from reduced
first pass metabolism, with increased bioavailability of drugs
that undergo significant first pass hepatic metabolism and
decreased activation of prodrugs. Pharmacodynamic
changes with aging are less well-characterized or
understood than pharmacokinetic changes.5
Since drug-related problems on the elderly population
has received worldwide attention, various measures
have been implemented to reduce the likelihood of such
complications like developing implicit and explicit criteria.
One of the first set of explicit criteria for inappropriate
drug use was developed by Mark H. Beers, MD, while a junior
faculty at the University of California, Los Angeles and was
published in 1991. He defined inappropriate prescribing as
the use of medication where the potential risks outweigh
the potential benefits.6 Hence derived the term “potentially
inappropriate medication” or “PIM”. The criteria were
subsequently revised in 1997 and 2003 to include all settings
of geriatric care. The 2012 version was a product of a
comprehensive, systematic review and grading of evidence
by an 11-expert interdisciplinary panel, on drug-related
problems and adverse drug events in adults with support
from The American Geriatrics Society. Fifty-three medications
or medication classes encompass the final updated criteria,
which are divided into three categories: PIMs and classes
to avoid in older adults, PIMs and classes to avoid in older
adults with certain diseases and syndromes that the drugs
listed can exacerbate, an finally medications to be used
with caution in older adults.7
Numerous researches on the subject of PIMs have been
done in different parts of the world – prevalence, risk factors,
and clinical outcomes. These studies revealed different
prevalence of PIM use in different settings. Harugeri et.al. in
2009 concluded that PIM was common (23.5% prevalence)
among elderly patients during their stay in medicine wards
in two tertiary care hospitals in India.8 One study of de Lima
et.al. in 2013 in Brazilian care homes revealed 82.6% of elderly
were taking at least one PIM according to updated Beers
2 Volume 55 Number 2 April - June, 2017
Prevalence of Potentially Inappropriate Medications Prescribed
criteria, with antipsychotics and analgesics being the most
commonly used.9 Another study by Al-Shamri in 2014 which
determined the prevalence of PIM use in recently admitted
geriatric patients in rural hospitals showed 60-70% were
taking at least one PIM when Beers and STOPP (Screening
Tool of Older Persons’ Potentially Inappropriate Prescriptions)
criteria were utilized.10
Some studies have determined the factors associated
with or predictors of PIM use. And these were polypharmacy,
psychiatric disorders, cerebrovascular diseases and
dependency. 9 While in the study by Undela in 2014, the
important predictors of PIM prescribing were found to be age
≥80 years, male sex, >three diagnoses, ≥six medications
prescribed, and ≥10 days of hospital stay.11
A study by Floroff et.al. revealed that PIM use is
associated with poor clinical outcomes and longer lengths
of stay in critically ill elderly patients with neurological
injury and they recommended further studies to determine
the impact of PIM use on mortality. 12 Rosemann et.al. in
2014 concluded that cumulative levels of PIM use acted
significantly as a factor related to greater hospitalization
rates in older patients in Swiss managed care plans.13 Onda
et al have found that adverse drug events caused by PIMs
had occurred in 8.0% of patients routinely visited by a
pharmacist. 14
Objectives
General Objective: To determine the prevalence of PIMs
prescription among geriatric patients admitted in a tertiary
teaching hospital in Valenzuela City from January 2014 to
December 2014.
Specific Objectives:
1. To describe the sociodemographic and clinical
profile of admitted geriatric patients included in the
study
2. To determine the frequency of PIMs commonly
prescribed to admitted geriatric patients included in
the study
M ethods
This is a retrospective cross-sectional study and involved
medical charts of all patients aged ≥65 years admitted
under the Department of Internal Medicine from January
2014 to December 2014.
Inclusion Criteria: Medical charts of patients aged 65 years
and above who were admitted in the ward and ICU for more
than 24 hours up to 60 days.
Prevalence of Potentially Inappropriate Medications Prescribed Iturralde HP, et al.

Exclusion Criteria: Medical records of patients who: Table I. The Sociodemographic and Clinical Profile of Admitted
1. Died <24 hours of admission Geriatric Patients
2. Went home against medical advice
3. Were transferred to different service within the All With
Patients % %
hospital PIM
(n=618)
4. Were transferred to different institution
Sex
5. Are in hospice care
Male 220 36 124 56
The study was done in an ISO certified, tertiary teaching Female 398 64 179 45
hospital in Valenzuela City, Metro Manila serving patients Age (Years)
coming from the Caloocan, Malabon, Navotas, Valenzuela 65-74 239 39 118 49
(CaMaNaVa) and the southern areas of Bulacan province
75-84 326 53 151 46
from June – October 2015. Medical charts of all patients
aged ≥65 years admitted under the Department of Internal >85 53 9 34 64
Medicine from January 2014 to December 2014 were No. of Comorbidities
retrieved from the Records Department and thoroughly 0 43 7 11 26
reviewed. A total of 618 patients’ charts were reportedly
1 204 33 93 46
available and evaluated.
2 242 39 129 53
A cross-sectional study design was used to form the 3 80 13 50 63
database for this study. In this design, there was a purposive 4 43 7 17 40
probe of all geriatric patients’ charts available covering
5 6 1 3 50
period January 2014 to December 2014 who were admitted
in the Department of Internal Medicine and then later arrive Comorbidities
at conclusions about the frequency of PIM use. All the 618 Hypertension 486 79
patients aged ≥65 years, receiving at least one medication Diabetes Mellitus type 2 216 35
during hospital stay were purposely sorted out to form the
Previous Stroke 123 20
database for this investigation. General demographic
Bronchial Asthma/COPD 89 14
characteristics such as age, gender, comorbidities,
maintenance medications, length of hospital stay, and Benign Prostatic Hyperplasia 37 6
number of drugs prescribed during hospital stay were noted. Pulmonary Tuberculosis 35 6
Beers Criteria 2012 were used to assess PIM use. Chronic Kidney Disease 33 5

Statistical Analysis: The various frequencies were entered

Ave. number of Maintenance
into Microsoft EXCEL for Windows (version 2013) and the 4 (0-9)
Drugs (range)
figures and tables all developed.
Ave. Length of Hospital Stay,
6 (2-32)
(range)
R esults Hospital Stay (days)
<4 281 45 119 42
A total of 618 patients aged ≥65 years were included
5—9 296 48 153 52
(Table I). The age is divided into subgroups ≥65-74 years
(“young old”), 75-84 years (“old old”), and ≥85 years 10—14 33 5 28 85
(“oldest old”). The number of comorbidities were from zero >15 8 1 3 38
to five diseases. The five most frequent comorbidities were
hypertension (79%), diabetes mellitus type 2 (35%), previous
Ave. No. of Medications
stroke (20%), bronchial asthma/COPD (14%), and benign 12
received during Hospital Stay
prostatic hyperplasia (6.0%). On an average, the patients
No. of Medications during
were taking four (range 0-9) maintenance medications. The hospital Stay
patients stayed in the hospital for an average of six (range
1—4 45 7 8 18
two to 32) days. During their admission, the patients received
an average of 12 drugs. 5—8 171 28 61 36
PIMs was observed in 124 (56%) males and 179 (45%) 9—12 179 29 84 47
females. The patient age subgroup with the highest 13-16 134 22 76 57
prevalence of prescribed PIM is the “oldest old” (34 out of 53,
>17 89 14 74 83
64%), while the “young old” and “old old” had a prevalence

Volume 55 Number 2 April - June, 2017 3

 Iturralde HP, et al. Prevalence of Potentially Inappropriate Medications Prescribed

Table II. Prevalence of prescribed potentially inappropriate one to four medications had PIM. While 36% (61 out of 101)
medications (PIMs) of those who were given five to eight medications during
hospital stay had PIM. Forty seven percent (84 out of 179)
No. of patients who were given nine to 12 medications, 57% (76
Patients Percentage
out of 134) patients who received 13-16 medications, and
Received at least one PIM during 303 49.0 83% (74 out of 89) patients who received > 17 medications
hospital stay
received PIM.
PIMs to be avoided in older adults regardless of disease/
condition
For the whole study population, PIMs were received by
Alprazolam 5 1.7 303 out of 618 (49%) patients (Table II). These patients received
Amiodarone 21 6.9 at least one PIM (range 1-3) during their hospital stay. The
Clonazepam 28 9.2 PIMs identified belong to three categories presented in Beers
Criteria 2012. PIMs to be avoided in older adults regardless of
Clonidine 22 7.3
disease/condition: alprazolam, amiodarone, clonazepam,
Diazepam 12 4.0 clonidine, diazepam, diclofenac, digoxin, hydroxyzine, insulin
Diclofenac 3 1.0 sliding scale, inhaled ipratropium, ketoprofen, ketorolac,
Digoxin 56 18.5 meloxicam, orphenadrine, and spironolactone. PIM to
avoid in older adults with certain diseases and syndromes:
Hydroxyzine 22 7.3
tramadol. PIM to be used with caution in older adults: aspirin
Insulin, sliding scale 69 22.8 and dabigatran. The three most common PIMs prescribed
Ipratropium, inhaled 35 11.6 were insulin sliding scale (69 out of 303, 22.8%), digoxin (56
Ketoprofen 4 1.3 out of 303, 18.5%), and orphenadrine (44 out of 303, 14.5%).

Ketorolac 30 9.9
Meloxicam 6 2.0 D iscussion
Orphenadrine 44 14.5
In this study, the observed majority of females (64.4%)
Spironolactone 21 6.9 in the sample is consistent with global figures of female
PIM to avoid in older adults with certain diseases and predominance in the elderly population. This is due to
syndromes the fact that women have greater life expectancy than
Tramadol 3 1.0 men because of the lower mortality rate in women. 1
PIM to be used with caution in older adults The observation that hypertension is the most common
comorbidity in the elderly population5 was also confirmed.
Aspirin 4 1.3
The main findings of these study are that in a tertiary teaching
Dabigatran 4 1.3 hospital in Valenzuela City, 49% of patients age ≥65 years
under the Department of Internal Medicine received at
of 49% (118 out of 239) and 46% (151 out of 326) respectively.
least one PIM during their hospital stay from January 2014 to
December 2014. The calculated prevalence was observed
In terms of number of comorbidities, patients with
to be higher than the prevalence in two teaching hospitals
no known comorbidities upon admission had 26% (11 out
in India 23.5% 8, and acute medical geriatric unit in France
of 43) prevalence of prescribed PIM. As the number or
43.6% 16 . The calculated prevalence of prescribed PIM
comorbidities increase from one to two and three, the
was observed to be lower than the prevalence reported
prevalence of PIM also increased to 46% (93 out of 204),
from the studies in Brazilian care homes 82.6%9, and Indian
53% (129 out of 242), and 63% (50 out of 80) respectively.
rural hospitals 62.92%. 10 The differences in the prevalence
Patients with four known comorbidities had 40% (17 out of
according to Harugeri is probably due to differences in
43) prevalence while patients with five known comorbidities
patient characteristics, disease prevalence, study settings,
upon admission had 50% (three out of six) prevalence of PIM.
and availability of drugs listed in Beers Criteria 2012. 8

As to length of hospital stay, 42% (119 out of 281) patients

The updated Beers criteria is applicable to patients
who stayed in the hospital for four days and below were
aged 65 years and above because the published systematic
given PIMs. The prevalence of PIM when patients stayed for
reviews and meta-analyses used during the formulation of
five to nine days, 10-14 days, and ≥15 days were 52% (153
the criteria were limited to the said age group.7
out of 296), 85% (28 out of 33), and 38% (three out of eight)

respectively.
Due to the dramatic increase in people reaching age
65 and above, this age group is divided into three subgroups
In terms of number of medications received during
– young old (65-74 years), old (75-84 years), and oldest old
hospital stay, 18% (eight out of 45) patients who received

4 Volume 55 Number 2 April - June, 2017

 Prevalence of Potentially Inappropriate Medications Prescribed
(≥85 years).17 From this study, it was noted that the oldest old
group had the highest chance of being prescribed with a
PIMs. Similar to other studies,11,18,19,20 older age was associated
with increased prevalence of PIM prescribed.
It was observed that the more comorbidities the patient
had, the higher was the chance of being given a PIM
compared with those without comorbidity (Table I). But it
also showed no correlation between increasing number of
comorbidities and frequency of prescribed PIM. This is similar
to the finding of Harugeri8 that the number of diseases was
not a predictor of PIM use.
When it comes to length of hospital stay, it was also
observed that the longer the patients stay, the higher is the
chance of being given a PIM, this is due to the proportional
relationship between length of stay and number of
medications used.8 But it also noted that those who stayed
for more than 15 days had lower prevalence of prescribed
PIM. This may be due to the fact that many of these patients
had an infection and antimicrobials are basically not in the
Beers Criteria.
In terms of number of medications during hospital stay, it
was observed in this study that as the number of medications
or drugs increased the prevalence of PIMs being prescribed
also increased. Polypharmacy is a common predictor of
exposure to PIMs as revealed by studies of Harugeri 8, de
Lima9, and Undela11. But Bushardt21 mentioned in 2008 that no
consensus existed in the medical literature on the definition
for polypharmacy. In his meta-analysis he revealed that the
two most commonly cited definitions of polypharmacy is “use
of a potentially inappropriate drug” or “use of six or more
concomitant drugs”. Harugeri8 stated in his findings that the
increased number (≥ nine) of concurrent medications’ use
during hospital stay was the only influential predictor of PIM
use.
Most of the observed PIMs prescribed in this study
belong to the category “PIMs to be avoided in older adults
regardless of disease/condition”. This category was referred
to as “high severity” PIMs in the study of Harugeri 8. The
observation of increased prevalence of prescribed PIMs
in this category was similar to the studies of Cartwright 21,
Mandavi 22, and Blalock 23
C onclusion
The prevalence of PIMs use as defined by the 2012
Beers Criteria in elderly patients admitted in a private,
tertiary, teaching hospital in Valenzuela City is 49%. Most
of the PIMs prescribed are under the medications to be
avoided in older adults regardless of disease/condition.
The three most common PIMs prescribed were insulin
sliding scale (69 out of 303, 22.8%), digoxin (56 out of
Iturralde HP, et al.
303, 18.5%), and orphenadrine (44 out of 303, 14.5%).
Limitations
This study has several limitations. It did not determine
whether PIMs prescribed in this setting is associated with
age, sex, number of comorbidities, length of hospital stay,
number of drugs prescribed. It did not determine whether
the patients were already taking PIMs as part of their
maintenance medications which could be related to their
hospital admission. It also did not use other explicit criteria
for PIM use like the STOPP criteria. The result of this study
is different from other studies due to the fact that it was
conducted in a tertiary hospital wherein many physicians
are subspecialists and are more aware of possibilities of PIM
use.
Recommendations
The researcher recommends that a similar study could
be replicated in other tertiary hospitals and compared
in other settings of geriatric care – government hospitals,
private nonteaching hospital, “homes for the aged”, etc.
Another study on whether PIM use can lead to the proven
“predictors” like polypharmacy, increased length of hospital
stay or if PIM as defined by Beers or STOPP criteria or both
is associated with increased adverse drug events, clinical
outcomes (e.g. mortality). Aside from clinical outcomes,
association of PIMs with economic outcomes can also be
explored.
R eferences
1. United Nations, Department of Economic and Social Affairs,
Population Division. World Population Ageing 2013.
2. Elloso R. Concerns for the aging population. Manila Bulletin.
2013 October
3. Simonson W. Feinberg J.L. Medication-related problems in the
elderly: defining the issues and identifying solutions. Drugs Aging.
22(7); 559-69, 2005.
4. Bushardt R. Massey E. Simpson T. Ariail J. Simpson
K. Polypharmacy: Misleading, but manageable. Clin Interv
Aging.3(2):383–389, 2008.
5. Halter J. Ouslander J. Tinetti M. Studenski S. High K. Asthana
S. Hazzard’s Geriatric Medicine and Gerontology, 6th Edition.
The McGraw-Hill Companies, Inc. United States. 2009.
6. Marcum Z. “Commentary in the New American Geriatric Society
Beers Criteria for Potentially Inappropriate Medication Use in older
Adults”. American Journal of Geriatric Pharmacotherapy. 2012.
7. American Geriatrics Society Updated Beers Criteria for
Potentially Inappropriate Medication Use in Older Adults The
American Geriatrics Society 2012 Beers Criteria Update Expert
Panel. New York. 2012.
8. Harugeri A. Joseph J. Parthasrathi G. Ramesh M. Guido S.
Potentially inappropriate medication use in elderly patients: A
Volume 55 Number 2 April - June, 2017 5
 Iturralde HP, et al. Prevalence of Potentially Inappropriate Medications Prescribed

study of prevalence and predictors in two teaching hospitals. J 23. Blalock S.J. Byrd J.E. Hansen R.A. Yamanis T.J. McMullin K.
Postgrad Med, 56(3), 186-191, 2010. De Vellis B.M. Factors associated with potentially inappropriate
9. de Lima T.J. Garbin C. Garbin A. Sumida D. Saliba O. drug utilization in a sample of rural community-dwelling older
Potentially inappropriate medications used by the elderly: adults. Am J Geriatr Pharmacother. 3:168-79, 2005.
prevalence and risk factors in Brazilian care homes. BMC
Geriatrics. Brazil. 2013.
10. Al-Shamri H. Prevalence of Potentially Inappropriate Medication
Use Among Recently Admitted Geriatric Patients in Rural
Hospitals. 2014.
11. Undela K. Bansal D. D’Cruz S. Sachdev A. Tiwari P.Prevalence
and determinants of use of potentially inappropriate medications
in elderly inpatients: a prospective study in a tertiary healthcare
setting; Geriar Gerontol Int 14(2);251-8, 2014.
12. Floroff C.K. Slattum P.W. Harpe S.E. Taylor P. Brophy G.M.
Potentially inappropriate medication use is associated with
clinical outcomes in critically ill patients with neurological injury.
Neurocrit Care 21(3), 526-33, 2014 Dec.
13. Rosemann T. Rapold R. Blozik E. Senn O. Potentially
Inappropriate Medication Use in Older Patients in Swiss Managed
Care Plans: Prevalence, Determinants and Association with
Hospitalization. PLoS ONE 9(8) University of Glasgow, United
Kingdom. 2014.
14. Onda M. Imai H. Takada Y. Fujii S. Shono T. Nanaumi
Y.Identification and prevalence of adverse drug events caused
by potentially inappropriate medication in homebound elderly
patients: a retrospective study using a nationwide survey in Japan.
BMJOpen ;5:e007581, 2015.
15. Page R. Ruscin J.M. The Risk of Adverse Drug Events and
hospital-Related Morbidity and Mortality Among Older Adults
with Potentially Inappropriate Medication Use; The American
Journal of Geriatric Pharmacotherapy. 2007.
16. Laroche M.L. Charmes J.P. Nouaille Y. Fourrier A. Merle L.
Impact of hospitalization in an acute medical geriatric unit on
potentially inappropriate medication use. Drugs Aging. 23:49-
59, 2006.
17. Pirkl J. The Demographics of Aging, Transgenerational Design
Matters, [online]. Available: http://www.transgenerational.org/
aging/demographics.htm [2015, Oct].
18. Lin H.Y. Liao C.C. Cheng S.H. Association of potentially
inappropriate medication use with adverse outcomes in ambulatory
elderly patients with chronic diseases: Experience in a Taiwanese
medical setting. Drugs Aging. 25:49-59, 2008.
19. Goulding M.R. Inappropriate medication prescribing for elderly
ambulatory care patients. Arch Intern Med. 164:305-12, 2004.
20. Maio V. Yuen E.J. Novielli K. Smith K.D. Louis D.Z. Potentially
inappropriate medication prescribing for elderly outpatients in
Emilia Romagna, Italy: A population-based cohort study. Drugs
Aging. 23:915-24, 2006.
21. Cartwright O.M. Moulin J. Hale L.S. A Retrospective evaluation
of potentially inappropriate medication use in hospitalized elderly
patients. Proceedings of the 3rd annual GRASP Symposium.
Wichita State University . p.41-2, 2007.
22. Mandavi K. Tiwari P. Kapur V. Inappropriate drug prescribing
identified among Indian elderly hospitalized patients. The
International Journal of Risk and Safety in Medicine. 19:111-6,
2007.

6 Volume 55 Number 2 April - June, 2017

 Philippine Journal of Internal Medicine
A Case of Eccrine Carcinoma Presenting with Neurological
Manifestations
Lynne Michelle B. Soldivillo., M.D.*; Rosalina Espiritu Picar M.D.**; Allen Evaristo.,M.D.***
Abstract
Introduction: Eccrine carcinoma is an extremely rare skin
tumor where only 1/13000 specimens have been submitted
to dermatopathological laboratories in the United States.
There is no data yet to compare the Philippines with the
international incidence of eccrine carcinoma. This is a
case of a 69-year-old Filipino female who presented with a
recurring invasive indolent tumor at the right fronto-parietal
area who presented with left sided hemiparesis and seizure.
Case: The patient was presented with a recurrent invasive
indolent mass on her right front-parietal area, grossly
measuring five by four centimeters, nodular flesh colored,
which extended intracranially. This was associated with
left sided hemiparesis and due to the extent of the tumor
encroaching through the brain parenchyma, patient was
noted to have seizure episodes. The patient was given
surgical and radiologic options however, she did not comply
and died last December 2015.
I ntroduction
Malignant cutaneous adnexal neoplasms are a large
and varied group of tumors that exhibit morphological
differentiation. Some tumors are rarely aggressive and have
potential for nodal involvement and distant metastasis with
poor clinical outcome. 1 In particular, eccrine carcinoma
which are tumors that may be derived denovo from
any portion of an eccrine apparatus or a result from
the transformation of an excising benign eccrine tumor.
Hence, are said to be the most challenging areas of
dermatopahology.1,2 Eccrine carcinoma is a rare histologic
subtype of adnexal tumors which is a rare cutaneous
condition characterised by a plaque or a nodule most
commonly found on the scalp, trunk or extremities.1 These
tumors grow either slowly over the years or may progress
*Resident-in-Training, University of Perpetual Help Binan Laguna
**Neurologist, University of Perpetual Help Binan Laguna
***Oncologist, University of Perpetual Help Binan Laguna
Corresponding Author: Lynne Michelle Soldivillo, M.D., University of
Perpetual Help Binan Laguna, Philippines
Email: mitchsoldivillo@yahoo.com
The PHILIPPINE JOURNAL OF INTERNAL MEDICINE is a peer reviewed journal and a copyrighted publication of the Philippine College of Physicians
Case Report
Results: A cranial MRI with MRA showed a heterogenous
enhancing intracranial mass with extracranial component
with compressed entrapped and depressed superior sagittal
sinus by the axial mass witin calvarial penetration and
scalp involvement compressing on the right parietal lobe
with parenchyma edema. Biopsy was eventually done and
findings were consistent with an eccrine carcinoma.
Conclusion: This is the first case of eccrine carcinoma in our
institution. Due to the paucity of data, there are no guidelines
to the management of an eccrine carcinoma. Hence the
imperative need to raise awareness regarding this rare tumor
because, without a high index of suspicion this rare entity
may be overlooked or misdiagnosed. When presented with
an indolent invasive recurrent tumor a high index of suspicion
that an eccrine Carcinoma may be suspected. Excision
biopsy may be done for correct identification of the tumor.
Keywords: eccrine carcinoma, brain parenchyma,
neurological symptoms, adnexal neoplasm
rapidly and reaching a size of several centimetres in
diameter.3 Due to the rare nature of this cancer, there is
a great paucity in experience and literatures related to
its treatment.4 This paper aims to discuss a case of eccrine
carcinoma presenting with neurological manifestations.
Objectives
The objectives of this paper are as follows: 1) to discuss
the history and the pertinent physical examination findings
in the patient presenting with tumor in an unlikely location;
2) to discuss the pathophysiology of an eccrine tumor and
the probable diferrential diagnosis, and; 3) to discuss the
diagnostics and treatment regimen that may be offered to
patients presenting with eccrine tumors.
C ase
V.E., a 69-year-old, female, married, Filipino, Roman
Catholic, born in Cavite and currently residing in Laguna.
She has been admitted several times due to generalized
body malaise accompanied by weakness, which then
Volume 55 Number 1 Jan - March., 2017
 Soldivillo, LM et al.
eventually led to generalized seizure, this was primarily due
to a recurring mass at the left fronto-parietal area of her
head with a 11-year history.
Clinical History
Patient presented with an 11-year history of a recurrent
mass initially a pea-sized located at the left fronto-parietal
area of her head, it was allegedly nonmovable, non painful,
well circumscribed there was no associated headache or
dizziness no consult done and no medications were taken.
On the same year the mass was noted to gradually enlarge
which was equated to the size of a “table tennis ball” Still
no consult nor were any medications taken.
Six years PTA, mass was noted to be the size of a small
“golf ball” which was then noted to have ulcerations and
occasional episodes of bleeding, but still non painful, non
movable, no medications were taken but approximately the
same year the mass was noted to have multiple ulcerations
with bleeding and purulent features which prompted consult
with a surgeon, Total excision and histopath was done and
revealed a (5.5x 3.0 cm) malignant adnexal tumor suggesting
a hidraadenoma, (A skin adnexal tumor subtype). The
patient was advised chemotherapy however patient did
not comply hence was lost to follow up.
Five years PTA, patient noted the recurrence of the
mass allegedly at the same area (left fronto-parietal) mass
was approximately the size again of a golf ball there was
no associated headache, dizziness, motor weakness nor any
slurring of speech, patient noted mass now not to increase
in size no consult done no medications taken.
Six months PTA, patient noted a minimal enlargement
of the said mass no associated headache nor dizziness was
noted no consult done.
Three months PTA, mass was noted to increase in
size with progression of neurologic deficits, a cranial MRI
with Gadolinium revealed a probable meningioma with
malignant features extracalvarial secondary to contiguous
spread. During the course of admission patient was noted
to have rapid progression of weakness both her lower
extremities until she lost motor control over both her lower
extremities this was associated with left grip weakness, and
when walking she was noted to drag her left foot hence
repeat Cranial MRI with MRA noted compressed entrapped
and depressed superior sagittal sinus by the axial mass
with calvarial penetration and scalp involvement. Medical
decompression with mannitol was given but the patient
noted more spasticity on the right extremities. Patient was
advised to be referred to a neurosurgeon and was scheduled
for a craniotomy, however, patient was noncompliant.
After three days of admission, since there was no resolution
in symptoms the family decided to be discharged against
2 Volume 55 Number 1 Jan - March., 2017
A Case of Eccrine Carcinoma Presenting with Neurological
medical advise. Patient was maintained on decilone
(Dexamethasone) 4.0 mg three times a day.
Two months PTA Patient decided to seek second opinion
at the Philippine General Hospital where patient was seen
by a neurosurgeon who decided to do an FNAB of the mass
which revealed a cell findings consistent with a low grade
malignancy. The histopathological report revealed that “An
eccrine carcinoma is highly considered”, patient was again
advised surgery however opted to defer and was lost to
follow up.
Two weeks PTA was noted to be wheelchair borne with
recurrence of left sided body weakness accompanied by
pain hence was given dexamethasone 5.0 mg/IV every six
hours, mannitol 50ml every four hours, Repeat imaging with
Cranial MRI with gadolinium, MRA of intracranial vessels
and MRV was done on the third day of admission which
showed heterogenous enhancing intracranial mass with
extracranial component or maybe the other way around.
The mass compresses on the underlying right high parietal
lobe with associated parenchymal edema. The mass is
also inseperable from superior sagital sinus. Patient noted
persistence of pain on the left extremity hence was referred
to surgery. However on preoperative evaluation patient was
stratified as high risk hence relatives opted not to proceed
with the surgical plan. Hence patient was advised home
transfer until she was more stable for the procedure.
One day PTA patient was noted to have an increase in
her sleeping pattern and with a flat affect, and was unable
to feed properly, but no consult was made. No medications
were taken. Few hours PTA patient was noted to have seizure
episodes hence was again admitted.
Past Medical History
Patient is a known hypertensive for more than 15 years
currently and is maintained on Carvedilol 6.25mg ½ tab
OD, for her Ischemic heart disease she takes trimetazidine
one tablet twice a day. She was also diagnosed with type
II diabetes mellitus and is maintained on insulin. The patient
has no other known co morbids of tuberculosis, asthma and
allergies.
Family Medical History
The patient’s maternal and paternal side has a history
of hypertension and a history of nasopharyngeal CA in her
paternal side. Other hereditary / familial diseases were
not noted, such as diabetes mellitus, cancer, allergies and
asthma. No one in the family has a history of any other
masses.
Patient was initially admitted for 14 days managed as
a case of seizure secondary to intra and extracranial mass
 A Case of Eccrine Carcinoma Presenting with Neurological Soldivillo, LM et al.

with concomitant pneumonia in the immunocompromised
host, ischemic heart disease. Initially was drowsy GCS 10 (E1
V3 M6) but with stable vital signs (BP:120/80 HR:105 RR:20
T: 36.7˚c and an O2 saturation of 97%) Initial medications of
diazepam for frank seizures, levetiracetam, mannitol 100cc
via IV dexamethasone, piperacillin-tazobactam, ipratropium
bromide, acetylcysteine was given for the concomitant
pneumonia.
when seen the plan was for the patient to undergo CT based
RT planning initially, followed series of radiation, patient and
her relatives were adamant regarding the procedure and
opted surgical options. However due to the intraparencymal
invasion of the tumor surgical options were unfavourable at
the time. Since some studies5,6 have not showed benefits in
chemotherapy and radiotherapy of eccrine tumors these
options were not advised.

Upon physical examination, the patient had senile skin The patients crainial MRI (Figure 1) showed heterogenous
turgor and conjunctivae was pale to pink. She had a nodular enhancing intracranial mass with extracranial component.
mass on right fronto-parietal area of scalp soft non-movable The mass compresses on the underlying right high parietal
5x4cm well circumscribed, with hypopigmented patches lobe with associated parenchymal edema. Mass is also
on face trunk and extremities. Both lower extremities were inseparable from superior saggital sinus.
noted to be atrophied indicative of patients’ inability to
ambulate. Cardiovascular findings showed an adynamic Repeat cranial MRI with MRA noted compressed
precordium normal heart rate regular rhythm. Chest and entrapped and depressed superior sagittal sinus by the axial
lung examination revealed symmetrical chest expansion mass with calvarial penetration and scalp involvement.
with intercostals retractions with decreased breath sounds
on the left lower lung field and fine crackles on both lung FNAB of the mass was done and revealed a low grade
fields and no wheezes were noted. Patients abdomen was malignancy, eccrine carcinoma is highly considered.
soft normoactive and nontender. Findings in the extremities
noted no limitation in range of motion patient had atrophy of
both lower extremities but pulses were full and equal. Patient
was drowsy but conversant however, with incomprehensible
speech. Cranial nerve examination showed no anosmia,
pupillary reflex was 2.00 mm EBRTL pupils, with intact direct
and consensual pupillary reflex on both eyes. Fundoscopy
was done and a clear media with an artreriovenous ratio
was noted,2;3 flat disc distinct disc boarders, no haemorrhages
and intact EOMs movements. Symmetrical facial movement
decreased, gross hearing, able to swallow, intact but weak
gag reflex, uvula was in midline patient, weak left shoulder
shrug and patient’s tongue is midline on protrusion with no
fasciculations, nor atrophy noted. Upon examination of the
Motor System patient had intact muscle tone on left upper Figure 1. Patient’s MRI showing heterogenous intracranial mass
and lower extremities, Upon gross motor examination patient
was noted to have 2/5 on left upper extremities 0/5 on left
lower extremities 5/5 on right upper extremities 5/5 on right
lower extremities . The left upper and lower extremities were
Spastic. Patient has no sensory deficits to pain, temperature,
position sense and vibration on all extremities. Patient was
hyperreflexive on the left extremities and normoreflexive in
right extremities. No neck rigidity was noted hence, patient
was initially placed on O2 inhalation via nasal cannula.
Nasogastric tube (NGT) was inserted, Initially treated as
seizure disorder secondary to malignant brain tumor and
pneumonia in the immunocompromised host.

Patient was also referred to an oncologist due to the

cranial mass. He then recommended either surgery or
radiation therapy. Option 1. Surgery involved significant
risk but without assurance of total resectability 2. Radiation
therapy was less invasive however no current therapeutic
claims may be benefited out of radiation for a mucinous Figure 2. HEENT: 5cm x 4cm x 3cm firm, non-mobile, well-
type of carcinoma. Patient was referred to radio oncologist circumscribed mass at right parietal area

Volume 55 Number 1 Jan - March., 2017 3

 Soldivillo, LM et al. A Case of Eccrine Carcinoma Presenting with Neurological

nodes, which may present as a solid, cystic, tubular mass.1

Electroencephalogram Findings:
1. Diffuse delta theta slowing of background activity
consistent with an encephalopathic process
2. Area of focal slowing over the right vertex and temporal
areas
3. Intermittent theta sharp potentials over the right temporal
area.
Upon microscopy Solid areas contain several kinds of cells:
pale (or sometimes clear) cells and dark (with eosinophilic
cytoplasm), sometimes squamoid and mucinous cells are
present as well.9 Cystic areas usually contain eosinophilic
amorphous material. The lining is flat. Tubules are lined by
cubic or cylindric epithelium. Mitotic activity is present even
in benign tumors, the diagnostic criteria of malignity are
cellular polymorphism and invasive growth. Which on biopsy

D iscussion was not evident in the patient discussed in this case report.
But its malignant counterpart however, the a Malignant
hidradenoma, which is a rare neoplasm which is slow-
Skin adnexal carcinomas are a spectrum of benign and
growing, painless papule or nodule on the head, neck, or
malignant tumors that exhibit morphological differentiation
extremities incidence between 50 and 70 years of age. The
towards different type of adnexal epithelium present
tumor may grow slowly for a long time but suddenly increase
in normal skin either the pilosebaceous unit, eccrine or
in size, thus prompting the patient to seek treatment lesions
apocrine. However what makes skin adnexal complicated
may be red and ulcerated, this tumor has the propensity to
is the fact that they may exhibit more than one type of
invade locally. 3 However this patient showed no ulceration
differentiation.7
nor any lesions and a biopsy done showed tissue consistent
with an eccrine carcinoma.10
Normal histology of skin appendages is that it comes from
the ectoderm at fourth week of development a single thick
The clinical scenario presents a 69-year old female who
ectoderm and underlying mesoderm begin to proliferate
came in with a chief complaint of left-sided body weakness.
and differ towards various structures including skin adnexal
She initially presented with an asymptomatic tumor on her
structures, thus, these specialized structure located within
scalp for approximately 11 years with no associated fever,
the dermis including the deep dermis and locally within the
but which was then accompanied by progressive left
subcutaneous fatty tussue represented by three histologically
wrist pain associated with generalized body malaise and
distinct structures the pilosebaceous unit, eccrine sweat
left sided body weakness. The tumor measured 5x4cm in
glands and apocrine glands vary to form one part of the
widest diameter, non-movable with a smooth contour, well
skin to another. The distribution and arrangement of these
circumscribed and with no ulcerations nor erythema was
appendages vary from one part of the skin to another, but
noted. This tumor was noted to extend intracranially which
the overall general basic morphogenesis is maintained.
then resulted to left-sided body weakness and seizure.

The initial differential diagnosis was a Chondroid

Eccrine carcinoma is a rare cutaneous lesion
syringoma, which is a mixed tumor of the skin uncommon
characterized a plaque like nodule located on the scalp
adnexal neoplasm abd behaves in a benign manner where
trunk or extremities which are slow growing.11 Eccrine type
the most common location is the head and neck regions, but
of carcinoma come from the genre of epithelial cyst which
malignant counterpart notes to be more common in the trunk
are common lesions formed by the down growth and cystic
and extremities. Diagnosis is based upon histopathological
expansion of the epidermis of the epithelium forming the
characteristics, this type of tumor which has a propensity
hair follicle. These cysts are filled with keratin and variable
for malignant differentiation but metastatic spread may be
amounts of admixed lipids lipid containing debris derived
via hematogenous or lymphatic routes. In our observation,
from sebaceous secretions. The eccrine unit is a type of
this was not consistent with what we saw in this patient and
differentiation of skin adnexal tumors, which are a part
histological findings were strong factors to rule out this type
of the the adnexal epithelium present in normal skin. The
of tumor.
other two types of differentiation in skin adnexal epithelium
which comes from the pilosebaceous unit and apocrine
The second differential is pilomatrical carcinoma which
unit. Clinically, they are subcutaneous well-circumscribed
is another adnexal tumor, a rare tumor with a predilection
firm and often movable nodules when large they may be
for the head and neck. Its age of incidence is bimodal,
dome shaped and flesh colored and become painful upon
but is noted to be more common in the first two decades
traumatic rupture Histologically epithelial cysts are divided
of life, prevalent among males. Other characteristics of
into several types according to the structural components
this tumor is that they generally appear as solitary tumors
of their walls. 1 When symptomatic, common findings include
however multiple or recurring tumors have been reported
numbness, tenderness, anesthesia, paresthesia of the
in association with myotonic dystrophy.8 Another differential
affected site which can relate to the frequent perineural
diagnosis was hidraadenoma which presents as a well
invasion of the tumor.9 This description is consistent of that
circumscribed tumor, consisting of one or more tumorous
of what we observed in this case discussion. A patient with a

4 Volume 55 Number 1 Jan - March., 2017

 A Case of Eccrine Carcinoma Presenting with Neurological
well circumscribed recurrent nodule dome shaped and flesh
colored tumor located at the left frontro parietal area of her
head, When biopsy of the tumor was done histopathological
findings showed clusters and sheets and dispersed round
to ovoid cells with prominent nucleoli with a consistent
with the cytopathological diagnosis of eccrine carcinoma.
The adnexal neoplasm has a wall nearly identical to the
epidermis and is filled with laminated strands of keratin the
pilar to tricilemmal cyst has a wall that resembles follicular
epithelium. The dermoid cyst is a similar to epidermal inclusion
cyst but it also shows multiple appendages budding outward
from its wall. Finally stetocystoma multiplex constitutes a
curious cyst with wall resembling the sebaceous cyst.1
There are literally hundreds of benign neoplasms
arising from adnexal structure. Although some show no
aggressive behavior and and remain localized they may be
confused with certain types of cutaneous cancers Certain
adnexal tumors are associated with Mendelian patterns
of inheritance and occur as multiple disfiguring lesions. 12
Eccrine and aporcine are often confused with metastatic
adenocarcinoma to the skin because of their tendency
for abortive gland formation.1 However, it is important that
eccrine carcinoma should be considered as a differential
diagnosis in patients older than fifty years old with long
standing tumors in the limbs and head. 13 Other subtypes
of eccrine carcinoma exists such as mucinous eccrine
carcinoma, eccrine porocarcinoma and MAC.14 Basically,
microscopy may be imperative in diagnosis however alone
it is insufficient to establish an eccrine lineage neoplasm
because there is no specific miscroscopic features. 13 Eccrine
gland carcinomas posses no distinctive clinical features
making diagnosis by gross appearance virtually impossible.
They usually manifest as non-tender, subcutaneous nodules,
primarily in elderly individuals as earlier mentioned. Individual
malignant cells are rich in glycogen and stain with PAS and
are diastase sensitive with prevalent nuclear changes and
propensity for lymphatic invasion. 15 Studies have suggested
the use of immunohistochemistry (p53) however it does
not distinguish cutaneous eccrine tumors form cutaneous
metastases hence clinical and radiologic correlation is
critical. 5
MAC (Microcystic Adnexal Carcinoma) is a locally
aggressive neoplasm, which is a subtype of an eccrine
carcinoma which occurs in middle aged to elderly patients.
Which, if we were to subclassify the type of eccrine
carcinoma it would be a good differential. It was first
described in 1882 by Goldstein et al. It is also synonymous
to malignant syringingoma, even an eccrine adnexal
tumor. MAC is generally slow growing a solitary nodule flesh
colored plaque or nodule with indistinct boarders Lesions
may be assymptomatic but if symptoms do occur they
may include numbness burning anesthesia or perinuclear
invasion.9 It is also said to be an aggressive locally destructive
cutaneous appendageal neoplasm with high rate of local
Soldivillo, LM et al.
recurrence.9 It occurs Predominantly in the white population
with predilections for the head and neck,15 But unlike the
other primary cutaneous malignancies MAC has a slight
female predominance.9 MAC is locally aggressive The rule
in criteria would be the solitary nodule which occurs in
middle aged to elderly patients with a predilection for the
head and neck consistent to this patient. MAC has a clear
prediection for the head and neck (86-88%) particularly the
central face (73%). Histologically MAC is a tumor of pilar and
eccrine differentiation.9 Hence in recent literature it has also
been synonymous with that of an eccrine carcinoma.10,16
The histological findings for MAC is nest and cords of small
bassaloid cells and scant keratin, the histological findings
of the patient discussed in this case showed clusters, sheets
and dispersed round to ovoid cells with prominent nucleoli
similar to an eccrine carcinoma/ MAC.11
The invasion of the tumor into the brain parenchyma
which was evident in the MRI showing that, the mass
compresses on the underlying right high parietal lobe with
associated parenchymal edema. The evident parenchymal
edema may explain or is the most likely reason for the
patients seizure, which may have resulted from abnormal
neuronal discharge. Lesions of the Parietal lobe may lead
to a variety of clinical phenomena such as a Corticosensory
syndrome and sensory extinction, Mild hemiparesis which
may be variable Homonymous hemianopsia or visual
inattention, Abolition of optokinetic nystagmus with target
moving toward the side of the lesion, Visuospatial disorders
topographic memory loss and confusion to name a few.15 In
this case the patient she noted progressive left sided body
weakness which eventually led to difficulty in ambulation,
Although no other parietal lobe deficit were noted in this
patient such as the homonymous hemianopsia MRI findings
proved that the neoplasm extended to the parietal lobe
where on repeat Cranial MRI with MRA noted compressed
entrapped and depressed superior sagittal sinus by the axial
mass with calvarial penetration and scalp involvement.
Treatment of eccrine carcinomas is difficult, not only due
to the paucity of data, but recent randomized controlled
trials are lacking to guide proper therapy. Management
currently involves excision with Mohs micrographic surgery
when feasible.9
R esults
Given the rarity of eccrine carcinoma and the variable
prognosis reported in the literature there has still yet to be
an apt protocol for management. However current data
suggests that surgery is the first choice for management
of such eccrine carcinoma but since this type of cancer
typically recurs there is a fair response to chemotherapy
and radiotherapy. 16 There also have been current data that
states that wide deep surgical excision of the tumor with fine
margins should offer a reasonable chance of a long term
Volume 55 Number 1 Jan - March., 2017 5
 Soldivillo, LM et al.
control of an eccrine Carcinoma. 17 Treatment modalities
used for MAC include Wide local Excision, Mohs micrographic
surgery, RT and chemotherapy, Current standard of care is to
surgically remove the tumor in its entirety whenever feasible.
This task can be challenging in clinical practice because the
tumor often extends microscopically centimeters beyond the
clinical apparent margins.9 Margins reported in the literature
for WLE vary from a few millimetres to 3.0-5.0 cm. Extirpation
of tumor by MMS (Mohs micrographic surgery) may prove
beneficial for the management of eccrine Carcinoma. 9
However there is still a high recurrence rate.8 Recurrence
rates vary significantly between the two surgical techniques
with rates after WLE and MMS ranging from 40% to 60%
and 0% to 12% respectively. 8 RT has been used as mono or
adjuvant therapy for eccrine carcinoma however in case
reports results weren’t favourable. 8,16,17 Bier- Laning et al.
Reported an unsuccessful trial of chemotherapy (Cisplatin
and 5FU) in the management of MAC, (a subtype of eccrine
carcinoma). 8 During an annual convention done in 2012
(Avraham et al.) discussed a report which studied the risk
factors and survival of patients with eccrine using a large
population-based database, to provide useful information
for the optimal management of this disease. The researchers
used data from the Surveillance, Epidemiology, and Ends
Results (SEER) 17-registry database, which houses relevant
data from about one quarter of the population in the United
States. The cohort consisted of 1,045 patients diagnosed with
eccrine carcinoma from 1973 to 2008. Carcinoma subtypes
were microcystic adnexal carcinoma (32%), general eccrine
adenocarcinoma (23%), hidradenocarcinoma (22%),
porocarcinoma (19%), and spiradenocarcinoma (4.0%).
The researchers analyzed patient demographics, histologic
subtype, use of adjuvant radiation, and the stage, size, and
location of tumors. Overall survival at a median follow-up
of 48 months was 78%. Age-adjusted survival, according
to 2000 census data, was 94%. In 92% of cases, patients
were treated with surgical resection, either alone (85%)
or in combination with radiation (7.0%). Five-year overall
survival rates were similar (78.0% and 75.7%, respectively),
and were not statistically significant. Although node-staging
data were available for only 10% of patients, node positivity
was significantly associated with decreased survival (P
= .02). Well- or moderately differentiated tumors were
associated with better five-year overall survival, compared
with high-grade disease (P = .005). No associations were
found between overall survival and ethnicity, tumor size,
or tumor location. Adjuvant radiotherapy has not been
found to be effective in controlling recurrent or metastatic
disease. The benefit of regional lymph node dissection is
uncertain.18 Hence to date management with regards to
eccrine Carcinoma is still conflicting.3,16,18,19
6 Volume 55 Number 1 Jan - March., 2017
A Case of Eccrine Carcinoma Presenting with Neurological
C onclusion
Cutaneous mucinous eccrine carcinoma is a tumor
characterized by histocytologic features and abundant
extracellular pools of mucin. Without a high index of
suspicion, this rare entity may be overlooked or misdiagnosed.
Numerous benign and malignant mucin-producing primary
and secondary tumors exist and immunohistochemistry
stains offer limited benefits in differentiating them.
Cytologic diagnosis of primary mucinous carcinoma of
the skin is possible; however, it would be best if there is
correlation of clinical, radiologic and pathologic features
which is necessary to arrive at an accurate diagnosis. The
correct identification of the origin of the tumor is of utmost
importance for appropriate therapy and prognosis. In this
patient given the histopathological findings and cranial
MRI and the behaviour of the tumor, we were convinced
that it was an Eccrine Carcinoma, Supposedly a Wide local
excision was deemed curative however it was not amenable
for the patient due to the extent of the tumor, and unstable
comorbid conditions (IHD, CAD and DM) there is still yet
data to be published to confirm the use of Radiotherapy
and Chemotherapy. Hence the imperative need to raise
awareness that this tumor exists. Patient succumbed to the
disease December 2015.
R eferences
1. Williams D., Janes T., Timothy J ET AL., Andrews Diseases of
the Skin 11th edition pp 348
2. Nidal A. Khaled O. Danny G: Skin adnexal neoplasms: an
approach to tumors of cutaneous sweat glands. J Clin Pathology
2007, 60 145-159
3. Society of Surgical Oncology (SSO) 65th Annual Cancer
Symposium: Abstract 7.
4. Vikiram D. Hink E. Kahook M.: Mucinous Eccrine
Adenocarcinoma of the periocular Region. 2006 vol 22 30-35
5. Wallace ML. Longace TA., Smoler BR., Estrogen and
Progesterone receptors and anti gross cystic disease Fluid protein
(BRCA 2) fail to distinguish metastatic Breast Carcinoma From
Eccrine Neoplasm 1995 897-901
6. Storm., Seykora et al. Summary of Cutaneous and Adnexal
Neoplasms, April 2002
7. Friedman PM., Friedman RH., Jiang SB. Et al., Microcystic
Adnexal Carcinoma Collaborative series and Update 1991 255-235
8. Allan H. Ropper., Martin A. Samuels Adams and Victors
Principles of Neurology 9th edition, 2009
9. De Vita, Hellman and Rosenberg. Cancer Principles of Oncology
9th edition, 2011
10. Klein W, Chan E, Seykora J T. Tumors of the epidermal
appendages. In: Elder DE, Editor‐in‐Chief. Lever’s histopathology
of the skin. 9th edn. Philadelphia, PA: Lippincott Williams &
Wilikins, 2005. 867–926.926
11. Jung, YH., Jo, HJ., Kang, MS. Squamoid Eccrine Ductal
Carcinoma of the Scalp. Korean J Pathol. 2012 Jun; 46(3): 278–281.
 A Case of Eccrine Carcinoma Presenting with Neurological Soldivillo, LM et al.

12. Braunwald, Fauci, Hauser, Jameson., Harrisons Principle of

Internal Medicine 18TH edition, 2012.
13. Timothy H. Calmont M. Batman and Adnexal Neoplasm 2010
37: 401-402
14. Chauhan A., Ganguly M., Takkar P. Dutta V. Primary
mucinous carcinoma of the eyelid: a rare clinical entity., Indian J.
Opthamology. Mar-Apr 2009;57
15. Snow S, Madjar DD, Hardy S, Bentz M, Lucarelli MJ, Bechard
R, Aughenbaugh W, McFadden T, Sharata H, Dudley C,
Landeck A. Microcystic adenexal carcinoma: report of 13 cases
and review of the literature. Dermatol Surg.2001;27:401–408. doi:
10.1046/j.1524-4725.2001.00208.x.
16. Sassmannshausen J., Charrish M. Pilomatrix Carcinoma: A
report of a case arising from a previous excised pilomatrixoma
and review of literature., Acad Dermatol 2001 44:358-361
17. Cincitamani, Sharma, Badran R., Shunghalu et al. Metastatic
Sweat gland Adenocarcinoma; A Clinicopathological Dilemna Apr
2007
18. Storm.,Seykora et al. Summary of Cutaneous and Adnexal
Neoplasms, April 2002
19. Vinod B. Richard A. Jinoby K. Androgen receptor expression in
Metastatic Adenocarcinoma in Females Digan Pathol 2006 1:34

Volume 55 Number 1 Jan - March., 2017 7

 Philippine Journal of Internal Medicine
Acute Renal Infarction Secondary to Membranous
Glomerulopathy
Frederick E. Ogbac, M.D.*; Kristine T. Gapuz, M.D.*; Cherisse Ann P. Panlilio, M.D.** and Alicia N. Baldonado, M.D.*
Abstract
Background: Acute renal infarction often presents with
abdominal pain, nausea, vomiting, and fever. With other
more common illnesses presenting with the same symptoms,
it is often misdiagnosed leading to delayed treatment.
We present a case of a young female diagnosed to have
Membranous Glomerulopathy who presented with sudden
onset flank pain in whom was initially treated as urinary
tract infection.
Case: A 19-year-old female diagnosed with membranous
glomerulopathy presented at the Emergency Room (ER) with
severe, right sided, flank pain of acute onset, associated
with nausea and vomiting. No fever, dysuria, hematuria, or
history of trauma. Her vital signs were within normal range.
Abdominal examination revealed a distended but soft
non-tender abdomen with positive shifting dullness and
fluid wave test. Right sided costovertebral angle tenderness
was elicited. Initial diagnostics showed leukocytosis with
neutrophilic predominance, serum creatinine of 0.77mg/
dL, and proteinuria of >600mg/dL. Abdominal ultrasound
showed non-specific findings, thus contrast-enhanced
computed tomography scan (CT-Scan) of the abdomen
was done which revealed areas of non-enhancement in
I ntroduction
Acute renal infarction occurs when blood flow stops
to a part of the kidney causing damage to the renal
parenchyma. It has an estimated incidence of 0.007% out of
the 250,000 patients and clinically diagnosed only in 0.014%
of patients in the ER.1,2 It commonly presents with abdominal
pain, nausea, vomiting, and fever. Since abdominal pain is
a common complaint at the ER and is associated with other
more common illnesses, it is often misdiagnosed leading to
delayed treatment. We present a case of a young female
diagnosed to have Membranous Glomerulopathy who
*
Section of Nephrology, Deparmtnent of Internal Medicine,
St. Luke’s Medical Center – Quezon City
**
Department of Internal Medicine, St. Luke’s Medical Center –
Quezon City
Corresponding Author: Frederick E. Ogbac, MD, St, Luke’s Medical
Center – Quezon City, Quezon City, Philippines
Email: frederickogbac@yahoo.com
The PHILIPPINE JOURNAL OF INTERNAL MEDICINE is a peer reviewed journal and a copyrighted publication of the Philippine College of Physicians
Case Report
the upper to middle portions of the right kidney which may
relate to areas of ischemia and/or infarction, likely due to
thrombosis involving the more distal portion of the right
renal artery and massive ascites. Result was confirmed by
computed tomography angiography (CTA) of the kidneys
showing right renal artery thrombosis. Evaluations for other
causes of renal artery thrombosis aside from patient’s
concurrent membranous glomerulopathy were done and
were negative. Anti-coagulation therapy was initiated using
low molecular weight heparin (LMWH) and was thereafter
maintained on warfarin.
Conclusion: A high index of clinical suspicion is needed
to diagnose acute renal infarction because of its non-
specific symptoms which can mimic other conditions. Early
diagnosis and prompt initiation of anti-coagulation therapy
is important to avoid irreversible kidney damage. Acute
renal infarction should be considered as a cause of acute
onset flank pain in patients with risk factors and normal initial
screening test.
Keywords: acute renal infarction, membranous
glomerulopathy, flank pain, case report
presented with sudden onset flank pain in whom a diagnosis
of acute renal infarction secondary to renal artery thrombosis
was confirmed after contrast enhanced CT-Scan of the
abdomen and CTA of the kidneys, respectively.
C ase
A 19-year-old woman was admitted at St Luke’s Medical
Center Quezon City due to sudden onset, right sided flank
pain accompanied by nausea and vomiting episodes. She
had no history of fever, dysuria, hematuria, constipation,
loose bowel movement, or trauma. She was recently
diagnosed to have membranous glomerulopathy stage II
and is maintained on steroid and diuretic therapy. No history
of surgery or allergies. Her last menstrual period was a week
prior to her admission. There was no family history of kidney
disease, connective tissue disease or vascular diseases. There
was neither any history of oral contraceptive use.
Volume 55 Number 1 Jan - March., 2017
 Ogbac FE, et al. Acute Renal Infarction Secondary to Membranous Glomerulopathy

In the emergency room, she was awake, not in distress,

with a blood pressure of 110/70 mmHg, heart rate of 82
beats/minute with regular rhythm, respiratory rate of 18
breaths/min, and afebrile. Physical examination findings
were unremarkable except for the abdominal examination
which revealed a distended abdomen with normoactive
bowel sounds, and soft to touch. Shifting dullness and fluid
wave test were positive. There were no scars, no tenderness
nor organomegaly. Right sided costovertebral angle
tenderness was elicited on percussion. Grade 1 pitting
bipedal edema was also noted.

Differential diagnosis during that time included

Figure 1: Contrast-enhanced whole abdomen CT-Scan showing filling defects
on the right kidney (white arrow)
infections like urinary tract infection or acute gastroenteritis,
and surgical abdomen like acute appendicitis and acute
cholecystitis. Initial diagnostic investigations showed
leukocytosis with neutrophilic predominance in complete
blood count, proteinuria with 2 RBC/hpf in urinalysis, and
normal serum creatinine (0.77 mg/dL), which were non-
specific. Thus, whole abdomen ultrasound was requested
and showed prominent gallbladder wall; perihepatic,
perisplenic and pelvic ascites; normal pancreas; and an
anteverted uterus. However, the right kidney appeared to
be isoechoic when compared to the liver parenchyma,
which was not present in the kidney ultrasound done 10 days
prior, raising the possibility of non-specific renal parenchymal
disease.

Figure 2: CT-angiography of the kidneys showing tubuar filling defects involving the right superior renal arteries (white arrow)

2 Volume 55 Number 1 Jan - March., 2017

 Acute Renal Infarction Secondary to Membranous Glomerulopathy
Due to persistence of right-sided flank pain despite
aggressive pain control and non-specific findings in the
whole abdomen ultrasound, further investigation for the
cause of flank pain was done. Contrast enhanced CT scan
of the whole abdomen showed cortico-medullary areas of
non-e
nhancement from a portion of the upper pole down to
the middle third of the right kidney. There was adequate
enhancement of the right renal artery from its take-off at
the aorta up to about 3.3 cm distally wherein a tubular
filling defect was noted into one of its branches, likely
containing thrombosis and massive ascites (Figure 1). This was
confirmed with a tubular filling defect relating to thrombosis
involving the right superior, anterior superior and anterior
inferior segmental renal arteries on computed tomography
angiography of the kidneys (Figure 2).
She was immediately started on anti-coagulation
therapy using low molecular weight heparin. With the
diagnosis of renal artery thrombosis, further evaluation for
the probable cause of hypercoagulability was requested.
Results showed elevated lactate dehydrogenase (2,508
U/L), normal bleeding parameters, decreased homocysteine
levels (3), decreased protein S (45%), elevated protein C
(176%), decreased anti-thrombin III (51%), negative LAC,
and hypoalbuminemia, which were inconclusive for specific
hypercoagulable disorders.
She was managed as a case of acute renal infarction
secondary to right renal artery thrombosis due to membranous
glomerulopathy stage II since other possible causes of
hypercoaguability were inconclusive. Patient underwent
pulse steroid therapy with methylprednisolone 1gm / day
for three days. During the course of her admission, she
developed vaginal bleeding and hematuria with presence
of fine and course casts on urinalysis. Anti-coagulation
therapy was temporarily stopped and was resumed at
a lower dose after the bleeding subsided. Warfarin was
overlapped with low molecular weight heparin and after
achieving an INR range of 2-3, LMWH was discontinued.
She was eventually discharged with warfarin and monitored
closely on an out-patient basis.
D iscussion
The patient was brought to the ER with severe right flank
pain with no fever or hematuria and inconclusive abdominal
examination findings. Abdominal pain is the most common
reason for consult at the ER with non-specific abdominal
pain as the main operative diagnosis. 3,4 This is despite
the presence technological advances in laboratory and
imaging.4
Acute renal infarction due to thromboembolic occlusion
of the renal artery was first reported by Traube in 1856
Ogbac FE, et al.
in Germany. 5 Renal infarction is rare. It has an estimated
incidence of 0.007% out of the 250,000 patients and is
clinically diagnosed only in 0.014% of patients in the ER.1,2 In
1940, a study showed that the incidence of renal infarction
was only 1.4% out of 14,411 autopsies. 10 The frequency of
renal infarction is probably higher since the clinical diagnosis
is frequently missed or delayed because the symptoms
mimic other common conditions like nephrolithiasis and
pyelonephritis.
Our patient is 19 years old, contrary to the mean age
of 53 years when acute renal infarct usually occurs.5,7,9 But
she presented the typical symptoms of acute renal infarct
like acute onset flank pain with nausea, vomiting, and fever.
Her abdominal findings were vague and non-specific. A
patient with acute renal infarct would reveal costovertebral
angle tenderness.6 Laboratories that could have support the
diagnosis include hematuria, leukocytosis, and elevated
lactate dehydrogenase (LDH).1 Our patient had leukocytosis
and elevated LDH.
The gold standard for diagnosing renal infarction is
revealing a non-opacified kidney of normal or increased size
with non-dilated pelvicalyceal system, cortical rim sign, and
a wedge-shaped area of non-enhancement in patients with
branch occlusion that can be seen in contrast-enhanced
CT scan.2 Our patient had these findings at her right kidney
concluding the diagnosis of acute renal infarct.
With no apparent risk factor for renal infarction,
nephrotic syndrome, which is present in our patient, is a
possible cause of renal infarction in our patient. In a case
series of renal infarction, nephrotic syndrome is present
in only one out of 94 patients diagnosed with nephrotic
syndrome.5 Patients with nephrotic syndrome have a higher
frequency of arterial thromboses compared to the general
population with an annual incidence of 5.5%.11-14 Among the
causes of nephrotic syndrome, membranous glomerulopathy
appears to have the highest risk of thrombosis, which is
present in our patient.11,15-18
With no apparent risk factor for renal infarction,
nephrotic syndrome, which is present in our patient, is a
possible cause of renal infarction in our patient. In a case
series of renal infarction, nephrotic syndrome is present
in only one out of 94 patients diagnosed with nephrotic
syndrome.5 Patients with nephrotic syndrome have a higher
frequency of arterial thromboses compared to the general
population with an annual incidence of 5.5%.11-14 Among the
causes of nephrotic syndrome, membranous glomerulopathy
appears to have the highest risk of thrombosis, which is
present in our patient.11,15-18
Treatment options include anticoagulation, thrombolysis
and embolectomy. Anticoagulation typically consists of
Volume 55 Number 1 Jan - March., 2017 3
 Ogbac FE, et al. Acute Renal Infarction Secondary to Membranous Glomerulopathy

giving low molecular weight Heparin followed by Warfarin 14. Singhal R, Brimble KS; Thromboembolic Complications in the
and low dose aspirin. Selective intra-arterial thrombolysis is Nephrotic Syndrome: Pathophysiology and Clinical Management.
considered for unilateral renal infarction.2 The prognosis of Throm Res, 118:397-407, 2006.
acute renal infarction is determined by the etiology and 15. Tarry WC, Moser AJ, Makhoul RG; Peripheral Arterial
the size of the infarct and the success of the intervention is Thrombosis in the Nephrotic Syndrome. Surgery, 114:618-623,
limited by the duration of the ischemia.2,5 1993.
16. Parag KB, Somers SR, Seedat YK, Byrne S, Da Cruz CM,
Kenoyer G; Arterial Thrombosis in the Nephrotic Syndrome. Am
C onclusion J Kidney Dis, 15:176-177, 1990.
17. Mahmoodi BK, ten Kate MK, Waanders F, et al; High Absolute
A high index of clinical suspicion is needed to diagnose
Risks and Predictors of Venous and Arterial Thromboembolic
acute renal infarction because of its non-specific symptoms,
Events in Patients with Nephrotic Syndrome: Results from a Large
which can mimic other conditions such as nephrolithiasis
Retrospective Cohort Study. Circulation, 117:224-230, 2008.
and pyelonephritis. Early diagnosis and prompt initiation of
18. Barbour SJ, Greenwald A, Djurdjev O, et al; Disease-Specific
anti-coagulation therapy is important to avoid irreversible
Risk of Venous Thromboembolic Events is Increased in Idiopathic
kidney damage. Acute renal infarction should be considered
Glomerulonephritis. Kidney Int, 81:190-195, 2012.
as a cause of acute onset flank pain in patients with risk
19. Lionaki S, Derebail VK, Hogan SL, et al; Venous Thromboembolism
factors and normal initial screening tests. This should be
in Patients with Membranous Nephropathy. Clin J Am Soc Nephrol,
an eye opener to physicians to think of other less common
7:43-51, 2012.
differentials for flank pain.
20. Llach F, Papper S, Massry SG; The Clinical Spectrum of Renal
Vein Thrombosis: Acute and Chronic. Am J Med, 69:819-827, 1980.
R eferences 21. Chugh KS, Malik N, Uberoi HS, et al; Renal Vein Thrombosis in
Nephrotic Syndrome – A Prospective Study and Review. Postgrad
1. Yuan K, Wei-Jing L, Ping-Jang K, Hung-Jung L; Renal Infarction Med J, 57:566-570, 1981.
with Right Lower Quadrant Pain: A Pitfall in the Emergency
Department. J Emerg Crit Care Med, 22:86-88, 2011.
2. Al-Dossary JA, Krishna V, Al-Hamar NE; Acute Flank Pain
due to Renal Infarction: Limitations of Unenhanced CT. Bahrain
Medical Bulletin, 35:163-165, 2013.
3. Macaluso CR, McNamara RM; Evaluation and Management of
Acute Abdominal Pain in the Emergency Department. Int J Gen
Med, 5:789-797, 2012.
4. Caporale N, Morselli-Labate AM, Nardi E; Acute Abdominal
Pain in the Emergency Department of a University Hospital in
Italy. United European Gastroenterol J, 4:297-304, 2016.
5. Fu ZF, Zhang ZG, Liu XM; A Rare Case of Acute Renal Infarction
due to Idiopathic Renal Arterial Thrombosis. Chin Med J (Engl),
121:185-187, 2008.
6. Baig A, Ciril E, Contreras G, Lenz O, Borra S; Acute Renal
Infarction: An Underdiagnosed Disorder. J Med Cases, 3:197-200,
2012.
7. Paris B, Bobrie G, Rossignol P, Le Coz S, Plouin PF; Blood
Pressure and Renal Outcomes in Patients with Kidney Infarction
and Hypertension. J Hypertens, 24:1649-1654, 2006.
8. Bourgault M, Grimbert P, Verret C, et al; Acute Renal Infarction:
A Case Series. Clin J Am Soc Nephrol, 8:392-398, 2013.
9. Domanovits H, Paulis M, Nikfardjam M, et al; Acute Renal
Infarction: Clinical Characteristics of 17 Patients. Medicine
(Baltimore), 78:386-394, 1999.
10. Hazanov N, Somin M, Attali M, et al; Acute Renal Embolism:
Forty-Four Cases of Renal Infarction in Patients with Atrial
Fibrillation. Medicine (Baltimore), 83:292-299, 2004.
11. Chu PL, Wei YF, Huang JW, Chen SI, Chu TS, Wu KD; Clinical
Characteristics of Patients with Segmental Renal Infarction.
Nephrology (Carlton), 11:336-340, 2006.
12. Antopolsky M, Simanovsky N, Stalnikowicz R, Salameh S, Hiller

4 Volume 55 Number 1 Jan - March., 2017

 Philippine Journal of Internal Medicine
Disease Characteristics of Filipino Ankylosing Spondylitis
Patients in Metro Manila Rheumatology Clinics
Ma. Lucila Dianongco, M.D.*; Marc Gregory Yu, M.D.** and Ester Penserga, M.D.*
Abstract
Objectives: The study aims to describe the disease
characteristics of Filipino patients diagnosed with ankylosing
spondylitis (AS) in different rheumatology clinics in Metro
Manila, Philippines.
Methods: The study retrospectively reviewed the records
of all Filipino AS patients aged 18 years old and above,
diagnosed by the Rome Criteria and seen from January 2000
to May 2012 at the rheumatology outpatient clinic of the
Philippine General Hospital and in different rheumatology
clinics in Metro Manila. Demographics, joint manifestations,
radiographic findings, and medications were described
and tabulated. Descriptive statistics included mean and
standard deviation for quantitative variables and frequency
and percentage for qualitative variables. .
Results: Forty-seven Filipino AS patients were included in the
study. The male to female ratio was 46:1. The mean age at
diagnosis was 33.2 +/- 10.93 years while the mean disease
duration was 7.04 +/- 4.28 years. Seven (14.8%) patients had
I ntroduction
Ankylosing spondylitis (AS) is a chronic autoimmune
spondyloarthropathy which may be associated with
systemic complications. 1 It has a predilection for the spine,
sacroiliac joints, and on occasion the big joints of the lower
extremities. Clinically, the disease manifests as chronic and
oftentimes debilitating joint and back pain with progressive
limitation of spinal mobility, leading to irreversible structural
changes and to impaired physical function and health-
related quality of life (HRQoL.) The global prevalence of AS
ranges from 0.1-1.4% with geographic, racial, and ethnic
differences.2 The onset is usually in young adulthood. Men
are preferentially affected and tend to have a more severe
disease course.3 HLA-B27 seropositivity, family history, and
frequent gastrointestinal infections also confer increased
risk for the disease.4
*
Section of Rheumatology, Department of Medicine, Philippine General
Hospital
**
Section of Endocrinology, Diabetes, and Metabolism Department of
Medicine, Philippine General Hospital
Corresponding Author: Marc Gregory Yu, M.D., Philippine General
Hospital, Manila, Philippines
Email: marcgreggy@yahoo.com
The PHILIPPINE JOURNAL OF INTERNAL MEDICINE is a peer reviewed journal and a copyrighted publication of the Philippine College of Physicians
Original Paper
a family history of AS while twelve (70.6%) tested positive for
HLA-B27. The lumbar spine was the most commonly affected
site in the majority (80.9%) of subjects. A significant number
of participants (70.2%) also had peripheral joint involvement,
with the knee being the most common peripheral joint
involved (72.7%). In terms of imaging, sacroiliitis was found
in the majority (87.5%) of patients. All patients received
standard rehabilitation exercises and almost all (97.9%) were
on NSAIDs. Nine (19.1%) patients each received opioids and
DMARD therapy, while eight (17%) received anti-TNF therapy.
Conclusion: Filipino patients with AS are mostly young males
presenting with chronic lumbar pain and HLA-B27 positivity.
The data gathered in this study may help local physicians
identify AS early in affected patients, giving them access
to early intervention and thereby preventing progressive
structural and functional deterioration.
Keywords: ankylosing spondylitis, rheumatology, Philippines
Published data on the prevalence of rheumatic diseases
in the Philippines previously did not detect AS in the general
population.5,6,7 However, an unpublished study by Ngo, JD
and Navarra, SV entitled “Demographic and clinical features
of ankylosing spondylitis among Filipinos”, presented thirty
Filipino AS patients in a single tertiary center and found
the mean age of the patients to be 29.73 years, with an
approximately five-year mean duration from symptom onset
to diagnosis. Most of the study subjects presented with low
back pain and stiffness (63%), while others manifested with
knee, shoulder, ankle (23%) and hip (13%) pain. Another
study on twenty-four Filipino AS patients found significant
correlations between the disease activity, functional
capacity, and HRQoL of these patients.8 As the course of AS
is generally persistent for several decades, rarely entering
long-term remission, patients with the disorder face a lifetime
of progressive structural deterioration and associated pain
and functional disability. 9 The relative lack of published
studies on AS in the Philippines reflects the low rate of early
identification and timely referral of these patients. Data
obtained from this study can serve to assist local physicians
in acquiring a high index of suspicion and identifying the
disease early in affected patients, allowing them access
Volume 55 Number 1 Jan - March., 2017
Yu, MG, et al. Disease Characteristics of Filipino Ankylosing Spondylitis Patients

to early intervention and thereby preventing progressive in the single patient who underwent magnetic resonance
structural and functional deterioration. imaging (MRI). Other notable radiographic manifestations
included squaring of lumbar vertebrae (16.7%), sclerosis
Objective
Table I. Demographic Characteristics (n=47).
The study aimed to describe the disease characteristics of
Filipino patients diagnosed with AS in different rheumatology
Characteristics Results
clinics in Metro Manila, Philippines.
Mean age at diagnosis 33.24 +/- 10.93
M ethods (year, SD)
Sex
All Filipino AS patients aged 18 years old and above, Male – number (%) 46 (97.9%)
Female – number (%) 1 (2.1%)
diagnosed by the Rome Criteria and seen from January
2000 to May 2012 at the rheumatology outpatient clinic Mean disease duration (year, SD) 7.04 +/- 4.28
of the Philippine General Hospital as well as in different
arthritis clinics in Metro Manila, were included. Those Mean BMI (kg/m2, SD) 23.98 +/- 4.01
currently or previously diagnosed with undifferentiated
spondyloarthritis, psoriatic arthritis, reactive arthritis, HLA-B27 positivity – number (%) 12/17
enteropathic spondyloarthritis, spondylosis, stiff man (70.6%)
syndrome, and movement disorders were excluded. A Positive family history – number (%) 7 (14.8%)
systematic and thorough search of outpatient logbooks,
censuses, and clinic files was performed for records of Mean erythrocyte sedimentation rate 37 +/- 12.49
(n=24; mm/h, SD)
eligible subjects, which were reviewed for demographic
characteristics, joint manifestations, radiographic findings,
and management plans. Descriptive statistics included
mean and standard deviation for quantitative variables and Table II. Joint Involvement (n=47).
frequency and percentage for qualitative variables.
Joint affected – number (%) Results

R esults Lumbar spine 38 (80.9%)

Forty-seven patients were included in the study, with a

Cervical spine 22 (46.8%)
male to female ratio of 46:1. The mean age at diagnosis was
33.2 +/- 10.93 years while the mean disease duration was 7.04
Peripheral joints 33 (70.2%)
+/- 4.28 years. Seven (14.8%) patients had at least one first-
degree family member with AS, and more than half (70.6%) Knees 24 (51.1%)
of those tested were HLA-B27 positive. The mean body mass
index (BMI) of the study subjects was 23.98 +/- 4.01 kg/m 2 Shoulders 12 (25.5%)
while the mean erythrocyte sedimentation rate (ESR) was
37 +/- 12.49 mm/h. The results of the patients’ demographic Hips 11 (23.4%)
characteristics are summarized in Table I.
Ankles 9 (19.1%)
In terms of joint involvement, the lumbar spine was
the most commonly affected site in the majority (80.9%) Wrists 5 (10.6%)
of subjects, while about half (46.8%) had cervical spine
involvement. A significant number of the participants (70.2%) Proximal interphalangeal joints 4 (4.3%)
also had peripheral joint involvement, the most common
of which are the knees (51.1%), shoulders (25.5%), and hips Positive Schober’s test – number (%) 32 (68.1%)
(23.4%.) Around two-thirds (68.1%) of the subjects tested
positive with the Schober’s test. Table II summarizes the
results of the different joint manifestations found in the study
patients.

Only about a third of the study subjects underwent

imaging. Of these, a significant majority (87.5%) manifested
with sacroiliitis on plain radiographs; this was found, too,

2 Volume 55 Number 1 Jan - March., 2017

Disease Characteristics of Filipino Ankylosing Spondylitis Patients Yu, MG, et al.

Table III. Radiographic Characteristics.

and erosions (11.1%), and the presence of syndesmophytes
and enthesophytes (5.6%). The various radiographic findings
found in the study subjects are summarized in Table III.
Radiographic Test Results

X-ray – number (%) The overall management of AS patients included

physical therapy and rehabilitation exercises (100%) and
Sacroiliitis 13/18 (87.5%) NSAIDs (97.9%). Nine (19.1%) patients received disease-
modifying anti-rheumatic drugs (DMARDs), with methotrexate
Squaring of lumbar vertebrae 3/18 (16.7%) being the most common DMARD administered (12.8%). Nine
patients also received opioids in the form of either tramadol
Sclerosis 2/18 (11.1%) (12.8%) or combination tramadol and paracetamol (6.4%).
Meanwhile, eight (17%) patients were started on anti-
Erosions 2/18 (11.1%)
tumor necrosis factor (TNF) alpha therapy – consisting of
Syndesmophytes 1/18 (5.6%) etanercept in seven (14.9%) patients and infliximab in one
patient. Table IV summarizes the pharmacologic and non-
Enthesophytes 1/18 (5.6%) pharmacologic treatment of these patients.

Magnetic Resonance Imaging – number (%)

D iscussion
Sacroiliitis 1/1 (100%)
Our study described the disease characteristics of
Filipino AS patients in different rheumatology clinics in the
country. The relatively low number of patients – 47 – seen
Table IV. Management (n=47). over a twelve-year period reflects either the generally
perceived low incidence of the disease in the country or
Management Results merely a low index of suspicion among local physicians
leading to under-diagnosis. The latter reason highlights the
Non-Pharmacologic – number (%) need for more studies to raise awareness regarding the
different presentations of AS in Filipinos.
Physical therapy and rehabilitation 47 (100%)
The overwhelming predominance of male patients in
Pharmacologic – number (%) the study is consistent with the observed higher prevalence
of AS in men.3 The mean age at diagnosis, however, was
NSAIDs 46 (97.9%) slightly higher than that cited in foreign literature and can be
explained by several reasons. 4 First, a possible delay in the
DMARDs 9 (19.1%) time to diagnosis can be due to the difficulty in diagnosing
AS in its early stages, particularly when the index of suspicion
Methotrexate 6 (12.8%)
is low and also when the presenting symptoms suggest
an alternative form of arthritis. 10 Second, patients in the
Sulfasalazine 3 (6.4%)
Philippines are likely to consult traditional healers and similar
Anti-TNF therapy 8 (17%) alternative forms of medicine for musculoskeletal complaints
prior to seeking medical advice, stressing the importance
Etanercept 7 (14.9%) of greater public awareness and patient education in
improving prompt diagnosis.11
Infliximab 1 (2.1%)
The presence of family history and a positive HLA-B27 in
Tramadol 6 (12.8%) the majority of participants confirms the established role of
genetics in disease development. In particular, the HLA-B27
Combination tramadol and paracetamol 3 (6.4%)
subtypes that might possibly predominate in the Philippines
include B2705 and B2706, which are both linked to endemic
Baclofen 1 (2.1%)
bacterial pathogens such as Salmonella, Shigella, and
Cyclophosphamide 1 (2.1%) Chlamydia and may, therefore relate to the high prevalence
of infectious diseases in the country.12

The lumbar spine was revealed to be the most common

joint affected. This correlates with the positive Schober’s test

Volume 55 Number 1 Jan - March., 2017 3

 Yu, MG, et al.
found in most participants and is consistent with the typical
disease presentation of chronic low back pain.13 The high
incidence (70.2%) of peripheral joint involvement is consistent
as well with findings in Singaporean-Chinese patients and
may suggest the fact that Asians as a whole seem to have
a higher incidence of peripheral arthritis as compared to
their Caucasian counterparts.1,11 The high mean BMI of the
study subjects may have contributed to the development
of knee arthritis, for which obesity is already an established
risk factor.14 Conversely, a high mean BMI can likewise be
explained by the physically incapacitating nature of the
disease, thus hindering patients from performing necessary
physical exercises.
The fact that only a third of AS patients had some
form of radiologic evaluation reflects the current lack of
access to proper medical facilities in the country. In those
who underwent imaging studies, sacroiliitis was the most
common finding. It is a well-known hallmark of the disease
and is usually the first radiologic manifestation, being
characteristically bilateral and symmetrical in AS. 15 Plain
radiographs, however, may appear normal early in the
disease; hence, MRI is an ideal tool as it has better sensitivity
for detecting sacroiliitis.16
In terms of management, it is worthwhile to note that
all patients were on some form of physical therapy and
rehabilitation, a key element in the overall approach to AS
patients. Almost all patients, too, were on NSAIDs, which have
been shown in trials to improve spinal and peripheral joint
pain and function in AS. 17 Although there is little evidence
to support the use of DMARDs in AS, the use of TNF inhibitor
therapy has revolutionized the treatment of the disease.18
Studies have shown rapid and substantial clinical effects
from the use of these drugs, including marked persistent
reduction of spinal inflammation and higher remission rates. 19
However, these drugs are also prohibitively costly, and in a
resource-limited setting like the Philippines, these may not
be easily accessible for indigent patients afflicted with the
disease.
C onclusion
The typical presentation of AS in Filipinos is that of
a young male presenting with chronic lumbar pain and
HLA-B27 positivity. The data gathered in this study may help
local physicians identify AS early in affected patients, giving
them access to early intervention and thereby preventing
progressive structural and functional deterioration. More
studies on this disease are recommended in the Philippine
population.
4 Volume 55 Number 1 Jan - March., 2017
Disease Characteristics of Filipino Ankylosing Spondylitis Patients
Ethical Considerations
The study was conducted in accordance with the
principles of the Declaration of Helsinki regarding biomedical
research. The study protocol was approved by both the
technical and ethics review board of the institution prior
to actual field work. We declare no conflicts of interest.
No financial compensation of any kind was involved in the
conduct of this study.
Acknowledgments
UP-PGH Section of Rheumatology and other participating
Institutions: Asian Hospital, East Avenue Medical Center,
Makati Medical Center, Manila Doctors Hospital, Rayuma
at Iba Pa Klinik, St. Luke’s Medical Center Quezon City, San
Juan de Dios Hospital, UP-PGH Medical Center.
R eferences
1. Carbone, LD; Cooper, C; Michet, CJ; Atkinson, EJ; O’Fallon,
WM; Melton, LJ. Ankylosing spondylitis in Rochester, Minnesota:
1935-1989. Is the epidemiology changing? Arthritis Rheum,
35:1476-82, 1992.
2. Akkoc, N. Are spondyloarthropathies as common as rheumatoid
arthritis worldwide? Curr Rheumatol Rep,10:371-8, 2008.
3. Jimenez-Balderas, FJ and Mintz, G. Ankylosing spondylitis in women
and men. J Rheumatol, 20:2069-72, 1993.
4. Brophy, S and Calin, A. Ankylosing spondylitis: interaction between
genes, joints, age of onset, and disease expression. J Rheumatol,
28:2283-8, 2001.
5. Dans, LF; Tankeh-Torres, S; Amante, CM; Penserga, EG. The
prevalence of rheumatic diseases in a Filipino urban population: a
WHO-ILAR COPCORD study. J Rheum, 24:1814-9, 1997.
6. Wigley, R; Manahan, L; Muirden, KD; Caragay, R; Pinfold,
B; Couchman, KG. Rheumatic disease in a Philippine village:
a WHO-ILAR-APLAR COPCORD study Phases II and III.
Rheumatol Int, 11:157-61, 1991.
7. Manahan, L; Caragay, R; Muirden, KD; Allander, E; Valkenburg,
HA; Wigley, RD. Rheumatic pain in a Philippine village. A WHO-
ILAR COPCORD study. Rheumatol Int, 5:149-53, 1985.
8. Yu, MG, Mangubat, JH and Penserga, EG. Correlation between
disease activity, functional capacity, and health-related quality of
life among Filipino patients with ankylosing spondylitis. Phil J Int
Med, 52(1):100-6, 2014.
9. Khan, MA. Ankylosing spondylitis: introductory comments on its
diagnosis and treatment. Ann Rheum Dis, 61(Suppl III):iii3-iii7,
2002.
10. Braunstein, EM, Martel, W and Moidel, R. Ankylosing spondylitis
in men and women: clinical and radiographic comparison.
Radiology, 144:91-4, 1982.
11. Koh, WH, Howe, HS and Boey, ML. Ankylosing spondylitis in
Singaporean Chinese: a clinical profile. Sing Med J, 34:518-20,
1993.
12. Howe, HS. HLA and non-HLA genes in ankylosing spondylitis
 Disease Characteristics of Filipino Ankylosing Spondylitis Yu, MG, et al.

and seronegative spondyloarthropathies in Asia. Curr Rheum Rev,

4:95-8, 2008.
13. Khan, MA. Update on spondyloarthropathies. Ann Intern Med,
18:896-907, 2002.
14. Sowers, MF and Karvonen-Gutierrez, CA. The evolving role of
obesity in knee osteoarthritis. Curr Opin Rheumatol, 22(5):533-
37, 2010.
15. Berens, DL. Roentgen features of ankylosing spondylitis. Clin
Orthop Relat Res, 74:20-33, 1971.
16. Yu, W; Feng, F; Dion, E; Yang, H; Jiang, M; Genant, HK.
Comparison of radiography, computed tomography and magnetic
resonance imaging in the detection of sacroiliitis accompanying
ankylosing spondylitis. Skeletal Radiol, 27:311-20, 1998.
17. Zochling, J; van der Heijde, D; Dougados, M; Braun, J.
Current evidence for the management of ankylosing spondylitis:
a systematic literature review for the ASAS/EULAR management
recommendations in ankylosing spondylitis. Ann Rheum Dis,
65:423-32, 2006.
18. Akkoc, N, van der Linden, S and Khan, MA. Ankylosing
spondylitis and symptom-modifying vs disease-modifying therapy.
Clin Rheumatol, 20(3):539-57, 2006.
19. Baraliakos, X; Brandt, J; Listing, J; Haibel, H; Sorensen,
H; Rudwaleit, M. Outcome of patients with active ankylosing
spondylitis after two years of therapy with etanercept: clinical
and magnetic resonance imaging data. Arthritis Rheum, 53:856-
63, 2005.

Volume 55 Number 1 Jan - March., 2017 5

 Philippine Journal of Internal Medicine
Efficacy and Safety of Subcutaneous Insulin Analogue Versus
Intravenous Insulin Infusion Among Patients with Mild to
Moderate Diabetic Ketoacidosis at the University of Santo
Tomas Hospital
Charlene Ann V. Balili, M.D.* and Maria Honolina S. Gomez, M.D.**
Abstract
Introduction: Diabetic ketoacidosis (DKA) remains a
significant complication of diabetes in the world and is
associated with high rates of hospital admissions. In mild,
uncomplicated cases of DKA a subcutaneous regimen of
newer rapid-acting insulin analogues has been proposed
as a safe and effective alternative to intravenous regular
insulin in prospective, randomized trials. Our primary
objective is to compare the efficacy and safety of
intermittent subcutaneous (SC) rapid insulin administration
with continuous intravenous (IV) regular insulin infusion in
the treatment of mild to moderate DKA.
Methodology: A retrospective chart review of all adult
Filipino patients admitted for mild to moderate DKA at UST
Hospital private and clinical divisions from 2012 – 2015 was
done. Chart cases were divided into two groups, namely:
group one who received IV infusion of regular insulin
and group two who received SC rapid insulin analog as
treatment. The clinical and biochemical characteristics
of the patients on admission were obtained. Efficacy and
safety of both treatment regimens were compared as to the
duration of time and amount of insulin administered from
I ntroduction
Diabetic ketoacidosis (DKA) remains a significant
complication of diabetes in the world and is associated
with high rates of hospital admissions. 1 At our institution,
six to twelve cases of DKA were admitted yearly for the
past four years. Thus, it is important for us physicians to be
able to manage this crisis. Though management of DKA
has followed a set of algorithm for many years, we now
have new alternatives on the horizon such as subcutaneous
insulin analogues for mild to moderate cases of DKA. 1
*
Section of Endocrinology, Diabetes and Metabolism of the Department
of Medicine, University of Santo Tomas Hospital, Manila, Philippines
**
Head, Research Committee, Section of Endocrinology, Diabetes
and Metabolism of the Department of Medicine, University of Santo Tomas
Hospital, Manila, Philippines
Corresponding Author: Charlene Ann V. Balili, M.D., University of Santo
Tomas Hospital, Manila, Philippines
Email address: drcharleneannbalili@gmail.com
The PHILIPPINE JOURNAL OF INTERNAL MEDICINE is a peer reviewed journal and a copyrighted publication of the Philippine College of Physicians
Original Paper
admission until resolution of DKA was achieved, occurrence
of hypoglycemia and hypokalemia, mortality and length of
hospitalization.
Results: Twenty-one chart cases were included, twelve
in the continuous IV insulin infusion group and nine in
the intermittent SC rapid insulin group. The baseline
characteristics of patients were almost similar. There was
no significant difference between the treatment groups in
the duration of time and amount of insulin administered to
achieve DKA resolution, occurrence of hypoglycemia, and
death. Hypokalemia occurred more frequently and hospital
stay was longer in the IV insulin group.
Conclusion: Intermittent subcutaneous rapid insulin regimen
is an effective, safe, and potentially cost-effective alternative
to continuous intravenous insulin infusion for treatment of mild
to moderate cases of DKA.
Keywords: Diabetic ketoacidosis, rapid insulin analogue,
regular insulin infusion, efficacy and safety
Rapid insulin analogues have been available for clinical
use over the last two decades and have proven to be
beneficial in reducing the incidence of hypoglycemia while
providing better control of post-prandial hyperglycemia
with less weight gain and offering a possible little better
overall glycemic control in terms of HbA1c reduction. 1
DKA, resulting from absolute insulin deficiency and
counter-regulatory hormone excess, can potentially lead
to increased morbidity and fatal complications. 2 The
increased morbidity and death among patients with DKA,
in turn, are most often due to poor hospital care and the
severity of the underlying factor which precipitated DKA. 2
The mainstay of treatment includes hydration to restore
adequate circulating volume, correction of electrolyte
deficits, insulin administration to reverse ketosis and
promote gradual reduction in blood sugar levels and
identification of precipitating events. 1 Implementation of
effective standardized treatment protocols and timely
identification and treatment of precipitating causes and
co-morbidities are important factors affecting outcome.
Experts have recommended intravenous insulin infusion as
Volume 55 Number 1 Jan - March., 2017
 Balili CAV, et al.
the treatment of choice in the intensive care setting,
as it is a predictable means of administration allowing for
maximal peak insulin within the first hour of treatment.1
Continuous intravenous insulin infusion with hourly blood
sugar monitoring can become more costly compared
to a regimen of subcutaneous rapid insulin analogue
administered every two hours with two-hourly blood sugar
monitoring. Refusal of the patient to be admitted into the
intensive care unit of the hospital can become a limiting
factor in administering continuous intravenous insulin
infusion. One major barrier is inadequacy of nursing staff
on general ward floors to implement the strict monitoring
protocol. In mild cases of DKA, a subcutaneous regimen of
newer rapid-acting insulin analogues (aspart, lispro, glulisine)
has been proposed as a safe and effective alternative
to the use of intravenous regular insulin in prospective,
randomized trials. 2,3,4,5,6 In the Philippines, a developing
country where health insurance coverage is limited and
where patients would have to shoulder almost all medical
expenses, use of a less expensive treatment that would still
offer quality medical care would be of great benefit to our
diabetic patients. Treatment of mild to moderate DKA using
a regimen of subcutaneous rapid-acting insulin analogue
with a loading dose of 0.3 units/kg body weight followed by
0.1 unit/kg/hour or 0.2 units/kg every two hours until blood
glucose level reached 200 to 250 mg/dL could be more
cost-effective than continuous intravenous insulin infusion
in patients without major co-morbidities.3 There has been
no recently published study in the Philippines comparing
treatment outcomes of patients with mild to moderate
DKA treated with continuous intravenous insulin infusion
versus intermittent subcutaneous rapid insulin analogue.
Therefore, the primary objective of this study is to compare
the efficacy and safety of intermittent subcutaneous
rapid insulin regimen with continuous intravenous insulin
infusion in the treatment of mild to moderate DKA as to
the length of time and amount of insulin administered to
achieve resolution of DKA, occurrence of hypoglycemia
and hypokalemia, length of hospital stay, and mortality.
Secondary objectives are to describe the baseline clinical
and biochemical characteristics of patients admitted for
mild to moderate DKA and to estimate costs of treatment
for twenty-four hours at the private and clinical divisions
of UST Hospital using both insulin regimen. Clinical and
biochemical profile include the age on admission, gender,
precipitating factors, co-morbidities, initial blood glucose,
arterial blood pH, bicarbonate and serum potassium levels.
M ethods
Study Design and Population
Approval of the UST Hospital institutional review board
was secured prior to commencement of the study. Review
of in-patient hospital records of all adult Filipino patients
with admitting diagnosis of diabetic ketoacidosis at the
2 Volume 55 Number 1 Jan - March., 2017
Efficacy and Safety of Subcutaneous Insulin Analogue Versus Intravenous Insulin
UST Hospital Private and Clinical Divisions from January
2012 up to December 2015 was done. Chart cases which
fulfilled the criteria for mild to moderate DKA and given
either continuous intravenous regular insulin infusion or
intermittent (one to two hourly) subcutaneous rapid-acting
insulin analogue were screened further. Diagnostic criteria
for mild DKA1 are blood glucose elevation of > 250 mg/
dL, arterial pH of 7.25 to 7.30, serum bicarbonate of 15
to 18 meq/L, anion gap of >10, positive blood and/or
urine ketones and an alert mental state. Moderate DKA,1
meanwhile, is defined by blood glucose of > 250 mg/dL,
positive blood and/or urine ketones, arterial pH of 7.0 to
7.24, serum bicarbonate of 10 to < 15 meq/L, anion gap of
> 12, and drowsiness. Chart cases classified under severe
DKA, characterized by a blood glucose of > 250 mg/dL,
arterial pH of < 7.00, serum bicarbonate of < 10 meq/L,
anion gap of > 12 with stupor or coma, and those with
severe, persistent hypotension defined as systolic blood
pressure of less than 90 mmHg requiring vasopressor, acute
and chronic decompensated liver disease with serum
transaminase levels more than three times the upper limit
of normal range, chronic kidney disease with estimated
creatinine clearance of less than 15 cc/min using the
Cockroft-Gault formula, decompensated heart failure,
dementia, coma, steroid use, pregnant at the time of
admission, and initially treated using combined intravenous
and subcutaneous insulin were excluded. Chart cases
were classified into two groups. The first group consisted
of subjects who were given continuous intravenous
insulin infusion while the second group consisted of those
who were given intermittent subcutaneous rapid insulin
analogue. To assess the response to therapy in both groups,
the following data were gathered from in-patient hospital
records: length of time and amount of insulin administered
from admission until resolution of DKA was achieved as
defined by blood glucose of less than 200 mg/dL plus two
of the following: arterial pH of >7.3, plasma bicarbonate
level of >15 meq/L, and calculated anion gap of <12
meq/L,1 occurrence of hypoglycemia defined as capillary
blood or plasma glucose level of <70 mg/dL, occurrence
of hypokalemia with serum potassium level of <3.5 meq/L,
length of hospital stay and mortality. The clinical and
biochemical characteristics of patients on admission were
likewise recorded such as age, gender, diabetes duration,
precipitating factors, co-morbid conditions, blood glucose,
serum potassium, arterial pH, and bicarbonate levels.
Statistical analysis
The age on admission, initial blood glucose, serum
potassium, arterial pH, and plasma bicarbonate levels,
total amount of insulin administered and length of time
to achieve DKA resolution are expressed as mean and
standard deviation in continuous variables. Diabetes
duration and length of hospitalization are reported in
median and range while gender, precipitating factors,
 Efficacy and Safety of Subcutaneous Insulin Analogue Versus Intravenous Insulin Balili CAV, et al.

co-morbid conditions, hypoglycemia, hypokalemia, and pH of 7.250 + 2.19 vs. 7.230 + 0.07, plasma bicarbonate of
mortality are reported in frequency and percentage. Chi- 13.58 + 2.63 vs. 15.00 + 3.35 meq/L, and potassium of 4.59 +
square analysis was used for comparison of categorical 0.85 vs. 4.06 + 0.56 meq/L, for the IV and SC insulin groups,
variables and Mann-Whitney U Test for numerical respectively.
(continuous) variables. A total sample size of 20 patients
was needed, ideally 10 in each group, to achieve a power Table I. Clinical profile of patients on admission
0.80 given an α error of 0.05, computed using the G*Power
Software. IV insulin SC insulin
infusion group analogue group
N=12 N=9
R esults
Age (years)* 58.00 ± 12.31 50.33 ± 19.08
A total of thirty charts with admitting diagnosis of DKA
Sex*
were retrieved from the medical records of our institution Male 4 (33) 7 (78)
from January 2012 up to December 2015. Of these, nine Female 8 (67) 2 (22)
charts were excluded from the study: three charts with
severe DKA, two with incomplete data, two with initial
Diabetes duration (years)* 6 (0-22) 5 (0-15)
treatment using combined subcutaneous and intravenous
insulin, one with end-stage renal disease, and another one Co-morbidities*
with concomitant steroid use. Coronary artery disease 4 (33) 1 (11)
Hypertension 8 (67) 3 (33)
Twenty-one chart cases fulfilled the inclusion and Obesity 2 (17) 2 (22)
exclusion criteria, of which, nine received subcutaneous Others 2 (17) 0 (0)
rapid insulin analogue every two hours and twelve
received continuous intravenous insulin infusion until the Precipitating factors*
DKA resolved. Infection 8 (67) 8 (89)
Missed insulin 2 (17) 0 (0)
New-onset diabetes 5 (42) 1 (11)
The age on admission, diabetes duration, co-morbid
conditions and precipitating causes of DKA did not differ * Data are expressed as mean or median ± standard deviation or frequency (%)
significantly between the two treatment groups (Table or range (years)

I). Age on admission was 58.00 ± 12.31 years in the

intravenous infusion group and 50.33 ± 19.08 years in the
subcutaneous insulin group. Majority of patients were male. Table II. Biochemical profile of patients on admission
In the intravenous insulin infusion group, nine (75%) had
IV insulin SC insulin P-value+
associated co-morbidities, of which hypertension (67%) was infusion analogue
most common followed by coronary artery disease (33%), group group
obesity (17%), urolithiasis (1.0%), and polycystic ovarian N=12 N=9
syndrome (1.0%). Five (42%) had newly diagnosed diabetes
mellitus. Five (56%) in the subcutaneous rapid insulin group Blood glucose level
451.55 + 75.61 390.57 + 93.54 0.171
(mg/dL)*
had associated co-morbidities with hypertension being
the most common (33%) followed by obesity (22%) and
coronary artery disease (11%). Only one (11%) had newly-
Arterial pH
diagnosed diabetes. The most common precipitating cause 7.250 + 2.19 7.230 + 0.07 0.642
(units)*
of DKA was infection, which was recorded in eight patients
for both groups (67% and 89% for IV insulin infusion group
Arterial plasma
and SC rapid insulin group, respectively). Urinary tract
bicarbonate level 13.58 + 2.63 15.00 + 3.35 0.399
infection and pneumonia were most common followed (meq/L)*
by skin, soft tissue (cellulitis/diabetic foot/abscess), and
intra-abdominal (acute cholecystitis) infection. Another
Serum potassium
precipitating cause of DKA was omission of insulin 4.59 + 0.85 4.06 + 0.56 0.126
level (meq/L)*
treatment. Others presented with DKA as the initial
manifestation of their diabetes. * Data are expressed as mean ± standard deviation
+ Significant difference if P value is <0.05
The biochemical characteristics of patients on admission
were almost similar, satisfying the criteria for mild to
moderate DKA (Table II). Mean blood glucose was 451.55 +
75.61 vs. 390.57 + 93.54 mg/dL (P-value 0.171), with arterial

Volume 55 Number 1 Jan - March., 2017 3

 Balili CAV, et al. Efficacy and Safety of Subcutaneous Insulin Analogue Versus Intravenous Insulin

There was no significant statistical difference between IV Ersoz HO et al5 did a similar prospective, randomized,
and SC rapid insulin in the length of time and in the amount open trial in a Turkish population comparing hourly
of insulin administered to achieve resolution of DKA as shown subcutaneous lispro with intravenous insulin infusion for
in Table III. DKA resolved within 44 hours in both groups with mild to moderate DKA. Similar to the first two studies, the
mean duration of 26 hours for the IV insulin group and 24 duration of time from the onset of DKA until normoglycemia
hours for the SC insulin group. Total insulin given was 89.08 was achieved did not differ significantly between the
units ± 25.99 (1.49 ± 0.57 units/kg body weight) for the IV subcutaneous and intravenous insulin group.
insulin group and 85.13 ± 28.37 units (1.19 ± 0.66 units/kg body
weight) for the SC insulin group. Length of hospital stay was Lastly, an Indian study by Prasad A. and Gupta A,6 which
significantly shorter by a mean of six days for those on the compared the efficacy and safety of intermittent (hourly
SC insulin group compared to those on the IV insulin group. and two-hourly) subcutaneous aspart and continuous
intravenous regular insulin among patients with mild to
The occurrence of hypoglycemia during insulin therapy moderate DKA, showed no significant statistical difference
was similar between the two groups (Table IV). Two patients among the three groups in the mean duration of time to
(17%) in the IV insulin group and one patient (11%) in the SC achieve resolution of ketoacidosis, length of hospital stay,
insulin group developed hypoglycemia. The lowest blood occurrence of hypoglycemic episodes, and mortality.
sugar level recorded was 62 mg/dL and none required the
assistance of a medical personnel to administer glucose. Table III. Comparison of efficacy of IV and SC insulin
Hypokalemia occurred more frequently in the IV insulin group
in mild to moderate DKA
compared with the SC insulin group and this difference was
statistically significant. None developed arrhythmia during IV insulin SC insulin P-value+
the course of therapy. infusion analogue
group group
N=12 N=9
One patient died in the SC insulin group due to septic
Time from
shock secondary to a hospital-acquired infection which he admission until
developed several days after resolution of the ketoacidosis 25.67 ± 8.56 24.11± 7.70 0.668
resolution of DKA
and hyperglycemia. No mortality was reported in the IV (hours)*
insulin group. Amount of insulin
administered from
The estimated cost of therapy for 24 hours at the admission until 89.08 ± 25.99 85.13 ± 28.37 0.757
private and clinical division of UST hospital showed higher resolution of DKA
(units)*
cost with IV regular insulin infusion compared to SC rapid
insulin analogue regimen (Table V and Table VI). Amount of insulin
administered from
admission until 1.49 + 0.57 1.19 + 0.66 0.320
D iscussion resolution of DKA
(units/kg BW)*

Our study showed that intermittent subcutaneous rapid Length of hospital

11.42 (4-28) 5.22 (3-11) 0.027
stay (days)*
insulin regimen is equally effective, safe, and potentially
cost-effective alternative to continuous intravenous insulin * Data are expressed as mean or median ± standard deviation range(days)
+ Significant difference if P value is <0.05
infusion for treatment of mild to moderate cases of DKA.

Table IV. Comparison of safety of IV and SC insulin

Several studies done internationally compared the
efficacy and safety of intermittent administration of in mild to moderate DKA
subcutaneous rapid insulin analogue with continuous
IV insulin SC insulin P-value+
intravenous insulin infusion in the treatment of mild to infusion group analogue group
moderate DKA. Similarly, both studies of Umpierrez GE et N=12 N=9
al, 2,4 which compared intermittent subcutaneous aspart or
Occurrence of
lispro with intravenous regular insulin infusion, did not show 2 (17) 1 (11) 0.719
hypoglycemia*
significant statistical difference between the treatment
groups in the length of time and in the amount of insulin Occurrence of
6 (50) 1 (11) 0.072
administered until the ketoacidosis resolved as well as in hypokalemia*
the occurrence of hypoglycemia, and death. Furthermore, Number of deaths* 0 (0) 1 (11) 0.231
there was a significant decrease in medical care costs in
* Data are expressed in frequency (%)
the subcutaneous insulin group. + Significant difference if P value is <0.05

4 Volume 55 Number 1 Jan - March., 2017

 Efficacy and Safety of Subcutaneous Insulin Analogue Versus Intravenous Insulin Balili CAV, et al.

Table V. Estimated cost of therapy (in peso) of mild to moderate DKA for 24 hours with continuous IV insulin infusion and
intermittent (two-hourly) SC rapid insulin analogue at the UST Hospital Private division

IV insulin infusion group SC insulin analogue group

Frequency of Every hour Every two hours
blood sugar
monitoring

Type of insulin Insulin Insulin Insulin Insulin Insulin Insulin

regular regular aspart glulisine lispro pen lispro vial
vial vial
A B
1938.20 766.50 1063.00 1070.00 1175.00 2276.75
Glucose 1164.00 582.00
meter strip
Lancet 144.00 72.00
Pen needle NA* 312.00 NA*
Insulin NA* NA* 180.00
syringe
Daily rental of 1350.00 NA*
infusion set

Infusion set 1337.00 NA*

TOTAL: P 5933.20 P 4761.50 P 2029.00 P 2036.00 P 2141.00 P 3110.75

*NA – not applicable

Table VI. Estimated cost of therapy (in peso) of mild to moderate DKA for 24 hours with continuous IV insulin infusion and
intermittent (two-hourly) SC rapid insulin analogue at the UST Hospital Clinical division

IV insulin infusion group SC insulin analogue group

Frequency of Every hour Every two hours
blood sugar
monitoring
Type of insulin Insulin Insulin Insulin Insulin Insulin Insulin
regular regular aspart glulisine lispro pen lispro vial
vial vial
A B
1536.75 613.25 843.00 850.75 940.00 2276.75
Glucose 930.00 465.00
meter strip
Lancet 144.00 72.00
Pen needle NA* 312.00 NA*
Insulin NA* NA* 180.00
syringe
Daily rental of 925.00 NA*
infusion set

Infusion set 420.00 NA*

TOTAL: P 3955.75 P 3032.25 P 1692.00 P 1699.75 P 1789.00 P 2993.75

*NA – not applicable

Volume 55 Number 1 Jan - March., 2017 5

 Balili CAV, et al.
In our study, the clinical and biochemical characteristics
of patients on admission were almost similar except that
majority of our patients were male. Infection was the most
common precipitating cause of DKA while omission of insulin
and new-onset diabetes accounted for the rest. These
findings were similar to the study of Prasad et al in India6 but
somewhat different from that of Umpierrez GE et al,2 which
showed that omission of insulin and new-onset diabetes were
more common precipitating causes of DKA than infection.
Hypertension, obesity and coronary artery disease were the
most common underlying co-morbid conditions. None had
hypokalemia on admission, reflecting the insulin-deficient
state of DKA. Occurrence of hypoglycemia during the course
of insulin therapy was similar using either regimen, which
is consistent with the results of other studies. 2,4,6 However,
hypokalemia during insulin treatment occurred with greater
frequency in those given IV insulin. None of the prospective,
randomized trials 2,4,5,6 comparing IV insulin infusion with
intermittent SC rapid insulin for treatment of mild to moderate
DKA used hypokalemia as one of the measures of safety of
therapy. Hospital stay was longer for those on IV insulin than
those on SC insulin, in contrast to studies done by Umpierrez
GE et al 4 and Prasad A and Gupta A, 6 wherein length of
hospitalization was similar among treatment groups. The
underlying co-morbidities and precipitating cause of DKA
including the severity of infection could have contributed
largely to the longer duration of hospital stay of patients
on IV insulin more than the insulin regimen used to achieve
resolution of hyperglycemia and ketoacidosis. Lastly, mortality
was low and not significantly different in both groups, similar
to results from other studies.2,4,5,6
Based on these results, a regimen using intermittent
subcutaneous rapid insulin administered every two hours is
equally effective and probably safer, with less occurrence
of hypokalemia, in achieving resolution of hyperglycemia
and ketoacidosis in mild to moderate DKA with the additional
advantage of potentially lower cost because of less strict
monitoring protocols and admission to the general ward
instead of the intensive care unit, which is very appropriate
in our clinical setting where financial resources are limited.
However, a greater number of subjects is needed to
derive stronger conclusions from this study and prospective,
randomized trials in adult diabetic Filipino patients would have
been a better research endeavor compared to a retrospective
chart review. Also, performing cost-effectiveness analysis can
provide a more objective assessment of the cost and health
effects of these particular types of therapy.
C onclusion
Intermittent subcutaneous rapid insulin regimen is an
effective, safe, and potentially cost-effective alternative to
continuous intravenous insulin infusion for treatment of mild
6 Volume 55 Number 1 Jan - March., 2017
Efficacy and Safety of Subcutaneous Insulin Analogue Versus Intravenous Insulin
to moderate DKA.
Acknowledgements
This research work was accomplished through review of
in-patient hospital records; thus, no funding was required.
However, we would like to thank Ms. Angelica Fabillar for
her assistance in the statistical analysis of our data.
R eferences
1. KitabchiAE. Umpierrez GE. Miles J. FisherJ. Hyperglycemic crises
in adult patients with diabetes. Diabetes Care. 32(7):1335- 43, 2009 Jul.
2. Umpierrez GE. Cuervo R. Karabell A. Latif K. Freire A. Kitabchi
AE. Treatment of diabetic ketoacidosis with subcutaneous insulin
aspart. Diabetes Care. 27(8):1873-8, 2004 Aug.
3. Umpierrez GE. Murphy M. Kitabchi AE. Diabetic ketoacidosis
and hyperglycemic hyperosmolar syndrome. Diabetes Spectrum.
15(1):28-36, 2002 Jan.
4. Umpierrez GE. Latif K. Stoever J. Cuervo R. Park L. Freire
AX. Kitabchi AE. Efficacy of subcutaneous insulin lispro versus
continuous intravenous regular insulin for the treatment of patients
with diabetic ketoacidosis. Am J Med. 117(5):291-6, 2004 Sep.
5. Ersoz HO. Ukinc K. Kose M. Erem C. Gunduz A. Hacihasanoglu
AB. Karti SS. Subcutaneous lispro and intravenous regular insulin
treatments are equally effective and safe for the treatment of mild
and moderate diabetic ketoacidosis in adult patients. Int J ClinPract.
60(4):429-33, 2006 Apr.
6. PrasadA. Gupta A. Role of Insulin Aspart in Management of Diabetic
Ketoacidosis. Indian Journal of Research. 4(7):61-2, 2015 Jul.
7. Wallace TM. Matthews DR. Recent advances in the monitoring and
management of diabetic ketoacidosis. QJM. 2004. 97(12):773- 80,
2004 Dec.
8. Otieno CF. Kayima JK. Omonge EO. Oyoo GO. Diabetic
ketoacidosis: risk factors, mechanisms and management strategies
in sub-Saharan Africa: a review. East African Medical Journal. 82(12
Suppl):S197–203, 2005 Dec.
9. Lin SF. Lin JD. Huang YY. Diabetic ketoacidosis: comparisons of
patient characteristics, clinical presentations and outcomes today and
20 years ago. Chang Gung Med Journal. 28(1):24-30, 2005 Jan.
10. Chiasson JL. Aris-Jilwan N. Belanger R. Bertrand S. Beauregard
H. Ekoé JM. Fournier H. Havrankova J. Diagnosis and treatment of
diabetic ketoacidosis and the hyperglycemic hyperosmolar state.
CMAJ. 168(7):859–66, 2003 Apr.
11. Newton CA. Raskin P. Diabetic ketoacidosis in type 1 and type 2
diabetes mellitus: clinical and biochemical differences. Arch Intern
Med. 164(17):1925–31, 2004 Sep.
12. Menaka R. Narendra BS. Sandeep J. Bhattacharyya A.
Comparing conventional and analogue insulin in hospitalised
patients. Journal of the Association of Physicians of India. 62:705-
706, 2014 Aug.
13. Ko KJ. Tomor V. Nathanson BH. Bouchard JR. Aagren M.
Dubois RW. Retrospective cohort analysis of outcomes between
patients receiving analogue versus human insulin. Clin Ther.
32(11):1954-66, 2010 Oct.
 Philippine Journal of Internal Medicine
Efficacy of Selenium Supplementation on Autoantibody Titers in
Graves’ Ophthalmopathy
Marc Gregory Yu, M.D.*; Antonio Faltado, Jr., M.D.* and Laura Rosario Acampado, M.D.*
Abstract
Background: Selenium (Se) shows potential benefit in
Graves’ disease (GD) especially those with active Graves’
ophthalmopathy (GO).
Objectives: To evaluate the efficacy of Se supplementation
among patients with GD and GO.
Methodology: We performed a meta-analysis of trials
evaluating the efficacy of Se supplementation among adult
patients with GD and active GO, versus either placebo or
an alternative drug, and on top of standard therapy. Results
were presented as mean differences, standard errors, and
95% confidence intervals, and graphically presented as
forest plots. Estimates were calculated using the inverse
variance method for continuous variables and pooled using
the fixed effects model. I2 and Chi2 tests were used to assess
heterogeneity.
Results: Only two trials were ultimately included in the
analysis. Both studies totaled 197 participants with GD and
I ntroduction
Graves’ disease (GD) is characterized by the presence
of activating autoantibodies (TRAB) against the thyroid-
stimulating hormone (TSH) receptor.1 These lead to signs and
symptoms of excessive thyroid hormone production and in
approximately half of patients, Graves’ ophthalmopathy
(GO). 2 Standard treatment for GD involves medications
blocking thyroid hormone synthesis, radioiodine (RAI)
therapy, and thyroidectomy, which all render the patient
euthyroid. 3 However, despite effectively addressing the
*
Section of Endocrinology, Diabetes and Metabolism, Department of
Medicine, Philippine General Hospital, Manila, Philippines
This paper was presented at the following scientific meetings:
1. ESE Meeting Grant Award and selected as part of guided poster
tours, 2016 European Congress of Endocrinology, Munich,
Germany, May 28-31, 2016
2. Poster Presentation, 46th Annual Convention of the Philippine
College of Physicians, Manila, Philippines, April 30-May 3, 2016
3. Poster Presentation, Philippine Society of Endocrinology,
Diabetes, and Metabolism Annual Convention, Manila,
Philippines, March 16-18, 2016.
4. Finalist, Research Poster Competition (Thyroid Category), 18th
ASEAN Federation of Endocrine Societies Congress, Kuala
Lumpur, Malaysia, December 10-13, 2015
Corresponding Author: Marc Gregory Yu, M.D.ORCID # 0000-0002-
0376-9574
Email: marcgreggy@yahoo.com
The PHILIPPINE JOURNAL OF INTERNAL MEDICINE is a peer reviewed journal and a copyrighted publication of the Philippine College of Physicians
Meta-Analysis
non-severe GO on standard therapy, and compared Se
supplementation to placebo. The only common outcomes
of interest were changes in TSH receptor antibody (TRAB)
and thyroid peroxidase antibody (TPOAB) titers. We found
no statistically significant difference in either TRAB (95% CI,
-1.38 [-3.19, 0.44], p=0.14) or TPOAB (95% CI, 36.66 [-32.56,
105.88], p=0.30) titers between Se and placebo groups on
follow up. However, our analysis was limited by the small
number of included studies, a small sample size, and lack
of other synthesizable outcomes.
Conclusion: This is the first meta-analysis summarizing the
available data on Se supplementation in patients with GD
and non-severe GO. We found no statistically significant
differences in both TRAB and TPOAB titers between Se and
placebo groups. We recommend larger studies to validate
these findings.
Keywords: selenium, Graves’ disease, Graves’
ophthalmopathy, autoantibodies, thyroid gland
glandular component, these therapies have proven
suboptimal for patients with GO, adversely affecting daily
activities and health-related quality of life (HRQoL).4
Selenium (Se) is a trace element incorporated in several
key human enzymes.5 Levels in food and in humans reflect
soil content, which vary worldwide due to factors such
as flora and agriculture.6,7,8 The thyroid has the highest Se
concentration per weight among all body tissues. 9 As a
component of selenoproteins such as glutathione peroxidase
(GPx) and thioreduxin reductase (TRx), Se helps combat the
highly oxidative milieu in GD and GO and further appears to
influence the immune system by decreasing levels of TRAB
and thyroid peroxidase antibodies (TPOAB), which are found
in 80% of patients with GD.10,11 Conversely, Se deficiency has
been associated with increased thyrocyte damage and
greater production of reactive oxygen species (ROS), an
important aspect of the inflammatory process in GD and
GO. 12 Decreased levels of Se were found in GD patients
compared to controls, with significantly lower levels found in
GD patients with GO as compared to those without GO.13,14
Yet another study showed that GD patients in remission had
the highest Se levels and the lowest TRAB levels compared
to those with active disease and relapse.15
Volume 55 Number 1 Jan - March., 2017
 Yu MG, et al.
Given the crucial role of Se in the pathogenesis of GD
and GO, this study aims to consolidate current available
information and evaluate the possible efficacy of Se
supplementation in patients with GD and GO.
M ethods
The study was performed in accordance with the
PRISMA guidelines for reporting systematic reviews and
meta-analyses.
Search Strategy
Electronic databases including MEDLINE, Scopus,
Embase, Hinari, ClinicalTrials.gov, Google Scholar, and
the Cochrane Central Register of Controlled Trials were
systematically searched by two independent investigators
for inclusion of articles in the study. The following terms
were used individually and in combination: “selenium”,
“selenite”, “selenoprotein”, “thyroid”, “Graves’ disease”,
“Basedow disease”, “thyrotoxicosis”, “hyperthyroidism”,
“ophthalmopathy”, “orbitopathy”, and “thyroid-related
eye disease.” These key terms were utilized as text words,
Medical Subject Headings (MeSH), and Clinical Queries.
Cross-references of original publications, books of abstracts,
and conference proceedings from the WHO Network of
Collaborating Clinical Trial Registers, US FDA registry, and
International Committee of Medical Journal Editors (ICMJE)
were searched as well. Manufacturers of selenium brands
were also contacted via email for possible inclusion of any
unpublished studies. The search was not restricted to any
study design, language, or time frame, and any discrepancy
was resolved by discussion and consensus through a third
author.
Study Selection
Randomized controlled trials (RCTs) or meta-analyses
involving Se supplementation in adult GD patients with active
GO, as compared to placebo or alternative interventions,
and on top of standard therapy, were included in this study.
There were no restrictions on ethnicity or gender. Exclusion
criteria included pregnancy, comorbid systemic or ocular
disease, severe GO requiring steroid use at outset, and
previous or ongoing use of Se-containing supplements.
Outcome measures must include any or a combination of
the following: clinical activity of GO as measured through
objective examination or symptom scores; levels of selenium
or selenoproteins, TSH, thyroid hormones, TRAB and TPOAB;
and overall HRQoL.
Data Extraction and Management
Three authors independently screened potential
2 Volume 55 Number 1 Jan - March., 2017
Efficacy of Selenium Supplementation on Autoantibody Titers
studies using a data eligibility form. Studies agreed upon
for exclusion were excluded at this stage, with the reason
for exclusion documented. Eligible studies then underwent
methodological quality assessment based on the Cochrane
Collaboration’s tool for assessing risk of bias. The validity
criteria included randomization, allocation concealment,
baseline characteristics, blinding, and adequacy of follow-
up. Any disagreements were resolved by consensus. Studies
that passed all screenings underwent independent data
extraction by all authors, with the following data extracted
from each trial: author, year of publication, duration of
therapy, intervention, type of comparator, sample size and
type of population, and study outcomes.
Statistical Analysis
The study was analyzed using Review Manager, version
5. Results were presented as mean differences and standard
errors with 95% confidence intervals, and graphically
presented as forest plots. Estimates were calculated using
the inverse variance method for continuous variables and
pooled using the fixed effects model. Heterogeneity was
defined as I 2>50% and p<0.1 utilizing the I 2 and Chi 2 tests,
respectively. Unit of analysis issues were resolved by looking
for uniformity among the analyses of the individual studies.
In cases of multiple observations for the same outcome, it
was agreed upon that the last measure will be included in
the study. Missing data was dealt with by contacting the
trial authors.
R esults
Search Results
Fourteen potentially relevant articles were retrieved.
On initial deliberation, only nine were deemed eligible for
inclusion; the other five articles were excluded because they
were animal studies, editorials, or review articles. Of the nine
initially screened-in articles, seven were further excluded
because they either had no or different interventions,
different disease populations, different outcome measures,
or were still ongoing trials. Two studies ultimately satisfied
the selection criteria and were included in the analysis.
Figure 1 shows the general flowchart for study selection,
while the list of the two included studies, together with their
corresponding characteristics, is outlined in Table I. Table II,
on the other hand, summarizes the methodological quality
assessment results for each of the included studies, while
Table III summarizes the excluded studies and the reasons
for exclusion.
Study Characteristics
Both selected studies were conducted in Europe and
were published within the last four years. Duration of therapy
 Efficacy of Selenium Supplementation on Autoantibody Titers Yu MG, et al.

was six months in one study (with additional exploratory evaluations at twelve months) and nine months in
the other. A total of 197 participants aged 18-70 years old were enrolled in the two studies, and all had GD
with non-severe GO. Both studies compared Se with placebo; with one study

Figure 1. Flowchart of the process of retrieval and selection of studies for the review.

Table I. Characteristics of the studies included in the review.

Study Marcocci 201118 Calissendorff 201519

Title Selenium and the course of mild Graves’ A prospective investigation of Graves’
ophthalmopathy disease and selenium: thyroid hormones,
auto-antibodies, and self-rated symptoms

Design RCT RCT

Therapy Duration 6 months 9 months

Sample Size 159 38

Population Adult GD patients aged 18-70 with mild Adult GD patients aged 18-55 without
GO <18 mo duration severe GO

Outcomes Eye evaluation, GO-QoL score, clinical Selenoprotein concentration, self-rated

activity score, diplopia score, TRAB, symptom score, anxiety and depression
TPOAB score, TSH, ft4, fT3, TRAB, TPOAB

Intervention Se 200 ug/day Se 200 ug/day

Comparator Placebo, pentoxifylline Placebo

Volume 55 Number 1 Jan - March., 2017 3

 Yu MG, et al.
Table II. Methodological quality assessments for studies included in the review.
Study Marcocci 201118
Randomization Adequate
Allocation Concealment Yes
Baseline Characteristics No significant difference
Blinding Double blind
Follow-up Rates Adequate
Figure 2. Mean difference in TRAB titers between the selenium and placebo groups.
Figure 3. Mean difference in TPOAB titers between the selenium and placebo groups.
further comparing Se with pentoxifylline, another drug with
putative anti-oxidative properties. The outcomes of interest
were objective eye evaluations, HRQoL scores (as measured
via the GO-QoL Questionnaire), clinical activity scores, and
diplopia scores in the first study; and self-rated symptom
scores (as assessed via a modified version of the Rivermead
Post-Concussion Questionnaire), anxiety and depression
scores (as measured via the Hospital Anxiety and Depression
Questionnaire), and levels of TSH, thyroid hormones, TRAB,
and TPOAB in the second. With regards to methodological
quality, both studies were randomized, double-blind RCTs
with adequate follow-up rates. The baseline characteristics
of the groups being compared yielded no significant
differences in either study.
For this meta-analysis, the placebo arm was used as the
control group in all outcome measures. Moreover, since TRAB
and TPOAB measurements were common to both studies, we
4 Volume 55 Number 1 Jan - March., 2017
Efficacy of Selenium Supplementation on Autoantibody Titers
Calissendorff 201519
Adequate
Yes
No significant difference
Double blind
Adequate
focused on autoantibody titers as the outcomes of interest
in this meta-analysis.
Data Synthesis
Effects of Se Supplementation on TRAB Titers
Both studies reported TRAB titers at baseline and on follow
up. No statistically significant difference (95% CI, -1.38 [-3.19,
0.44], p=0.14) was found in TRAB titers among patients
given Se supplementation as compared to the placebo
group (Figure 2.) Significant heterogeneity (I2=36%) was not
observed in this analysis.
Effects of Se Supplementation on TPOAB Titers
Both studies also reported TPOAB titers at baseline and
on follow up. No statistically significant difference (95% CI,
 Efficacy of Selenium Supplementation on Autoantibody Titers Yu MG, et al.

Table III. List of excluded studies and reasons for exclusion.

studies. We were unable to pool results from other clinical
endpoints – objective eye evaluations and diplopia, clinical
activity, and GO-QoL scores in one study; and symptom
Study Reason for Exclusion
scores, anxiety and depression scores, and selenoprotein,
Watt 201317 Ongoing trial, no data yet available TSH and thyroid hormone levels in the other. Specifically,
we were unable to pool results from self-rated outcomes
Wertenbruch 200715 Case control design, as different questionnaires and scoring systems were used,
no intervention with no known longitudinal correlations of change and
similarities of responsiveness between them. An alternative
Kwong 201414 Case control design,
no intervention recourse would have been to pool data in a dichotomous
fashion, however dichotomous data was not presented in
Pedersen 201313 Cross-sectional design,
no intervention the trials included (one study did not report the number of
patients who improved in the placebo arm while the other
Vrca 200320 Different intervention
and outcome measures presented the data entirely as mean scores for the whole
study population).
Smith 20114 Review article

More importantly, neither study evaluated other

Duntas 201121 Review article
important outcomes such as rates of mortality, hospitalization,
Dharmasena 201422 Review article remission, relapse, and treatment failure. Serum Se levels
were also not measured in one study (given the premise
Sturniolo 201323 Editorial that patients with GD and GO have lower serum Se levels.)
It must be noted that both trials were conducted in one
Toulis 201024 Different disease population geographical area (Europe) alone, with different diets,
genetics, and Se soil content as compared to other regions,
Fan 201416 Different disease population and hence any conclusions made may not always apply to
populations living in other parts of the world.
Xu 201125 Animal study

Nevertheless, both studies included in this review were

36.66 [-32.56, 105.88], p=0.30) in TPOAB values was similarly
detected among patients given Se supplementation as
compared to the placebo group (Figure 3). Significant
heterogeneity (I2=0%) was also not observed in this analysis
D iscussion
This is the first meta-analysis summarizing the current
available data on the effect of Se supplementation on
autoantibody titers in patients with GD and non-severe GO.
We found no statistically significant difference in both TRAB
and TPOAB levels among patients given Se supplementation
as compared to the placebo group. In contrast, a meta-
analysis performed in patients with autoimmune thyroiditis
showed a significant decrease in TPOAB titers among the
Se-administered population as compared to controls at a
similar time frame of six months.16
Several limitations may have accounted for the
differences in the key findings of our study in contrast to
the theorized mechanisms of Se cited in literature. First, our
meta-analysis only included two trials both with relatively
small sample sizes, thus affecting the power of the study to
gauge overall treatment effect. In terms of outcomes, the
study was also limited to the evaluation of autoantibody
titers as these were the only measures common to both
generally of good quality, with adequate randomization,
blinding, and rates of follow-up. Despite the fact that no
significant heterogeneity was found during the analysis of
both TRAB and TPOAB titers, it must be remembered that the
utility of the I2 and Chi2 tests in this regard is limited, since
these possess low power in the situation of a meta-analysis
involving only a few studies or small sample sizes. For this
study, a relative lack of data on the role of Se in GD and
GO was encountered, largely due to the novelty of its use
in the disease. A funnel plot to assess publication bias was
rendered unfeasible by the presence of only two studies.
Minimization of selection bias was done via pre-specified
inclusion and exclusion criteria, performance of a systematic
search, and independent evaluation of trial quality by the
reviewers.
The results of this study reinforce the fact that our present
knowledge on the efficacy of Se supplementation in GD
remains much to be desired. An ongoing study, the selenium
supplementation for patients with Graves’ hyperthyroidism
(GRASS) trial, possesses a larger sample size and focuses
on other still unevaluated outcomes such as proportion of
participants with treatment failure. 17 This plus other trials
registered at ClinicalTrials.gov may help enhance our
understanding on the true benefit of Se supplementation in
GD and GO.

Volume 55 Number 1 Jan - March., 2017 5

 Yu MG, et al. Efficacy of Selenium Supplementation on Autoantibody Titers

C onclusion 80: 905-10, 2014.

15. Wertenbruch, T, Willenburg, HS and Sagert, C. Serum selenium
levels in patients with remission and relapse of Graves’ disease.
Se supplementation in patients with GD and non-
Med Chem, 3 (3): 281-4, 2007.
severe GO was not associated with statistically significant
16. Fan, YF; Xu, SH; Zhang, HF; Cao, W; Wang, K; Chen, GF et al.
differences in both TRAB and TPOAB titers. We recommend
Selenium supplementation for autoimmune thyroiditis: a systematic
studies with larger populations and more clinical outcomes to
review and meta-analysis. Int J Endocrinol, 1-8, 2014.
validate these findings. Such investigations will help improve
17. Watt, T; Cramon, P; Bjorner, JB; Bonnema, SJ; Feldt-
current guidelines on the optimal management of patients
Rasmussen, U; Gluud, C et al. Selenium supplementation for
with GD and GO.
patients with Graves’ hyperthyroidism. Trials, 119: 14, 2013.
18. Marcocci, C; Kahaly, GJ; Krassas, GE; Bartalena, G; Prummel,
Conflicts of Interest
M; Stahl, M et al. Selenium and the course of mild Graves’
orbitopathy. New Engl J Med, 364 (20): 1920-31, 2011.
The authors declare no competing interests. No external
19. Calissendorff, J; Mikulski, E; Larsen, EH; and Moller, MA. A
funding source was involved in the conduct of this study.
prospective investigation of Graves’ disease and selenium: thyroid
hormones, autoantibodies, and self-rated symptoms. Eur Thyroid
R eferences J, 4 (2): 93-8, 2015.
20. Vrca, VB; Skreb, F; Cepelak, I; Romic, Z; and Mayer, L.
1. Weetman, A.P. Graves’ disease. New Engl J Med, 343 (17): Supplementation with antioxidants in the treatment of Graves’
1236-48, 2000. disease; the effect on glutathione peroxidase and concentration of
2. Bartalena, L., Pinchera, A and Marcocci, C. Management of selenium. Clinica Chimica Acta, 341 (1-2): 55-63, 2004.
Graves’ ophthalmopathy: reality and perspectives. Endocr Rev, 21. Duntas, L. The evolving role of selenium in the treatment of Graves’
21: 168-99, 2000. disease and ophthalmopathy. J Thyroid Res, 736161, 2012.
3. Cooper, DS. Antithyroid drugs. New Engl J Med, 352: 905-917, 2005. 22. Dharmasena, A. Selenium supplementation in thyroid associated
4. Smith, TJ and Douglas, RS. Does selenium supplementation improve ophthalmopathy: an update. Int J Ophthal, 7 (2): 365-75, 2014.
Graves’ ophthalmopathy? Nat Rev Endocrinol, 7: 505-6, 2011. 23. Sturniolo, G and Mesa, J. Selenium supplementation and
5. Weeks, BS, Hanna, MS and Cooperstein, D. Dietary selenium and autoimmune thyroid diseases. Endocrinol Nutr, 60 (8): 423-6, 2013.
selenoprotein function. Med Sci Monit, 18 (8): 127-132, 2012. 24. Toulis, KA; Anastasilakis, AD; Tzellos, TG; Goulis, DG; and
6. Xia, Y; Hill, KE; Byrne, DW; Xu, J; and Burke, RF. Effectiveness Kouvelas, D. Selenium supplementation in the treatment of
of selenium supplements in a low-selenium area in China. Am J Hashimoto’s thyroiditis: a systematic review and a meta-analysis.
Clin Nutr, 81 (4): 829-834, 1998. Thyroid, 10: 1163-73, 2010.
7. Hira, CK, Partal , K and Dhillon, KS. Dietary selenium intake by 25. Xu, J; Liu, XL; Yang, XF; Guo, HL; Zhao, LN; Sun, XF et al.
men and women in high and low selenium areas of Punjab. Public Supplemental selenium alleviates the toxic effects of excessive
Health Nutr, 7 (1): 39-43, 2004. iodine on thyroid. Biol Trace Elem Res, 141 (1-3): 110-118, 2011.
8. Rayman, MP. The argument for increasing selenium intake. Proc
Nutr Soc, 61: 203-15, 2002.
9. Drutel, A, Archambeaud, F and Caron, P. Selenium and the thyroid
gland: more good news for clinicians. Clin Endocrinol, 78 (2):
155-64, 2013.
10. Abalovich, M; Llesuy, S; Gutierrez, S; and Repetto, M. Peripheral
parameters of oxidative stress in Graves’ disease: the effects of
methimazole and 131 iodine treatments. Clin Endocrinol, 59 (3):
321-7, 2003.
11. Eskes, SA; Endert, E; Fliers, E; Birnie, E; Hollenbach, B;
Schomburg, L et al. Selenite supplementation in euthyroid
subjects with thyroid peroxidase antibodies. Clin Endocrinol, 80:
444-451, 2014.
12. Rayman, MP. The importance of selenium to human health. The
Lancet, 356 (9225): 233-41, 2000.
13. Pedersen, IB; Knudsen, N; Carle, A; Schomburg, L; Kohrle, J;
Jorgensen, T et al. Serum selenium is low in newly-diagnosed
Graves’ disease: a population-based study. Clin Endocrinol, 79
(4): 584-90, 2013.
14. Kwong, JJ; Goldstein, RF; Sanders, KM; Schneider, H; Pope, J;
Burdon, KP et al. Serum selenium status in Graves’ disease with
and without orbitopathy: a case-control study. Clin Endocrinol,

6 Volume 55 Number 1 Jan - March., 2017

 Philippine Journal of Internal Medicine
Prescribing Dangerous Drugs and the Law (Part 4)
Atty. Rodel V. Capule, M.D.*
Physicians must be aware that morphine, an easily
available drug in medical practice, is specifically
addressed by the law. The law states that “[t]he penalty
of life imprisonment to death and a fine ranging from
Five hundred thousand pesos (P500,000.00) to Ten million
pesos (P10,000,000.00) shall be imposed upon any person,
who, unless authorized by law [PDEA-licensed physician],
shall possess “Ten grams or more of morphine.”40 But if
the quantity of morphine is at least five grams or more
but less than ten grams an imprisonment of 20 years and
one day to life imprisonment and a fine ranging from four
hundred thousand pesos (P400,000.00) to five hundred
thousand pesos (P500,000.00) shall be imposed. 41 Further,
if the quantity of morphine is less than five grams an
imprisonment of 20 years and one day to life imprisonment
and a fine ranging from four hundred thousand pesos
(P400,000.00) to five hundred thousand pesos (P500,000.00)
shall be imposed. 42
It is also interesting to note that the law also
penalizes possession or [have under his/her control] “any
equipment, instrument, apparatus and other paraphernalia
fit or intended for administering, injecting, ingesting, or
introducing any dangerous drug into the body.” 43 The
penalty of imprisonment ranging from six months and one
day to four years and a fine ranging from ten thousand
pesos (P10,000.00) to fifty thousand pesos (P50,000.00)
shall be imposed. 44 The possession of such equipment,
instrument, apparatus and other paraphernalia fit or
intended [for smoking, consuming, administering, injecting,
ingesting, or introducing any dangerous drug into the body,
during parties, social gatherings or meetings, or in the
proximate company of at least two persons] shall be prima
facie evidence that the possessor has smoked, consumed,
administered to himself/herself, injected, ingested or used
a dangerous drug and shall be presumed to have violated
the law.45
However, “PDEA-registered practitioners and dangerous
drug operators are authorized to possess and use
syringe and/or other instruments or equipment for the
administration or use of dangerous drugs and/or drugs
containing controlled chemicals for medical, dental,
veterinary, research or laboratory purposes.” 46 In other
words, if a physician is not a S2-licensed practitioner,
possession of a parenteral dangerous drug and a syringe
might expose him/her to criminal liabilities.
A PDEA-licensed physician must not engaged in
diversion of dangerous drugs. “Diversion of dangerous
drugs” means the unlawful obtaining and channeling of
*Dr. R.V. Capule is an attorney specializing in medical malpractice,
physical injuries and food torts. He is a law professor of Legal Medicine at
Arellano University School of Law and a consultant in Legal Medicine at
Manila Adventist Medical Center and Makati Medical Center.
The PHILIPPINE JOURNAL OF INTERNAL MEDICINE is a peer reviewed journal and a copyrighted publication of the Philippine College of Physicians
Legal Prescription
pharmaceutical dangerous drugs like over-prescription
by medical practitioners or collection of drug leftovers
and unused prepared parenteral dose in hospitals. 47
Although a PDEA-licensed practitioner is authorized by
law to prescribe dangerous drugs, such authority does not
include “[obtaining] controlled substances for the purpose
of general dispensing/selling to his/her patient or for his
own use.”48
The provisions of the Comprehensive Dangerous
Drugs Act of 2002, as amended and the Dangerous Drug
Regulation No. 1 Series of 2014 must be well understood
by every medical practitioners. In this regard, physicians,
PDEA-licensed or not, should be very conscientious when
dealing with dangerous drugs or controlled substances
in every day medical practice. It is best to remember
that generally, a PDEA-licensed physician may prescribe
dangerous drugs but they are not allowed to sell them.
References
40. Sec. 11. “Possession of Dangerous Drugs”; Article II “Unlawful
Acts and Penalties””; Comprehensive Dangerous Drugs Act of
2002 (R.A. 9165, as amended)
41. Id.
42. Id.
43. Sec. 12. “Possession of Equipment, Instrument, Apparatus and
Other Paraphernalia for Dangerous Drugs”; Article II “Unlawful
Acts and Penalties”; Comprehensive Dangerous Drugs Act of
2002 (R.A. 9165, as amended)
44. Id.
45. Sec. 15. “Use of Dangerous Drugs”; Comprehensive Dangerous
Drugs Act of 2002 (R.A. 9165, as amended)
46. Section 6. “Requirements of Licenses and/or Permits for
Operators or Handlers of Controlled Substance and Payment of
Corresponding Fees”; Article III “Registration, Licensing and
Permit System”; [Dangerous Drug] Board Regulation No. 1 Series
of 2014
47. Section 1. “Definitions” (q): “Diversion of dangerous drugs”
means the unlawful obtaining and channeling of pharmaceutical
dangerous drugs for illegal purposes among others, e.g. in drug
dens, dives or resorts and other places by methods such as forged or
altered prescriptions, feigning sickness and obtaining prescription
from medical practitioners, theft and robbery, fraudulent import
permit, over-prescription by medical practitioners, doctors
shopping, collection of drug leftovers and unused prepared
parenteral dose in hospitals, obtaining drugs via e-mail and post,
and use of invalidated local order form instead of prescription
form”; [Dangerous Drug] Board Regulation No. 1 Series of 2014
48. “A prescription shall not be issued in order for an individual PDEA-
licensed practitioner to obtain controlled substances for the purpose
of general dispensing/selling to his/her patient or for his own use.”
Section31. “Prescriptions”, par. 6(g); Article III “Registration,
Licensing and Permit System”;[Dangerous Drug] Board Regulation
No. 1 Series of 2014
Volume 55 Number 1, Jan-March 2017 IV
 Philippine Journal of Internal Medicine
Prevalence of Elevated TSH and its Association with
Dyslipidemia and NAFLD Among Filipino Adult Executive
Check-Up Patients in a Tertiary Hospital
Rochelle C. Lingad-Sayas, M.D.*; Carolyn N. Montano, M.D.** and Maria Jocelyn C. Isidro, M.D.**
Abstract
Objectives: The study examined the prevalence of elevated
thyroid stimulating hormone (TSH) and its association with
dyslipidemia and non-alcoholic fatty liver disease (NAFLD)
among Filipino adults undergoing executive check-up.
Methods: Clinical characteristics such as age, vital signs,
anthropometrics, FBS, lipid profile, liver function tests, TSH
and hepatobiliary ultrasound were reviewed from the
charts of 580 patients to determine the prevalence of
elevated TSH, NAFLD, and dyslipidemia. Binary logistic
regression analysis was performed to determine association
between TSH levels, NAFLD, and dyslipidemia.
Results: The prevalence of elevated TSH was 3.10%. Patients
I ntroduction
For years, it was demonstrated in numerous studies that
there is a clear association between overt hypothyroidism
and metabolic abnormalities- dyslipidemia, and non-
alcoholic fatty liver disease (NAFLD) that translates to
higher cardiovascular risks. 1,2,3,4 With this, there is a growing
interest to its precedent conditions:- asymptomatic patients
with mildly elevated thyroid stimulating hormone (TSH) and
subclinical hypothyroidism (SH)- defined as having elevated
TSH and normal Free T4 levels, as the latter is more prevalent
than overt hypothyroidism even in our country, with the
PhilTiDes study showing SH to be the second most common
form of thyroid dysfunction in Filipinos at 2.18%.5
On population studies looking at elevated TSH alone,
like the Colorado Thyroid Prevalence Study, the prevalence
of elevated TSH level is 9.5%. 6 The TROMSO study data,
on the other hand, showed the prevalence of elevated
TSH (initial 5th TROMSO study without concurrent FT4
determination) to be only 2.0%.7
*
Fellow-in-training, Section of Endocrinology, Diabetes and
Metabolism, Makati Medical Center
**
Consultant, Section of Endocrinology, Diabetes and Metabolism,
Makati Medical Center
Corresponding Author: Rochelle C. Lingad-Sayas, M.D., Makati
Medical Center, Makati, Philippines
Email: rlingadsayasmd@gmail.com
The PHILIPPINE JOURNAL OF INTERNAL MEDICINE is a peer reviewed journal and a copyrighted publication of the Philippine College of Physicians
Original Paper
with increased total cholesterol was approximately 4.18
times as likely (95% CI 1.20 to 14.61%, p = 0.025) to have
elevated TSH. However, after adjusting for age and sex, we
had insufficient evidence to demonstrate an association
between NAFLD and lipid levels with elevated TSH levels.
Conclusion: The prevalence of elevated TSH in this group
of patients from a highly urbanized area was 3.1%. We
had insufficient evidence to demonstrate an association
between NAFLD, lipid levels, and elevated TSH levels after
adjusting for age and sex.
Keywords: thyroid stimulating hormone, dyslipidemia, non-
alcoholic fatty liver disease, subclinical hypothyroidism
In an unpublished study done in our institution year
2007, investigating executive check-up patients at Makati
Medical Center, the prevalence of elevated TSH levels is as
high as 8.28%. Mean total cholesterol, LDL and triglyceride
were found to be greater in the group with high TSH, with
most of the patients being female and considered obese
by BMI category. However, patients with a prior history of
thyroid disorders, surgery and those taking medicines that
may affect thyroid function were not excluded in this study.
Although it is well-established how overt hypothyroidism,
that is with the combined influence of elevated TSH and
low free T4, can cause elevated cholesterol and LDL, it is
only recently that evidence were presented on the possible
mechanism on how TSH alone can cause abnormal lipid
levels. According to Tian et al, TSH acts on hepatocyte
cell membrane TSH receptors causing an upregulation
in the expression of HMG-CoA Reductase (the rate-
limiting enzyme in cholesterol synthesis) and stimulates
the cyclic adenosine monophosphate / protein kinase A
/ cyclic adenosine monophosphate-responsive element
binding protein (cAMP/PKA/CREB) signaling system. They
concluded that TSH elevates cholesterol levels both in
vivo and in vitro by promoting liver cholesterol synthesis.8
Furthermore, other studies provided evidence that TSH can
cause preadipocyte differentiation and adipogenesis, 9
stimulates metabolism and breakdown of lipids leading
to increased serum free fatty acid levels in vivo 10 and has
effects on leptin.11
Volume 55 Number 1 Jan - March., 2017 1
 Lingad-Sayas RC, et al.
Hence numerous studies attempted to test the
relationship between TSH alone with lipid profile, ranging
from population based surveys to the more recent cross
sectional studies, however results are conflicting and studies
reported disparate results.7,14-18
Looking at TSH, a study investigated its association with
serum lipid concentrations despite being in the “Normal”
range and the study found that even within the normal
range of TSH, a higher (high normal) level of TSH was
associated with less favorable lipid concentrations. The
association with serum lipids was linear across the entire
reference range of TSH.12 And on the 11th year follow-up
of the HUNT study, participants with a higher TSH levels at
baseline have higher non-HDL cholesterol and triglyceride
levels and lower HDL cholesterol levels at follow-up, but the
associations were very modest and not consistent between
the sexes.13
In the analysis of the data of the fifth TROMSO study,
it was noted that in both genders, there were significant
correlations between serum TSH levels and serum Total
cholesterol and serum LDL-C. 7 Also in a study done in
Korea, TSH was positively associated with total cholesterol in
both the subclinical hypothyroid and euthyroid overweight
participants. 14
In a study done in an older biracial population, a
TSH higher than 5.5 mIU/mL was associated with a 9.0
mg/dL (0.23 mmol/L) higher cholesterol level. 15 Similarly,
a community-based study in Australia showed that total
cholesterol and LDL is associated with elevated TSH ( ≤ 10
mU/l), as well as it is positively correlated with triglyceride. 16
Chao Xu et. al. evaluated the relationship between TSH and
lipid profile independent of thyroid hormone in coronary
heart disease patients and found that TSH can increase the
total cholesterol level in CHD patients independent of FT4,
FT3 and reverse T3 and that for each 1.0 mIU/L increase
in the TSH level might be linked to a 0.015580712 mmol/L
elevation of the serum total cholesterol value.17
In the study of Sarzosa Teran, V. et al. (2012) a statistical
association was shown between dyslipidemia and altered
TSH levels. However, they added that the strength of this
association was very weak, and they concluded that TSH
has no value as a clinical predictor of dyslipidemia. 18
Non-alcoholic fatty liver disease (NAFLD) is a
clinicopathologic entity increasingly being recognized
as a major health burden. Being the most common liver
disease, worldwide it has a reported prevalence of six to
35% with a median of 20 percent and it is at five to 30%
in the Asia-Pacific regions. 19,20,21 Locally, in a retrospective
study done at Philippine General Hospital via review
of case records from January 1999 to December 2004,
from a total of 1102 patients with fatty liver, 134 patients
2 Volume 55 Number 1 Jan - March., 2017
Prevalence of Elevated TSH and its Association with Dyslipidemia and NAFLD
(12.2%) were diagnosed with NAFLD, based on clinical and
histopathological findings or ultrasound findings suggestive
of fatty liver.22
If dyslipidemia and metabolic diseases like diabetes
are linked with hypothyroidism, it is not unlikely that NAFLD
is also prevalent in patients with thyroid hypofunction. In a
scientific review done in an effort to clarify the mechanism
for the relationship of NAFLD and thyroid dysfunction, the
role of leptin and Fibroblast growth factor (FGF-21) in
hepatic insulin resistance and overproduction of damaging
reactive oxygen species (ROS) from accumulation of free
fatty acid in hepatocytes due to elevated cholesterol
and triglyceride from decreased lipoprotein lipase activity
were the possible mechanisms found to be involved in the
association of NAFLD and thyroid hypofunction.23
In a case-control study in a Chinese population by Xu
et. al., the incidence of NAFLD increased in patients across
different TSH subgroups (from euthyoid level to severely
elevated) and they noted that subjects with higher baseline
TSH levels were more likely to develop NAFLD during the
follow-up period and the association is significant even
after adjustment for indicators of metabolic syndrome. 24 In
a study of euthyroid patients, NAFLD prevalence increased
gradually with increasing quartiles of TSH levels and that
TSH is an independent risk factor for NAFLD [odds ratio
(OR): 2.21, 95% confidence interval (CI): 1.21–4.02, p = 0.01,
for TSH levels). 25 However, the result of the study done
by Zhang et. al., TSH was not seen as an independent risk
factor of NAFLD, hence they concluded that a change of
TSH level would not influence the prevalence of NAFLD. 26
Furthermore, in a study done in an Iranian population, no
significant difference was seen in TSH and even in free T4,
and free T3 levels between the participants with NAFLD
and without NAFLD.27
In a systematic review of 11 studies investigating
on NAFLD and thyroid dysfunction (2014), the authors
concluded that the results of current studies are conflicting
about the association between thyroid abnormalities and
NAFLD and that physicians caring for patients with NAFLD
may be led to test thyroid hormone profiles as part of initial
clinical assessment of patients with NAFLD because some
of the reviewed studies still propose thyroid dysfunction as
a risk factor for NAFLD.28
Guidelines on thyroid diseases suggest the use of
TSH as a screening test to detect thyroid dysfunction.29,30
These are the guiding principles which are used as the
basis of its incorporation of TSH in the diagnostic work-up
of essentially healthy patients that avails of standard tests
to assess their over-all health like the Executive Check-up
package. Yearly, approximately 800 patients are admitted
under Executive Check-Up Plans A and B in Makati Medical
Center. The package includes laboratory testing to assess
 Prevalence of Elevated TSH and its Association with Dyslipidemia and NAFLD
metabolic problems and screening for thyroid function
abnormalities (TSH determination using radioimmunoasay).
Ultrasound of the whole abdomen, a sensitive screening tool
for fatty liver, is also included, as well as HBsAg (Hepatitis B
antigen) which is used to rule out occult hepatitis B infection.
Hence clinicians, even in our institution, are often faced with
a patient with elevated lipid tests alongside the finding of
fatty liver disease in which the TSH is elevated. With only
these tests on-hand, without the benefit of a free T4 result,
is there an association between dyslipidemia and fatty liver
disease with the elevated TSH?. Also, if in case faced with
an elevated TSH in an asymptomatic patient, would it be
enough to justify work-up for dyslipidiemia and fatty liver
disease even without yet the benefit of a Free T4 result? To
help answer these questions, this study aims to determine the
prevalence of elevated TSH among patients who availed the
Executive Check-Up Plans from January 1, 2013 to December
31, 2013 in Makati Medical Center and its association with
dyslipidemia and fatty liver disease.
This is the first local study looking at the association
of non-alcoholic fatty liver disease and elevated TSH in
essentially healthy Filipino adult patients with/without stable
comorbid disease. Data that will be generated from this
research has the potential for clinical utility by revealing the
prevalence of elevated TSH in executive check-up patients
in a Tertiary hospital and their metabolic profile, to prove if
it is indeed worthwhile to continue screening this subset of
patients for possible thyroid hypofunction using only TSH. In
addition, the study can also validate if screening of patients
with mildy elevated TSH for dyslipidemia and fatty liver
disease must be recommended and advocated for Filipino
patients, similar to some international recommendations. This
is a timely study due to the current increasing prevalence
of the metabolic disorders of interest, namely dyslipidemia
and fatty liver disease, in the Filipino population.
M ethodology
Study design and population
This is a cross-sectional analytic study utilizing a
retrospective review of charts. We included Filipino adults
aged 18 years or older, admitted at Makati Medical Center
under Executive Health Package A or B from January until
December 2013, and who finished all diagnostic tests
covered by their package. We excluded patients with
hepatitis and hepatobiliary infections, hepatic malignancy,
biliary tract disease, portal hypertension, previously known
thyroid disease, pituitary disease, previous radioactive
therapy or intake of thyroid hormones or anti-thyroid
medications, and surgeries that may lead to secondary
NAFLD such as gastropexy, jejunoileal bypass, extensive
small bowel resection, biliopancreatic diversion, and small
bowel diverticulosis).
Lingad-Sayas RC, et al.
Sample size estimation
We required a minimum of 467 adults for this study
using 95% confidence interval and a desired confidence
width of 5%. We assumed the prevalence of elevated TSH
to be at 8.28% based on MMC records (Aquino et al, 2007,
unpublished).
Data collection
A record review of all eligible patients was conducted
after procurement of the Institutional Review Board approval
for the study granted September 2014. Information was
noted on a data collection tool. All efforts to maintain the
anonymity and confidentiality of all data was exercised.
The “within normal” results of all laboratory tests in this study
were based on Makati Medical Center laboratory reference
values.
Study Variables/Operational Definition
1. Executive Check-up patient defined as healthy adult
patients, with or without stable or controlled comorbid
disease/s who in their own volition was admitted for general
work-up
2. High TSH defined as having a TSH value above 4.5 mIU/L
without previous history of thyroid disease and not taking
levothyroxine or anti-thyroid medications. For this study
mildly elevated TSH is between 4.51 mIU/L and 10 mIU/L.
3. Dyslipidemia defined as elevated values of Total
Cholesterol, LDL, or Triglyceride or low HDL compared to the
reference normal value/s of the following lipid parameters:
total cholesterol (above 200mg/dl), triglyceride (above
150mg/dl), and LDL (above 100mg/dl); values below
reference normal for HDL (less than 40mg/dl for both men
and women)
4. Fatty Liver Disease as documented by ultrasound done
in the Makati Medical Center Ultrasound Section, described
as diffuse increase in hepatic echogenicity, or “bright liver”,
due to increased reflection of ultrasound from the liver
parenchyma, which is caused by intracellular accumulation
of fat vacuoles 31
5. Demographic data: age and gender
6. Comorbid diseases: Impaired fasting glucose (IFG)/
impaired glucose intolerance (IGT)/ diabetes mellitus (DM),
hypertension/ cardiovascular disease (CVD)/ coronary artery
disease (CAD)
Volume 55 Number 1 Jan - March., 2017 3
 Lingad-Sayas RC, et al.
7. Anthropometric measures: height, weight, Body Mass
Index (BMI) and classification based on WHO Asia-Pacific
definitions (32):
` • Underweight: <18.5
• Normal: 18.5-22.9
• Overweight: 23-24.9
• Obese Class 1: 25-29.9
• Obese Class 2: 30-40
• Morbidly Obese: >40
8. Liver function tests namely SGPT and SGOT and abnormal
levels defined as high if levels are above 35 mg/dl.
9. Other metabolic parameters: Fasting blood sugar (an
abnormal high value falling at 100mg/dl and above) and
blood uric acid (an abnormal high value for females that is
above 5.7 mg/dl and for men it is above 7 mg/dl)
STATISTICAL ANALYSIS
Descriptive statistics was used to summarize the clinical
characteristics of the patients. Frequency and proportion
was used for nominal variables, and mean and SD for
interval/ratio variables. Independent Sample T-test, and
Chi-square/Fisher’s Exact test was used to determine the
difference of means and proportions between elevated
and normal TSH level groups, respectively. Odds ratios and
corresponding 95% confidence intervals were determined.
We conducted a binary logistic regression to determine the
association of fatty liver disease, lipid levels, and TSH levels,
adjusted for age and sex. All valid data was included in
the analysis. Missing variables was neither replaced nor
estimated. Null hypotheses were rejected at 0.05 α-level of
significance. STATA 12.0 was used for data analysis.
R esults
A total of 917 patients were admitted for routine
Executive Check-Up under package A or B from January
1, 2013 to December 31, 2013. While most exclusions were
due to incomplete data, a number of patients were also
excluded for HbsAg positivity and having a history of heavy
alcohol drinking, thyroid disorder (namely goiter, thyroid
nodule, hypothyroidism, hyperthyroidism and Hashimoto’s
thyroiditis) and thryoid surgery. Only 580 patients remained
for analysis. Of these, 18 patients (3.10%) had elevated TSH
levels. The average TSH value of the elevated TSH group
was 5.61 + 0.90 (units). The normal and elevated TSH groups
were comparable in terms of age, gender, weight, height,
BMI and comorbidities (Table I).
Fatty liver disease on ultrasound, abnormal lipid profile and
liver enzymes, elevated fasting blood sugar and high serum
uric acid were compared between groups of patients
4 Volume 55 Number 1 Jan - March., 2017
Prevalence of Elevated TSH and its Association with Dyslipidemia and NAFLD
with elevated TSH and normal TSH (Table II). Elevated total
cholesterol, triglyceride, low density lipoprotein, fasting
blood glucose and serum uric acid were more common
in the elevated TSH group, while fatty liver disease and
deranged liver enzymes were more frequent among
those with normal TSH. However, only total cholesterol was
significantly increased in the elevated TSH group (83% versus
55%, p = 0.015).
We determined whether age, sex, BMI, fatty liver disease,
liver function tests, lipid profile, fasting blood glucose, and
uric acid had an association with elevated TSH levels (Table
III). On bivariate analysis, we had insufficient evidence to
demonstrate an association for these parameters except
for total cholesterol > 200. Patients with increased total
cholesterol was approximately 4.18 times as likely (95% CI
1.20 to 14.61%, p = 0.025) to have elevated TSH.
We conducted a binary logistic regression to determine
whether NAFLD and lipid levels are associated with elevated
TSH levels. On adjusting for age and sex, we had insufficient
evidence to demonstrate an association between NAFLD
and lipid levels with elevated TSH levels (Table IV).
D iscussion
For this study, the rate of elevated TSH is 3.1%, near the
estimated prevalence of elevated TSH in the Tromso
study. 7
There is a higher frequency of high Total Cholesterol,
Triglyceride and LDL in the elevated TSH group, in the
frequency of 83%, 44% and 89%.. The same is not seen for
low HDL and fatty liver disease, showing a slightly higher
frequency of these conditions in patients with normal TSH.
The association of high or higher TSH (high-normal)
with total cholesterol, as well as other lipid parameters has
been seen in several studies.12-17 For the association of total
cholesterol with elevated TSH, the same relationship is seen in
our study (Table III), in that total cholesterol was significantly
higher in the elevated TSH group wherein patients with
increased total cholesterol was approximately 4.18 times as
likely (95% CI 1.20 to 14.61%, p = 0.025) to have elevated TSH.
However, on adjusting for age and sex, the said association
was not significant. The said result maybe because part
of the association between TSH and total cholesterol is
explained by age and gender. In the study by Lu et. al., on
initial analysis, total cholesterol, LDL and triglyceride were
not different between the two groups after adjusting for age,
sex and BMI. However after further analysis, they found that
the relationship of TSH and lipids levels were different in the
overweight and normal weight populations, along with those
in men and women, wherein the said lipid parameters were
Prevalence of Elevated TSH and its Association with Dyslipidemia and NAFLD Lingad-Sayas RC, et al.

Table I. Clinical profile of 580 executive check-up patients admitted in MMC from January to December 2013 (n=580)

Elevated TSH Normal TSH

(n=18) (n=562) P-Value
Frequency (%); Mean + SD
Age 46.67 + 9.89 48.58 + 11.36 0.480*
TSH level 5.61 + 0.90 1.66 + 0.85 0.000*
BMI 25.36 + 4.28 26.32 + 5.17 0.434*
Height (cm) 162.72 + 7.97 163.27 + 12.29 0.851*
Weight (kg) 67.64 + 14.47 72.21 + 17.10 0.263*
Sex 0.851Ɨ
Male 11 (61.11) 331 (58.90)
Female 7 (38.89) 231 (41.10)
BMI category 0.265§
Underweight 1 (5.56) 2 (0.36)
Normal 3 (16.67) 113 (20.11)
Overweight 5 (27.78) 114 (20.28)
Obese 1 7 (38.89) 216 (38.43)
Obese 2 2 (11.11) 103 (18.33)
Morbid Obese 0 14 (2.49)
Comorbidities
IFG, IGT or overt diabetes 2 (11.11) 102 (18.15) 0.754§
Hypertension 5 (27.78) 207 (36.83) 0.432Ɨ
CAD or CVD 0 22 (3.92) 1.000§
Statistical test used: * – Independent T-test; Ɨ – Chi-square analysis; § – Fisher’s exact test

Table II. Diagnostic and laboratory parameters of 580 patients by TSH levels

Elevated TSH Normal TSH

(n=18) (n=562) P-Value
Frequency (%)
Fatty liver disease 46.67 + 9.89 48.58 + 11.36 0.480*
Liver function tests (U/L) 25.36 + 4.28 26.32 + 5.17 0.434*
SGOT > 35 162.72 + 7.97 163.27 + 12.29 0.851*
SGPT > 35 67.64 + 14.47 72.21 + 17.10 0.263*
BMI category
Total cholesterol > 200 15 (83.33) 306 (54.45) 0.015
Triglyceride > 150 8 (44.44) 154 (27.40) 0.113
LDL ≥ 100 16 (88.89) 443 (78.83) 0.301
HDL < 40 3 (16.67) 98 (17.44) 1.000§
Fasting blood glucose ≥ 100 mg/dL 5 (27.78) 150 (26.69) 1.000§

Uric acid (mg/dL): male: ≥ 7; female ≥ 5.7 13 (72.22) 304 (54.09) 0.128
Statistical test used: Chi-square analysis; § – Fisher’s exact test

Volume 55 Number 1 Jan - March., 2017 5

 Lingad-Sayas RC, et al. Prevalence of Elevated TSH and its Association with Dyslipidemia and NAFLD

Table III. Association of clinical profile, diagnostic, and laboratory parameters of 580 patients to elevated TSH level

Elevated TSH Normal TSH Unadjusted Odds

(n=18) (n=562) Ratio P-Value
Frequency (%) (95% CI)
Aged > 50 years old 6 (33.33) 255 (45.37) 0.60 (0.22 to 1.63) 0.317
Male 11 (61.11) 331 (58.90) 1.10 (0.42 to 2.87) 0.851
BMI > 23 14 (77.78) 445 (79.18) 0.92 (0.30 to 2.85) 0.885
Fatty liver disease 8 (44.44) 307 (54.63) 0.66 (0.26 to 1.71) 0.396
Liver function tests (U/L)
SGOT > 35 0 70 (12.46) - -
SGPT > 35 3 (16.67) 195 (34.70) 0.37 (0.11 to 1.32) 0.126
Lipid profile tests (mg/dL)
Total cholesterol > 200 15 (83.33) 306 (54.45) 4.18 (1.20 to 14.61) 0.025
Triglyceride > 150 8 (44.44) 154 (27.40) 2.12 (0.82 to 5.47) 0.120
LDL ≥ 100 16 (88.89) 443 (78.83) 2.15 (0.49 to 9.48) 0.312
HDL < 40 3 (16.67) 98 (17.44) 0.95 (0.27 to 3.33) 0.932
Fasting blood glucose ≥ 100
5 (27.78) 150 (26.69) 1.06 (0.37 to 3.01) 0.918
mg/dL
Uric acid (mg/dL): male: ≥ 7;
13 (72.22) 304 (54.09) 2.21 (0.78 to 6.27) 0.138
female ≥ 5.7

Table IV. Association of non-alcoholic fatty liver disease and lipid levels with elevated TSH levels in Filipino adults,
adjusted to age and sex (n = 580)

Elevated TSH Normal TSH Unadjusted Odds

(n=18) (n=562) Ratio P-Value
Frequency (%) (95% CI)

Aged > 50 years old 6 (33.33) 255 (45.37) 0692 (0.24 to 1.97) 0.490
Male 11 (61.11) 331 (58.90) 1.03 (0.37 to 2.91) 0.952
BMI > 23 14 (77.78) 445 (79.18) 0.92 (0.30 to 2.85) 0.885
Non-alcoholic fatty liver
8 (44.44) 307 (54.63) 0.53 (0.18 to 1.55) 0.243
disease
Lipid profile tests (mg/dL)
Total cholesterol > 200 15 (83.33) 306 (54.45) 4.29 (0.90 to 20.58) 0.069
Triglyceride > 150 8 (44.44) 154 (27.40) 2 (0.68 to 5.89) 0.211
LDL ≥ 100 16 (88.89) 443 (78.83) 0.71 (0.11 to 4.53) 0.717
HDL < 40 3 (16.67) 98 (17.44) 0.97 (0.24 to 3.85) 0.965
Fasting blood glucose ≥ 100
5 (27.78) 150 (26.69) 1.28 (0.39 to 4.20) 0.689
mg/dL

6 Volume 55 Number 1 Jan - March., 2017

 Prevalence of Elevated TSH and its Association with Dyslipidemia and NAFLD
found to be positively associated with TSH when their
relationship was analyzed per population e.g. overweight
population vs. normal weight and overweight female
population vs. overweight male population. The said study
illustrates that the combination of serum TSH, sex, and BMI
has important effects on serum lipid parameters. In this
light, in our study the non-association of triglyceride and LDL
with TSH can also be a result of the relatively homogenous
population of our study in terms of BMI, because for both high
and normal TSH about 70% of the patients are overweight
or obese (BMI >23), making the effects of TSH on these
lipid parameters to be not significantly different between
two groups (high vs. normal TSH) derived from a relatively
homogenous population in terms of BMI.
In our study, fatty liver disease was not found to be more
prevalent in the elevated TSH group. Conditions related to
insulin resistance, like prediabetes, diabetes and body fat
or obesity are well studied and documented risk factors for
NAFLD.33 Aside from most of the patients in both the high and
normal TSH group having a BMI above normal, the patients
in the normal TSH group, also have a higher mean BMI and
higher number of prediabetic or diabetic patients than in the
elevated TSH group. This setting may have put the patients
in both groups at already high risk for having NAFLD, the
normal TSH group more than the high TSH because of higher
prevalance of elevated BMI and insulin resistance state in
the normal TSH group. In the same light, the group of Lee
et al. conducted a four-year retropective cohort study on
the impact of differing levels of thyroid dysfunction on the
development of NAFLD and found that both TSH and free
T4 were not associated with the development of NAFLD. In
the same study, the NAFLD group has significantly higher
BMI, plasma glucose, plasma insulin and HOMA-IR (a marker
of insulin resistance, computed as fasting insulin(µIU/mL) ×
fasting glucose (mmol/L)]/22.5). 34
C onclusion
For this study, the rate of elevated TSH is 3.1%, and when
tested for its relationship with lipid parameters and NAFLD,
only total cholesterol was significantly higher in the elevated
TSH group compared to those with normal TSH wherein
increased total cholesterol was approximately 4.18 times
as likely (95% CI 1.20 to 14.61%, p = 0.025) to have elevated
TSH. However, on adjusting for confounding factors like age
and sex, we have insufficient evidence to demonstrate an
association between lipid levels (including total cholesterol)
and NAFLD with elevated TSH levels. These findings illustrates
that serum TSH, sex, and BMI has important effects on serum
lipid parameters and NAFLD and that part of the association
between TSH with lipid parameters and NAFLD is modified
by gender and BMI as seen by some recent studies.
Lingad-Sayas RC, et al.
With this, we recommend for future studies to investigate
the effect of TSH on lipid parameters and NAFLD in a
population and study design wherein their relationship can
be observed in mutually exclusive groups of varying BMI or
levels of insulin resistance and gender.
R eferences
1. Lai Y., Wang J, Jiang F, Wang B, Chen Y, Li M, Liu H, Li C,
Xue H, Li N, Yu J, Shi L, Bai X, Hou X, Zhu L,Lu L, Wang S,
Xing Q, Teng X, Teng W, Shan Z. The relationship between serum
thyrotropin and components of metabolic syndrome. Endocr J. 58:
23–30, 2000.
2. Kanaya AM, Harris F, Volpato S, Perez-Stable EJ, Harris T,
Bauer DC. Association between thyroid dysfunction and total
cholesterol level in an older biracial population: the health, aging
and body composition study. Arch Intern Med. 162:773–79, 2002.
3. Paschos P, Paletas K. Non alcoholic fatty liver disease and
metabolic syndrome. Hippokratia. 13(1):9–19, 2009 Jan-Mar.
4. Lynnda JN, Tienhoven-Wind V, Dullaart R. Low-normal Thyroid
function and Novel Cardiometabolic Biomarkers. Nutrients.
7(2):1352-1377, 2015 February.
5. Carlos-Raboca J, Jimena C, Kho S, Andag-Silva A, Jasul Jr. G,
Nicodemus Jr. N, Cunanan E, Duante C. The Philippine Thyroid
Diseases Study (PhilTiDeS 1): Prevalence of Thyroid Disorders
Among Adults in the Philippines. JAFES. Vol. 27 No. 1, 2012 May.
6. Canaris GJ, Manowitz NR, Mayor G, Ridway EC. The Colorado
thyroid disease prevalence study. Arch Intern Med. 160:526–34,
2000.
7. Iqbal A, Jorde R, Figenschau Y. Serum lipid levels in relation
to serum thyroid-stimulating hormone and the effect of thyroxine
treatment on serum lipid levels in subjects with subclinical
hypothyroidism: the Tromsø Study. Journal of Internal Medicine.
260(1):53–61, 2006 Jul.
8. Tian L, Song Y, Xing M, Zhang W, Ning G, Li X, Yu C, Qin
C, Liu J, Tian X, Sun X, Fu R, Zhang L, Zhang X, Lu Y, Zou
J, Wang L, Guan Q, Gao L, Zhao J: A novel role for thyroid-
stimulating hormone: up-regulation of hepatic 3-hydroxy-3-
methyl-glutaryl-coenzyme A reductase expression through the
cyclic adenosine monophosphate/protein kinase A/cyclic adenosine
monophosphate-responsive element binding protein pathway.
Hepatology. 52: 1401-1409, 2010.
9. Lu M, Lin RY: TSH stimulates adipogenesis in mouse embryonic
stem cells. J Endocrinol. 196: 159-169, 2008.
10. Gagnon A, Antunes TT, Ly T, Pongsuwan P, Gavin C, Lochnan
HA, Sorisky A: Thyroid-stimulating hormone stimulates lipolysis
in adipocytes in culture and raises serum free fatty acid levels in
vivo. Metabolism. 59: 547-553, 2010.
11. Santini F, Galli G, Maffei M, Fierabracci P, Pelosini C, Marsili
A, Giannetti M, Castagna MG, Checchi S, Molinaro E, Piaggi
P, Pacini F, Elisei R, Vitti P, Pinchera A: Acute exogenous
TSH administration stimulates leptin secretion in vivo. Eur J
Endocrinol.163: 63-67, 2010.
Volume 55 Number 1 Jan - March., 2017 7
 Lingad-Sayas RC, et al. Prevalence of Elevated TSH and its Association with Dyslipidemia and NAFLD

12. Asvold BO, Vatten LJ, Nilsen TI, Bjoro T. The association in euthyroid subjects. J Huazhong Univ Sci Technolog Med Sci.
between TSH within the reference range and serum lipid 32(1):47-52, 2012 Feb.
concentrations in a population-based study. The HUNT Study. Eur 27. Eshraghian A, Dabbaghmanesh MH, Eshraghian H, Fattahi
J Endocrinol. 156(2): 181-6, 2007 Feb 1. MR, Omrani GR. Nonalcoholic fatty liver disease in a cluster of
13. Asvold BO, Vatten LJ, Bjoro T. Associations of TSH levels Iranian population: thyroid status and metabolic risk factors. Arch
within the reference range with future blood pressure and lipid Iran Med. 16(10):584-9, 2013 Oct;
concentrations: 11-year follow-up of the HUNT study. Eur J 28. Eshraghian A and Jahromi AH. Non-alcoholic fatty liver
Endocrinol. 169: 73-82, 2013 Jul 1. disease and thyroid dysfunction: A systematic review. World J
14. Lu L, Wang B, Shan Z, Jiang F, Teng X, Chen, Lai Y, Wang J, Gastroenterol. 20(25): 8102–8109, 2014 Jul 7.
Xue H, Wang S, Li C, Liu H, Li N, Yu J, Shi L, Hou X, Xing 29. Gharib H, Tuttle RM, Baskin HJ, et al. Subclinical thyroid
Q, Bai X, Teng W. The Correlation between Thyrotropin and dysfunction: a joint statement on management from the American
Dyslipidemia in a Population-based Study. J Korean Med Sci. Association of Clinical Endocrinologists, the American Thyroid
26(2):243-249, 2011 Feb. Association, and the Endocrine Society. J Clin Endocrinol Metab.
15. Kanaya AM, Harris F, Volpato S, Perez-Stable EJ, Harris T, 90:581, 2005.
Bauer DC. Association between thyroid dysfunction and total 30. Garber JR, Cobin RH, Gharib H, et al. Clinical practice
cholesterol level in an older biracial population: the health, aging guidelines for hypothyroidism in adults: cosponsored by the
and body composition study. Arch Intern Med. 162:773–79, 2002. American Association of Clinical Endocrinologists and the
16. Walsh JP1, Bremner AP, Bulsara MK, O’leary P, Leedman American Thyroid Association. Thyroid 2012; 22:1200.
PJ, Feddema P, Michelangeli V. Thyroid dysfunction and 31. Tchelepi H, Ralls P, Radin R, Grant E. Sonography of Diffuse
serum lipids: a community-based study. Clin Endocrinol (Oxf). Liver Disease. Journal of Ultrasound Medicine. vol. 21 no. 9
63(6):670-5, 2005 Dec. 1023-1032, 2002 Sept.
17. Xu C, Yang X, Liu W, Yuan H, Yu C, Gao L, Zhao J. Thyroid 32. WHO Expert Consultation. Appropriate body-mass index for
stimulating hormone, independent of thyroid hormone, can elevate Asian populations and its implications for policy and intervention
the serum total cholesterol level in patients with coronary heart strategies. The Lancet. 363(9403):157–63, 2004.
disease: a cross-sectional design. Nutrition & Metabolism. 9:44, 33. Ortiz-Lopez C, Lomonaco R, Orsak B, Finch J, Chang Z,
2012 May. Kochunov VG, Hardies J, Cusi K. Prevalence of prediabetes and
18. Sarzosa TV, Astudillo CM. Relationship of thyroid-stimulating diabetes and metabolic profile of patients with nonalcoholic fatty
hormone levels to development of dyslipidemia and determination liver disease (NAFLD). Diabetes Care. 35(4):873-8, 2012 Apr.
of an ideal cut-off point for start replacement therapy. Endocrinol 34. Lee KW, Bang KB, Rhee EJ, Kwon HJ, Lee MY, Cho YK. Impact
Nutr. 59:575–82, 2012. of hypothyroidism on the development of non-alcoholic fatty liver
19. Paschos P, Paletas K. Non alcoholic fatty liver disease and disease: A 4-year retrospective cohort study. Clin Mol Hepatol. .
metabolic syndrome. Hippokratia. 13(1):9–19, 2009 Jan-Mar. 21(4): 372–378, 2015 Dec.
20. Sheth SG, Chopra S. Epidemilogy, clinical features and diagnosis
of nanalcoholic fatty liver disease in adults [Internet]. UpToDate;
2012 Nov 20 [updated 2013 Mar; cited 2014 Jun 16]. Available
from: http://firedrops.centelia.net/uptodate/contents/mobipreview.
htm?37/13/38105/abstract/45,46#H147569346
21. Fan JG, Saibara T, Chitturi S, Kim BI, Sung JJ, Chutaputti A;
Asia-Pacific Working Party for NAFLD. What are the risk factors
and settings for non-alcoholic fatty liver disease in Asia-Pacific?
J Gastroenterol Hepatol. 22(6):794-800, 2007 Jun.
22. De Lusong MA, Labio E, Daez L, Gloria V. Non-alcoholic fatty
liver disease in the Philippines: Comparable with other nations?
World J Gastroenterol. 14(6):913-7, 2008 Feb 14.
23. Eshraghian A, Jahromi AH. Non-alcoholic fatty liver disease and
thyroid dysfunction: A systematic review. World J Gastroenterol.
20(25):8102-8109, 2014 July 7.
24. Xu L, Ma H, Miao M, Li Y. Impact of subclinical hypothyroidism
on the development of non-alcoholic fatty liver disease: a
prospective case-control study. J Hepatol. 57(5):1153-4, 2012 Nov.
25. Tao Y, Gu H, Wu J, Sui J. Thyroid function is associated with
non-alcoholic fatty liver disease in euthyroid subjects. Endocr Res.
40(2):74-8, 2015.
26. Zhang J, Sun H, Chen L, Zheng J, Hu X, Wang S, Chen T.
Relationship between serum TSH level with obesity and NAFLD

8 Volume 55 Number 1 Jan - March., 2017

 Philippine Journal of Internal Medicine
ST-Segment Elevation in Acute Cholecystitis with Uncontrolled
Hyperthyroidism
Joanavi Montesclaros Ordoña-Miranda, M.D.*; Sharon Rose Mortel, M.D.** and Daisy Angeles Jarcia, M.D.,***
Abstract
Synopsis: A variety of non-cardiac conditions have been
reported to present with ischemic heart disease clinically
and electrocardiographically like cholecystitis which leads
to nonspecific T-wave inversions or ST-segment depressions,
rarely it leads to ST-segment elevation.
Clinical Presentation: We report a case of a 58-year-old,
male, hypertensive, diabetic, and with hyperthyroidism
on medication. Patient presents with two weeks history
of epigastric pain associated with nausea and vomiting.
Symptoms spontaneously resolved until one day prior to
admission patient developed persistent abdominal pain.
Patient was seen at a local hospital wherein work-up
was done which showed leukocytosis on CBC, hydrops
of gallbladder on ultrasound. Further work-up were
anteroseptal wall ST elevation on ECG with negative cardiac
enzymes. Patient was advised transfer to our institution.
Physical Findings: Pertinent Physical exam includes
tachycardia, epigastric tenderness and positive Murphy’s
sign. During the course, patient developed fever and
jaundice.
I ntroduction
A variety of noncardiac conditions have been reported
to mimic ischemic heart disease both clinically and with ECG
changes. Some of these include cholecystitis, pancreatitis,
and pneumonitis. Usually these conditions lead to diffuse
ECG changes, such as nonspecific T-wave inversions or ST-
segment depressions. Although chest pain with ST-segment
elevation frequently indicates cardiac ischemia, it has also
been reported with gastric distension, acute cholecystitis,
pericarditits, neoplastic invasion of the myocardium, acute
cor pulmonale, and hypothermia. Awareness of these
differentials is crucial to ensuring appropriate diagnostic
investigations, and early confirmation of the alternative
diagnoses.1
*
Resident-in-Training, Department of Internal Medicine, Medical Center
Muntinlupa
**
Fellowship-in-Training, Department of Nephrology, Makati Medical
Center
***
Cardiology Consultant, Philippine Heart Center, Medical Center
Muntinlupa
Corresponding Author: Joanavi Montesclaros Ordoña-Miranda, M.D.,
Medical Center Muntinlupa, Muntinlupa, Philippines
Email: angevilpink@gmail.com
The PHILIPPINE JOURNAL OF INTERNAL MEDICINE is a peer reviewed journal and a copyrighted publication of the Philippine College of Physicians
Case Report
Laboratory Work-up: Repeat CBC still showed leukocytosis
with neutrophilia. Repeat electrocardiogram showed
anteroseptal wall ST elevation with negative Troponin.
Echocardiogram showed adequate ejection fraction and
adequate wall motion contractility. Thyroid function test
showed increased FT4 and decreased TSH.
Treatment: Patient was initially started with acute coronary
syndrome regimen. Antibiotics were initiated and anti-
thyroid and anti-diabetes drugs were adjusted accordingly.
There was noted progressive abdominal pain; hence,
patient was referred to surgery. Patient was cardio-
pulmonary and endocrinologically prepared and cleared
for the procedure. Patient tolerated the procedure.
Outcome: Patient was discharged improved with noted
improvement of the electrocardiogram.
Keywords:Cholecystitis, ST-segment elevation, impending
thyroid storm, cholecystectomy
C ase
This is a case of a 58-year-old male, married, Filipino,
known hypertensive hyperthyroid and diabetic who was
admitted due to a two weeks history of epigastric pain,
burning, non-radiating with a pain score of 2/10 precipitated
by caffeine intake, associated with nausea and one episode
of vomiting. There was no medication taken, nor any consult
was done. Symptoms spontaneously resolved until one
day prior to admission, the patient developed persistent
abdominal pain. Patient was seen at a local hospital
wherein work-up was done which showed leukocytosis
(16,900) with neutrophilic predominance (90%) on CBC,
hydrops of gallbladder on ultrasound. Further work-up were
anteroseptal wall ST elevation on ECG with negative cardiac
enzymes. Patient was advised transfer to our institution.
Patient is a known hypertensive and hyperthyroid for 10
years and diabetic for five years who was maintained on
felodipine 5.0 mg/ tab OD, methimazole 20 mg/tab BID and
glimepiride + metformin 5/500 mg/tab BID. No previous
surgery. He had a family history of hypertension and diabetes
Volume 55 Number 1 Jan - March., 2017 1
 Ordona-Miranda JM, et al. ST-Segment Elevation in Acute Cholecystitis

Figure 1. Anteroseptal wall ST-segment elevation

Figure 2. Resolution of Anteroseptal wall ST-segment elevation

2 Volume 55 Number 1 Jan - March., 2017

 ST-Segment Elevation in Acute Cholecystitis
on both sides. He is a non smoker and an occasional
alcoholic beverage drinker.
Physical examination showed a BP of 150/90, tachycardia
at 110 bpm with a BMI of 24.9kg/m2, palpable non-tender
non-movable 1x1cm mass on the anterior neck area, (+)
Murphy’s sign and epigastric tenderness. There was no
jaundice and icterisia. Initial Impression was ST segment
elevation myocardial infarction, acute cholecystitis,
hyperthyroidism, diabetes mellitus (DM) type 2.
At the ER, diagnostics were a repeat ECG that showed
persistent anteroseptal wall ST-segment elevation and
negative cardiac enzymes.
Acute coronary syndrome regimen was initiated;
Nitrates, ARB, and anticoagulant. Echocardiogram showed
normal ejection fraction (69%); concentric LVH with
adequate wall motion and contractility. Other medications
were methimazole 20 mg/ tab BID, bolus insulin, and
ampicillin sulbactam 1.5 g IV every eight hours.
On the first hospital day, patient developed jaundice,
icterisia and fever documented at 38°C. Patient was referred
to surgery and was then scheduled for cholecystectomy
with common bile duct exploration with intraoperative
cholangiogram. Patient’s thyroid function tests were FT4
29.69 (increased), TSH 0.0005 U/mL (decreased) which was
indicative of uncontrolled hyperthyroidism. The impression
was Impending thyroid storm (total score of 35 based Burch
and Wartofsky). A repeat CBC showed increase in the WBC
to 19,400, hence, sepsis secondary to cholecystitis was
highly considered. Antibiotics were shifted to Piperacillin-
tazobactam 4.5g IV every eight hours. The decision for
surgery was done. Endocrine and cardio clearance were
sought. Patient was prepared for surgery - Methimazole
was shifted to Propylthiouracil 50 mg/tab four tablets every
four hours, Dexamethasone 4.0 mg IV every 12 hours and
propranolol 60 mg BID were also started.
On the fourth hospital day, patient underwent
cholecystectomy. Intraoperative finding was gangrenous
cholecystitis. Patient tolerated the procedure. Post
operatively, there was resolution of symptoms and a repeat
ECG showed resolution of the previous ST-segment elevation.
Patient was then discharged on the eighth hospital
day improved with a final diagnosis of acute cholecystitis,
HASCVD, Hyperthyroidism, DM type 2.
D iscussion
We described a case with a chief complaint of
epigastric pain and based on history and physical exam
of the patient, an impression of acute cholecystitis was
Ordona-Miranda JM, et al.
made. It was further backed by ultrasonographic findings
of hydrops of the gallbladder and a leukocytosis of 19,400
cell/uL. Hydration, antibiotics and surgery are the treatment
approach to the patient.
However, on further work-up, the ECG showed an
ST-segment elevation on leads v1-3 (anteroseptal wall)
which denotes an acute ischemic cardiac event. The
clinical hallmark of acute coronary syndrome is chest
pain. Though the patient did not present with chest pain
rather an epigastric pain, according to Harrison’s Principle
of Internal Medicine, dyspnea and epigastric pain are
angina equivalents. Also, the patient is diabetic which may
contribute to the atypical presentation of ischemic heart
disease. In diabetic patients, it is suspected that partial or
complete autonomic denervation may contribute to the
prevalence of silent ischemia. 2 The cardiac enzymes of the
patient were negative, however, 2/3 diagnostic criteria for
acute coronary syndrome were fulfilled. An acute coronary
event was considered and cannot be ruled out at this
time. The patient was initially managed as a case of acute
coronary syndrome with acute cholecystitis.
Serial ECGs done showed persistent ST-segment elevation
with persistent negative repeat enzymes. On further cardiac
work-up, two-dimensional ECG showed adequate ejection
fraction with normal left ventricular dimension and adequate
wall motion contractility. According to Coven, absence of
segmental wall-motion abnormality on echocardiogram
during active discomfort is a highly reliable indicator of a
nonischemic origin of symptoms.4 Also, most patients initially
presenting with ST-segment elevation ultimately evolves to
Q waves on the ECG.3 With the series of ECG done for the
patient, there was no conversion of ST-segment elevation
to Q waves. With the recent data, a nonischemic origin of
ST-segment elevation was entertained.
A variety of noncardiac conditions have been reported
to mimic ischemic heart disease both clinically and with ECG
changes. Some of these include cholecystitis, pancreatitis,
and pneumonitits. Usually these conditions lead to diffuse
ECG changes, such as nonspecific T-wave inversions or
ST-segment depressions.5 Rarely does it lead to ST-segment
elevation.
The patient tolerated the procedure and was
discharged improved. There was resolution of symptoms
and a resolution of the ST-segment elevation on ECG.
Biliary colic and cholecystitis are in the spectrum of
biliary tract disease. Gallstones are divided into cholesterol
stones (80%) and pigment stones (20%). Patients with
gallstones may be asymptomatic or symptomatic once
a stone obstructs or passes the cystic duct or common
bile duct. Cholecystitis occurs when obstruction at the
cystic duct is prolonged resulting in inflammation of the
Volume 55 Number 1 Jan - March., 2017 3
 Ordona-Miranda JM, et al.
gallbladder wall. It may occur in approximately 20% of
patients.5 Mucocele (hydrops) of the gallbladder is a term
denoting an overdistended gallbladder filled with mucoid
or clear and watery content. The condition can result from
gallstone disease. The gallbladder mucocele distention,
which is usually non-inflammatory, results from an outlet
obstruction of the gallbladder and is commonly caused by
an impacted stone in the neck of the gallbladder or in the
cystic duct.1
The most common symptom is a constant pain in the
epigastrium or right upper quadrant. Peritoneal irritation by
direct contact with the gallbladder localized the pain to the
right upper quadrant. Nausea, vomiting, and low-grade fever
are associated more commonly with cholecystitis. Jaundice
is unusual in the early stages of acute cholecystitis and may
be found in fewer than 20% of patients. Frank jaundice may
be seen with concomitant choledocholithiasis. Tachycardia
and tachypnea maybe also be seen. A positive Murphy’s
sign is 97% sensitive and has positive predictive value of 93%
for cholecystitis according to Singer et al. Diagnostics may
include CBC. In an unpublished article by Steel et al entitled
“Acute Cholecystitis and Biliary Colic”, an elevated WBC of
11,000 cells/uL may suspect cholecystitis and a WBC greater
than 15,000 cells/uL may indicate perforation or gangrene.
Ultrasonography is 90-95% sensitive for cholecystitis and has
a 78-80% specificity. 3
On the first hospital day, patient still has persistent
abdominal pain and new onset of fever and jaundice.
Impression was sepsis secondary to acute cholecystitis,
t/c gangrenous gallbladder, beginning cholangitis, r/o
impending thyroid storm. The patient was referred to
surgery for possible cholecystectomy, which is the definitive
treatment.
Diabetic patients with cholecystitis are more likely to
experience complications. Complicated cholecystitis has
up to a 25% mortality rate. In men and diabetic patients
with emphysematous gallbladder, there is a mortality rate
of 15% and 25% mortality among patients with empyema
or gangrenous gallbladder.4 When gangrene or perforation
are suspected, or if patients develop signs of instability
(progressive fever, intractable pain) while on supportive
therapy, intervention must be considered on an emergent
basis to remove the offending inflamed, gangrenous, or
perforated gallbladder. The decision to operate on the
patient was done. However, pre-operative assessment and
clearance proved to be difficult because the patient’s
comorbidities.
Thyrotoxic patients should ideally be as close as
possible to clinical and biochemical euthyroidism before
undergoing surgery. It is a clinical challenge to achieve
perioperative control of thyrotoxicosis in acutely ill patients,
most often requiring combined therapy or less than optimal
4 Volume 55 Number 1 Jan - March., 2017
ST-Segment Elevation in Acute Cholecystitis
control. For urgent or emergent surgery, rapid preoperative
preparation could be attained using thionamides with
Propylthiouracil 200mg every four hours. This could be
combined with Betablockers, and high dose glucocorticoids.
Dexamethasone will decrease T4-to-T3 conversion and have
been used in the treatment of thyroid storm. Prognosis for
adequately prepared patients is better, with decreased
morbidity and mortality of adequately prepared patients.8
Adrenal reserve may be low in thyrotoxic patient. If time
does not allow for completely adequate preparation prior to
emergent surgery in the patient with severe hyperthyroidism,
or if thyroid storm occurs, hydrocortisone can be given 100
mg IV every eight hours. This will not only treat possible
adrenal insufficiency but may block peripheral conversion
of T4 to T3 as well. Treatment of thyroid storm includes beta
blockade, thioamides, iodinated contrast agents, iodine,
and corticosteroids.9
The presence of Q waves or significant ST segment
elevation or depression has been associated with an
increased incidence of perioperative cardiac complications.9
The patient was preoperatively cleared as high risk for
surgery.
According to Patel et al in 2011, their case report9 was
only the fifth reported case of ST-segment elevation in acute
cholecystitis, making our case report the sixth reported case,
but the first one with uncontrolled hyperthyroidism.
The exact mechanism for the appearance of ST-segment
elevation in acute cholecystitis is still unknown. According to
a case report by Patel, the proposed mechanisms are the
following:
1. Inflammation of the hepatobiliary system and pancreas,
along with viral myocarditis has been noted to produce
changes in the electrocardiogram.
2. Acute inflammatory and ulcerative conditions involving
the gallbladder or duodenum cause irritation and
spasticity of surrounding structures.
3. The pain induced by the irritation and spasticity of
surrounding structures can create reflex stimuli through
the autonomic pathways to restrict or alter the coronary
blood supply.
4. It is possible that acute upper abdominal disease can
prematurely reveal subclinical changes in the coronary
circulation
5. The alterations in the ECG could have been caused
by temporary myocardial ischemia, since the changes
disappeared.
 ST-Segment Elevation in Acute Cholecystitis Ordona-Miranda JM, et al.

C onclusion

ST-segment elevation with a clinical setting suggestive of
myocardial infarction justifies reperfusion therapy. However,
clinicians should be aware of the uncommon causes of
ST-segment elevation, as to our case acute cholecystitis,
because the risk of reperfusion therapy outweighs any
potential benefit. It is of importance for clinicians to diagnose
acute cholecystitis right away as to avoid any complications
such as sepsis, cholangitis or pancreatitis which can
furthermore deteriorate patient’s condition if not surgically
managed. The dilemma to operate or not to operate is
further complicated by the risk of the patient to develop
thyroid storm because of the uncontrolled hyperthyroidism.
Thus, a team approach in the management of this case as
well as excellent clinical judgment proved beneficial to the
patient.

R eferences
1. Fauci et. Al. Ischemic Heart Disease. Harrison’s Principle of
Internal Medicine, 18th ed. 2012. 293: 1578-1593.
2. Tabibiazar, Ramin, et al. Silent Ischemia in People with Diabetes;
A Condition that must be heard. Clinical Diabetes, 2003.
3. Shea JA, Berlin JA, Escarce JJ, et al. Revised estimates of
diagnostic test sensitivity and specificity in suspected biliary tract
disease. Arch Intern Med. 1994 Nov 28. 154(22):2573-81
4. Hickman MS, Schwesinger WH, Page CP. Acute cholecystitis
in the diabetic. A case-control study of outcome. Arch Surg. 1988
Apr. 123(4):409-11
5. Demehri FR, Alam HB. Evidence-based management of common
gallstone-related emergencies. J Intensive Care Med. 2016 Jan. 31
(1):3-13
6. Coven, David et. Al. Acute Coronary Syndrome: Practice
Essentials, Background, Etiology. September 2015.
7. Patel, Nimesh, et al. Acute Cholecystits Leading to Ischemic ECG
Changes in a Patient with No Underlying Cardiac Disease. Journal
of the Society of Laparoendoscopic Surgeons, 2011; 15:105-108.
8. Burch HB, Wartofsky L., Diagnostic Criteria for Diagnosis of
Thyroid Storm. Endocrinol Clin North Am, 1993.
9. Robert Schiff et.al. Perioperative evaluation and management of
the patient with endocrine dysfunction. Med Clin North Am 2003;
87:175-192
10. Langley RW, et al. Perioperative management of the thyrotoxic
patient. Endocrinol Metab Clin N AM 2003; 32:519-534.
11. A. Tsatsoulis, et. al. The effect of thyrotoxicosis on thyrotoxicosisi
on adrenocoritcal reserve. European Journal of Endocrinology
(2000); 142 231-235
12. Baron JF, et al. Dipyridamole-thallium scintigraphy and gated
radionuclide angiography to assess cardiac risk before abdominal
aortic surgery. N Engl J Med 1994; 330:663.

Volume 55 Number 1 Jan - March., 2017 5

 Philippine Journal of Internal Medicine
The Joint Philippine Society of Gastroenterology (PSG) and
Philippine Society of Digestive Endoscopy (PSDE) Consensus
Guidelines on the Management of Colorectal Carcinoma
Jose D. Sollano, M.D. 1; Marie Antoinette dC. Lontok, M.D. 2; Mark Anthony A. de Lusong, M.D. 3; Rommel P. Romano, M.D. 1; Therese C.
Macatula, M.D. 3; Diana A. Payawal, M.D. 4; Joseph C. Bocobo, M.D. 2; Frederick T. Dy, M.D. 1; Edgardo M. Bondoc, M.D. 2; Ernesto G. Olympia,
M.D.5; Jaime G. Ignacio, M.D. 6; Felicisimo C. Agas, M.D. 4; Marichona C. Naval, M.D. 7; Evan G. Ong, M.D. 8; Arsenio L. Co, M.D. 9; Bernadette A.
Moscoso, M.D. 10; John Arnel N. Pangilinan, M.D. 2; Marie Michelle S. Cloa, M.D. 11; Jose Augusto G. Galang, M.D. 12; Albert E. Ismael, M.D. 1; Ma.
Lourdes O. Daez, M.D. 3; Peter P. Sy, M.D. 4; Yvonne L. Mina, M.D. 13
Background and Objectives:
Colorectal cancer (CRC) is an increasingly prevalent
malignancy in the Philippines. According to the 2010
Philippine Cancer Facts and Estimates it is the most
common cancer of the gastrointestinal tract. 1 In the
2012 IARC Globocan Report, CRC ranks fifth among all
cancers in both sexes in the Filipinos, even higher than liver
cancer. Except for Japan and Singapore, the incidence
rates of CRC have been increasing in Asia, including the
Philippines. 2-5
The natural history of CRC presents a unique opportunity
for early intervention because the colon is accessible
to examinations which enable early identification and
efficient removal of precursor premalignant and/or
early malignant lesions. Many of these examinations are
available in the country. CRC has a high survival rate if
detected in its early stages. Advances in the understanding
of its epidemiology and carcinopathogenetic pathways, as
well as, availability of better diagnostic tests and treatment
approaches have improved the cure rates, survival and
outlook of patients with CRC.
In developed countries, initiatives by their national
health care systems directed at increasing public
awareness and promoting screening programs have
contributed further to these strides.6-10 In Asia, awareness
and knowledge on the symptoms and risk factors of CRC
are extremely low, as well as, the need and compliance
to undergo CRC screening even when asymptomatic. In
addition to physician practices and health insurance status
which impact substantially on testing, many perceived
health, psychological, and access barriers to testing also
exist.11 In the Philippines, the awareness on CRC is relatively
1
University of Santo Tomas Hospital, 2St. Luke’s Medical Center,
3
UP-Philippine General Hospital, 4Cardinal Santos Medical Center,5Makati
Medical Center, 6Veterans Memorial Medical Centre, 7East Avenue Medical
Center, 8Metropolitan Hospital, 9Chinese General Hospital, 10Cebu Doctors
University Hospital, 11 Manila Doctors Hospital, 12 Angeles University
Foundation Medical Center, 13Victor R Potenciano Medical Center
Corresponding Author: Jose D. Sollano, M.D., University of Santo
Tomas Hospital, Manila, Philippines
Email: joeys_812@yahoo.com
The PHILIPPINE JOURNAL OF INTERNAL MEDICINE is a peer reviewed journal and a copyrighted publication of the Philippine College of Physicians
Consensus Guidelines
high largely because CRC claimed the life of an iconic,
high-profile public figure. Thus, we must take advantage
of this important first step in our strategy to control CRC
in the country.12
Many experts argue that a comprehensive and well-
executed program in early detection and appropriate
t re a t me n t will h e lp p re v e nt de a t hs a nd morbidit y
associated with CRC. A European review opined that
it is no longer acceptable that a cancer which can be
detected early by widely-available screening methods
and can be treated adequately with currently-available
surgical/endoscopic procedures should continue to cause
so many deaths.13
The objective of this clinical practice guideline is
to provide evidence-based recommendations on the
appropriate approach to the management of CRC,
encompassing early detection, proper treatment and
efficient follow-up care, as well as, addressing the need
for the national healthcare system of the country to adopt
a strategy to achieve these ends.
Methods
A core working party composed of nine members
(JDS, MDCL, RPR, MAAL, JCB, ECB, TCM, DAP, FTD) was
convened to determine the needs and concerns of local
medical practitioners, as well as, evaluated the national
health policies regarding screening, diagnosis, treatment,
and follow-up surveillance for CRC. The members were
chosen for their active clinical practice and researches
focused on colorectal cancer, expertise in evidence-based
medicine and academic affiliations. Review of scientific
papers from different accredited training institutions of
the Philippine Society of Gastroenterology (PSG) and
Philippine Society of Digestive Endosocopy (PSDE) which
dealt with CRC was performed. An electronic survey was
conducted on 12 training institutions all over the country to
gather current information on the clinical presentation of
CRC and the attitudes and practices of gastroenterology
colleagues regarding screening, colonoscopy, surveillance
and use of CRC guidelines in their care of the CRC
Volume 55 Number 1 Jan. - March, 2017 1
 Sollano JD, et al. PSG and PSDE Consensus Guidelines on the Management of Colorectal Carcinoma

patients and the at-risk population. Several pre-consensus
development meetings were held to evaluate the results
of the surveys, identify the needs of the local physicians
in tackling efficiently the important concerns about CRC,
scrutinize appropriate scientific articles and formulate
draft recommendations relevant to the scope of this CRC
consensus guidelines. Twelve recommendations were
drafted utilising the literature retrieved from Medline,
Embase, the Cochrane Central Register of Controlled Trials
and ISI Web of Knowledge, including manual searches in
bibliographies of key articles, proceedings of abstracts of
major gastroenterology and endoscopy meetings held in
the past five years (Asian Pacific Digestive Week (APDW),
Digestive Disease Week (DDW) and United European
Gastroenterology Week (UEGW) and articles published in
the Philippine Journal of Internal Medicine and Philippine
Journal of Gastroenterology, as well as, the outcome of
the electronic survey as basis.
as follows; a) strong b) conditional.14 The participants were
constantly reminded that care is needed so as to recognize
that ‘quality of evidence’ is not necessarily synonymous
with ‘strength of recommendation’ and vice versa; and
that their informed judgment is necessary. An unrestricted
educational grant from the PSG and PSDE made possible
the preparation and completion of this document. During
the entire duration of the consensus process, as well
as, in the writing of the manuscript, no interference or
representations from any third party were allowed by the
consensus development group.
S tatement 1
Colorectal cancer (CRC) is an increasingly prevalent
malignancy in the Philippines. Currently, it is the most
common cancer of the gastrointestinal tract among
Filipinos.

Through a modified Delphi process, the 12

Level of evidence: high;
recommendations proposed by the core working party
Strength of recommendation: strong
were circulated to all training program directors/chiefs of
A – 95%; B – 5%
GI section for electronic voting by email. Voting for every
statement was done as follows; (A) Accept completely;
In the last three decades, the incidence of colorectal
(B) Accept with some reservation; (C) Accept with
cancer in Asia, the Philippines included, has increased
major reservation; (D) Reject with reservation; (E) Reject
rapidly. Except for Japan and Singapore, CRC-related
completely. Additional comments were encouraged for
mortality has increased similarly. This rising trend in
each statement and revisions made accordingly during
CRC incidence appears to be more pronounced in
subsequent deliberations of the core working party.
economically-advanced than in poorer societies.3,15
After the electronic voting, a consensus development
conference was held and participated in by the training
From 1988-2002, data from two population-based
program directors and the core working party (CWP).
cancer registries of Metro Manila and Rizal province
Each CWP member was assigned to present and defend
showed an increasing trend in the age-standardized
a statement/recommendation using appropriate studies
incidence rates (ASRs) for colorectal and prostate cancers.
to support his/her argument. During the conference, a
Interestingly, ASRs significantly above the average, i.e.,
pre-assigned panel composed of the training directors
ASRs 14.0–21.7 were observed among the most urbanized
served as resource experts and together with the presenters
and affluent cities in these two sites in the country.2, 5, 16, 17
were required to evaluate appropriate publications,
Towards the end of 2002, CRC was more common than liver
taking special care to include publications from the
and gastric cancers. In the Globocan 2012 IARC report,
Philippines and where there were none, studies from Asia
CRC was the most common cancer of the gastrointestinal
were preferred. After a robust discussion and debate,
tract among Filipinos.
voting on every statement was conducted anonymously
using a wireless keypad system. If the pre-determined
agreement of 85% was not achieved, the statement was S tatement 2
rejected. The level of evidence and the strength for each
Older age, male gender, obesity, cigarette smoking,
recommendation were rated by the participants using the
increased consumption of red meat, alcohol, physical
Grading of Recommendations Assessment, Development,
inactivity, or a family history of CRC or advanced adenoma
and Evaluation (GRADE) process, as follows; a) High —
increases the risk of CRC.
Further research is very unlikely to change our confidence
in the estimate of effect b) Moderate — further research is
Level of evidence: high;
likely to have an important impact on our confidence in the
Strength of recommendation: strong
estimate of effect and may change the estimate c) Low —
A – 55%; B – 45%
further research is very likely to have an important impact
on our confidence in the estimate of effect and is likely to
Increasing age is the most significant risk factor for
change the estimate d) Very low — any estimate of effect
CRC.18,19 Most cases of CRCs (>90%) are diagnosed at age
is uncertain. The strength of recommendation was classified

2 Volume 55 Number 1 Jan - March, 2017

 PSG and PSDE Consensus Guidelines on the Management of Colorectal Carcinoma
50 years or above.19,20 Between 2001-2010, data from the
US indicate that the while the incidence of CRC has been
declining for patients >50 years old, it has been slowly
increasing for patients 40-49 years old.21
A recent meta-analysis which included 18 large studies
from Asia, America and Europe showed strong evidence
that men are at greater risk for advanced colorectal
neoplasia across all age groups. Relative risk (RR) for
advanced neoplasia was 1.83 (95%Cl, 1.69-1.97) and CRC
was 2.02 (95%CI, 1.53-2.66), respectively. 22
Obesity has been repeatedly mentioned as a risk factor
not only in colon cancer, but also for other malignancies.
A meta-analysis of 31 prospective studies revealed an
association of obesity with CRC in both men (RR-1.30,
95%CI, 1.25-1.35) and women (RR-1.12, 95%CI, 1.07-1.18).
This association was seen to be stronger with males than
females (p <0.0001).23-25 Interestingly, high BMI is associated
with an increased rectal cancer risk in males (RR 1.12,
1.09-1.16) but not in females (RR-1.03, 95%CI, 0.99-1.08).
This observation is corroborated by several other meta-
analyses. 23-25
There is also evidence demonstrating a direct
relationship between smoking and CRC risk. Tsoi et al
pooled 28 prospective studies of more than a million
subjects from around the world and demonstrated that
“ever smokers” have a higher risk CRC than “never
smokers” (RR 1.20, 1.10-1.30). This risk is more pronounced
with male smokers.26 Another meta-analysis of 121 articles
reported similar results and estimated that this risk is most
significant in those who smoked for >30 pack years.27
In a meta-analysis of cohort and case-control
studies, Norat et al showed an increased risk of CRC with
consumption of red meat (RR 1.35, 95%CI, 1.21 - 1.51)28 and
processed meat (RR 1.31, 95%CI, 1.13- .51). 28 An increased
risk for CRC is associated with consumption of 120g/day
of red meat (RR 1.28, 95%CI, 1.15 - 1.42) and 30g/day of
processed meat (RR 1.20, 1.11-1 31). 29,30
In 2008, the NIH-AARP Diet Health Study revealed
that spending more than nine hours watching TV per
day increased the risk for CRC (RR 1.61, 95%CI, 1.14 - 2.27;
p<0.001). Inversely, engaging in exercise or sports more than
five times a week compared to never or rarely exercising
reduced the risk of colon cancer in men (RR 0.79. 95%CI,
0.68 - 0.91; p<0.001). 31 The risk of CRC is increased with
longer TV viewing time (RR 1.54, 95%CI,1.19-1.98), longer
occupational sitting time (RR 1.24, 95%CI, 1.09-1.41) and
general total sitting time (RR 1.24,95%CI, 1.03-1.50).32 A recent
meta-analysis showed sedentary behavior increased the
risk of colon cancer (RR 1.30, 95%CI, 1. 22-1.39) but not for
rectal cancer (RR 1.05, 95%CI, 0.98-1.13). 33
Sollano JD, et al.
Fedirko et al reported that moderate (RR 1.21, 95%CI,
1.13 - 1.28) and heavy, i.e., more than four drinks per
day or >50g/day (RR 1.52, 95%CI, 1.27 - 1.81) alcoholic
drinking increased the risk of CRC. This association was
weaker for females compared to males and stronger for
Asians compared to Caucasians.34 With increasing grams
of alcohol consumed per day, there is an exponential
increase in CRC mortality.35
The risk for CRC is also increased for both men
and women with increasing number of CRC affected
first degree relatives. 36 There is a two-fold increase in
individuals with one affected first degree relative (RR 2.24,
95%CI, 2.06 - 2.43) and an even higher risk for individuals
with two or more affected first degree relatives (RR 3.97,
95%CI, 2.60 - 6.06). 37 The risk is also higher for siblings or
parents of patients with a history of colorectal adenomas
(RR 1.78, 95%CI, 1.18 – 2.67). A prospective cohort study
involving >5000 participants reported that first-degree
relatives of patients with newly diagnosed adenomas,
particularly those diagnosed younger than 50 years old,
are at increased risk of CRC. The risk increasing to more
than four times greater as compared to relatives of CRC
patients diagnosed at >60 years old (RR 4.36, 95%CI, 2.24-
8.51). 38 Patients with second degree relatives diagnosed
with adenomas are also at risk for CRC (RR 1.15, 1.07-1.23).39
S tatement 3
CRC can be prevented by early detection and removal of
precursor colonic polyps. Diagnosis and treatment at an
early stage is associated with good survival.
Level of evidence: high;
Strength of recommendation: strong
A – 89.5%; B – 10.5%; C - 0%, D - 0%, E=0%
CRC is a common malignancy with a long asymptomatic
phase. Most colon cancers arise in pre-existing colonic
polyps, thus, it offers an enviable opportunity where early
detection and removal of advanced adenomas, i.e.,
polyps > 10 mm or with significant villous features or with
high grade dysplasia, can impact on the natural history
of CRC. Advanced adenomatous polyps are associated
with a higher risk of CRC and are recognized as its non-
obligate precursor. 40-46 In a study among 2,602 patients
who had adenomas removed and followed for 15.8 years,
the standardized incidence-based mortality ratio was
0.47 (95% CI, 0.26 – 0.80) in those who had colonoscopic
polypectomy, suggesting that this approach contributed
to a 53% reduction in CRC-associated mortality.47 In the
US, recent declines reported by national surveys and
microsimulation modelling have attributed the recent
consistent decrease in the incidence and mortality of
CRC largely to the impact of CRC screening and to a
lesser degree, the contributions of improved treatment
Volume 55 Number 1 Jan. - March, 2017 3
 Sollano JD, et al.
and risk factors modification. 48 A large number of
patients with adenomas are now being diagnosed as a
result of the increased utilization of colorectal cancer
screening, particularly the dramatic increase in screening
colonoscopy. The preference towards colonoscopy is
largely due to its additional ability to remove colonic
polyps during the same screening examination. In the
Philippines, colonoscopy services are not available outside
urban centres and thus, may not be readily available to
a) patients who test positive from other screening tests b)
symptomatic patients requiring diagnostic colonoscopy
and, c) patients who need surveillance colonoscopy after
removal of an adenoma or CRC. A national comprehensive
program on CRC risk factor reduction, screening, early
treatment and surveillance, using a relatively inexpensive,
culturally acceptable and widely available examination,
is badly needed.
S tatement 4
Screening for CRC should start at 50 y/o for average-risk
and earlier for high-risk individuals.
Level of evidence: moderate;
Strength of recommendation: strong
A – 60%; B – 35%; C – 5%
Patients who have a personal history of inflammatory
bowel disease, polyps or colorectal cancer, or a family
history of polyposis syndromes have an increased risk of
CRC. Patients who have none of the mentioned risk factors
are considered average-risk individuals. 49
The US Preventive Services Task Force found that
among average-risk individuals, starting screening at age
50 resulted in the best balance between life-years gained
and risks associated with colonoscopy. The evidence
supporting screening at an earlier age is weak. 50,51 The
incidence of CRC rises dramatically from approximately six
to seven per 100,000 among individuals 0-49 years old to
approximately 60-80 per 100,000 among individuals 50-64
years old.52 Ninety-three percent of CRC deaths also occur
at age 50 and older.53
In a prospective multinational survey in 2007, the Asia
Pacific Working Group on Colorectal Cancer found that
the prevalence of colorectal neoplasm was 11.2% among
those <50 years old and 23.9% among those >50 years
old. 54 The prevalence of advanced neoplasm was 2.0%
versus 5.8% in the younger and older group, respectively.
This significant observation led to age as being a criterion
included in the Asia Pacific Colorectal Cancer Score to
stratify the risk of CRC in Asian individuals. 20
In multiple unpublished retrospective and prospective
studies in the Philippines, adenomas are found in only 4-6%
4 Volume 55 Number 1 Jan. - March, 2017
PSG and PSDE Consensus Guidelines on the Management of Colorectal Carcinoma
of patients <50 years old. CRC is diagnosed in 4.0% of all
patients who underwent a lower GI endoscopy. The mean
age at CRC diagnosis is 59 and most are in Stage III.
S tatement 5
Routine CRC screening for patients >75 y/o should
be individualized depending on life expectancy and
associated risks.
Level of evidence: moderate;
Strength of recommendation: strong
A – 78.9%; B – 21.1%
Screening beyond 75 years after consecutive negative
screenings from age 50 adds very little benefit because
the chance of having a missed adenoma or developing
a new lesion that can progress to cancer is very small.51
The survival benefit of routine CRC screening may be
observed not earlier than five years after its performance
thus, limiting its value among the elderly with short life
expectancy. In a retrospective cohort study, age and the
validated Charlson comorbidity index 55 co-dependently
predicted overall mortality. The median survival was less
than five years regardless of comorbidity among the
subjects 80 years and older, and over five years among
patients aged 75-79 with fewer comorbidities, i.e., Charlson
score <4.56 Likewise, among patients diagnosed with CRC,
increasing comorbidities resulted in significant reduction in
life-expectancy across all stages of the disease.57
Using evidence-informed statistical models, Lin et al
showed the estimated extension of life expectancy after
removal of an adenoma during a screening colonoscopy
is significantly higher among younger subjects, i.e., 50-54
years old, compared to subjects >75 years old.58 The number
needed to screen and number needed to prevent one
CRC death increase as a function of age and is inversely
related to the life expectancy.59, 60
Aside from shorter life expectancy, screening elderly
patients entails a higher risk for complications, mostly related
to unnecessary colonoscopic examinations. In a systematic
review of 12 studies, the rate of total serious complications,
including perforations, hemorrhage, cardiovascular
events and death, is 2.8 per 1000 procedures. 8 The odds
of developing these complications in the elderly is 1.66
compared to younger individuals.61
 PSG and PSDE Consensus Guidelines on the Management of Colorectal Carcinoma
S tatement 6
Fecal occult blood tests, preferably using fecal
immunochemical test [FIT], flexible sigmoidoscopy and
colonoscopy are recommended screening examinations
for CRC.
Level of evidence: high;
Strength of recommendation: strong
A – 78.9%; B –21.1%
Statement 6A
Annual fecal based occult blood testing (FOBT), preferably
fecal immunochemical testing (FIT), is the recommended
first line screening test for CRC in average risk individuals
50 years old and above.
Level of Evidence : High
Strength of Recommendation: Strong
Fecal occult blood test (FOBT) is known to detect
cancer more than adenomas. It is a non-invasive and
simple test that needs to be repeated annually or at least
every two years to increase its sensitivity and specificity.
Multiple studies have proven that FOBT decreases CRC and
CRC-related mortality.62-64 FOBT is further differentiated as
gFOBT (guaiac-based fecal occult blood test) or iFOBT/
FIT (fecal immunochemical test). Several Australian and
Asian cost analysis studies consistently showed that FOBT
is the most cost-effective CRC screening test.65 iFOBT/FIT
does not need the dietary restrictions imposed by gFOBT
thus, improving patient compliance. It is also better than
gFOBT in detecting adenomas.66-73
A cohort study of 1,041 asymptomatic high-risk patients
who underwent FIT prior to elective colonoscopy showed
that CRC detection rates were comparable between FIT
and colonoscopy.74 An interim analysis of an ongoing study
comparing FIT with colonoscopy in average risk patients
also showed no significant difference in detecting CRC.75
Many countries consider FOBT as the best screening
approach to CRC because of its wide acceptance. In
resource-limited countries, FOBT is the most affordable
test and may be used to direct higher-risk individuals for
colonoscopy. FOBT, preferably iFOBT/FIT, is the screening
test of choice for CRC detection.20
Sollano JD, et al.
Statement 6B
Flexible sigmoidoscopy every five years and colonoscopy
every 10 years are recommended screening examinations
for CRC.
Level of Evidence: High
Strength of Recommendation: Strong
Using flexible sigmoidoscopy (FS) as the CRC screening
tool, the Norwegian Colorectal Cancer Prevention Trial
(NORCCAP), the US Prostate, Lung, Colorectal, and
Ovarian Cancer Screening Trial (US PLCO), the UK Flexible
Sigmoidoscopy (UKFS) screening trial, and the Italian
once-only sigmoidoscopy (SCORE) trial reported reductions
in CRC incidence by 18-23% and, in CRC mortality by
22-31%. 76-80 Five-yearly FS is cost effective compared with
FOBT and colonoscopy, although no studies have been
performed to verify its cost-effectiveness in the Philippine
setting.65
Currently, colonoscopy is the gold standard to detect
and treat CRC precursor lesions, i.e., adenomas. Simple
white light colonoscopy (WLE) can detect adenomas in
asymptomatic individuals above 50 years by at least 30%
and CRC around 0.1-1%.20,81 In a head-to-head comparison
of detection rates of adenomas, polyps, and flat lesions
using advanced high-resolution scopes, i.e., HD-NBI and
HD-WLE, no significant difference in the performance of
either models of high-definition (HD) colonoscopes was
found.82
Large studies, although most indirect and
observational, have shown that both colonoscopy and
proctosigmoidoscopy significantly reduce the risk of
and deaths due to CRC.83 Nishihara et al, have shown
that CRC mortality after screening colonoscopy can be
reduced by up to 68%.84 The added advantage of being
able to remove precursor lesions have been shown by
the US National Polyp Study to drastically prevent up to
53% of colorectal cancers. In the Philippines, given the
limited availability, expense and expertise associated with
colonoscopy, its utility may be best prioritized to those
populations who may have an increased risk for CRC or
those who test positive on the other less-invasive, less-
expensive screening tests.
Statement 6C
Colonoscopy should be performed for patients with
an increased risk for CRC or have positive findings on
sigmoidoscopy, FOBT, CTC, or DCBE.
Level of Evidence: Moderate
Strength of Recommendation: Moderate
Volume 55 Number 1 Jan. - March, 2017 5
 Sollano JD, et al.
Colonoscopy is the gold standard for detecting and
treating colonic neoplasms but is still a relatively expensive
and invasive procedure and, requires availability of well-
trained endoscopists. In resource-limited countries like
the Philippines, colonoscopy may not be feasible as a
population-based screening test for CRC. However, when
there is a positive finding with other modalities, such as,
FS, double-contrast barium enema (DCBE), FOBT, CT
colonography (CTC), Stool DNA (SDNA, not yet available
locally), and Capsule Endoscopy (CE), colonoscopy
provides the patients that enviable opportunity for a non-
operative removal of adenomas and/or early CRC.46, 47, 85
Statement 6D
Stool DNA, DCBE, and CTC are not recommended
screening tests for CRC
Level of Evidence: Moderate
Strength of Recommendation: Moderate
Due to its unavailability, higher cost compared to FIT,
uncertainties of screening intervals and unknown approach
to patients with a positive stool DNA (SDNA) but negative
colonoscopy, this guideline does not recommended SDNA
as a screening test for CRC .
The sensitivity of DCBE is lower than that of CTC, FS
and colonoscopy and is solely diagnostic. 86 In addition to
associated radiation risks and the decline in its use in the
country, DCBE is not recommended as a screening option
for CRC. It can be reserved as an alternative screening tool
in patients who cannot undergo the other recommended
screening tests or in centres without endoscopy facilities.
Unlike DCBE, there is increasing evidence that CTC
may be an accurate screening method in asymptomatic
average-risk adults. 87 A review of several CTC studies in a
screening setting reported a sensitivity of 83% in detecting
polyps >10 mm in size and 68% for polyps measuring 6-9mm.
The specificity of CTC for polyp detection was above
95%. 88-90 The use of multidetector scanner equipped with
3-D colonoscopy simulators may increase the sensitivity
of CT colonography, however, they are not available yet
even in urban centres in the Philippines.
In addition, the disadvantages of CTC are numerous,
i.e., risks of radiation, under-reporting of polyps <6mm,
need for expensive equipment and expertise.20,89,91 Patients
also found that CTC was more burdensome, more painful
and caused more embarrassment than conventional
colonoscopy.92,93 Most importantly, CTC is only a diagnostic
procedure. Currently, CT colonography, if available, may
be used as an alternative screening tool for patients who
cannot undergo colonoscopy or have had an incomplete
colonoscopy.
6 Volume 55 Number 1 Jan. - March, 2017
PSG and PSDE Consensus Guidelines on the Management of Colorectal Carcinoma
S tatement 7 A
Currently, colonoscopy is the preferred modality in the
detection and treatment of premalignant colonic lesions.
Level of evidence: moderate;
Strength of recommendation: strong
A – 94.7%; B – 5.3%
The joint guideline of the American Cancer Society,
USMTFCC and the American College of Radiology
differentiates the screening test(s) which can detect
adenomatous polyps from test(s) which detect primarily
colorectal cancer.1 Screening tests that detect primarily
colon cancer include FOBT, FIT and stool DNA. Tests which
detect both adenomatous polyp and cancer include DCBE,
CTC, FS and colonoscopy (Table I).49,94
Polypectomy, usually performed when polyps are
found during a diagnostic colonoscopy, has contributed
to a significant reduction in the incidence of colorectal
carcinoma by 43-90%. 46,84,95 Based on a comparison with
expected mortality in the general population Zauber et
al calculated a reduction in mortality from 25.4 to 12
deaths in 20 years for patients who have had endoscopic
polypectomy.47 An Asian study reported that the proportion
of colorectal neoplasms prevented by FS is 37.1% and
for colonoscopy, 54.1%, respectively. 65 In this context,
colonoscopy is usually performed after a non-invasive
screening test have shown positive results. Among the
screening examinations available for CRC, only endoscopic
modalities allow the removal of premalignant colorectal
lesions. The choice between flexible sigmoidoscopy and
colonoscopy may be influenced by the frequency of right-
sided colonic (proximal) lesion in the population being
screened. Sung et al compared the frequency of advance
colorectal neoplasm (ACRN) in the proximal colon between
western and eastern studies and showed a comparable
distribution, i.e., 23.7-45% and 19.6-43.6% respectively. 96
The Asia Pacific Working Group on Colorectal Cancer
found that colonoscopy performed among symptomatic
patients yielded 512 ACRN out of 5464 patients (9.4%),
136 of them (3.0%) have proximal lesions. Advanced age
was also identified as a risk factor for proximal colonic
lesions. 97 A recent review showed that even though
population-based case-control and cohort studies have
indicated that colonoscopy with polypectomy reduces
CRC incidence by 67-77% and mortality by 31-65%, these
are observational studies and results may have biases in
adherence, sampling and design. Hence, the magnitude
of effectiveness of colonoscopy remains unclear. 98 The
benefits of colonoscopy, however, made it the preferred
and recommended CRC prevention test by the American
College of Gastroenterology.18
 PSG and PSDE Consensus Guidelines on the Management of Colorectal Carcinoma Sollano JD, et al.

S tatement 7 B Table I. Advantages and disadvantages of different tests to detect

and treat premalignant colonic lesions
Colonic polyps should be removed, preferably with a well-
performed endoscopy-based polypectomy.
Tests Advantages Limitations

Level of evidence: high; Double contrast Non-invasive, almost Lack of RCTs to reduce
Strength of recommendation: strong Barium enema always evaluates the incidence or mortality
A – 85%; B – 15% entire colon, useful from CRC in average
when colonoscopy is risk adults, requires
incomplete bowel preparation,
Colonoscopic polypectomy reduces the incidence
expertise, exposure to
of CRC compared with that expected in the general radiation, no opportunity
population.46,84,95,99 Nishihara et al demonstrated that when f o r p o l y p e c t o m y,
comparing groups who underwent endoscopy and no findings of polyp >6mm
endoscopy, the multivariate hazard ratios for CRC were requires colonoscopy;
perforation rate: 1 in
0.57 after polypectomy, 0.60 after negative sigmoidoscopy,
25,000
and 0.44 after negative colonoscopy.84
CT colonography Less invasive, high No evidence of
All visible polypoid lesions of the colon should be sensitivity for the reduction in CRC
removed. Although most are diminutive (<0.5cm) and detection of lesions incidence, requires
small (0.6-0.9cm) polyps, majority of these warrant >10mm bowel preparation,
special resources and
attention because 40-50% of these diminutive polyps may
expertise, treatment
be neoplastic.100-103 A recent Asian study reported that a of patients with <6mm
substantial proportion of high-grade dysplasia was seen polyps uncertain,
in diminutive polyps (18.7%) and small polyps (37.6%). detection of flat polyp
The proportion of polyps containing villous histology uncertain, repeat testing
unknown
in diminutive and small polyps were 3.0% and 12.5%,
respectively.104 An unpublished study from the Philippines by
Peña et al showed congruent results, i.e., 24% of diminutive Flexible Office-based, sedation Does not detect
polyps have neoplastic histology. 105 sigmoidoscopy n o t n e c e s s a r y, p r e - proximal lesions, less
malignant colonic effective in elderly and
lesions can be removed, in women, sensitivity
Techniques in polyp removal vary but the best options case control studies and specificity in clinical
are those which can achieve complete removal with very showed 60% reduction practice unknown
minimal associated risks. Cold forceps polypectomy is in mortality from distal
suitable for polyps less than 3.0 mm because they can be colon cancers
completely removed with a single bite, the entire sample
Colonoscopy 90% sensitivity for Lack of RCTs showing
is retrieved for histopathological examination and the
lesions >10mm, case- reduced incidence or
associated risks are exceptionally low. Hot biopsy applies control studies show mortality from colorectal
diathermy through the forceps to ablate residual polyp a 53-72% reduction carcinoma. Requires
tissue. It is suitable for polyps up to 5.0 mm in size, however, in incidence of CRC bowel preparation,
this technique has fallen out of favor due to the risk of and 31% reduction in special resources
mortality, premalignant and expertise,
post-polypectomy bleeding and perforation. Cold snare
colonic lesions can be Expensive, invasive,
polypectomy is fast, effective, and safe and is currently the removed and is the 3-5 adverse events
preferred technique for small sessile polyps up to 7.0 mm recommended test to per 1000 examinations
in size while hot snare is recommended for sessile lesions evaluate the colon when and sensitivity and
more than 7.00–8.00mm. Pedunculated lesions are better other screening tests specificity in clinical
show positive result practice unknown
snared and cut with diathermy when larger than a few
millimeters to avoid bleeding risk.106, 107 Endoscopic mucosal
resection (EMR) may be performed for removal of small (<
2.0 cm), sessile or flat neoplasms confined to the superficial The polyp must be completely excised and submitted
layers (mucosa and submucosa). EMR may be utilized in toto for pathological examination – to properly classify
also for piecemeal removal of larger lesions. Endoscopic the polyp, determine presence or absence of malignancy;
submucosal dissection (ESD) has been developed for evaluate grade, vascular and lymphatic involvement
en bloc removal of large, more than 2.0cm, flat GI tract and proximity to the margin of resection if malignant. 41
lesions. EMR and ESD may be used for definitive therapy of Invasion of the stalk of pedunculated polyps, by itself,
premalignant and early stage (T1M0N0) malignant lesions.108 is not an unfavorable finding, for as long as the cancer
does not extend to the margin of resection. In addition,

Volume 55 Number 1 Jan. - March, 2017 7

 Sollano JD, et al.
there must be no vascular or lymphatic involvement. The
estimated risks of residual cancer or nodal metastases
from endoscopically-resected pedunculated and sessile
malignant polyps with favorable criteria are 0.3% and 1.5%,
respectively. 109 Endoscopically-resected malignant polyps
associated with poor prognosis include polyps which have
a poorly differentiated histology, positive resection margin,
or with lymphatic or vascular invasion. The reported residual
cancer is 8.5% and 14.4% in pedunculated and sessile
malignant polyps, respectively.
The decision to proceed with surgical resection needs
to be individualized, taking into account the age of and
comorbidities present in the patient.
S tatement 8
A proper bowel preparation prior to colonoscopy is
essential for an optimal assessment of the entire colonic
mucosa.
Level of evidence: moderate;
Strength of recommendation: strong
A – 95%; B – 5%
The Asia Pacific guidelines on colorectal screening
emphasize that the effectiveness of colonoscopy in the
detection of colonic neoplasms is dependent on the
quality of the colonoscopic examination.96
Thus, adequate pre-endoscopic preparation of the
large bowel to ensure a complete visual examination of the
colonic lumen and mucosa is mandatory. The importance
of the quality of bowel preparation is reflected in the
diagnostic yields, polyp missed rates, difficulty, speed and
completeness of colonoscopies, CRC rates after screening
colonoscopy and the adenoma detection rate (ADR) of
individual endoscopists. 110-114 Most missed polyps, blamed
as an important reason of post-polypectomy CRCs, occur
not uncommonly on inadequately prepared colons.115-117
In both Western and recent Asian studies, poor
bowel preparation also reduced cecal intubation rates,
prolonged colonoscopy time, lowered diagnostic yields
and contributed to frequent repeat colonoscopies outside
the recommended interval with more patients experiencing
discomfort.111, 118
Several patient and procedure-related factors that
may influence adequacy of bowel preparation prior to
colonoscopy have been described, namely; calcium
channel blocker use, age, male gender, constipation,
d iabetes, l ow ed uc a ti ona l b a c kground , his tory of
appendectomy, colorectal resection and hysterectomy,
previous poor preparation and lag time >16 weeks from
8 Volume 55 Number 1 Jan. - March, 2017
PSG and PSDE Consensus Guidelines on the Management of Colorectal Carcinoma
scheduling to actual performance of the colonoscopy.119
Recognition of these factors prior to colonoscopy and
adequate manipulation of the bowel preparation will help
reduce poor quality colonoscopy.
The quality of preparation must be included in the
endoscopy report. This will serve as a quality indicator of
colonoscopy and it is recommended that a 93% reporting
rate should be achieved. 113 Quality of preparation is
usually reported as excellent, when there is no or minimal
solids with minimal fluid requiring suctioning; good, when
there is more fluid that require suctioning; fair, when there
is semisolid material that are difficult to clear; and poor,
when there are solid/semisolid materials which cannot
be cleared.119
There are three validated bowel preparations scales
often used in clinical trials, namely; Aronchik, Ottawa and
Boston Bowel Preparation Scales (BBPS). 119-121 For uniformity
in reporting for bowel preparation in endoscopy units in
the country, we recommended that BBPS be adopted.
The BBPS rates the three segments of the colon only after
cleansing is done as one withdraws the scope. This is more
important clinically since follow up recommendation is
based upon how much colon was visualized adequately.
Meanwhile, the American Society of Anesthesia
recommends that clear liquids may be taken up to two
hours before the procedure.
There are several bowel cleansing formulas available
in the Philippines thus, a good knowledge of their safety
and side-effect profiles, drug-drug interaction, dosing and
administration scheme is highly recommended. One of the
ultimate goals of this guideline is to narrow the gaps in
bowel preparation in order to achieve consistently a high
quality colonoscopy.
S tatement 9
Surveillance colonoscopy is recommended in asymptomatic
individuals with previously-identified precancerous lesions.
The interval of surveillance colonoscopy depends on the
adenoma risk level after baseline examination.
Level of evidence: moderate;
Strength of recommendation: strong
A – 94.1% B – 5.9%
Colonoscopic surveillance is performed to “identify
recurrent or metachronous neoplasia in an asymptomatic
individual with previously identified precancerous lesions.”122
The surveillance interval depends on the findings on baseline
or previous colonoscopy and on the assumption that the
procedure adequately visualized all segments of the colon
and all identified polyps were adequately removed.
 PSG and PSDE Consensus Guidelines on the Management of Colorectal Carcinoma Sollano JD, et al.

Table II. Predictors for metachronous advance neoplasia and cancer on surveillance colonoscopy

No of Size of
Villous High grade
STUDY adenoma adenoma
component dysplasia
OR for ≥3 ≥10mm
Winawer (NEJM 1993)46 2.4 (1.7-3.5) not significantly not significantly not significantly
RCT associated associated associated
Saini (Gastroint Endosc 2006)127 2.52(1.07-5.97) 1.39 1.26 1.84 (1.06-3.19)
SR/Metaanalysis
5 studies

Martinez (Gastroenterology 2009)128 SR/ p<0.0001 p<0.0001 1.28 not independently

pooled analyses, associated
8 studies
Huang (J Gastroenterol 2012)129 p<0.05 p<0.05 HR 2.57 HR 1.61
Retrospective cohort (N=1356) (1.24-5.32) (1.07-2.42)
de Jonge (Endoscopy 2011)126 1.64 1.66
SR - 27 studies
Chung (Gut 2011)125 HR 3.06 HR 3.02
Prospective (N=2452) (1.51 - 6.57) (1.80 - 5.06)
Ji 2009124 (correcting for miss rates) HR 2.44 not not independently not independently
Miss rate: 21.2% (1.11-5.35) independently associated associated
Prospective (N=120 associated

Table III. 2012 Recommendations for Surveillance and Screening Intervals in individuals with
Baseline Average Risk according to the USMSTF

Recommended surveillance
Baseline colonoscopy; most advanced findings
interval (y)
No polyps 10
Small (<10 mm) hyperplastic polyps in rectum or sigmoid 10
1-2 small (<10 mm) tubular adenomas 5-10
3-10 tubular adenomas 3
>10 adenomas <3
One or more tubular adenomas ≥10mm 3
One or more villous adenomas 3
Adenoma with HGD 3
Serrated lesions
Sessile serrated polyp(s) <10 mm with no dysplasia 5
Sessile serrated polyp(s) ≥10mm 3
OR
Sessile serrated polyp with dysplasia
OR
Traditional Serrated Adenoma
Serrated polypsis syndromea 1

IMPORTANT.
These recommendations presume that the baseline colonoscopy was of high quality and complete ate and that all polyps seen
were removed completely.
a
Based on the World Health Organization definition of serrated polyposis syndrome (SPS), with one of the following criteria:
(1) at least 5 serrated polyps proximal to sigmoid, with 2 or more >10 mm; (2) any serrated polyps proximal to sigmoid with
family history of serrated polyposis syndrome; and (3) >20 serrated polyps of any size throughout the colon.

Volume 55 Number 1 Jan. - March, 2017 9

 Sollano JD, et al.
This guideline adapted the 2006 US Multi-Specialty Task
Force (USMSTF) classification of adenoma risk based on size
and histologic characteristics, as follows; low risk adenomas
are defined as one to two tubular adenomas, <10mm in size;
high risk or advanced adenomas are adenomatous polyps
with any of the following features: multiple (≥ 3 adenomas),
≥10 mm in size, presence of villous component or with high
grade dysplasia.123 These feature have also been identified
as predictors for metachronous advanced neoplasia and
cancer, particularly the number of adenomas identified,
i.e., (HR 2.44, 95% CI, 1.11 - 5.35 124 to 3.06, 95% CI, 1.51-
6.57) 125 and OR 2.52, 95% CI,1.07-5.97. 126 (Table II).
Depending on the lesion identified and removed
during the prior colonoscopy, the recommended interval
of surveillance colonoscopy according to the 2012 USMSTF
is enumerated in Table III. An every ten year-interval for
continued screening of patients with negative colonoscopy
on baseline examination is based on prospective
and retrospective cohort studies which showed the
protective effect extends ≥10 years after a negative prior
colonoscopy.130, 131
Surveillance is also recommended for serrated polyps.
Serrated polyps are classified into hyperplastic polyp,
traditional serrated adenoma (TSA) and sessile serrated
adenoma (SSA). Hyperplastic polyps are small, <0.5 cm,
sessile or slightly raised and mostly seen at the left colon.
Majority of serrated polyps are hyperplastic. TSAs may
be pedunculated or broad based large polyps, usually
seen in the left colon. SSAs are smaller polyps, which are
difficult to differentiate endoscopically from adenoma or
other serrated types, and seen usually at the right colon
and on crests of mucosal folds. Annual surveillance is
recommended for patients with serrated adenomatous
polyposis or serrated polyposis syndrome (SPS) due to the
aggressive nature of this condition. In one cohort, 61-83% of
patients with SPS have SSA, with development of recurrent
SSA on retained colorectum within a median of two years
after colon resection. 132 After a clearing colonoscopy
of patients with SPS, the cumulative risks after three
consecutive colonoscopies for cancer, advance adenoma
or adenoma >10mm are 0%, 9% and 34% respectively.133
S tatement 10
Surveillance is recommended after resection of colorectal
cancer.
Level of evidence: high;
Strength of recommendation: strong
A – 94.7%; B – 5.3%
Recommendations about the timing of colonoscopy
after colorectal cancer (CRC) resection should be directed
towards the early detection and timely polypectomy of
10 Volume 55 Number 1 Jan - March, 2017
PSG and PSDE Consensus Guidelines on the Management of Colorectal Carcinoma
metachronous adenomas while meeting the general
objectives of CRC surveillance. In 23 studies (1983-2003)
involving more than 9000 patients, 57 of 137 patients
developed metachronous cancers within 24 months of
surgery. Such a rate of cancer detection is comparable
to the rate of prevalent cancer detection in the setting
of screening colonoscopy.134 The weight of evidence from
the literature support performing the initial post-operative
surveillance colonoscopy at one year. If this examination
does not reveal a metachronous neoplasia, the intervals
between subsequent colonoscopies should be three and
five years, depending on the number, size and histologic
type of polyps (if any) removed.
A systematic review of eight RCTs of 2,923 patients
with CRC undergoing curative resection revealed that
overall mortality rate improved significantly for patients who
had more intensive surveillance (21.8%) versus less intensive
surveillance (25.7%) [OR = 0.74; p = 0.01].135 Trials utilizing serum
CEA demonstrated that an intensive surveillance schedule,
three monthly for first two years, has a significant impact on
overall mortality (p =0.03). In six studies, the incidence of
asymptomatic recurrence was significantly higher in patients
who had more intensive follow-up (OR, 3.42; p <0.00001).
Another six studies reported that a more intensive follow-up
detected the first recurrence 5.91 months earlier (p <0.0001)
and significantly increased reoperation rate with curative
intent for recurrent disease, irrespective of the diagnostic
strategy adopted, p <0.05. This improvement in curative
reoperation rates was demonstrated also with more frequent
application of individual tests, i.e., serum CEA level, p = 0.0006;
colonoscopy, p = 0.01; liver US, p = 0.0006; CT scan, p = 0.01.135
We recommend to perform colonoscopy one year after
the resection of a sporadic CRC. If the colonoscopy at one
year reveals advanced adenoma, the interval of the next
colonoscopy should be three years. If the colonoscopy at one
year is normal, the interval of the next colonoscopy should
be five years. Colonoscopy should be performed three to six
months after resection of an obstructing CRC, especially if a
complete perioperative colonoscopy was not done. After
CRC resection, CEA, and CT scan of the abdomen and
chest, should be done every six months and annually,
respectively, for five years.
S tatement 11
Primary care physicians and other specialists should be
engaged to promote public awareness on CRC screening
and prevention.
Level of evidence: moderate;
Strength of recommendation: strong
A – 86.7% B – 13.3%
 PSG and PSDE Consensus Guidelines on the Management of Colorectal Carcinoma
Physician recommendation increases the likelihood of
a patient undergoing CRC screening.11,12,136-140 People in
the Asia Pacific countries with a low CRC screening test
uptake have also the least knowledge of CRC symptoms,
risk factors and screening tests. These countries have
also the lowest physician recommendation rates for CRC
screening. Japan and the Philippines have high physician
recommendation rates and consequently had the
highest participation rate.12 Sung reported that physician
recommendation increased the likelihood of undergoing
a CRC screening test by 23 times in a randomly surveyed
population of Chinese residents in Hong Kong.11
Fenton showed that physician counselling is associated
with increased perceived CRC susceptibility and greater
intention to undergo CRC screening. Within six months,
17 of 38 patients (45%) who discussed CRC screening
with their physician underwent a test compared with 0
of 12 who did not discuss screening (p =0.01). 136 The US
Preventive Services Task Force recommends using the
5 As (Assess, Advise, Agree, Assist and Arrange) when
counselling. Patients whose visit contained more than one
to two steps are more likely to undergo screening. A CRC
screening recommendation (Advise) that also describes
patient eligibility (Assess) and provides help to obtain a
screening exam (Assist and Arrange) will lead to improved
adherence to CRC screening.137
Despite the crucial role doctors play in increasing the
CRC screening uptake, why are doctors not recommending
CRC screening to eligible patients? Factors identified as
barriers to physicians offering CRC screening include lack
of knowledge and training, lack of time and opportunity,
forgetfulness and, an assessment that cost could be
prohibitive to the patient. Likewise, inconsistencies in
guideline recommendations may make doctors reluctant
to give advice to their patients.138, 141
Given their pivotal role in a successful CRC screening
strategy and in order for the Philippines to reach an uptake
of 65-70%, every physician, primary care or otherwise, is
therefore enjoined to grab every opportunity to promote
colon cancer prevention and early cancer detection
among their patients.
S tatement 12
CRC screening should be a part of the national health
program of the Philippines and must be performed for all
at-risk individuals.
Level of evidence: moderate;
Strength of recommendation: strong
A – 84.2%; B – 15.8%
Sollano JD, et al.
The primary aim of CRC screening as a tool for cancer
control is to lower the burden of cancer in the population
thru discovery and effective treatment of early and latent
disease. CRC screening is more cost saving compared
to multi-drug intensive chemotherapy for advanced
colorectal cancer.142
The secondary aim of CRC screening is to reduce
cancer mortality and, in some instances, cancer incidence
across the population. In England, results from the phased
implementation of the United Kingdom Bowel Cancer
Screening Programme (BCSP) launched in 2006, using
gFOBT as screening strategy, showed participation of up
to 52% after the first 1.08 million tests. If maintained, they
project a decrease in overall CRC mortality by 16%.143
The Consensus Group advocate that CRC screening
should be part of the national health program of the
Philippines. Studies show that almost all standard options
of CRC screening is more cost effective compared to
no screening. 142,144-146 To reduce cancer mortality and
cancer incidence there must be adequate uptake and
participation by the target population.147 From experiences
in the European Union, it takes a minimum of 10 years
to plan, pilot and implement an organized population-
based CRC screening program.148 For the Philippines, this
consensus guideline may be a good start going forward.
We recognize that several important issues need to
be addressed. First, what will be the screening strategy:
iFOBT/FIT or colonoscopy? We await results of three ongoing
randomized controlled trials (2 European studies and 1
US study) evaluating colonoscopy as a primary screening
tool. 75,149,150 The Asia Pacific Guidelines state that iFOBT/
FIT is the preferred screening test for resource-limited
countries. 3 We recommend further that a cost-effective
analysis study for CRC screening program in the Philippine
setting be done.
Second, where will the funding for the screening
program come? Funding has to be established and
perhaps legislated. In Europe, most organized programs
are subsidized fully or partially by the government. 148 In
the US, the Affordable Care Act requires that all private
health plans cover CRC screening tests without any out-of-
pocket costs to patients. Cost for screening tests, including
colonoscopy, is waived for Medicare beneficiaries, as well.
An incentive is given to states that offer CRC screening to
Medicaid beneficiaries.151 For the Philippines, the Consensus
Group recommends that the national health policy must
require the Philippine Health Insurance Corporation and/or
health maintenance organizations (HMOs) to cover CRC
screening costs.
Third, are there enough qualified gastroenterologists to
perform colonoscopy and polypectomy in patients who test
Volume 55 Number 1 Jan - March, 2017 11
 Sollano JD, et al.
positive for iFOBT/FIT? It is recommended that the Philippine
Societies of Gastroenterology and Digestive Endoscopy to
create colonoscopy hubs and craft programs to ensure
that qualified gastroenterologists are distributed equitably
in all areas of the country.
An opportunistic screening scheme is the current
approach to CRC screening in the country. Only
patients who are advised by their physicians or who
have knowledge about CRC screening from elsewhere
and desire to undergo the screening test are examined.
Increasing public awareness on CRC and the value of
screening and early intervention must be waged relentlessly
by multi-sectoral groups.
The planning and implementation of an organized CRC
screening program will be difficult. The support from the
government, various professional and patient advocacy
groups will be essential. The screening strategy chosen will
arguably be dependent on medical evidence, availability
of resources and funding and the cultural acceptance of
the Filipinos to this program.
As we move forward, we put in mind the words of
Sydney Winawer, Co-chair of IDCA (international Digestive
Cancer Alliance): “The best screening test is the one that
gets done…and gets done well. Do what you can with
what you have.”
C onclusion
In the Philippines, colorectal cancer is currently the
most common cancer of the gastrointestinal tract and
its incidence and associated mortality are still rising. This
common cancer, however, can be prevented by early
detection and removal of precursor colonic adenomas.
CRC has a high survival rate if detected and removed
in its early stages. Due to our better understanding of its
natural history and pathogenesis, there is a well-described
at-risk population for whom a screening and surveillance
strategy can be directed.
Most importantly, the ability of currently-available,
relatively cheap, reliable, and simple tests for early
diagnosis and the increased survival of patients wherefrom
precursor polyps or early staged CRC have been removed
make the case why we must adopt a national program
to promote CRC awareness, implement a fully-funded
CRC screening and surveillance strategy, as well as,
increasing the availability of experts and qualified centres
for minimally-invasive CRC treatments.
12 Volume 55 Number 1 Jan. - March, 2017
PSG and PSDE Consensus Guidelines on the Management of Colorectal Carcinoma
A cknowledgements
Special acknowledgements and recognition for
contributions which ensured the efficient conduct of the
Consensus Development Conference and manuscript
writing are extended to: Karen Estelle G. de Lunas, MD
for the analysis and summary report of the national CRC
survey results, Rommel P. Romano, MD for final edits of
the manuscript and, Diana Jhoy Maquilan-Bernardo as
rapporteur and her secretarial assistance.
R eferences
1. Laudico AV, Medina V, Lumague MRM, et al. 2010 Philippine
Cancer Facts and Estimates. Manila: Philippine Cancer Society,
Inc., 2010.
2. Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence
and mortality worldwide: sources, methods and major patterns in
GLOBOCAN 2012. Int J Cancer 2015;136:E359-86.
3. Sung JJ, Lau JY, Goh KL, et al. Increasing incidence of colorectal
cancer in Asia: implications for screening. Lancet Oncol 2005;6:871-
6.
4. Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012.
CA Cancer J Clin 2015;65:87-108.
5. Vineis P, Wild CP. Global cancer patterns: causes and prevention.
Lancet 2014;383:549-57.
6. Holme O, Loberg M, Kalager M, et al. Effect of flexible
sigmoidoscopy screening on colorectal cancer incidence and
mortality: a randomized clinical trial. JAMA 2014;312:606-15.
7. Iversen LH. Aspects of survival from colorectal cancer in Denmark.
Dan Med J 2012;59:B4428.
8. Whitlock EP, Lin JS, Liles E, et al. Screening for colorectal cancer:
a targeted, updated systematic review for the U.S. Preventive
Services Task Force. Ann Intern Med 2008;149:638-58.
9. Wong MC, John GK, Hirai HW, et al. Changes in the choice of
colorectal cancer screening tests in primary care settings from
7,845 prospectively collected surveys. Cancer Causes Control
2012;23:1541-8.
10. Wu TY, Kao JY, Hsieh HF, et al. Effective colorectal cancer
education for Asian Americans: a Michigan program. J Cancer Educ
2010;25:146-52.
11. Sung JJ, Choi SY, Chan FK, et al. Obstacles to colorectal cancer
screening in Chinese: a study based on the health belief model. Am
J Gastroenterol 2008;103:974-81.
12. Koo JH, Leong RW, Ching J, et al. Knowledge of, attitudes
toward, and barriers to participation of colorectal cancer screening
tests in the Asia-Pacific region: a multicenter study. Gastrointest
Endosc 2012;76:126-35.
13. Altobelli E, Lattanzi A, Paduano R, et al. Colorectal cancer
prevention in Europe: burden of disease and status of screening
programs. Prev Med 2014;62:132-41.
14. Guyatt GH, Oxman AD, Vist GE, et al. GRADE: an emerging
consensus on rating quality of evidence and strength of
 PSG and PSDE Consensus Guidelines on the Management of Colorectal Carcinoma
recommendations. BMJ 2008;336:924-6.
15. Hyodo I, Suzuki H, Takahashi K, et al. Present status and
perspectives of colorectal cancer in Asia: Colorectal Cancer Working
Group report in 30th Asia-Pacific Cancer Conference. Jpn J Clin
Oncol 2010;40 Suppl 1:i38-43.
16. Laudico AV, Mirasol-Lumague MR, Mapua CA, et al. Cancer
incidence and survival in Metro Manila and Rizal province,
Philippines. Jpn J Clin Oncol 2010;40:603-12.
17. Redaniel MTM, Laudico AV, Lumague MRM, et al. Cancer in the
Philippines. Vol. IV Part 1 - Cancer Incidence 1998-2002. Manila:
Philippine Cancer Society, 2008.
18. Rex DK, Johnson DA, Anderson JC, et al. American College of
Gastroenterology guidelines for colorectal cancer screening 2009
[corrected]. Am J Gastroenterol 2009;104:739-50.
19. American Cancer Society. Cancer Facts & Figures 2014. Atlanta:
American Cancer Society, 2014.
20. Sung JJ, Ng SC, Chan FK, et al. An updated Asia Pacific Consensus
Recommendations on colorectal cancer screening. Gut 2015;64:121-
32.
21. Nguyen SP, Bent S, Chen YH, et al. Gender as a risk factor for
advanced neoplasia and colorectal cancer: a systematic review and
meta-analysis. Clin Gastroenterol Hepatol 2009;7:676-81 e1-3.
22. Larsson SC, Wolk A. Obesity and colon and rectal cancer risk: a
meta-analysis of prospective studies. Am J Clin Nutr 2007;86:556-
65.
23. Dai Z, Xu YC, Niu L. Obesity and colorectal cancer risk: a meta-
analysis of cohort studies. World J Gastroenterol 2007;13:4199-206.
24. Ma Y, Yang Y, Wang F, et al. Obesity and risk of colorectal cancer: a
systematic review of prospective studies. PLoS One 2013;8:e53916.
25. Moghaddam AA, Woodward M, Huxley R. Obesity and risk of
colorectal cancer: a meta-analysis of 31 studies with 70,000 events.
Cancer Epidemiol Biomarkers Prev 2007;16:2533-47.
26. Tsoi KK, Pau CY, Wu WK, et al. Cigarette smoking and the risk
of colorectal cancer: a meta-analysis of prospective cohort studies.
Clin Gastroenterol Hepatol 2009;7:682-688 e1-5.
27. Botteri E, Iodice S, Bagnardi V, et al. Smoking and colorectal
cancer: a meta-analysis. JAMA 2008;300:2765-78.
28. Norat T, Lukanova A, Ferrari P, et al. Meat consumption
and colorectal cancer risk: dose-response meta-analysis of
epidemiological studies. Int J Cancer 2002;98:241-56.
29. Chan DS, Lau R, Aune D, et al. Red and processed meat and
colorectal cancer incidence: meta-analysis of prospective studies.
PLoS One 2011;6:e20456.
30. Larsson SC, Wolk A. Meat consumption and risk of colorectal
cancer: a meta-analysis of prospective studies. Int J Cancer
2006;119:2657-64.
31. Howard RA, Freedman DM, Park Y, et al. Physical activity,
sedentary behavior, and the risk of colon and rectal cancer in
the NIH-AARP Diet and Health Study. Cancer Causes Control
2008;19:939-53.
32. Schmid D, Leitzmann MF. Television viewing and time spent
sedentary in relation to cancer risk: a meta-analysis. J Natl Cancer
Inst 2014;106.
33. Cong YJ, Gan Y, Sun HL, et al. Association of sedentary behaviour
with colon and rectal cancer: a meta-analysis of observational
studies. Br J Cancer 2014;110:817-26.
Sollano JD, et al.
34. Fedirko V, Tramacere I, Bagnardi V, et al. Alcohol drinking and
colorectal cancer risk: an overall and dose-response meta-analysis
of published studies. Ann Oncol 2011;22:1958-72.
35. Cai S, Li Y, Ding Y, et al. Alcohol drinking and the risk of
colorectal cancer death: a meta-analysis. Eur J Cancer Prev
2014;23:532-9.
36. Fuchs CS, Giovannucci EL, Colditz GA, et al. A prospective
study of family history and the risk of colorectal cancer. N Engl J
Med 1994;331:1669-74.
37. Butterworth AS, Higgins JP, Pharoah P. Relative and absolute
risk of colorectal cancer for individuals with a family history: a
meta-analysis. Eur J Cancer 2006;42:216-27.
38. Ahsan H, Neugut AI, Garbowski GC, et al. Family history of
colorectal adenomatous polyps and increased risk for colorectal
cancer. Ann Intern Med 1998;128:900-5.
39. Tuohy TM, Rowe KG, Mineau GP, et al. Risk of colorectal
cancer and adenomas in the families of patients with adenomas: a
population-based study in Utah. Cancer 2014;120:35-42.
40. Amersi F, Agustin M, Ko CY. Colorectal cancer: epidemiology,
risk factors, and health services. Clin Colon Rectal Surg
2005;18:133-40.
41. Bond JH. Polyp guideline: diagnosis, treatment, and surveillance
for patients with colorectal polyps. Practice Parameters Committee
of the American College of Gastroenterology. Am J Gastroenterol
2000;95:3053-63.
42. Imperiale TF, Wagner DR, Lin CY, et al. Risk of advanced
proximal neoplasms in asymptomatic adults according to the distal
colorectal findings. N Engl J Med 2000;343:169-74.
43. Lieberman DA, Weiss DG, Bond JH, et al. Use of colonoscopy to
screen asymptomatic adults for colorectal cancer. Veterans Affairs
Cooperative Study Group 380. N Engl J Med 2000;343:162-8.
44. Mandel JS, Bond JH, Church TR, et al. Reducing mortality from
colorectal cancer by screening for fecal occult blood. Minnesota
Colon Cancer Control Study. N Engl J Med 1993;328:1365-71.
45. Schoenfeld P, Cash B, Flood A, et al. Colonoscopic screening
of average-risk women for colorectal neoplasia. N Engl J Med
2005;352:2061-8.
46. Winawer SJ, Zauber AG, Ho MN, et al. Prevention of colorectal
cancer by colonoscopic polypectomy. The National Polyp Study
Workgroup. N Engl J Med 1993;329:1977-81.
47. Zauber AG, Winawer SJ, O’Brien MJ, et al. Colonoscopic
polypectomy and long-term prevention of colorectal-cancer deaths.
N Engl J Med 2012;366:687-96.
48. Edwards BK, Ward E, Kohler BA, et al. Annual report to the
nation on the status of cancer, 1975-2006, featuring colorectal
cancer trends and impact of interventions (risk factors, screening,
and treatment) to reduce future rates. Cancer 2010;116:544-73.
49. Levin B, Lieberman DA, McFarland B, et al. Screening and
surveillance for the early detection of colorectal cancer and
adenomatous polyps, 2008: a joint guideline from the American
Cancer Society, the US Multi-Society Task Force on Colorectal
Cancer, and the American College of Radiology. CA Cancer J Clin
2008;58:130-60.
50. U. S. Preventive Services Task Force. Screening for colorectal
cancer: U.S. Preventive Services Task Force recommendation
statement. Ann Intern Med 2008;149:627-37.
Volume 55 Number 1 Jan. - March, 2017 13
 Sollano JD, et al.
51. Zauber AG, Lansdorp-Vogelaar I, Knudsen AB, et al. Evaluating
test strategies for colorectal cancer screening: a decision analysis
for the U.S. Preventive Services Task Force. Ann Intern Med
2008;149:659-69.
52. American Cancer Society. Colorectal Cancer Facts & Figures
2014-2016. Atlanta: American Cancer Society, 2014.
53. Surveillance, Epidemiology, and End Results (SEER) Program
SEER*Stat Database: Mortality – All COD, Aggregated
With State, Total U.S. (1969-2010) <Katrina/Rita Population
Adjustment>, National Cancer Institute, DCCPS, Surveillance
Research Program, Cancer Statistics Branch, released April 2013.
Underlying mortality data provided by NCHS 2013.
54. Byeon JS, Yang SK, Kim TI, et al. Colorectal neoplasm in
asymptomatic Asians: a prospective multinational multicenter
colonoscopy survey. Gastrointest Endosc 2007;65:1015-22.
55. Charlson ME, Pompei P, Ales KL, et al. A new method of
classifying prognostic comorbidity in longitudinal studies:
development and validation. J Chronic Dis 1987;40:373-83.
56. Kahi CJ, Azzouz F, Juliar BE, et al. Survival of elderly persons
undergoing colonoscopy: implications for colorectal cancer
screening and surveillance. Gastrointest Endosc 2007;66:544-50.
57. Gross CP, McAvay GJ, Krumholz HM, et al. The effect of age
and chronic illness on life expectancy after a diagnosis of colorectal
cancer: implications for screening. Ann Intern Med 2006;145:646-
53.
58. Lin OS, Kozarek RA, Schembre DB, et al. Screening colonoscopy
in very elderly patients: prevalence of neoplasia and estimated
impact on life expectancy. JAMA 2006;295:2357-65.
59. Ko CW, Sonnenberg A. Comparing risks and benefits of
colorectal cancer screening in elderly patients. Gastroenterology
2005;129:1163-70.
60. Lin OS, Kozarek RA, Schembre DB, et al. Risk stratification
for colon neoplasia: screening strategies using colonoscopy
and computerized tomographic colonography. Gastroenterology
2006;131:1011-9.
61. Day LW, Kwon A, Inadomi JM, et al. Adverse events in older
patients undergoing colonoscopy: a systematic review and meta-
analysis. Gastrointest Endosc 2011;74:885-96.
62. Hewitson P, Glasziou P, Watson E, et al. Cochrane systematic
review of colorectal cancer screening using the fecal occult blood
test (hemoccult): an update. Am J Gastroenterol 2008;103:1541-9.
63. Mandel JS, Church TR, Bond JH, et al. The effect of fecal
occult-blood screening on the incidence of colorectal cancer. N
Engl J Med 2000;343:1603-7.
64. Mandel JS, Church TR, Ederer F, et al. Colorectal cancer
mortality: effectiveness of biennial screening for fecal occult blood.
J Natl Cancer Inst 1999;91:434-7.
65. Tsoi KK, Ng SS, Leung MC, et al. Cost-effectiveness analysis on
screening for colorectal neoplasm and management of colorectal
cancer in Asia. Aliment Pharmacol Ther 2008;28:353-63.
66. Allison JE, Tekawa IS, Ransom LJ, et al. A comparison of fecal
occult-blood tests for colorectal-cancer screening. N Engl J Med
1996;334:155-9.
67. Cole SR, Young GP, Esterman A, et al. A randomised trial of the
impact of new faecal haemoglobin test technologies on population
participation in screening for colorectal cancer. J Med Screen
14 Volume 55 Number 1 Jan. - March, 2017
PSG and PSDE Consensus Guidelines on the Management of Colorectal Carcinoma
2003;10:117-22.
68. Hol L, van Leerdam ME, van Ballegooijen M, et al. Screening
for colorectal cancer: randomised trial comparing guaiac-based
and immunochemical faecal occult blood testing and flexible
sigmoidoscopy. Gut 2010;59:62-8.
69. Park DI, Ryu S, Kim YH, et al. Comparison of guaiac-based
and quantitative immunochemical fecal occult blood testing in a
population at average risk undergoing colorectal cancer screening.
Am J Gastroenterol 2010;105:2017-25.
70. Roslani AC, Abdullah T, Arumugam K. Screening for colorectal
neoplasias with fecal occult blood tests: false-positive impact of
non-dietary restriction. Asian Pac J Cancer Prev 2012;13:237-41.
71. Smith A, Young GP, Cole SR, et al. Comparison of a brush-sampling
fecal immunochemical test for hemoglobin with a sensitive guaiac-
based fecal occult blood test in detection of colorectal neoplasia.
Cancer 2006;107:2152-9.
72. van Rossum LG, van Rijn AF, Laheij RJ, et al. Random comparison
of guaiac and immunochemical fecal occult blood tests for colorectal
cancer in a screening population. Gastroenterology 2008;135:82-90.
73. Wong BC, Wong WM, Cheung KL, et al. A sensitive guaiac
faecal occult blood test is less useful than an immunochemical test
for colorectal cancer screening in a Chinese population. Aliment
Pharmacol Ther 2003;18:941-6.
74. Terhaar sive Droste JS, van Turenhout ST, Oort FA, et al. Faecal
immunochemical test accuracy in patients referred for surveillance
colonoscopy: a multi-centre cohort study. BMC Gastroenterol
2012;12:94.
75. Quintero E, Castells A, Bujanda L, et al. Colonoscopy versus fecal
immunochemical testing in colorectal-cancer screening. N Engl J
Med 2012;366:697-706.
76. Atkin WS, Edwards R, Kralj-Hans I, et al. Once-only flexible
sigmoidoscopy screening in prevention of colorectal cancer: a
multicentre randomised controlled trial. Lancet 2010;375:1624-33.
77. Baxter NN, Goldwasser MA, Paszat LF, et al. Association of
colonoscopy and death from colorectal cancer. Ann Intern Med
2009;150:1-8.
78. Baxter NN, Warren JL, Barrett MJ, et al. Association between
colonoscopy and colorectal cancer mortality in a US cohort
according to site of cancer and colonoscopist specialty. J Clin Oncol
2012;30:2664-9.
79. Hoff G, Grotmol T, Skovlund E, et al. Risk of colorectal cancer
seven years after flexible sigmoidoscopy screening: randomised
controlled trial. BMJ 2009;338:b1846.
80. Schoen RE, Pinsky PF, Weissfeld JL, et al. Colorectal-cancer
incidence and mortality with screening flexible sigmoidoscopy. N
Engl J Med 2012;366:2345-57.
81. Selby JV, Friedman GD, Quesenberry CP, Jr., et al. A case-control
study of screening sigmoidoscopy and mortality from colorectal
cancer. N Engl J Med 1992;326:653-7.
82. Pasha SF, Leighton JA, Das A, et al. Comparison of the yield and
miss rate of narrow band imaging and white light endoscopy in
patients undergoing screening or surveillance colonoscopy: a meta-
analysis. Am J Gastroenterol 2012;107:363-70; quiz 371.
83. Singh H, Nugent Z, Demers AA, et al. The reduction in colorectal
cancer mortality after colonoscopy varies by site of the cancer.
Gastroenterology 2010;139:1128-37.
 PSG and PSDE Consensus Guidelines on the Management of Colorectal Carcinoma
84. Nishihara R, Wu K, Lochhead P, et al. Long-term colorectal-
cancer incidence and mortality after lower endoscopy. N Engl J Med
2013;369:1095-105.
85. Yeoh KG, Ho KY, Chiu HM, et al. The Asia-Pacific Colorectal
Screening score: a validated tool that stratifies risk for colorectal
advanced neoplasia in asymptomatic Asian subjects. Gut
2011;60:1236-41.
86. Rockey DC, Paulson E, Niedzwiecki D, et al. Analysis of air
contrast barium enema, computed tomographic colonography, and
colonoscopy: prospective comparison. Lancet 2005;365:305-11.
87. Kim DH, Pickhardt PJ, Taylor AJ. Characteristics of advanced
adenomas detected at CT colonographic screening: implications
for appropriate polyp size thresholds for polypectomy versus
surveillance. AJR Am J Roentgenol 2007;188:940-4.
88. de Haan MC, van Gelder RE, Graser A, et al. Diagnostic value of
CT-colonography as compared to colonoscopy in an asymptomatic
screening population: a meta-analysis. Eur Radiol 2011;21:1747-63.
89. Pickhardt PJ. Polyp detection at CT colonography: inadequate
primary 3D endoluminal reference standard precludes meaningful
comparison. Radiology 2007;244:316-7.
90. Pickhardt PJ, Choi JR, Hwang I, et al. Computed tomographic
virtual colonoscopy to screen for colorectal neoplasia in
asymptomatic adults. N Engl J Med 2003;349:2191-200.
91. Sung JJ, Luo DJ, Ng SS, et al. Patients with polyps larger than 5
mm in computed tomography colonoscopy screening have high risk
for advanced colonic neoplasia in Asia. Clin Gastroenterol Hepatol
2011;9:47-51.
92. Cotton PB, Durkalski VL, Pineau BC, et al. Computed tomographic
colonography (virtual colonoscopy): a multicenter comparison with
standard colonoscopy for detection of colorectal neoplasia. JAMA
2004;291:1713-9.
93. Pickhardt PJ, Taylor AJ. Extracolonic findings identified in
asymptomatic adults at screening CT colonography. AJR Am J
Roentgenol 2006;186:718-28.
94. Lieberman DA. Clinical practice. Screening for colorectal cancer.
N Engl J Med 2009;361:1179-87.
95. Citarda F, Tomaselli G, Capocaccia R, et al. Efficacy in standard
clinical practice of colonoscopic polypectomy in reducing colorectal
cancer incidence. Gut 2001;48:812-5.
96. Sung JJ, Lau JY, Young GP, et al. Asia Pacific consensus
recommendations for colorectal cancer screening. Gut
2008;57:1166-76.
97. Leung WK, Ho KY, Kim WH, et al. Colorectal neoplasia in
Asia: a multicenter colonoscopy survey in symptomatic patients.
Gastrointest Endosc 2006;64:751-9.
98. Garborg K, Holme O, Loberg M, et al. Current status of screening
for colorectal cancer. Ann Oncol 2013;24:1963-72.
99. Sano Y, Fujii T, Oda Y, et al. A Multicenter Randomized Controlled
Trial Designed to Evaluate Follow-up Surveillance Strategies for
Colorectal Cancer: The Japan Polyp Study. Digestive Endoscopy
2004;16:376-378.
100. Christodoulou D, Kandel G, Tsianos EV, et al. Endoscopic
resection of colonic polyps - a review. Ann Gastroenterol
2007;20:180–194.
101. Tappero G, Gaia E, De Giuli P, et al. Cold snare excision of small
Sollano JD, et al.
colorectal polyps. Gastrointest Endosc 1992;38:310-3.
102. Tedesco FJ, Hendrix JC, Pickens CA, et al. Diminutive polyps:
histopathology, spatial distribution, and clinical significance.
Gastrointest Endosc 1982;28:1-5.
103. We s t o n A P, C a m p b e l l D R . D i m i n u t i v e c o l o n i c p o l y p s :
histopathology, spatial distribution, concomitant significant lesions,
and treatment complications. Am J Gastroenterol 1995;90:24-8.
104. UEG Week 2014 Poster Presentations. United European
Gastroenterology Journal 2014;2:A132-A605.
105. Pena AAU, Carpio RE, Dalupang CDD, et al. High Incidence of
Malignant Potential in Diminutive Polyps. Manila: University of
Santo Tomas Hospital, 2010.
106. East JE. Resection Techniques for Small Colonic Polyps: Cold
Forceps Polypectomy, Hot Biopsy, Cold Snare and Hot Snare. Video
Journal and Encyclopedia of GI Endoscopy;1:401-402.
107. Riley SA. Colonoscopic Polypectomy and Endoscopic Mucosal
Resection: A Practical Guide: British Society of Gastroenterology,
2008.
108. ASGE Technology Committee, Kantsevoy SV, Adler DG, et
al. Endoscopic mucosal resection and endoscopic submucosal
dissection. Gastrointest Endosc 2008;68:11-8.
109. Cranley JP, Petras RE, Carey WD, et al. When is endoscopic
polypectomy adequate therapy for colonic polyps containing
invasive carcinoma? Gastroenterology 1986;91:419-27.
110. Anderson JC, Butterly L, Robinson CM, et al. Impact of fair bowel
prep on adenoma and serrated polyp detection: Data from the New
Hampshire Colonoscopy Registry using a standardized preparation
quality rating. Gastrointestinal endoscopy 2014;80:463-470.
111. Froehlich F, Wietlisbach V, Gonvers JJ, et al. Impact of colonic
cleansing on quality and diagnostic yield of colonoscopy: the
European Panel of Appropriateness of Gastrointestinal Endoscopy
European multicenter study. Gastrointest Endosc 2005;61:378-84.
112. Hassan C, Bretthauer M, Kaminski MF, et al. Bowel preparation
for colonoscopy: European Society of Gastrointestinal Endoscopy
(ESGE) guideline. Endoscopy 2013;45:142-50.
113. Rex DK, Schoenfeld PS, Cohen J, et al. Quality indicators for
colonoscopy. Gastrointest Endosc 2015;81:31-53.
114. Sherer EA, Imler TD, Imperiale TF. The effect of colonoscopy
preparation quality on adenoma detection rates. Gastrointest Endosc
2012;75:545-53.
115. Chokshi RV, Hovis CE, Hollander T, et al. Prevalence of missed
adenomas in patients with inadequate bowel preparation on
screening colonoscopy. Gastrointest Endosc 2012;75:1197-203.
116. Hong SN, Sung IK, Kim JH, et al. The Effect of the Bowel
Preparation Status on the Risk of Missing Polyp and Adenoma
during Screening Colonoscopy: A Tandem Colonoscopic Study.
Clin Endosc 2012;45:404-11.
117. Lebwohl B, Kastrinos F, Glick M, et al. The impact of suboptimal
bowel preparation on adenoma miss rates and the factors associated
with early repeat colonoscopy. Gastrointest Endosc 2011;73:1207-
14.
118. Chan WK, Saravanan A, Manikam J, et al. Appointment waiting
times and education level influence the quality of bowel preparation
in adult patients undergoing colonoscopy. BMC Gastroenterol
2011;11:86.
Volume 55 Number 1 Jan. - March, 2017 15
 Sollano JD, et al.
119. Romero RV, Mahadeva S. Factors influencing quality of bowel
preparation for colonoscopy. World J Gastrointest Endosc 2013;5:39-
46.
120. Lai EJ, Calderwood AH, Doros G, et al. The Boston bowel
preparation scale: a valid and reliable instrument for colonoscopy-
oriented research. Gastrointest Endosc 2009;69:620-5.
121. Rostom A, Jolicoeur E. Validation of a new scale for the assessment
of bowel preparation quality. Gastrointest Endosc 2004;59:482-6.
122. Baron TH, Smyrk TC, Rex DK. Recommended intervals between
screening and surveillance colonoscopies. Mayo Clin Proc
2013;88:854-8.
123. Winawer SJ, Zauber AG, Fletcher RH, et al. Guidelines for
colonoscopy surveillance after polypectomy: a consensus update
by the US Multi-Society Task Force on Colorectal Cancer and the
American Cancer Society. Gastroenterology 2006;130:1872-85.
124. Ji JS, Choi KY, Lee WC, et al. Endoscopic and histopathologic
predictors of recurrence of colorectal adenoma on lowering the miss
rate. Korean J Intern Med 2009;24:196-202.
125. Chung SJ, Kim YS, Yang SY, et al. Five-year risk for advanced
colorectal neoplasia after initial colonoscopy according to the
baseline risk stratification: a prospective study in 2452 asymptomatic
Koreans. Gut 2011;60:1537-43.
126. de Jonge V, Sint Nicolaas J, van Leerdam ME, et al. Systematic
literature review and pooled analyses of risk factors for finding
adenomas at surveillance colonoscopy. Endoscopy 2011;43:560-72.
127. Saini SD, Kim HM, Schoenfeld P. Incidence of advanced adenomas
at surveillance colonoscopy in patients with a personal history of
colon adenomas: a meta-analysis and systematic review. Gastrointest
Endosc 2006;64:614-26.
128. Martinez ME, Baron JA, Lieberman DA, et al. A pooled analysis
of advanced colorectal neoplasia diagnoses after colonoscopic
polypectomy. Gastroenterology 2009;136:832-41.
129. Huang Y, Li X, Wang Z, et al. Five-year risk of colorectal neoplasia
after normal baseline colonoscopy in asymptomatic Chinese
Mongolian over 50 years of age. Int J Colorectal Dis 2012;27:1651-6.
130. Brenner H, Chang-Claude J, Seiler CM, et al. Protection from
colorectal cancer after colonoscopy: a population-based, case-control
study. Ann Intern Med 2011;154:22-30.
131. Singh H, Turner D, Xue L, et al. Risk of developing colorectal cancer
following a negative colonoscopy examination: evidence for a 10-
year interval between colonoscopies. JAMA 2006;295:2366-73.
132. Edelstein DL, Axilbund JE, Hylind LM, et al. Serrated polyposis:
rapid and relentless development of colorectal neoplasia. Gut
2013;62:404-8.
133. Hazewinkel Y, Tytgat KM, van Eeden S, et al. Incidence of colonic
neoplasia in patients with serrated polyposis syndrome who undergo
annual endoscopic surveillance. Gastroenterology 2014;147:88-95.
134. Rex DK, Kahi CJ, Levin B, et al. Guidelines for colonoscopy
surveillance after cancer resection: a consensus update by the
American Cancer Society and US Multi-Society Task Force on
Colorectal Cancer. CA Cancer J Clin 2006;56:160-7; quiz 185-6.
135. Tjandra JJ, Chan MK. Follow-up after curative resection of
colorectal cancer: a meta-analysis. Dis Colon Rectum 2007;50:1783-
99.
136. Fenton JJ, Jerant AF, von Friederichs-Fitzwater MM, et al.
Physician counseling for colorectal cancer screening: impact on
16 Volume 55 Number 1 Jan. - March, 2017
PSG and PSDE Consensus Guidelines on the Management of Colorectal Carcinoma
patient attitudes, beliefs, and behavior. J Am Board Fam Med
2011;24:673-81.
137. Lafata JE, Cooper G, Divine G, et al. Patient-physician colorectal
cancer screening discussion content and patients’ use of colorectal
cancer screening. Patient Educ Couns 2014;94:76-82.
138. Levy BT, Joshi M, Xu Y, et al. Perceptions of Iowa family physicians
regarding colorectal cancer screening. Med Care 2008;46:S103-8.
139. Steinwachs D, Allen JD, Barlow WE, et al. NIH state-of-the-
science conference statement: Enhancing use and quality of
colorectal cancer screening. NIH Consens State Sci Statements
2010;27:1-31.
140. Stockwell DH, Woo P, Jacobson BC, et al. Determinants of
colorectal cancer screening in women undergoing mammography.
Am J Gastroenterol 2003;98:1875-80.
141. Levy BT, Nordin T, Sinift S, et al. Why hasn’t this patient been
screened for colon cancer? An Iowa Research Network study. J Am
Board Fam Med 2007;20:458-68.
142. Lansdorp-Vogelaar I, van Ballegooijen M, Zauber AG, et al.
Effect of rising chemotherapy costs on the cost savings of colorectal
cancer screening. J Natl Cancer Inst 2009;101:1412-22.
143. Logan RF, Patnick J, Nickerson C, et al. Outcomes of the Bowel
Cancer Screening Programme (BCSP) in England after the first 1
million tests. Gut 2012;61:1439-46.
144. Lansdorp-Vogelaar I, Knudsen AB, Brenner H. Cost-effectiveness
of colorectal cancer screening - an overview. Best Pract Res Clin
Gastroenterol 2010;24:439-49.
145. Pignone M, Saha S, Hoerger T, et al. Cost-effectiveness analyses
of colorectal cancer screening: a systematic review for the U.S.
Preventive Services Task Force. Ann Intern Med 2002;137:96-104.
146. Zauber AG. Cost-effectiveness of colonoscopy. Gastrointest Endosc
Clin N Am 2010;20:751-70.
147. Moss S, Ancelle-Park R, Brenner H. European guidelines for
quality assurance in colorectal cancer screening and diagnosis.
First Edition – Evaluation and interpretation of screening outcomes.
Endoscopy 2012;44:SE49-SE64.
148. Benson VS, Patnick J, Davies AK, et al. Colorectal cancer
screening: a comparison of 35 initiatives in 17 countries. Int J Cancer
2008;122:1357-67.
149. Kaminski MF, Bretthauer M, Zauber AG, et al. The NordICC
Study: rationale and design of a randomized trial on colonoscopy
screening for colorectal cancer. Endoscopy 2012;44:695-702.
150. Robertson DJ. Digestive Diseases Week 2011: VA Cooperative
Study #577. Colonoscopy vs. Fecal Immunological Test in
Reducing Mortality from Colorectal Cancer (CONFIRM).
151. Colorectal Cancer Screening: Insurance Coverage. American
Cancer Society.
 Impact of revised management policies
on the efficiency of gynecologic operating room
processes in a tertiary training hospital*
By Glaiza S. de Guzman, MD and Cecilia L. Llave, MD, FPOGS, FSGOP
Department of Obstetrics and Gynecology, Philippine General Hospital, University of the Philippines-Manila

ABSTRACT

Background: A retrospective observational time motion study of elective gynecologic surgeries performed from January 2015 to
December 2016 was conducted at the Operating Room Complex of a tertiary training hospital. There was a change from three
operating suites with standard last stitch time in 2015 to only two with no cutoff times in 2016. This was due to the renovation of
the Operating Room Complex.

Objective: To determine the factors and problems affecting operating room processes

Materials and Methods: Different time motion parameters such as induction time, length of induction, cutting time, last stitch
time, total operation time, turnover time, and number of cases performed were collected from the nurses’ documentation records.
Average values from two different time periods were compared and analyzed.

Results: Results showed no improvement with the revised policies implemented in 2016. With only two rooms, surgeons were able
to cope with the number of patients by extending operating hours later through the day. Recurring problems on manpower and
lack of resources were noted.

Conclusion: There is a need to identify hindrance to efficient operating room utilization with the goal to decrease patient queue,
improve patient as well as staff satisfaction, and increase hospital revenue. Multi-disciplinary changes in practices, processes, and
attitudes are timely for improvements in operating room utilization and consequently better patient centric outcomes.

Keywords: Efficiency, Operating room, Time motion study

INTRODUCTION AND SIGNIFICANCE OF THE STUDY and doctor frustration. Methods to reduce delays are

E
fficiency is defined as producing a given output with
minimum input quantities. In terms of the operating
room (OR) system, it refers to utilizing its schedule
without overrunning or cancellation of cases. Enhancing
the efficiency of the operating rooms has always been
a challenging process. Balancing the needs to satisfy
surgeons, support staff, and meet patient expectations
require both clinical and cost effectiveness. This also
entails monitoring by the hospital management to ensure
resource supply, guarantee quality care, and maintain
sustainability.
The operating room setting requires adequate
resources. While it contributes to significant staff
workload, it is a major source of hospital revenue. Thus,
delays in the operating room can be sources of lost income
for the hospital. It may correspondingly lead to patient
*Third Place, Philippine Obstetrical and Gynecological Society
(Foundation), Inc. (POGS) Research Paper Contest, October 25, 2017,
3rd Floor POGS Building, Quezon City
important to maximize utilization of the operating rooms.
It is timely to evaluate the key factors affecting
the operating room processes and change longstanding
labor structures and practices hindering productivity
and efficiency. This was done using a comparison of time
motion parameters such as total number of procedures
scheduled and performed, mean induction time, mean
cutting time, mean last stitch time, mean length of
induction, and mean turnover time. These data were
obtained from elective surgeries conducted from January
to December 2015 and January to December 2016, during
which revised policies were implemented to cater the
renovation of operating rooms.
Efficiency of operating rooms depends on various
factors. Scheduling of cases, apportionment of staff and
surgical needs, preparation and induction of anesthesia,
actual surgical process, recovery from anesthesia,
turnover time, and other resources are factors which
significantly affect use of the operating rooms. Inefficient
management can result in case cancellations and long
patient waiting lists as in the setting in most of our tertiary

20 Volume 41, Number 5, September-October 2017

public hospitals. However, in most hospitals, efforts
to reduce time have mainly involved purchase of new
equipment and provision of additional rooms. Change in
labor managerial policies has infrequently been the target
of initiatives to improve efficiency.1
Overdyk et al. (1998) accomplished significant
improvements in operating room efficiency by analyzing
data on causes of delays. They developed strategies
for minimizing the most common causes of delay.
Personal accountability, streamlining of procedures,
interdisciplinary teamwork, and accurate data collection
were all-important contributors to improved efficiency.
They concluded that changes in practices, processes, and
attitudes are likewise needed to bring about improvements
in OR utilization.2
Efficient operating room systems have the ability
to increase the number of cases that can be completed
within a block of allocated time without incurring overtime
costs.3,4 Heiser (2013) suggested that a governance
structure led by an executive committee be instituted to
improve operating room dynamics. An operating room
director, chairpersons from different surgical fields, and
a representative from hospital administration should
comprise this executive committee. They will be in-charge
with growing surgical services by marketing the surgical
program, ensuring that patient and surgeon needs are
met, increasing operating room revenue, and developing
the surgical strategic plans.5
Delays to Start Time
In a single-center prospective observational study,
Porta et al. (2013) found that the average OR delay was
17.3 minutes depending on the surgical service. These
authors identified that delays were attributed to turnover
time, nurses and surgeon issues, and patient flow issues.6
An observational study by Higgins et al. (2011) determined
that OR delays were related to unforeseen problems
on patient condition and preparation prior to surgery.
Surgeon and anesthesiologist tardiness also contributes
to delays.7,8 The former causes cases to be cancelled,
which significantly impacts OR schedule and utilization
rates. The latter delays the case, which directly impacts
the start time of the case that follows, cause cancellations
to cases scheduled later in the day, and lead to overtime
costs due to the extension of the workday.8
Delays that are not within staff control cannot be
avoided; but those that are within staff control must be
addressed to improve OR efficiency. Does et al. (2009)
found that the most important factors in delays to start
times were poor planning and scheduling. Poor planning
was related to a vague process in which patients were
prepared for surgery, such as poor instructions regarding
the time the patient is expected to arrive in the pre-
operative area, time anesthesia should be available, and
time for premedication.9
Operating Room Turnover Time
Operating room turnover time (TOT) can be defined
in different ways. Meredith et al. (2011) defined turnover
time from the last stitch of a patient to the incision of the
next patient, specifically all activities excluding the actual
surgery.10,11
Delays in TOT can be impacted by equipment
availability, availability of staff to turn over the room, or
readiness of the next patient.11 Meredith et al. (2011)
observed that there are three critical phases in TOT: patient
removal, patient transition, and operational preparation.
The efficiency with which each of these phases is
completed contributes to the improvement of TOT. White
space, which is time with no surgical activity occurring,
contributes to inefficiency and waste. Examples of white
space include instrument preparation and positioning
of the patient as well as waiting for surgical staff or the
patient. The availability of surgeons in the OR suite also
impacted TOT as surgeons were observed to motivate and
assist staff with duties other than surgery.10,12
The Hospital Setting
Elective procedures are scheduled on weekdays.
There are two blocked time schedules for procedures. On
Mondays, Tuesdays, Wednesdays, and Fridays, induction
time is set at 6:30 AM with a cutting time of 7:00 AM
(early cutting). On Thursdays, induction time is 9:00
AM while cutting time is at 9:30 AM (late cutting). This
allowed for both anesthesiologist and surgeon to attend
their respective department meetings and conferences
on said days.
In 2015, there were three operating rooms dedicated
for gynecologic cases. One was used for laparoscopic
procedures performed by the Reproductive Endocrinology
and Infertility (REI) service, and two were used by the
General Services, Urogynecology, and Gynecologic
Oncology. On the average, three cases were scheduled
for each room for a total of nine procedures per day. The
number of cases actually performed depends on whether
cases were finished before the last stitch time designated
at 11:45 AM. If cases extended beyond this time, the
next cases will not be allowed to proceed. In 2016, the
operating room management policies were revised to
cater for the renovation of the Left Central Block (LCB)
Complex. Only two rooms were provided for gynecologic
cases, to be shared by all the services. To increase patient
load, there were no cut-off times for cases. All scheduled
cases were allowed to proceed regardless of the time of
day. Whether or not these changes led to better operating
room efficiency remains undetermined.
Volume 41, Number 5, PJOG September-October 2017 21

Figure 1. Conceptual framework of the study. The number of
cases actually performed daily depends on different factors
including the induction time, length of induction, cutting time,
last stitch time, total operation time, and turnover time. It
likewise depends on the surgeon, anesthesiologist, and staff
skills. It measures the efficiency of the operating room system
with the ultimate goals to reduce patient queue for operation,
satisfy patient, staff, and surgeon, and increase the hospital
revenue.
In this study, factors affecting the maximum
utilization of operating room suites were evaluated using
different time motion parameters as described.
OBJECTIVES OF THE STUDY
General Objective:
To determine the factors and problems affecting
operating room processes
Specific Objectives:
1) To determine the efficiency of the operating
rooms by analysis of the following data: total
number of procedures scheduled and performed,
mean induction time, mean cutting time, mean
last stitch time, mean length of induction, and
mean turnover time for two time periods
2) To determine causes of delay in procedures
3) To compare efficiency of the operating room
for two different periods (January to December
2015 and January to December 2016) using the
obtained data on operating room processes
MATERIALS AND METHODS
A. STUDY DESIGN
The study is a retrospective observational study.
B. OPERATIONAL DEFINITION OF TERMS
1. Efficiency is defined as producing a given
22 Volume 41, Number 5, September-October 2017
output with minimum input quantities. In the
operating room, the use of time is key to the
efficient production of surgical cases. An aim of
efficiency studies is to minimize time waste or
to maximize timesaving. Therefore, this study
defines OR process efficiency as maximizing
output in terms of actual number of operations
performed daily.
2. Induction time is the time anesthesia induction
starts.
3. Length of induction is the duration of anesthesia
induction. It is computed by subtracting the
induction time from cutting time.
4. Cutting time is the time the surgery starts when
the first incision is made.
5. Last stitch time is the time the surgery ends, when
the last stitch is made.
6. Turnover time is the time from the last stitch of
a patient to the induction of the next patient.
It refers to the period when no surgery takes
place. During turnover time, the operating room
is cleaned and instruments are prepared for the
next case.
C. DESCRIPTION OF STUDY PROCEDURES
Data were obtained from the nursing documentation
record and time motion tallies of elective surgeries of the
Operating Room Complex for the years 2015 and 2016.
Data obtained were the total number of procedures
scheduled and performed, induction time, cutting
time, last stitch time, length of induction, and turnover
time. The mean values for each of the parameters were
recorded and analyzed. Values for two time periods were
then compared. Other parameters noted were reasons
for cancellation and delay of cases as indicated in the
nurses’ logbook.
D. STUDY POPULATION and SAMPLE SIZE
All elective surgeries performed by the Gynecology
services were included in the study. Emergency procedures
were excluded. Duration of data collected is from January
2015 to December 2016.
E. DATA COLLECTION TOOLS AND ANALYSIS
Data were collected from the nursing documentation
record and time motion tally sheets (Appendix A) then
organized in an Excel file for analysis. In order to achieve
the goal of evaluating an explanatory model of efficiency
in OR processes, the mean values of each time motion
parameter were obtained and compared to their standard
or allowable values for both years
RESULTS
Total number of operations performed
In the year 2015, a total of 1198 elective
procedures were performed in 232 days. This is higher
compared to the 1158 elective procedures performed
in 241 days in the year 2016 (Table 1). There were 429
cases in 2015 that were scheduled but not performed.
On the other hand, only 172 cases were deferred in
2016. Common causes of cancellations in 2015 were
inability to comply with the cutoff time, after which
surgeons were not allowed to perform succeeding
cases. Due to this, patients were likely to be included
in the OR schedule, sometimes for days, before finally
being operated on. In both years, lack of preoperative
clearance and poor patient preparation (including lack
of blood or change in surgical plan) were noted as
reasons for cancellations.
Induction time and length of induction
The average time of induction in 2015 was
7:00 AM and 9:25 AM during early and late cutting,
respectively. It was later in 2016 at 7:14 AM and
9:46 AM, respectively. This was approximately 25 to
46 minutes late compared to the expected time of
induction of 6:30 AM during early cutting and 9:00 AM
during late cutting days. 50.8% of cases were induced
30 minutes after the standard time. The average length
of induction was 17 minutes in 2015 and 25 minutes in
2016. (Tables 1 and 2)
Cutting time
The average cutting time in 2015 was 7:30 AM and
9:55 AM during early and late cutting, respectively. It was
later in 2016 at 7:36 AM and 10:03 AM, respectively. This
was approximately 30 to 36 minutes late compared to
the expected cutting time of 7:00 AM during early cutting
and 9:30 AM during late cutting days. 23.1% of cases had
a cutting time more than 30 minutes after the standard
time.
Turnover time
Measured as the time from the last stitch of a
patient to the induction of the next patient, the mean
turnover times were 34 and 35 minutes for 2015 and
2016, respectively.
Causes of delay
Noted causes of delay were the lack of utility
workers and working elevators for patient transfers,
tardiness of doctors, inefficient intraoperative referral
systems, shortage of operative equipment and materials,
and delays in release of supplies from the Pharmacy.
DISCUSSION
Managerial aspects of providing healthcare are
increasingly becoming vital to reduce costs and improve
income. As a major source of revenue, the economic
viability of a hospital demands that operating rooms run
efficiently. Managing the operating rooms is particularly

Table 1. Number of Elective Procedures Scheduled and Performed

MONTH 2015 2016

Scheduled Performed OR Days Scheduled Performed OR Days

January 114 82 17 112 97 20

February 117 88 19 110 90 18
March 143 105 22 111 94 21
April 125 87 19 130 118 20
May 133 100 20 120 109 22
June 148 107 20 116 118 24
July 160 129 22 110 103 20
August 139 107 19 95 75 18
September 158 117 21 105 68 19
October 151 122 22 104 87 21
November 119 84 16 114 101 19
December 120 70 15 103 98 19
TOTAL 1627 1198 232 1330 1158 241

Volume 41, Number 5, PJOG September-October 2017 23

Table 2. Time Motion Parameters for 2015 and 2016 for Early Cutting*

MONTH 2015 2016

Induction Time Cutting Time Last Stitch Time Induction Time Cutting Time Last Stitch Time

January 6:54 AM 7:38 AM 10:56 AM 7:14 AM 7:46 AM 10:01 AM

February 6:56 AM 7:31 AM 10:43 AM 7:06 AM 7:31 AM 9:50 AM
March 6:54 AM 7:30 AM 10:22 AM 6:59 AM 7:30 AM 10:02 AM
April 6:57 AM 7:36 AM 10:34 AM 6:55 AM 7:31 AM 10:09 AM
May 6:52 AM 7:27 AM 10:21 AM 7:16 AM 7:42 AM 10:18 AM
June 7:03 AM 7:31 AM 10:14 AM 7:15 AM 7:36 AM 9:41 AM
July 7:00 AM 7:39 AM 10:10 AM 7:07 AM 7:34 AM 10:05 AM
August 7:05 AM 7:34: AM 9:57 AM 7:31 AM 7:50 AM 10:15 AM
September 7:06 AM 7:36: AM 9:58 AM 7:21 AM 7:30 AM 10:30 AM
October 7:00 AM 7:15 AM 10:30 AM 7:32: AM 7:40 AM 10:18 AM
November 7:09 AM 7:20 AM 10:40 AM 7:15 AM 7:31 AM 10:43 AM
December 7:07 AM 7:21 AM 10:40 AM 7:17 AM 7:38 AM 10:17 AM
AVERAGE 7:00 AM 7:30 AM 10:25 AM 7:14 AM 7:36 AM 10:10 AM

*Early cutting: Mondays, Tuesdays, Wednesdays, and Fridays. Induction of anesthesia is expected at 6:30 AM and cutting time is at
7:00 AM. Only the first cases were analyzed for comparison of the above time motion parameters.

Table 3. Time Motion Parameters for 2015 and 2016 for Late Cutting*

MONTH 2015 2016

Induction Time Cutting Time Last Stitch Time Induction Time Cutting Time Last Stitch Time

January 9:17 AM 9:52 AM 1:30 PM 9:53 AM 10:40 AM 12:23 PM

February 9:14 AM 10:01 AM 3:13 PM 9:41 AM 10:12 AM 12:56 AM
March 9:37 AM 10:26 AM 2:25 PM 9:23 AM 9:58 AM 1:54 PM
April 9:25 AM 9:51 AM 1:15 PM 10:20 AM 10:43 AM 1:19 PM
May 9:19 AM 9:51 AM 12:30 PM 10:18 AM 10:43 AM 1:36 PM
June 9:10 AM 9:3 AM 12:43 AM 10:03 AM 10:32 AM 12:51 AM
July 9:37 AM 10:10 AM 11:55 AM 9:32 AM 9:54 AM 11:25 AM
August 9:51 AM 10:22 AM 1:02 PM 9:51 AM 10:42 AM 12:25 PM
September 9:41 AM 10:06 AM 12:39 AM 9:30 AM 9:42 AM 1:00 PM
October 9:15 AM 9:40 AM 1:27 PM 9:40 AM 9:54 AM 12:30 PM
November 9:19 AM 9:38 AM 12:39 PM 9:31 AM 10:01 AM 1:15 PM
December 9:17 AM 9:31 AM 1:29PM 9:41 AM 7:40 AM 12:55 PM
AVERAGE 9:25 AM 9:55 AM 1:13 PM 9:46 AM 10:03 AM 12:52 PM

*Late cutting: Thursdays. Induction of anesthesia is expected at 9:00 AM and cutting time is at 9:30 AM. Only the first cases were
analyzed for comparison of the above time motion parameters.

problematic due to scarcity of resources and conflicting
priorities of the staff and surgeons. There is a need to
forestall problems and stress the need for efficiency
by development of adequate planning and scheduling
processes.
24 Volume 41, Number 5, September-October 2017
There were less cases performed in 2016 compared
to 2015, which may be due to having one less operating
room for elective cases. On the other hand, there was a
decrease in the number of cancelled cases in 2016 owing
to the new management policy of having no cut-off time
for one of the operating rooms. This allowed surgeons to
schedule their patients without having to worry about
not meeting the last stitch time. This also decreased the
number of hospital days patients would have to wait for
their procedure. Ultimately, it decreased patient queue
and makes utility of the operating room suite to function
more hours daily.
It is imperative in a tertiary hospital setting to
investigate the causes of delays in the operating room.
This has been addressed by the OR management team.
Rules on admitting as well as scheduling patients for
elective procedures have already been put it place.
Compliance to these rules is monitored.
This study illustrated delays in the time of anesthesia
induction and surgeon cutting time. The 25 to 46 minute
tardiness in induction reflects of the inefficiency of OR
utilization. Steps must be undertaken to investigate
reasons for these delays, which may include but are
not limited to anesthesiologist and surgeon tardiness,
problems with patient transfer to the OR, or lack of
equipment for OR use. Regarding the length of induction,
shorter time periods were spent on anesthesia induction
in 2015. This may be attributed to new rules on scheduling
longer cases, i.e. malignant cases were scheduled first,
in 2016. These cases were more commonly induced
with epidural anesthesia rather than spinal because of a
projected longer operation time.
There was no significant difference in the turnover
time between the two years. This signifies no improvement
in staffing and resource management of the hospital. Idle
operating rooms means wasted revenue for the hospital
due to underutilization of the suite. It is imperative
for hospitals to strive to attain decreased turnover
times. This may be done by having a process mapping
and delegating responsibilities to specific personnel.
Different personnel should be dedicated for cleanup
and setup for the next patient as well as transporting
patients and equipment to and from the operating room.
Patients should be brought immediately into the room
after completion of the setup. Better communication is
also needed between the staff, anesthesiologists, and
surgeons. Planning of personnel duty schedules should
also be enforced. A postoperative debriefing of the staff
may also be helpful.
CONCLUSION
In conclusion, the change in management policies in
the year 2016 did not increase the number of procedures
performed. In fact, there were more cases done with
three operating rooms even with a required last stitch
time. Surgeons were able to cope up with demands to
increase the number of procedures in 2016 by staying
later in the day. Careful selection of patients and
strategic planning of schedule to decrease cancellation
of cases should be strictly implemented. The induction
and cutting time for both years were similar. Both were
considerably late from standard allowable times. Efforts
should be made to monitor these time parameters
to achieve anesthesiologist and surgeon punctuality.
Moreover, improvement in turnover time was not
apparent with revised policies. This may be improved by
setting up an approved systems process, delegation of
tasks, and ensuring that manpower and resources are
able to keep up with patient queues for operations. The
culture in the delivery of care in the OR must change
from what is best for the surgeon and nurses to what is
best for the hospital and patients.
LIMITATIONS OF THE STUDY
There are several limitations to this study. First,
as the data are from a single hospital, the results
may be difficult to generalize to other hospitals with
different functional characteristics such as size, services
provided, and case mix. Variability of case duration also
makes it difficult to predict actual utilization. Even for
straightforward, common operations, actual case time
is uncertain. Each patient is different, and the actual
time for a given operation cannot be predicted. This fact
means that in a series of cases that are scheduled to
follow, the actual start time of cases after the first case
cannot be determined in advance. Likewise, surgeon
and nursing staff skills and experience affect the actual
operating time.
RECOMMENDATIONS
The investigators will present the findings of the
study to the operating room management team. As
discussed, there is a need for a structured and timely
monitoring of the different time motion parameters.
Monthly or quarterly evaluations may be needed for
prompt mediation. Interventions may be discussed
during meetings with immediate reassessment of
operating room efficiency. Further studies may be done
after revision of policies and implementation of strict
rules adherence to operating room standard times.
Volume 41, Number 5, PJOG September-October 2017 25
REFERENCES
1. Kocher R and Sahni NR. 2011. Rethinking health care labor. The
New England Journal of Medicine. 365; (15):1370-1372.
2. Overdyk FJ, Harvey SC, Fishman RL, and Shippey F. 1998. Successful
strategies for improving operating room efficiency at academic
institutions. Anesthesia & Analgesia. 86(4):896-906.
3. Guerriero F and Guido R. 2011. Operational research in the
management of the operating theatre: A survey. Health Care
Management Science. 14(1):89-114.
4. Ferrari LR, Micheli A, Whiteley C, Chazaro R, and Zurakowski
D. 2011. Criteria for assessing operating room utilization in a
freestanding children’s hospital. Pediatric Anesthesia. 22:696-706.
5. Heiser R. 2013. Using a best-practice perioperative governance
structure to implement better block scheduling. Association of
Operating Room Nurses. 97(1):125-131.
6. Porta CR, Foster A, Causey MW, Cordier P, Ozbirn R, Bolt S, and
Rush R. 2013. Operating room efficiency improvement after
implementation of a postoperative team assessment. Journal of
Surgical Research. 180:15-20.
8. Wright JG, Roche A, and Khoury AE. 2010. Improving on-time
surgical starts in an operating room. Canadian Journal of Surgery.
53(3):167-170.
9. Does R, Vermaat T, Verver J, Bisgaard S, and Heuvel J. 2009.
Reducing start time delays in operating rooms. Journal of Quality
Technology. 41(1):95-109.
10. Meredith J, Grove A, Walley P, Young F, and Macintyre M. 2011.
Are we operating effectively? A lean analysis of operating theatre
changeovers. Operations Management Research. 4:89-98.
11. Li D, Wang S, and Powers C. 2013. A systematic strategy for
perioperative process improvement. Proceedings of the Industrial
and Systems Engineering Research Conference, Puerto Rico, 626-
634.
12. Masursky D, Dexter F, Isaacson S and Nussmeier N. 2011. Surgeons’
and anesthesiologists’ perceptions of turnover times. Anesthesia
and Analgesia. 112(2):440-444.

7. Higgins VJG, Bryant MJ, Villanueva EV, and Kitto SC. 2011.
Managing and avoiding delay in operating theatres: A qualitative,
observational study. Journal of Evaluation in Clinical Practice.
19:162-166.

26 Volume 41, Number 5, September-October 2017

 Isolated metastasis to the uterine cervix from
primary breast carcinoma: A case report*
By Joan Marice C. Toh, MD and Leo Francis N. Aquilizan, MD, FPOGS, FSGOP
Department of Obstetrics and Gynecology St. Luke’s Medical Center - Quezon City

ABSTRACT

Metastasis of malignancy to the uterine cervix is a rare event in itself. Breast cancer is a commonly diagnosed malignancy in
women that has been extensively studied, and it has been known that common areas of metastasis are the lungs, skin, liver and
brain. Since the 1980s, there have been a handful of reported cases of metastasis to the uterine cervix. We present the case of a
64-year-old Gravida 4 Para 1 (1031) who developed postmenopausal bleeding 9 years after treatment of the primary breast cancer,
which after work-up, turns out to be an isolated metastatic lesion to the cervix. In cases such as this one, surgery is a reasonable
treatment option that is sufficient in itself without the need for chemotherapy or radiation. Our patient was offered a different
treatment option, which is chemotherapy, instead of proceeding straight to the treatment option presented by most case reports,
which is surgery. This paper aims to highlight a possible route of metastasis, to emphasize the need for regular gynecological
examination in patients with breast cancer, as well as the importance of aggressive treatment in the form of surgery in cases of
isolated cervical metastasis.

Keywords: Breast cancer, Cervical metastasis

INTRODUCTION and 1.2% to the vagina.4 There were no cases of cervical

B
reast cancer is one the most frequently diagnosed
malignancies in women worldwide. Over the last
few decades more women have been diagnosed
during early stages of the disease, presumably due to
increased awareness and knowledge of the disease, for
which curative approaches are still available at early
stages. Nevertheless, 20-85% of these patients will
develop distant metastasis within 5 years of their initial
diagnosis.1
In 2011, Langballe et al investigated the risk of
developing a second non-breast malignancy in pre
and post menopausal women, and found that women
diagnosed in the postmenopausal period had no overall
excess risk of developing a second primary, compared to
18% in those women diagnosed in the premenopausal
period.2 The study by Karrison et al in 1999 showed
that risk of recurrence of stage 1 disease such as in our
patient is 3.5% up to the third year and 1-1.5% every
year thereafter.3 In 1950, Abrams et al analyzed 1000
autopsied cases of malignancies of epithelial origin for the
incidence of metastases. Overall, metastasis to the cervix
was only 0.3%, and out of 167 cases of carcinoma of the
breast, 23% metastasized to the ovary, 8.4% to the uterus
*Second Place, Philippine Obstetrical and Gynecological Society
(Foundation), Inc. (POGS) Interesting Case Paper Contest,
September 21, 2017, 3rd Floor POGS Building, Quezon City
34 Volume 41, Number 5, September-October 2017
metastasis noted from a breast primary in this analysis.
The first objective of this case report is to discuss a
possible route of metastasis from a breast primary to the
uterine cervix. For cases of isolated cervical metastasis
such as our patient, surgical removal of the uterus, ovaries
and the uterine cervix may prove to be beneficial or even
curative. Lastly, this paper aims to emphasize the need
for a regular gynecologic examination especially after
diagnosis and treatment of breast carcinomas.
THE CASE
S.R. is a 64-year-old Gravida 4 Para 1 (1031) who
presented with a firm, tender, non-movable mass
approximately 1x1 cm at the 11 o’clock position of the left
breast 9 years ago. She is a known diabetic, maintained on
insulin, and surgical history reveals that patient has had a
previous cesarean section in 1987, and an appendectomy
in the 1980s. Patient had menarche at 11 years old and
had subsequent regular menses. She was menopause
at 50 years old. Family history was negative for any
malignancies. Patient has no history of intake of oral
contraceptive pills. She had one sexual partner.
Nine years prior to admission, during an annual
physical examination at the office, bilateral mammography
showed an irregular focal area suggestive of spiculations
in the left breast, seen only in the upper posterior and
mediolateral oblique view. A breast ultrasound was then
done, and the left breast shows a mass with ill-defined
slightly irregular margins and shows post-acoustic
shadowing at the 11 o’clock position, about 7cm from lung nodules. Three months prior, cervical biopsy was
the nipple. This was said to be suggestive of malignancy, repeated, showing poorly differentiated adenocarcinoma,
hence was advised surgery. Patient underwent a modified breast primary (Figure 1). Immunohistochemical stains
radical mastectomy of the left breast with frozen section showed the following results: p16 was negative (Figure
and axillary lymph node dissection. Histopathology 2), mammoglobin was positive (Figure 3) and GATA-
revealed invasive ductal carcinoma, histologic grade 3 was positive (Figure 4). Based on these results, the
1, nuclear grade 1, lymph nodes were all negative for diagnosis is a metastatic cancer to the uterine cervix
metastasis. Patient was asymptomatic after her surgery
and was on regular follow up every 3-6 months with her
surgeon for the next 5 years. During these five years, she
was maintained on tamoxifen.
One year prior to admission, patient she noted
postmenopausal bleeding, amounting to about 1-2
moderately soaked pads per day, lasting approximately 3
days, occurring intermittently. This was accompanied with
hypogastric pain graded 5-6/10 on the visual analogue
scale. When she sought consult with a gynecologist, a
papsmear was done showing “atypical squamous cells,
cannot exclude high grade squamous intraepithelial lesion,”
hence was referred to a gynecologic oncologist. A cervical
biopsy was done, and this showed results consistent with
breast metastasis to the cervix. She consulted with a
medical oncologist, who requested for a slide review of
her cervical biopsy, the following immunohistochemical
stains were done: mammoglobin was positive, gross cystic
disease fluid protein – 15 (GCDFP-15) was negative and
p16 was negative, pointing to a cervical metastasis from
the breast. A transvaginal ultrasound was done however Figure 1. Microsections disclose several invasive clusters and
no cervical lesion was noted. She was started on Letrozole nests of atypical epithelial cells with large hyperchromatic
2.5 mg/ tablet, 1 tablet once daily however patient took pleomorphic nuclei, prominent nucleoli and ample to fair
this for only 3-4 months before she decided to seek a amount of eosinophilic cytoplasm. Several areas also show
second opinion. She consulted with a gynecologist, and atypical epithelial cells with pleomorphic small nuclei arranged
was told that there were abnormal findings seen on the in single file.
cervix on speculum examination so a referral was made to
a gynecologic oncologist at our institution. She was seen
and examined 5 months prior. On examination, the right
breast was grossly normal. There was no skin dimpling,
no nipple retraction, no erythema. There was no noted
nipple discharge or palpable masses. Mastectomy scar of
the left breast was intact, with no palpable masses up to
the margins of the clavicle and the sternum. The bilateral
axillae were likewise unremarkable. Chest expansion was
symmetrical; breath sounds were clear. The precordium
was adynamic, no murmurs were appreciated, heart rate
and rhythm were regular. On bimanual pelvic examination,
the cervix measured 4x4 cm, the uterine corpus was
small and both parametria were smooth. A transvaginal
ultrasound showed a sonologically unremarkable cervix,
small retroverted uterus with myoma nodule and
adenomyosis, thin endometrium and atrophic ovaries.
PET-scan was also done for metastatic evaluation, and
this showed a hypermetabolic focus in the uterine cervical
region suspicious for a malignant lesion, as well as bilateral Figure 2. p16 staining negative.

Volume 41, Number 5, PJOG September-October 2017 35


Figure 3. Mammoglobin staining positive.
Figure 4. GATA-3 staining positive.
from primary carcinoma of the breast. Initially, the plan
was to do a total abdominal hysterectomy with bilateral
salpingo-oophorectomy, however the patient was not yet
amenable at that time and opted to do chemotherapy
with carboplatin and docetaxel instead. After 6 cycles
of chemotherapy, a bimanual pelvic examination was
done, the cervix measured 3x4 cm compared to the
last examination done 3 months prior to commencing
chemotherapy. At this time, imaging was repeated.
Transvaginal ultrasound showed that the cervix measured
1.6 x 2.8 x 3.1 cm, with a distinct canal and homogenous
stroma. The endometrial cavity was dilated to 1.9 cm,
with anechoic intracavitary fluid (10 milliliters). The
36 Volume 41, Number 5, September-October 2017
anterior endometrium was 0.27 cm, and the posterior
endometrium was 0.36 cm, a total thickness of 0.73 cm,
with regular endomyometrial junction, with minimal
color flow. The corpus was 5.5 x 4.9 x 5.7 cm, retroverted,
atrophic, with an intramural myoma measuring 1.52 x
1.51 x 1.27 cm at the anterior lower uterine segment.
Both ovaries were atrophic. Whole abdominal CT scan
only showed dilated and fluid filled endometrial cavity,
and chest CT scan were unremarkable. Since we did
not see a favorable response in the patient after the
chemotherapy, she was again offered surgery, to which
she now consented to. A total abdominal hysterectomy
with bilateral salpingo-oophorectomy was performed,
and intraoperatively, noted that there was no ascites, and
that the liver edge and subdiaphragmatic surfaces were
smooth. The uterus was symmetric with a reddish smooth
serosal surface, measuring 5 x 6 x 3.5 cm (Figure 5). The
cervix measured 2 x 1.5 cm, and was nodular with a firm
indistinct mass at the 3-4 o’clock position (Figure 6). On
cut section, the endometrial canal measured 0.5cm. The
myometrium was 3 cm. The endometrium was 0.4 cm
with no areas of necrosis. The endocervical canal was 1
cm long (Figure 7). Both ovaries were atrophic and grossly
unremarkable. Histopathologic diagnosis was as follows:
adenocarcinoma involving the endometrium and cervix,
compatible with breast carcinoma origin, intramural
myoma, and unremarkable ovaries and fallopian tubes.
DISCUSSION
Breast Cancer
Breast cancer is the most frequently diagnosed
cancer and the leading cause of cancer death in women
worldwide.5 Most breast malignancies arise from epithelial
elements hence are characterized as carcinomas. Invasive
breast carcinomas are of several diverse histologic
subtypes, the most common of which are invasive ductal
(76%) and invasive lobular (8%) types; mixed ductal-
lobular types account for 7%.6
Figure 5. The uterus was symmetric with a reddish smooth
serosal surface, measuring 5 x 6 x 3.5cm.

Figure 6. The cervix measured 2 x 1.5cm, and was nodular with
a firm indistinct mass at the 3-4 o’clock position.
Figure 7. On cut section, the endometrial canal measured 0.5cm.
The myometrium was 3cm. The endometrium was 0.4cm with
no areas of necrosis. The endocervical canal was 1cm long.
Invasive ductal carcinoma is the most common type
of invasive breast cancer and is characterized by cords
and nests of tumor cells with varying amounts of gland
formation, and cytologic features that range from bland
to highly malignant. The malignant cells induce a fibrous
response as they infiltrate the breast parenchyma, and
this reaction is responsible for the clinically and grossly
palpable mass, the radiologic density and solid sonographic
characteristics. Grading is based on architectural and
cytologic features. 5
Invasive lobular carcinoma is the second most
common type of invasive breast cancer. In many cases,
no mass lesion is grossly seen, and the excised specimen
may only look normal or be slightly firm. Microscopically,
lobular carcinomas are characterized by small cells that
infiltrate the stroma and adipose tissue individually and
in single file pattern, growing in a target-like configuration
around normal breast ducts, and frequently inducing only
minimal fibrous reaction.5
According to a study in 2000 by Caplan et al on
the time to diagnosis and treatment of breast cancer,
it was said that regardless of mammogram or clinical
breast examination result, median treatment intervals
were within 2 weeks – nearly 80% of the women began
treatment within 30 days after the diagnosis.7 For this
patient, the interval from diagnosis to treatment was
34 days. She presented with a small breast lump that
was small and non-tender, for which she wouldn’t
have sought consult for, if not for an annual physical
examination. The diagnosis was only made incidentally,
so to speak. From the time of a suspicious mammogram
and breast ultrasound, it took her 34 days before
a modified radical mastectomy with lymph node
dissection was performed.
The longest interval between primary treatment
of breast cancer and tumor recurrence defines the
appropriate length of follow up, the effectiveness of
treatment, and curability of disease. Karrison, et al
(1999) studied the recurrences and deaths, hazard rate
for first recurrence or death and excess mortality rate of
1547 patients from 1945 to 1987 and determined that
in this population, the limit of breast cancer dormancy
appears to be 20-25 years. Most recurrences were noted
to occur within the first ten years after mastectomy. In
this study, they found that for stage 1 cases such as in our
patient, the rate of recurrence or death was low at about
3.5% per year in the third year, but generally remaining
within 1% to 1.5% per year thereafter. As expected
for more advanced stages, hazard rates were much
higher: in stage II, 14% per year in the second year after
mastectomy; in stage III, 28% per year in the first 2 years
after mastectomy.3 A more recent update on this concept
was reviewed by Brackstone et al in 2007, bringing into
light the fact that due to more advanced ideas and new
discoveries over the years in the diagnosis and treatment
of breast cancer, many more factors should be considered
in tumor dormancy such as sensitivity to hormone
receptors. In patients with hormonally sensitive tumors,
recurrence frequently occurs after completion of the
5 years of hormone therapy.8 Probably, during those 5
years, the changes in the host were not favorable for the
tumor cells. Our patient was only given hormone therapy
but was never started on chemoradiation and it seems
that in her very early stage of diagnosis of stage 1 node
negative cancer, it was deemed sufficient for her to only
Volume 41, Number 5, PJOG September-October 2017 37
have undergone a mastectomy. She was diagnosed with
stage IV metastatic breast cancer to the uterine cervix, 8
years after her mastectomy.
Breast Metastasis
In this case, the question is, is this a second primary,
or a metastatic disease from the earlier diagnosed breast
malignancy? And, if it is metastatic, what is the possible
route of spread? The majority of cancer mortalities are
due to the metastasis of tumor cells to other organs. The
most common route of spread of breast metastasis is the
lymphatic system. Invasive ductal carcinoma metastasizes
more commonly to the liver, lung and brain, while lobular
carcinomas metastasize more commonly to the bones,
peritoneum, retroperitoneum, gastrointestinal tract and
the genitourinary tract. Although no direct lymphatic
routes to these target organs have actually been
identified, one possible mechanism is that when tumor
cells seed into the lymphatic system, these eventually
exit via efferent vessels and utilize the venous system
to merge with the systemic circulation.9 The concept of
tumor dormancy says that breast cancer metastasis can
manifest years after successful treatment of the primary
tumor. During the protracted asymptomatic phase, tumor
cells can undergo intermittent growth and quiescence and
attain malignant potential in the new microenvironment
of the target organ, as postulated by the “seed and soil”
hypothesis.8
The postulated mechanism for the metastatic pattern
of lobular carcinoma is the loss of E-cadherin expression,
which leads to loss of cell to cell adhesion and signaling,
which may be the reason for the unusual sites of spread
for lobular type carcinomas.10 The reason for a different
metastatic pattern for lobular and ductal carcinoma is not
clear yet.
In 2008, Sanuki-Fujimoto et al retrospectively
analyzed 3783 patients treated for invasive breast cancer,
for frequency of usual and unusual metastases. Unusual
metastasis is defined as systemic failure with a frequency
of less than 1% at each site, of which gynecologic organs
are included. Overall, unusual metastasis is observed
in 2.2% of patients, and of this number, the unusual
metastasis was the first event in only 15 patients.10
Metastasis to cervix
In general, metastasis to the cervix from non-
gynecological primaries are rare. When present, these
non-gynecologic malignancies usually metastasize to the
ovaries, presumably due to its abundant blood supply,
especially in premenopausal women. In a study by
Mazur et al in 1988, out of 325 cases of metastasis to the
female genital tract, only 3.7% have involvement of the
uterine cervix, and out of this number, none were from
38 Volume 41, Number 5, September-October 2017
the breast.11 Abnormal uterine bleeding is often the first
sign in patients with metastatic disease to the cervix. Our
patient presented with postmenopausal bleeding, which
may at first seem like a probable endometrial or cervical
pathology. Since she did not have regular gynecologic
follow-up, a Pap smear done during her initial consult for
this new symptom showed a high probability for cervical
malignancy. If further work-up had not been done the
patient would have been treated inappropriately for a
primary cervical carcinoma.
A reason for the rarity of a cervical metastasis could
be due to its small organ size and minimal blood supply
as well as its fibromuscular structure. In the face of an
inflammatory reaction, cervical tissue undergoes fibrous
proliferation, hence, on physical examination, the finding
is usually an enlarged bulky cervix.12,13 When the anatomy
of the cervix is reviewed, the arterial supply of the uterine
cervix is derived from a branch of the uterine artery. These
run lateral to the cervix and encircle it. Venous drainage
accompanies these arteries. We can also note that there
are only efferent lymphatic vessels of the cervix, so
circulating tumor cells do not readily find their way to the
cervix through lymphatic vessels. Extravasated plasma
and proteins from blood are collected in the interstitial
space, which then form lymph fluid. These fluids will then
be reabsorbed into small veins, thus making their way
back into blood circulation. Perhaps in this case, after the
modified radical mastectomy, there were tumor cells that
seeded into the lymphatic system. The lymphatic vessels,
being highly permeable and having a slow flow rate, may
have harbored dormant tumor cells which eventually
was absorbed back into the veins and back to the blood
circulation of the pelvis.
In 2012, Bereza et al aimed to describe the
architecture of the vaginal and supravaginal parts of the
human uterine cervix by collecting uteri at autopsy and
creating vascular casts of the vasculature after perfusing
the uteri with resin. In so doing, they found four distinct
zones – an outer zone containing large arteries and
veins, an arteriole and venule zone, the endocervival
mucosal capillaries zone and the pericanalar zone
containing small veins and capillaries. This study was
the first to suggest that there may be the existence of
a countercurrent transport between adjoining veins
and arteries.14 With this information we figured that
a lymphatic and hematogenous route of metastasis is
easier to understand – from the breast, tumor cells seed
into the lymphatic system (in our case the patient had a
lesion on the left breast, so we assume that the lymph
has drained into the thoracic duct). All lymph drains back
into the venous system, and the venous system flows
back into the heart, which then pumps blood into the
arteries of the entire system. Now since it was found
that there may be adjoining venules and arterioles in
the cervix, dormant tumor cells finding its way to this
microvasculature is not so far a possibility.
Another possible route is through a lymphatic
network in the cervix. What has been widely accepted
is that in the uterine cervix, only efferent lymphatics
were present, and this was one of the basis of other
case reports on their hypotheses about the rarity of
cervical metastasis from the breast and other organs. The
concept of a blood brain barrier has been widely accepted
and the existence of lymphatic vessels in the brain was
proposed but evidence was lacking. Recently in 2015,
Dissing-Olesen et al published an article that identifies
a network of lymphatic vessels in the brain, as studied
in two laboratories. What they found was an expression
of lymphatic vessel endothelial hyaluronan receptor 1
(Lyve-1) and vascular endothelial growth factor receptor 3
(VEGFR-3), just like in peripheral lymphatic vessels.15 This
mechanism may perhaps be present in the cervix as well.
As we have learned of a possible countercurrent transport
between arteries and veins of the cervix, an afferent
and efferent lymphatic system may very well be present,
accounted for by signaling transduction by proteins similar
to VEGF-3 and Lyve-1.15
We postulate that the metastasis of breast carcinoma
to the uterine cervix may be through drop metastasis – a
term commonly used in neurology to mean the spread of
an intracranial tumor through cerebrospinal fluid to the
spinal cord. Rare as it may be, a drop metastasis in this
case could seem more improbable than easily explainable
by our knowledge of anatomy, but we propose the
hypothesis of drop metastasis as a possible mechanism
of spread. The efferent lymphatic vessels of the cervix
drain into the external iliac, internal iliac and sacral lymph
nodes, which drain into the common iliac nodes. Lateral
aortic nodes receive lymph from the common iliac node
and drains into the lumbar trunk, which then drains into
the cisterna chyli. From the breast, axillary lymph nodes
drain into the thoracic duct. Extra-axillary nodes such as
the internal mammary group of nodes also drain into the
thoracic duct. Based on a foundational knowledge of the
lymphatic system and Starling’s forces, the cisterna chyli is
a dilated sac that marks the distal end of the thoracic duct,
which is the major lymphatic vessel that drains from the
entire body except the right upper extremity and the right
thorax. From the cisterna chyli, an interplay between the
osmotic and hydrostatic forces may have allowed dormant
tumor cells to seed into peritoneal fluid and settle in the
cul de sac. These same forces may also be responsible
to a possible seeding of tumor cells through the very
absorbable lymphatics or veins in the cervix, causing it to
later be clinically evident, as hypothesized by the tumor
dormancy theory.
Role of Immunohistochemical Stains in Diagnosis
There is an undeniable need to accurately distinguish
between a metastatic disease versus a second primary
carcinoma because of the difference that will matter in
management and prognosis. Our patient presented with
postmenopausal bleeding, a sign that may be indicative
of a gynecologic disease, either endometrial or cervical.
Through physical examination, we find a bulky cervix, and on
transvaginal ultrasound, there is a thin endometrial stripe,
which then leads us to think that this is more of a cervical
than an endometrial pathology. After this, the Pap smear
that was done was suggestive of a cervical abnormality. At
this time, we have to take into consideration the possibility
of a metastasis aside from a primary carcinoma because of
her medical history. To aid in this, immunohistochemical
stains may be used to identify the origin of the tumor.
Our patient underwent cervical biopsy twice, and both
times immunohistochemical stains were used to confirm
whether the tumor was a primary cervical carcinoma or
metastasis from the initial breast primary. The following
stains were requested: mammoglobin, GCDFP-15, GATA-3
and p16.
In the study of Wang et al in 2009, the expression
profile of mammoglobin was tested among primary
breast carcinoma, matched ipsilateral axillary lymph node
metastasis, non-breast neoplasms and normal human
tissues and concluded that sensitivity was 76% with a
specificity of 90% in detection of breast carcinoma. This
study recommends caution in the detection of a metastatic
breast carcinoma since expression was also noted in
some samples of endometrial carcinoma, probably since
both tissues are similarly affected by estrogen.16 In 2007,
Bhargava et al compared mammoglobin to GCDFP-15 and
showed that lobular carcinomas are more strongly stained
with mammoglobin than ductal type. The mammoglobin
also stained the breast carcinomas more intensely and
among the positive cases, the number of cells stained
with mammoglobin is higher. Moreover all invasive
endocervical adenocarcinomas studied were all negative
or had equivocal staining.17 Miettinen et al examined
2500 epithelial and mesenchymal tumors for GATA-3 and
found that GATA-3 was detected in 92% of primary ductal
carcinoma, furthermore was retained in 96% of metastatic
breast cancer, making it a useful marker for evaluating
metastatic carcinomas arising in unusual sites.18
Treatment of Metastatic Breast Cancer
Despite breast cancer being one of the most common
malignancies worldwide, metastatic breast cancer still has
a low median survival time. Patients are usually given
endocrine therapy or chemotherapy.
One of the treatments initially started in our patient
was letrozole, 2.5 milligrams per tablet taken orally once
Volume 41, Number 5, PJOG September-October 2017 39
daily. She did not comply fully with this medication and
stopped after 3-4 months of taking it. Letrozole prevents
the conversion of androgens to estrogens by inhibiting
the aromatase enzyme which catalyzes this reaction.
In the Femara PO25 Trial done in 2007, Mouridsen
studied letrozole (Femara) as an effective alternative to
the standard first-line treatment, tamoxifen. This study
included postmenopausal women with advanced breast
cancer which they defined as stage IIIB locally advanced
disease, locoregionally recurrent disease that was not
amenable to surgery or radiotherapy, or metastatic
disease. 907 patients were randomized into the letrozole
group and the tamoxifen group until progressive disease
was detected, then the patients were allowed to crossover
into the other group. The primary endpoint was time to
progression, which was significantly longer with letrozole
than with tamoxifen. Objective response rate and overall
survival rate also showed a significant advantage of
letrozole over tamoxifen.19
Our patient was given carboplatin-docetaxel
combination chemotherapy for metastatic breast
cancer to the cervix. Carboplatin is a platinum based
chemotherapeutic drug that forms platinum compounds
within cells and causes intra- and interstrand cross-
linkage of DNA molecules, hence modifying its structure
and prevents further synthesis. Its action is available in all
phases of the cell cycle. Docetaxel induces mitotic arrest
by suppressing microtubule dynamics and causes G2M
cell cycle arrest.20
Jones et al directly compared the taxanes paclitaxel
and docetaxel as monotherapy for advanced breast
cancer, and have demonstrated that docetaxel is superior
to paclitaxel in time-to-progression, overall survival and
response duration. For both groups, the primary reason for
discontinuation of the treatment was disease progression,
although it was noted that there was a smaller percentage
from the docetaxel group than the paclitaxel group. For the
adverse reactions such as neuromotor toxicity, peripheral
edema and asthenia, there was a higher percentage from
the docetaxel group who opted to discontinue therapy.
For the intention-to-treat population, the overall response
rate was higher for docetaxel, and median response
duration was also longer for docetaxel, as well as for
overall survival. Overall, docetaxel demonstrated superior
efficacy and is expected to be more clinically beneficial
compared to paclitaxel, since rates of toxicities are higher
but are manageable. 20
Because of the cardiotoxicity caused by anthracycline
regimens previously used for metastatic breast cancer,
newer nonanthracycline agents are needed for this
purpose. Platinum based compounds such as cisplatin
and carboplatin have shown activity in breast cancer,
but carboplatin has shown to be a more appropriate
40 Volume 41, Number 5, September-October 2017
choice because it causes less severe nonhematologic
toxicities. Carboplatin as single agent chemotherapy
has elicited 20-35% response in previously untreated
patients with metastatic breast cancer, and this has led
to the investigation of its combination with a taxane. The
rationale for this was their complementary mechanisms
of action. It has also been shown that paclitaxel seems
to have a platelet sparing action that reduces the
thrombocytopenia caused by carboplatin alone. Perez
summarized the findings of 2 phase II trials on the use of
carboplatin-docetaxel combination and concluded that
this showed activity in the first-line setting of metastatic
breast cancer, and that the toxicity was deemed
acceptable.21 Our patient was monitored weekly with
complete blood count for hematologic toxicities. She
has experienced chemotherapy-induced gastroenteritis,
occasionally has fatigue but has not complained of
neuropathy or mucositis.
Therapeutic Approach in Literature
In most case reports on breast metastasis to the cervix,
the breast cancer is already in an advanced stage, and
most are synchronous, meaning that both the primary and
metastatic lesions were diagnosed almost simultaneously.
In 2010, Bogliolo et al reported on a case of synchronous
breast cancer with metastasis to the uterine cervix, in
a 78-year-old asymptomatic patient who was seen for
her mammography and Pap smear. Incidentally she was
diagnosed with pT1b/ N2a/ M1 lobular breast carcinoma,
and was then treated with radiotherapy on the breast 50
Gy for 5 weeks, and with chemotherapy 5-fluorouracil,
epirubicin and cyclophosphamide (FEC-75), then with
docetaxel. The patient was alive at 30 months however
with note of metastatic lesions in the liver at 19 months.13
A case report by Manci et al in 2007 was about a 41
year old with stage 1a breast cancer (pT1/N0/M0) who
underwent quadrantectomy with axillary lymph node
dissection for an infiltrating lobular breast carcinoma. On
histopathology lymphovascular invasion was absent and all
16 lymph nodes were negative for tumor. Postoperatively,
the patient received radiotherapy and was maintained
on tamoxifen for 5 years. Follow up examinations were
all normal until 9 years after, she underwent a routine
pelvic exam and found a cervical ectropion. This was
confirmed to be metastatic lobular mammary carcinoma
to the cervix. She then underwent a laparoscopic total
hysterectomy with lymph node dissection. Peritoneal
washings and all 14 lymph nodes were negative for tumor.
No further therapy was done after the surgery. Patient is
reported to have benefited well from the surgery, as she
was disease free at 20 months of follow up.22 This is case
is almost similar to our patient, the difference was that our
patient had a modified radical mastectomy instead of a
quadrantectomy, and the patient in this report underwent
radiotherapy and took tamoxifen. Otherwise, both are
similar in that they are very early stage cancers with no
lymphovascular spread or lymph node invasion.
In 1999, Bryson et al presented a case of a 47-year-
old Para 2 who had been treated for a well differentiated
infiltrating ductal carcinoma of the breat with extension to
the pectoralis major but not to the lymph nodes. She had
been on tamoxifen approximately 2 years. She had a history
of 2 abnormal Pap smears and so cervical biopsy was done
revealing a metastatic lesion on the uterine cervix from
a breast primary. Further metastatic workup turned out
negative. She underwent a total abdominal hysterectomy
with bilateral salpingo-oophorectomy and received
chemotherapy and radiotherapy. She was followed until 4
years post-treatment and was found to be well.12
There was another case of an isolated cervical
metastasis by Mousavi et al in 2005, unfortunately it was not
disclosed what stage the primary breast cancer was, or how
many years after treatment of the primary breast cancer it
has been before developing symptoms of postmenopausal
bleeding. They also performed a surgical procedure, a
hysterectomy with bilateral salpingo-oophorectomy. On
inspection of the abdomen there was no other evidence
of disease, and on microscopic examination of the surgical
specimen, only the cervix had pathology.23
REFERENCES
1. Cardoso F, Di Leo A, Lohrisch C et al. Second and subsequent lines
of chemotherapy for metastatic breast cancer: what did we learn
in the last two decades? Annals of Oncology. 2002; 13:197-207.
2. Langballe R, Olsen J, Anderson M, Mellemkjer L. Risk for second
primary non-breast cancer in pre and postmenopausal women
with breast cancer not treated with chemotherapy, radiotherapy
or endocrine therapy. European Journal of Cancer. 2011; 47:946-
952.
3. Abrams H, Spiro R, Goldstein N. Metastases in Carcinoma: Analysis
of 1000 Autopsied Cases.
4. Taghian A, El-Ghamry M, Merajver S. Overview of the treatment
of newly diagnosed, nonmetastatic breast cancer. In: UpToDate,
Hayes D (Ed), Waltham, MA. (Accessed April 24, 2016).
5. Bleiweiss I. Pathology of Breast Cancer. In: UpToDate, Chagpar A
(Ed), Waltham, MA. (Accessed April 24, 2016).
6. Caplan L, May D, Richardson L. Time to Diagnosis and Treatment
of Breast Cancer: Results from the National Breast and Cervical
Cancer Early Detection Program, 1991-1995. American Journal of
Public Health. 2000; 90 (1):130-133.
7. Karrison TG, Ferguson DJ, Meier P: Dormancy of mammary
carcinoma after mastectomy. J Natl Cancer Inst. 1999; 91:80-85.
The abovementioned two cases were isolated
cervical metastases that benefited from surgery. These
are the patients who need to be treated aggressively
since they have a very good chance of long term survival
because there is no other evidence of metastatic
disease.
CONCLUSION
Metastasis to the female genital tract is a rare
occurrence, especially to the uterine cervix. We need to
emphasize the need for regular gynecologic examination
after treatment of breast cancer of any stage, as
well as malignancies from other organs such as the
gastrointestinal tract. Surveillance for rare conditions
is important so that diagnoses are not missed, and
treatment, whether surgical or medical, can be started
early. Usually with isolated cases, surgery will suffice,
compared to a patient with multiple metastases. In our
patient, we gave chemotherapy in the hopes of being
able to avoid a major surgical procedure, however in this
case there was very little to no improvement clinically,
and on opening, we even noted that there was already
involvement of the endometrium, which, if we had
not proceeded with surgery, could have continued to
progress further.
8. Brackstone M, Townson J, Chambers A. Tumour dormancy in
breast cancer: an update. Breast Cancer Research. 2007; 9:208.
9. Rahman M and Mohammed S. Breast cancer metastasis and the
lymphatic system. Oncology Letters. 2015; 10:1233-1239.
10. Sanuki-Fujimoto N, Takeda A, Amemiya A, et al. Pattern of Tumor
Recurrence in Initially Nonmetastatic Breast Cancer Patients:
Distribution and Frequency at Unusual Sites. American Cancer
Society 2008, Volume 113, Number 4: 677-682.
11. Mazur MT, Hsueh S and Gersell DJ (1984) Metastases to the
female genital tract. Analysis of 325 cases Cancer 53(9):1978-84.
12. Bryson C, de Courcy-Wheeler R, Wallace R. Breast cancer
metastasizing to the uterine cervix. The Ulster Medical Journal.
1999; 68(1):30-32.
13. Bogliolo S, Morotti M, Valenzano Menada M, et al. Breast cancer
with synchronous massive metastasis in the uterine cervix: a
case report and review of literature. Arch Gynecol Obstet. 2010;
281:769-73.
14. Bereza T, Tomaszewski K, Balajewicz-Nowak M, et al (2012). The
vascular architecture of the supravaginal and vaginal parts of the
human uterine cervix: a study using corrosion casting and scanning
electron microscopy. Journal of Anatomy. 2012; 221: 352-357.
Volume 41, Number 5, PJOG September-October 2017 41
15. Dissing-Olesen L, Hong S, Stevens B. New Brain Lymphatic Vessels
Drain Old Concepts. EBiomedicine. 2015; 2:776-777.
16. Wang Z, Spaulding B, Sienko A, et al. Mammoglobin, a valuable
diagnostic marker for metastatic breast carcinoma. Int J. Clin Exp
Pathol. 2009; 2:384-389.
17. Bhargava R, Beriwal S, Dabbs D. Mammoglobin vs GCDFP-15: An
immunohistologic validation survey for sensitivity and specificity.
Am J Clin Pathol. 2007; 127:103-113.
18. Miettinen M, Mc Cue P, Sarlomo-Rikala M, et al. GATA 3 – a
multispecific but potentially useful marker in surgical pathology –
a systematic analysis of 2500 epithelial and nonepithelial tumors.
Am J Surg Pathol. 2014; 38(1):13-22.
19. Mouridsen, HT. Letrozole in advanced breast cancer: the PO25
trial. Breast Cancer Res Treat. 2007; 105:19-29.
42 Volume 41, Number 5, September-October 2017
20. Jones SE, Erban J, Overmoyer B, et al. Randomized Phase III
Study of Docetaxel Compared with Paclitaxel in Metastatic Breast
Cancer. Journal of Clinical Oncology. 2005; 2(24):5542-5551.
21. 21. Perez EA. Carboplatin in Combination Therapy for Metastatic
Breast Cancer. The Oncologist. 2004; 9:518-527.
22. Manci N, Marchetti C, Esposito F, et al. Late breast cancer
recurrence to the uterine cervix with a review of literature. Int J
Gynecol Pathol. 2007; 27:113-7.
23. Mousavi A, Zarchi M. Isolated Cervical Metastasis of Breast
Cancer: A Case Report and Literature Review. Journal of Lower
Genital Tract Disease. 2007; 11(4):276-278.
 Knowledge, attitudes, and practices of health care providers in
intimate partner violence screening in a private tertiary hospital*
By Auran Rosanne B. Cortes, MD, MBA and Irene B. Quinio, MD, FPOGS, FPSMFM, FPSUOG
Department of Obstetrics and Gynecology, The Medical City

ABSTRACT

Background: Intimate partner violence (IPV) is a public health problem and human rights concern that has an enormous impact
on physical, mental, reproductive and socioeconomic aspects of health. Several health professional organizations recommend
screening for violence though current screening rates tend to be low because healthcare providers are generally hesitant to be
involved in dealing with women who are victims of violence.

Objective: This study therefore attempted to assess the knowledge, attitudes, and practices of obstetricians and gynecologists on
screening for intimate partner violence in a private tertiary hospital.

Materials and Methods: The Physician Readiness to Manage Intimate Partner Violence Survey (PREMIS) tool was utilized among
123 obstetricians and gynecologists in a private tertiary hospital in Pasig, Metro Manila, with a response rate of 65.8% (81/123).

Results: Results showed that the sample participants did not have adequate knowledge on IPV; majority of the sample participants
were not fully prepared and equipped to handle patients who are victims of IPV; and the sample participants did not routinely
screen for IPV.

Conclusion: In the Philippines, the obstetricians and gynecologists generally act as the primary care physicians to the general female
population. This provides them a good opportunity to be involved in the secondary prevention of IPV. Recognition of barriers to
screening for IPV, development of strategies for increasing awareness to IPV, and education and training of physicians and allied
health care professionals may improve the screening practices for IPV. These in turn will help them to provide appropriate, effective,
and holistic care to their patients who are victims of violence.

Keywords: Intimate partner violence, domestic violence, physicians, tertiary care centers, Philippines

INTRODUCTION and/or threats or emotional abuse in the context of

V
iolence against women (VAW) is a global public
health problem and human rights concern that has
an enormous physical, mental and reproductive
impact on health.1 It is also a threat to social and
economic development.2 It takes many forms such as
women trafficking, female genital mutilation, murders in
the name of honor and dowry, early and forced marriage,
and sexual harassment and abuse by authority figures;
and includes physical violence, sexual violence, and
emotional violence.1-3 It also includes its consequences
that compromise the well-being of individuals, families,
and communities.4
One of the many forms of violence against women is
intimate partner violence (IPV). IPV, also called domestic
violence, is a type of violence in which a woman has
encountered any types of violence from an intimate
partner or ex-partner such as physical and sexual violence,
*Second Place, Philippine Obstetrical and Gynecological Society
(Foundation), Inc. (POGS) Research Paper Contest, October 25, 2017,
3rd Floor POGS Building, Quezon City
10 Volume 41, Number 5, September-October 2017
physical and sexual violence.2,5 Intimate partners include
current spouses, current non-marital partners, dating
partners, boyfriends or girlfriends, former marital
partners, divorced spouses, former common-law spouses,
separated spouses, former non-marital partners, former
dates, and former boyfriends/girlfriends.6 Established risk
factors associated with higher rates of IPV include young
age (less than 24 years old) or being a teenager, single
relationship status, minority race/ethnicity, and poverty.5
Mental health problems and substance use can be both
be risk factors or consequences of abuse.7
IPV is one of the most common forms of violence
experienced by women.2 Around one third of women or
35% of women worldwide have experienced violence,
and most of this violence is IPV. Globally, 30% of all ever-
partnered women worldwide experienced physical and/
or IPV at some point in their lives, and 38% of all murders
are committed by intimate partners. By World Health
Organization (WHO) region, the highest prevalence was
reported in African (36.6%), Eastern Mediterranean
(37.0%), and South-East Asia (37.7%) regions (Figure 1). By
age group, the highest prevalence was reported in 40 – 44
 Figure 1. Global map showing regional prevalence rates of intimate partner violence by
WHO region (2010)3
years old (37.8%), 35 – 39 years old (36.6%), and 25 – 29
years old (32.3%).3 In the Philippines, the 2008 National
Demographic and Health Survey (NDHS) revealed that
the prevalence of physical and sexual violence among
women aged 15 – 49 ranges from 4 to 20%.8
A woman who has experienced violence in her
lifetime has poorer self-perception of health status, and
her health-related quality of life is likely lower than that of
woman who has not experienced violence. The physical
and mental health consequences are proportional to the
severity of violence suffered, and the impact over time
is cumulative.1,7,9
There are three key pathways through which
IPV can lead to adverse health outcomes (Figure 2).3
Figure 2. Pathways and health effects on intimate partner
violence3
Aside from the adverse consequences on physical and
mental well-being, IPV can also lead to adverse sexual
and reproductive outcomes, which can be non-fatal or
fatal.1,3,5 The 2008 NDHS of the Philippines showed that
one in three women who experienced IPV reported
having physical injuries and three in five women
who experienced IPV reported having experienced
psychological consequences.8 IPV during pregnancy has
been shown to have bad effects on maternal health and
neonatal outcomes. It increases the risk of insufficient
or inconsistent prenatal care, perinatal death, preterm
birth, intrauterine growth retardation and/or low birth
weight, antepartum hemorrhage and/or abruption
placenta, uterine rupture, and fetal distress.5,7,9
Despite the prevalence of violence against women
and its tremendous impacts on health, it remains
hidden because many women do not report it nor
seek help. However, it is important to keep in mind
that a healthcare provider, especially an obstetrician
and gynecologist, is likely to be the first professional
contact for women suffering violence. They are the
professionals whom the women would most trust with
disclosure of violence. Aside from supporting disclosure,
providing treatment, care and support, referral and
follow-up, and creating documentation can be done
by healthcare providers. Provision of acute care during
clinical encounter includes recognition of the abuse,
proper clinical documentation of abuse, ascertainment
of patient safety and review of options for patient
referral. It is also important to consider ethical issues
when providing services to victims of violence.1,10 These
include providing information on how to recognize the
physical, social, and psychological manifestations of
violence; assuring confidentiality in documentation of
cases of violence; treating the physical and psychological
Volume 41, Number 5, PJOG September-October 2017 11
manifestations of the violence; upholding the right of the
women to information and self-determination; providing
affirmation to the women that violence towards them are
not acceptable; and advocating or supporting advocacies
for social infrastructures that provide security refuge
and counselling for women.10 These ethical obligations
can be met if the healthcare providers have an adequate
knowledge, attitudes, and skills.11
Women at risk of or experiencing violence can be
identified through routine screening in the healthcare
setting. This could also lead to interventions that
reduce violence and improve health outcomes. Several
professional organizations, such as the American
Congress of Obstetricians and Gynecologists (ACOG),
the American Medical Association, and the American
Academy of Pediatrics, recommend screening for IPV
violence by physicians.11-14 ACOG recommends that
screening should occur at routine checkup visits, family
planning visits, and preconception visits for non-pregnant
women. For pregnant women, screening should occur at
the first prenatal visit, at least once per trimester, and at
the postpartum checkup. 12-14
Although multiple organizations recommend
screening for IPV, current evidence suggests that actual
screening rates in the health care settings remain low.7,15
Healthcare providers are generally hesitant to be involved
in dealing with women who are victims of violence.8 Less
than 2% of women were asked about IPV by a healthcare
provider in family practice settings, and only about
0.1% of abuse victims were identified in emergency
settings.14 This is attributed to time constraints, attitudes
and perceptions (e.g. provider perception that patients
won’t be compliant, fear of offending patients, provider’s
personal experience with abuse, fears of being involved
with the judicial system), gaps in provider knowledge and
lack of education regarding domestic violence, lack of
training, lack of protocol and policies and procedures for
screening, and departmental or unit philosophies of care
that may contradict screening recommendations.7,8,14,15
In the Philippines, the Department of Health (DOH)
is one of the 12 agencies tasked to address VAW through
formulation of programs and projects that will eliminate
VAW, development of training programs for the providers
to address the needs of victims of VAW, and monitoring
of all VAW initiatives.16 The Women and Child Protection
units (WCPUs) were established in DOH-retained and local
government unit supported hospitals since the issuance
of Administrative Order 1-B or the “Establishment of a
Women and Children Protection Unit in All Department
of Health (DOH) Hospitals” in 1997, in response to the
increase in number of women and children who are
victims of violence.17 As of 2011, there are 38 working
WCPUs in 25 provinces of the Philippines. According
12 Volume 41, Number 5, September-October 2017
to DOH, doctors and social workers are hesitant to be
involved in WCPU due to heavy workload, lack of training
and feeling of inadequacy, and the nature of work e.g.,
responding to subpoenas and appearing in court.8
A survey study in Flanders, Belgium on knowledge,
attitudes, and practice among obstetricians and
gynecologists on IPV done in 2006 attempted to identify
barriers on IPV screening. In their setting, there were
no screening guidelines yet on IPV. The study concluded
that training of these physicians on IPV is essential for
a successful implementation of screening guidelines
on intimate partner violence.7 On the other hand, a
systematic review from Cochrane Library on screening
for IPV in healthcare settings shows that although
screening increases the identification of women
suffering from IPV, evidence is lacking for justification
of screening in healthcare settings. The systematic
review also concluded that there is a need for studies
comparing universal screening to case-finding for long
term well-being of women who are victims of violence.
These studies in turn will help in policy-making and
policy identification for IPV in healthcare settings.18
There are several survey tools for the assessment
of dimensions of IPV. The gathered information on
healthcare providers’ knowledge, attitudes, and
practices can help a healthcare institution understand
what issues need to be addressed. This information
can also be used to document a baseline data that can
measure changes in healthcare providers’ knowledge,
attitudes, and practices over time. Such information that
can be gathered from the healthcare providers includes
whether, how often, and when they have discussed
violence with patients; what they think are the barriers
to screening; what they do when they discover that a
patient has experienced violence; their discriminatory
or stigmatizing attitudes; attitudes toward women who
experience violence; knowledge about the consequences
of gender-based violence; and what types of training
they have received in the past.11,19
One of the validated instruments and questions
for the assessment of providers’ level of knowledge,
attitudes, and practices is the Physician Readiness to
Manage Intimate Partner Violence Survey (PREMIS) tool.
The PREMIS is a 15 to 25-minute survey that is valid,
comprehensive, reliable, and publicly available measure
of physicians’ knowledge, attitudes, and practices on
IPV. This tool is more current and more comprehensive
than previous standardized IPV assessment tools, and
has been psychometrically tested among physicians.
It can be also used as a pretest to measure physician
knowledge, attitudes, beliefs, behaviors, and skills, as a
training adjunct to orient physicians to the IPV issues, as
a posttest to measure changes in physician knowledge,
attitudes, beliefs, behaviors, and skills over time, or as a
comparative instrument to assess differences in knowledge,
attitudes, beliefs, behaviors, and skills between physicians
who have trained and those who have not. However, this
tool has also limitations. This include a lack of psychometric
data from non-physician healthcare providers and lack of
correlation with individual practices on IPV.20
Screening for violence against women in the
healthcare setting identifies survivors and increases
safety, reduces abuse, and improves clinical and social
outcomes.21 Although, screening, diagnosis, and
management of female patients who are victims of
violence are part of Obstetrics and Gynecology residency
training, there is no adequate knowledge, implementation
and infrastructure in most private institutions to support
IPV screening and to provide holistic care to patients
who are victims of IPV. Addressing these issues will
have direct and indirect contributions in achieving
the sustainable development goals (SDG), especially
the SDGs 5 – achieve gender equality and empower
all women and girls; and 16 – promote peaceful and
inclusive societies for sustainable development, provide
access to justice for all and build effective, accountable
and inclusive institutions at all levels.22 The data from
this study can be used to contribute in creation of policy,
training, and support for the department of obstetrics
and gynecology on violence against women, as well as
for other health care institutions.
OBJECTIVES
This study aims to assess the level of knowledge,
attitudes, and practices of obstetricians and gynecologists
on screening for IPV in a private tertiary hospital using
the PREMIS tool.
Specifically, the study aims to:
1. describe the background of obstetricians and
gynecologists,
2. measure the level of knowledge of obstetricians
and gynecologists on IPV,
3. describe the attitudes of obstetricians and
gynecologists on IPV,
4. describe the practices of obstetricians and
gynecologists on screening for IPV, and
5. determine the proportion of obstetricians and
gynecologists who routinely screen for IPV in
their private practice.
MATERIALS AND METHODS
Ethical consideration
This study received technical and ethical approval
from Institutional Review Board. Informed consent was
given to and secured from the participants. Participants’
responses were confidential.
Study setting and design
This is a descriptive study using the PREMIS tool
to conduct a survey among 123 OBGYN consultants in a
private tertiary hospital located at Pasig, Metro Manila.
Data Collection:
The study adapted and utilized the PREMIS tool
to obtain data from the participants. The PREMIS tool
has five sections: Respondent Profile, Background, IPV
Knowledge, Opinions, and Practice Issues. Within each
of the latter four sections, several items have been
combined to create scales. Perceived Preparation and
Perceived Knowledge are two composite items contained
in the Background section. Correct items are scored and
a composite created in the Knowledge section. Eight
scales are derived from the Opinion section. Items in
the Practice Issues section may be considered separately
or as a composite item.20 The first and last two sections
contained few revisions to tailor fit to local setting.
A survey kit was given to each attendee of the
three staff meetings held in March and April 2017.
The survey was also given to all the consultants with a
private clinic in the hospital. Those who were present in
at least two assemblies were noted in order to ensure
that a participant was only given a survey tool once. Each
survey kit contained an informed consent and PREMIS
tool questionnaire. Each survey kit was retrieved after the
assembly and/or after the participant finished answering
the questionnaires.
Data Analysis:
The PREMIS tool kit includes the codebook, SPSS
syntax and scoring information instrument. Coding of the
data was patterned to the codebook provided. Using SPSS,
mean scores with standard deviation were obtained for
each section. Each answer to question per section was also
measured using proportion, mean, and standard deviation.
Only participants who had responded to all items of the
PREMIS tool were included in the data analysis to reduce
the erroneous estimates resulting from missing data.
Results of the study were compared to the results of other
IPV screening studies that used the PREMIS tool.
Study Consultation
This study was reviewed and finalized with
contributions from a VAW expert.
RESULTS
Out of the 123 consultants, 81 returned the
completely filled survey with a response rate of 65.8%.
Volume 41, Number 5, PJOG September-October 2017 13
Table 1. Respondent Profile (n = 81)

Age (in years)

Average ± SD 50.63 ± 10.13
31 - 40 17 (21.3%)
41 - 50 29 (36.3%)
51 - 60 16 (20%)
61 - 70 16 (20%)
71 - 80 1 (1.3%)
81 - 90 1 (1.3%)
Gender
Male 8 (9.9%)
Female 73 (90.1%)
Other Hospital Affiliation
Yes 64 (79%)
Private Hospital 62 (76.5%)
Government Hospital 20 (24.7%)
No 17 (21%)
Subspecialty
Ultrasound 33 (40.7%)
Maternal and Fetal Medicine 8 (9.9%)
Urogynecology and Pelvic Reconstructive Surgery 2 (2.5%)
Pediatric Gynecology 0 (0%)
Infectious Disease 1 (1.2%)
Reproductive Endocrinology and Infertility 8 (9.9%)
Minimally Invasive Surgery 8 (9.9%)
Gynecologic Oncology 5 (6.2%)
Gestational Trophoblastic Disease 4 (4.9%)
Others 0 (0%)
General Ob-Gyn 23 (28.4%)
Year Grad from Med School
1900 – 1970 1 (1.2%)
1971 – 1980 17 (21%)
1981 – 1990 17 (21%)
1991 – 2000 27 (33.3%)
2001 – 2010 19 (23.5%)
Years Practicing
1 – 10 11 (13.6%)
11 – 20 21 (25.9%)
21 – 30 30 (37%)
31 – 40 15 (18.5%)
41 – 50 4 (4.9%)
Average Number of Patients per week
not seeing patients 1 (1.2%)
less than 20 15 (18.5%)
20 – 39 30 (37%)
40 – 59 12 (14.8%)
60 or more 23 (28.4%)

14 Volume 41, Number 5, September-October 2017

The remaining 32.5 % did not return the survey kit, and
1.6 % did not completely filled up the survey. The profile
of the participants and their practice are presented in
Table 1. The age of the participants ranged from 33 to
83 years (average = 50.63 ± 10.13). Of the participating
consultants, 9.9% were males, 17% did not have other
hospital affiliations, 40.7% were ultrasound subspecialists,
37% were on 21 to 30 years of practice, and 37% had an
average of 20 to 39 patients per week.
Table 2 shows the mean scores for each section
comparing it to other studies that used the PREMIS tool.
The participants’ scores were generally lower than that
of the participants of the original study and other studies
that utilized the PREMIS tool. Table 3 shows the perceived
background of participants on IPV. The mean scores
showed that they were “minimally to slightly” prepared
and had “very little to a little” knowledge on IPV. Also,
less than half of the participants did not receive previous
training on IPV at 49.4%.
Table 4 shows the proportion of agreement and
disagreement among participants about attitudes and
beliefs (opinions) on IPV. Table 5 presents the screening
practices of the participants. Of the participating
consultants, 45.7% of the participants screened certain
patient categories only – 38.3% for depressed/suicidal
women, 28.4% for women with alcohol or other substance
abuse, 18.5% for mothers of children with confirmed or
suspected child abuse or neglect. On the other hand,
39.5% of the participants did not screen. Presence of
injuries and depression/anxiety in patients were the top
two conditions that always prompt the participants to ask
about the possibility of IPV.
DISCUSSION
The key findings of the study showed that the sample
participants did not have adequate knowledge on IPV;
Majority of the sample participants were not fully prepared
and equipped to handle patients who are victims of IPV,
and the sample participants did not routinely screen for
IPV.
The low scores of the participants showed that a
majority of them lack adequate knowledge and skills, and
appropriate attitude for screening of IPV. Determination
of what care and support needed by the women who are
victims of violence can be delivered well if screening for
IPV is done appropriately.11 Screening for IPV not only
contributes to documentation of the VAW issues for the
survivor but also leads to formulation of interventions that
reduce IPV exposure and improve health outcomes.11,13
At present, no consensus has been made on the most
acceptable screening setting or modality for IPV.13 The ACOG
supports the universal screening for IPV. In developing
countries, such as Philippines, universal screening may

Table 2. Comparison of mean scale scores

Martin-Engel
SCORES Short et al20 McAndrew et al24
and Allen25
Control Group Treatment Group
n = 81 n = 67 n = 73
n=8 n = 17
Background
Perceived Preparation 2.97 ± 1.31 3.67 ± 1.05 3.81 ± 1.12 3.25 ± 0.98 3.48 ± 1.34
Perceived Knowledge 2.95 ± 1.19 3.55 ± 0.97 3.23 ± 1.44 3.21 ± 1.11 3.76 ± 1.36
IPV Knowledge
Actual Knowledge 23.22 ± 5.47 26 ± 5.18 21.25 ± 6.27 17.53 ± 5.00 18.03 ± 3.44
Opinions
Preparations 3.74 ± 1.02 4.20 ± 1.11 4.25 ± 1.61 3.91 ± 1.07 -
Legal Requirements 4.03 ± 1.15 3.92 ± 1.15 3.96 ± 1.76 3.78 ± 1.55 -
Workplace Issues 3.86 ± 0.85 4.18 ± 1.05 3.56 ± 1.94 3.82 ± 1.13 -
Self-Efficacy 3.89 ± 2.85 3.68 ± 1.26 2.71 ± 1.20 3.14 ± 0.94 -
Alcohol/Drugs 4.41 ± 0.78 4.46 ± 0.61 4.08 ± 0.46 4.12 ± 0.46 -
Victim Understanding 4.25 ± 0.82 5.06 ± 0.78 4.50 ± 0.68 4.29 ± 0.65 -
Victim Autonomy 4.34 ± 0.82 4.33 ± 0.83 4.29 ± 1.34 4.33 ± 0.83 -
Constraints 5.02 ± 1.21 4.65 ± 1.26 6.50 ± 0.53 6.00 ± 0.94 -
Practice Issues
Practice Issues 16.33 ± 8.29 12.35 ± 7.44 - - 16.97 ± 6.46

Volume 41, Number 5, PJOG September-October 2017 15

Table 3. Perceived Background of Respondents on Intimate Partner Violence (n=81)

Preparedness to 1 = Not 2 = Minimally 3 = Slightly 4 = Moderately 5 = Fairly 6 = Well 7 = Quite

perform the following: prepared prepared prepared prepared well prepared prepared well prepared
Ask appropriate 9 (11.1%) 18 (22.2%) 19 (23.5%) 18 (22.2%) 13 (16%) 1 (1.2%) 3 (3.7%)
questions about IPV
Appropriately respond 8 (9.9%) 12 (14.8%) 20 (24.7%) 18 (22.2%) 14 (17.3%) 5 (6.2%) 3 (3.7%)
to disclosures of abuse

Identify IPV indicators 9 (11.1%) 11 (13.6%) 18 (22.2%) 20 (24.7%) 17 (21%) 4 (4.9%) 2 (2.5%)
based on patient
history, and physical
examination

Assess an IPV victim’s 16 (19.8%) 14 (17.3%) 21 (25.9%) 18 (22.2%) 10 (12.3%) 1 (1.2%) 1 (1.2%)
readiness to change

Help an IPV victim 17 (21%) 13 (16%) 24 (29.6%) 15 (18.5%) 10 (12.3%) 1 (1.2%) 1 (1.2%)
assess his/her danger
of lethality

Conduct a safety 20 (24.7%) 23 (28.4%) 19 (23.5%) 9 (11.1%) 8 (9.9%) 1 (1.2%) 1 (1.2%)

assessment for the
victim’s children

Help an IPV victim 21 (25.9%) 22 (27.2%) 18 (22.2%) 8 (9.9%) 9 (11.1%) 2 (2.5%) 1 (1.2%)
create a safety plan

Document IPV 15 (18.5%) 16 (19.8%) 19 (23.5%) 11 (13.6%) 13 (16%) 5 (6.2%) 2 (2.5%)

history and physical
examination findings in
patient’s chart

Make appropriate 15 (18.5%) 13 (16%) 16 (19.8%) 11 (13.6%) 18 (22.2%) 3 (3.7%) 5 (6.2%)

referrals for IPV

Fulfill state reporting

requirements for:

IPV 26 (32.1%) 20 (24.7%) 16 (19.8%) 9 (11.1%) 7 (8.6%) 2 (2.5%) 1 (1.2%)

Elder abuse 26 (32.1%) 20 (24.7%) 16 (19.8%) 10 (12.3%) 6 (7.4%) 2 (2.5%) 1 (1.2%)
Child abuse 26 (32.1%) 20 (24.7%) 15 (18.5%) 9 (11.1%) 8 (9.9%) 2 (2.5%) 1 (1.2%)

not be feasible because of the scarcity of resources. Thus,
selected integration of screening into reproductive health,
mental health, and emergency services and selective
screening of women and girls exhibiting signs of abuse
in other health services are recommended.11 In the
study, very few of the participants tend to do universal
screening. This poses a public health concern in our
setting as screening is a form of secondary prevention.
Although universal screening may not be applicable in
our setting as a developing country, it must be reiterated
that the healthcare providers have ethical obligations to
women who are victims of violence, that there is low risk
of harm in screening, and screening is a key step in the
identification, intervention, and provision of appropriate
care to these women.7,10,11
16 Volume 41, Number 5, September-October 2017
The study reflects that inadequate attitudes
and skills of the participants on IPV screening are
consequences of inadequate knowledge. Most of them
have not fully fulfilled their role with regard to victims
of violence, as mandated by the Republic Act 9262. This
law, also known as The Anti-Violence Against Women
and Their Children Act Of 2004, states in Section 31
the role of healthcare providers to victims of violence.
Healthcare providers in our country are not legally
mandated to report IPV cases but assistance shall be
provided as mandated.23
In the Philippines, the obstetricians and gynecologists
generally act as the primary care physicians to the general
female population. This provides them a good opportunity
to be involved in the secondary prevention of IPV. The
Volume 41, Number 5, PJOG September-October 2017 17
Table 5. Screening Practices of Respondents on Intimate Partner Violence (n=81)

Not applicable – I am not in clinical practice 0 (0%)

I do not currently screen 32 (39.5%)
I screen all new patients 1 (1.2%)
I screen all new female patients 2 (2.5%)
I screen all patients with abuse indicators on history or exam 30 (37%)
I screen all female patients at the time of their annual exam 4 (4.9%)
I screen all pregnant patients at specific times of their pregnancy 2 (2.5%)
I screen all patients periodically 1 (1.2%)
I screen all female patients periodically 3 (3.7%)
I screen certain patient categories only (check below) 37 (45.7%)
Teenagers 6 (7.4%)
Young adult women (under 30 years old) 5 (6.2%)
Elderly women (over 65 years old) 3 (3.7%)
Single or divorced women 5 (6.2%)
Married women 5 (6.2%)
Women with alcohol or other substance abuse 23 (28.4%)
Single mothers 3 (3.7%)
Women of other races* 2 (2.5%)
Lesbian women 4 (4.9%)
Homosexual men 2 (2.5%)
Depressed/suicidal women 31 (38.3%)
Pregnant women 3 (3.7%)
Mothers of all my pediatric patients (if applicable) 0 (0%)
Mothers of pediatric patients who show signs of witnessing IPV 12 (14.8%)
Mothers of children with confirmed or suspected child abuse, neglect 15 (18.5%)
Others 3 (3.7%)
Women who are manifesting some form of STD obtained from a partner
I would probably ask leading questions to patients who would give me a hint or imply (on series of consultations) that
they are victims of IPV
Screen only if with signs of possible IPV

institution in the study does not have a clear-cut and
readily available protocol for screening of IPV. Also, in our
healthcare setting, neither the government, DOH, nor
the Philippine Obstetrical and Gynecological Society has
current recommendations or practice guidelines regarding
screening for IPV.
 
CONCLUSION
awareness to IPV, and education and training in IPV during
continuing medical education activities and residency
training may improve the IPV screening practices of
current and future obstetricians and gynecologists. These
in turn will help them to provide appropriate, effective,
and holistic care to their patients who are victims of
violence.

Majority of the obstetricians and gynecologists in this

study do not have an adequate knowledge, appropriate
attitudes, and competent skills for screening of IPV.
Screening for IPV is not routinely done by the obstetricians
and gynecologists in this study. Recognition of barriers to
screening for IPV, development of strategies for increasing

18 Volume 41, Number 5, September-October 2017

REFERENCES
1. Garcia-Moreno C and Temmerman M. Commentary: Actions to
end violence against women: A multi-sector approach. Global
Public Health. 2015; 10(2):186-188.
2. World Health Organization. Addressing violence against women
and achieving millennium development goals. Switzerland: WHO
Press, 2005.
3. World Health Organization. Global and regional estimates of
violence against women: prevalence and health effects of intimate
partner violence and non-partner sexual violence. Italy: WHO
Press, 2013.
4. Miller E, McCaw B, Humphreys BL, and Mitchell C. Integrating
intimate partner violence assessment and intervention into
healthcare in the United States: a systems approach. Journal of
Women’s Health. 2015; 24(1).
5. Alhusen, JL, Ray E, Sharps P, and Bullock L. Intimate partner
violence during pregnancy: maternal and neonatal outcomes.
Journal of Women’s Health. 2015; 24(1).
6. Krug EG, Dahlberg LL, Mercy JA, Zwi AB, and Lozano R. World
report on violence and health. World Health Organization Geneva,
editor. 2002.
7. Roelens K, Verstraelen H, Van Egmond K, and Temmerman M. A
knowledge, attitudes, and practice survey among obstetricians-
gynaecologists on intimate partner violence in Flanders, Belgium.
BMC Public Health. 2006; 6:238
8. Philippine Commission on Women. Statistics on violence against
Filipino women. [Internet]. 2009. [cited 6 February 2017].
Retrieved from http://www.pcw.gov.ph/ statistics/ 201405/
statistics-violence-against-filipino-women
9. Chisholm CA, Bullock L and Ferguson J. Intimate partner violence
and pregnancy: epidemiology and impact. American Journal of
Obstetrics and Gynecology, 2017. pii: S0002-9378(17)30659-2.
doi: 10.1016/j.ajog.2017.05.042
10. Ethical guidelines in obstetrical and gynecological practice, medical
education and research. Philippine Obstetrical and Gynecological
Society (Foundation), Inc. 2011.
11. Ward, J, Gay J, Deligiorgis D, Shepard B, Macdonald N, Lafrenerie
J, Billings D, Colombini M, Maman S, McKaw B. United Nations
Entity for Gender Equality and the Empowerment of Women.
2011. Programming module on working with the health sector to
address violence against women and girls.
12. Dutton MA, James L, Langhorne A, and Kelley M. Coordinated
public health initiatives to address violence against women and
adolescents. Journal of Women’s Health. 2015; 24(1).
13. Nelson HD, Bougatsos C, Blazina I. Screening Women for Intimate
Partner Violence and Elderly and Vulnerable Adults for Abuse:
Systematic Review to Update the 2004 U.S. Preventive Services
Task Force Recommendation. Evidence Synthesis No. 92. AHRQ
Publication No. 12-05167-EF-1. Rockville, MD: Agency for
Healthcare Research and Quality; May 2012.
14. American Congress of Obstetricians and Gynecologists. Screening
tools – domestic violence. [Internet]. 2016. [cited 5 November
2016]. Retrieved from www.acog.org/About-ACOG/ACOG-
Departments/Violence-Against-Women/Screening-Tools--
Domestic-Violence?
15. Walton, L. M., Aerts, F., Burkhart, H., & Terry, T. Intimate Partner
Violence Screening and Implications for Health Care Providers.
Online Journal of Health Ethics. 2015; 11(1). htt://dx.doi.
org/10.18785/ojhe.1101.05
16. 16Philippine Commission on Women. Inter-Agency council on
violence against women and their children (IACVAWC). [Internet].
2009. [cited 6 February 2017]. Retrieved from http://www.pcw.
gov.ph/focus-areas/violence-against-women/initiatives/iacvawc
17. Department of Health. Women and child protection program.
[Internet]. N.d. [cited 6 February 2017]. Retrieved from http://
www.doh.gov.ph/women-and-children-protection-program.
18. O’Doherty L, Hegarty K, Ramsay J, Davidson LL, Feder G, Taft A.
Screening women for intimate partner violence in healthcare
settings. Cochrane Database of Systematic Reviews 2015, Issue 7.
Art No.:CD007007. DOI: 10.1002/14651858.CD007007.pub3
19. Sexual Violence Research Initiative. Victimisation. [Internet]. 2015.
[cited 6 February 2017] Retrieved from http://www.svri.org/
research-methods/tools-and-questionnaires/victimisation?link-
section=victimisation.
20. Short LM, Alpert E, Harris JM, and Surprenant ZJ. A tool for
measuring physician readiness to manage intimate partner
violence. American Journal of Preventive Medicine. 2006;
30(2):173-180.
21. Hamberger LK, Rhodes K, and Brown J. Screening and intervention
for intimate partner violence in healthcare settings: creating
sustainable system-level programs. Journal of Women’s Health.
2015; 24(1).
22. United Nations. Transforming our world: the 2030 Agenda for
Sustainable Development. [Internet]. 2015. [cited 5 July 2017].
Retrieved from http://www.un.org/ ga/search/view_doc.
asp?symbol=A/RES/70/1&Lang=E
23. Philippine Commission on Women. Republic Act 9262. [Internet].
2009. [cited 5 July 2017]. Retrieved from http://pcw.gov.ph/law/
republic-act-9262.
24. McAndrew M, Pierre G, and Kojanis L. Effectiveness of an online
tutorial on intimate partner violence for dental students: A pilot
study. Journal of Dental Education. August 2014; 78(8):1176- 1181.
25. Martin-Engel L, and Allen J. Chicago. Improving provider readiness
to manage intimate partner violence in family medicine resident
continuity clinics in Illinois Academy of Family Physicians.
[Internet]. 2015. [cited 1 July 2017] Retrieved from http://www.
iafp.com/assets/docs/Residents/1%20martin-engel%20%20%20
violence%20ppt%20.pptx%20 1.pdf
Volume 41, Number 5, PJOG September-October 2017 19
 Mycotic aneurysm in pregnancy:
A case report*
By Ma. Kristine Paula M. Nidoy, MD and Genevieve Marie Potian, MD, FPOGS
Department of Obstetrics and Gynecology, Quirino Memorial Medical Center

ABSTRACT

Reported is a case of a 20-year old G2P1 (1001) Pregnancy Uterine 22 weeks age of gestation (AOG), who suffered three
episodes of aneurysmal rupture over a period of almost 8 weeks, the last being fatal occurring on the 27th week AOG, despite
aggressive antimicrobial treatment, insertion of ventriculo-peritoneal shunt and clinically improving neurologic status. The
patient succumbed to subarachnoid hemorrhage resulting from the third aneurysmal rupture. Mycotic aneurysm is a serious
and catastrophic clinical condition, more so in a pregnant patient wherein management options are limited in order to preserve
pregnancy.
This report will discuss the first documented case in the Philippines of mycotic aneurysm in pregnancy secondary to a
valvular heart disease, to increase awareness on such cases for timely diagnosis and management.

Keywords: Endocarditis, Mycotic Aneurysm, Pregnancy

INTRODUCTION left-sided weakness. Patient was on her 23nd week of

A
neurysm is a rare complication in pregnancy with
no existing definitive treatment guideline. The
term mycotic aneurysm was first coined by Osler
in 1885 to describe aortic aneurysms resembling “fungal
growths” in a man with endocarditis.1 The term is now
used to describe infectious arterial aneurysms in general.
Due to their friable walls, patients are predisposed
to spontaneous rupture which results in intracranial
hemorrhage causing significant morbidity and mortality
as high as 60–90% in earlier case studies, and 12–32% in
more recent literature reviews.2
This report will discuss a case of intracranial mycotic
aneurysm in pregnancy with a history of valvular heart
disease. The incidence of associated mycotic aneurysms
in patients with infective endocarditis has been reported
to be 2-10%. Frazee et al. reported an incidence of
mycotic cerebral aneurysms of 4% in all patients with
intracranial aneurysms and 3% of all patients with
infective endocarditis. However, the incidence of infective
endocarditis in pregnancy has been reported to be 1 in
8000 deliveries (0.0125%). Cox et al. reported it to be 1 in
16 500 (0.006%).3
CASE REPORT
A 20-year old, G2P1 (1001) presented at the
emergency room due to decreased sensorium and
*First Place, Philippine Obstetrical and Gynecological Society
(Foundation), Inc. (POGS) Interesting Case Paper Contest, September
21, 2017, 3rd Floor POGS Building, Quezon City
gestation, asymptomatic, until thirteen days prior to
admission when the patient developed headache,
vomiting and undocumented fever. Upon consult and
subsequent admission in a local hospital, the patient had
one episode of seizure followed by progressive left-sided
weakness. Plain cranial computed tomography (CT)
scan revealed an acute intraparenchymal hemorrhage
involving the right frontal lobe. Patient was given
Ampicillin 2g and Mannitol 150mL however, status
continued to deteriorate and patient was referred to our
institution for further management.
At the emergency room, the patient was seen
by Neurology service whose primary impression was
ruptured arteriovenous malformation. She had a
Glasgow Coma Scale (GCS) of 13 (E4V3M6), drowsy, with
spontaneous eye opening, minimal verbal output but
was able to follow commands. Patient was tachycardic at
113 beats per minute (bpm) but the rest of the vital signs
were unremarkable. Cardiac examination revealed an
adynamic precordium however a murmur was noted upon
auscultation. Focusing on the abdomen, fundic height
was 20 cm, with fetal heart rate of 150 bpm. Neurologic
examination revealed presence of nuchal rigidity and
hemiparesis, with a manual muscle testing grade of 0/5
and 4/5 on the left and right extremities, respectively.
Deep tendon reflexes of both lower extremities were
noted to be +1, while both upper extremities were graded
+2. Sensory function of all dermatomes and cranial nerves
were intact.
On further evaluation, medical history revealed that
the patient was diagnosed with an undocumented heart
condition at five years of age however no further consult
Volume 41, Number 5, PJOG September-October 2017 27
and management was done. In 2015, during the patient’s
first pregnancy, a 2d-echo done for cardiac clearance
revealed a valvular heart disease probably rheumatic.
The first pregnancy was carried to term and was delivered
via normal spontaneous delivery with no post-partum
complications. The rest of the patient’s medical history
were non-contributory. Patient was referred to Obstetrics
service for co-management and was admitted as a case
of Ruptured Arteriovenous Malformation, Gravidocardiac
secondary to Rheumatic Heard Disease, rule out
Preeclampsia.
Repeat cranial CT scan revealed a decrease in the
parenchymal hemorrhage and presence of subfalcine
herniation. Pelvic ultrasound revealed a viable pregnancy
with a gestational age that coincides with the last
menstrual period (LMP). With a resolving hematoma
13 days post-ictus, patient was managed conservatively
with Mannitol 150cc, Dexamethasone 4mg/tab and
Nimodipine 30mg/tab. CT Angiography showed non-
significant decrease in the parenchymal hemorrhage and
multiple saccular aneurysms were identified. At this time,
Neurology service was considering a Mycotic Aneurysm
secondary to Rheumatic Heart Disease. The patient
underwent a series of diagnostics (Table 1), all of which
revealed unremarkable findings. With normal laboratory
results and no episodes of blood pressure elevation,
Preeclampsia was ruled out.
Patient’s status gradually improved as manifested
by improving MMT scores, a GCS of 14 (E4V4M6) and no
further decrease in sensorium.
Twenty-four days post ictus, the patient was
again noted to be drowsy with GCS of 11 (E4V1M6)
and decreased MMT scores. Repeat CT scan revealed a
decrease in the previously noted hyperdensity. However,
a new hyperdensity was noted due to an acute rebleed.
Communicating hydrocephalus was seen necessitating
a ventriculo-peritoneal shunt insertion to which the
patient initially responded favorably. Neurosurgery
suggested that the patient be started on Ampicillin 2g
for the management of mycotic aneurysm. On the 25th
week of gestation, a multidisciplinary meeting was held
and it was agreed upon by the services of Obstetrics,
Neurology and Neurosurgery that this is a case of Mycotic
Aneurysm due to: occurrence at a young age, multiplicity,
history of a valvular heart disease, and febrile episodes
prior to neurologic symptoms. Neurosurgery opted for
conservative management because the hematoma was
resolving and clipping and coiling were not ideal at that
time. The Infectious Diseases service discussed that in the
absence of positive cultures, Vancomycin (Category C) plus
Piperacillin-Tazobactam (Category B) are the antibiotics
of choice but since the patient is pregnant, they opted
to step down and give Ampicillin-Sulbactam (Category B)
28 Volume 41, Number 5, September-October 2017
instead, for 4-6 weeks. Lastly, all the services agreed that
the patient may be discharged if improvement continues.
Remote from delivery, no aggressive measures were
contemplated with regards to the pregnancy.
Forty days post-ictus, repeat CT scan revealed an
almost complete resorption of the bleed. Patient was
noted to be GCS 15, with motor strength of 5/5 on the
right extremities and 4/5 on left extremities, with good
fetal heart tones and no signs of preterm labor. Patient
was then cleared for possible discharge. At 51 days post-
ictus, patient had sudden onset of severe headache,
weakness of the left extremities with motor strength of
1/5, and absent eye opening with isocoric pupils. An acute
rebleed was considered. Cranial CT scan was not done
due to the patient’s unstable status. Furthermore, fetal
heart tones were no longer appreciated. Patient expired
and was signed out as a case of G2P1 (1001) Pregnancy
Uterine at 27 weeks and 2 days AOG by ultrasound,
Transtentorial Herniation secondary to Intracerebral
Hemorrhage secondary to Ruptured Mycotic Aneurysm,
Valvular Heart Disease.
CASE DISCUSSION
An aneurysm is an abnormal focal dilation of the
artery which may become secondarily infected due to
bacteremia or septic embolization, as in the case of
mycotic aneurysm. Cerebral mycotic aneurysms represent
less than 5% of all intracerebral aneurysms.8 Although
some authors use the term “mycotic” to describe infected
aneurysm regardless of etiology, this report limits use of
the term to those aneurysms that develop when material
originating in the heart causes arterial wall infection and
subsequently dilation.4
Aneurysms may be classified into true aneurysms
which involve all three layers of the arterial wall, or false
aneurysms which is a collection of blood which leaked
out of the artery but still confined within the tissue. In
the index patient, a history of valvular heart disease
increases the risk of developing an infected aneurysm, and
endocarditis is identified as the likely etiology in 17 to 29 %
of cases.4 Mycotic aneurysms most commonly develop in
the cerebral vessels typically at arterial bifurcations. Septic
embolism from the heart can occlude the vasa vasorum
of the vessel or the vessel lumen leading to vascular wall
infection and mycotic aneurysm formation. Because of its
embolic nature, mycotic aneurysms are often multiple,
but they can also be solitary.
Mycotic aneurysm should be suspected in any patient
with endocarditis who has neurological symptoms that
are not explained by systemic illness. In a case series of 28
documented mycotic aneurysms by Burst et. al., 8 patients
had a known valvular heart disease and 27 had infective
Table 1. Laboratories

Complete Blood Count

3/20/17 3/23/17 3/30/17 4/5/17 4/6/17

Hemoglobin 111 104 100 102 86

Hematocrit 0.35 0.32 0.29 0.28 0.25
WBC 10.1 12.2 10.1 8.7 10.1
Platelet Count 386 329 319 292 237
Coagulation Studies

3/20/17 4/5/17 4/6/17

Protime (PT) 11.6 11.2 13.0

PT % activity 130 142 100
PT INR 0.87 0.83 1.00
PT N Control 13.0 13.0 13.0
Activated Plasma Thromboplastin Time (APTT) 20.0 22.9 30.6
APTT N control 32.7 32.5 30.9
Blood Chemistry

3/20/17 3/23/17 3/25/17 3/27/17 3/30/17 4/5/17 4/6/17 4/13/17

Glucose 4.79
Na 137 138 134 135 137 138
K 3.73 3.17 3.87 3.86 4.15 2.78
Cl 104 102 104 106
Ca 2.14
Mg 0.79
SGOT 100 71
SGPT 189 181
LDH 330
BUN 4.70 1.40 1.90 1.50
Creatinine 36.76 34.45 29.67 18.97
ESR 30 130
CRP 18
Urinalysis

3/20/17

Dark Yellow Slightly Turbid pH 6 1SG 1.03

(-) Sugar +1 Albumin WBC 5-10 RBC 15-20
Gram Stain and Culture Studies

Blood Gram Stain/Culture Stain Right Arm Few growth of contaminants

Blood Gram Stain/Culture Stain Left Arm No growth after 5 days of incubation
Urine Gram Stain WBC 3-6/OIO
Gram Negative Bacilli
Urine Culture Stain No growth after 2 days incubation
Sputum Gram Stain/Culture Stain Gram Negative Bacilli

Volume 41, Number 5, PJOG September-October 2017 29

Table 2. Serial Pelvic Ultrasound

Pelvic Ultrasound

March 21, 2017 March 28, 2017 April 11, 2017

Single, live, intrauterine pregnancy Single, live, intrauterine pregnancy Single, live, intrauterine pregnancy
23 weeks and 5 days 23 weeks and 5 days 24 weeks and 6 days
Breech Cephalic Breech
EFW 494 g EFW 590 g EFW 729 g
Placenta fundal, gr. 1 Placenta anterior Placenta anterofundal, gr. 2
AFI 7.60 cm AFI 11.39 AFI 12.63 cm
Oligohydramnios for AOG (5th
percentile at 95mm)

Table 3. Previous Imaging Procedures

2d Echocardiogram

October 16, 2015

Valvular heart disease, probably rheumatic

Dilated mitral valve annulus with severe mitral regurgitation
Eccentric left ventricular hypertrophyy with normal wall motion, contractility and systolic function
Normal right ventricular dimension with normal wall motion and systolic function
Normal right atrium, main pulmonary artery and aortic root
Normal mean pulmonary artery pressure

Plain Cranial CT Scan

March 10, 2017

Acute Intraparenchymal hemorrhage (approximately 47.8 cc) involving the right frontal lobe with associated intraventricular
extension, perilesional edema, mild obstructive hydrocephalus and mild right to left subfalcine herniation. Consider small
subacute hematoma within the right posterior parietal lobe with minimal perilesional edema

endocarditis.1 Lee et. al., stated that mycotic aneurysms
can develop from hematogenous spread of infectious
microemboli into the vasa vasorum of a normal-caliber
artery or a preexisting aneurysm.9 In the index patient, a
history of a valvular heart disease may have resulted in
a hematogenous spread of an embolus from the heart.
Mycotic cerebral aneurysms can cause headache, seizures,
or focal neurologic symptoms but many are asymptomatic
until aneurysmal rupture and hemorrhage occur. The
index patient initially presented with a seizure episode
followed by left sided weakness.
The suspicion of a mycotic aneurysm should be
supported by laboratory results and imaging and CT
angiography is the most useful for its diagnosis.5 Findings
on CT angiography suggestive of a mycotic aneurysm
30 Volume 41, Number 5, September-October 2017
include the following 4:
• Saccular, eccentric aneurysm or multilobulated
aneurysm
• Soft tissue inflammation or mass around a vessel
• Aneurysm with intramural air
• Perivascular fluid collection
The wide availability of computerized tomographic
(CT) scanning has revolutionized the management
of intracranial hemorrhage in pregnancy. It is safe
for both mother and fetus. A CT scan will accurately
demonstrate the bleeding and its extent. In a study by
Sun and Slivka, a 29-year-old woman on her 30th week
of gestation, who presented with headache and seizure
episoxodes, was diagnosed with mycotic aneurysm
through a series of imaging studies such as CT scan,
magnetic resonance angiogram and catheter digital
subtraction angiography. The patient met the following
criteria for mycotic aneurysm – angiographic features,
multiplicity, distal location, and young age. According to
Sun and Slivka, CT angiography is as sensitive as digital
subtraction angiography in detecting the aneurysm.
Lee et. al., stated that CT angiography is the current
imaging modality of choice for the evaluation of
suspected mycotic aneurysms. In a study by Kannoth,
new generation CT angiograms have a sensitivity of
90-98% with specificity of 100%. In the index patient,
initial imaging modality used was plain cranial CT scan
due to financial constraints. CT angiography was done
once and revealed a mass effect due to the presence of
subfalcine herniation. Also noted were multiple saccular
aneurysms on the right middle cerebral artery, posterior
cerebral artery, right anterior cerebral artery and
another whose exact location cannot be ascertained.
This multiplicity suggests mycotic aneurysm.
Using the Kannoth Diagnostic Criteria6 (see Box 1),
the patient scored a total of 3 for (1) the presence of
multiple aneurysms on angiography, (2) an age of less
than 45 years and (3) the presence of an intraparenchymal
hemorrhage on CT scan. The patient had undocumented
febrile episodes prior to onset of neurologic symptoms
however, it did not last for more than 7 days. The patient
also had a history of valvular heart disease but recent
endocarditis was not confirmed. Box 1. Kannoth Diagnostic Criteria 6
In a case report by El Gawly, a 31-year old pregnant
woman on her 39th week of gestation was admitted
due to severe frontal headache, photophobia, vomiting consideration. Moreover, there is an expected rise back to
and neck pain.7 Provisional diagnosis was subarachnoid or above the normal maternal blood pressure in the post
hemorrhage. A live male infant was eventually delivered. partum period and this hemodynamic change can increase
Cerebral angiography revealed suspected multiple the risk of aneurysm rupture. In a study by Barbarite et
aneurysms and was managed with craniotomy and al, 78% of ruptured aneurysms occurred during the 3rd
clipping of the aneurysm. The postoperative period was trimester, compared to only 8% and 11% in the 1st and
eventful and the patient made a complete recovery. 2nd trimester respectively.10 In mycotic aneurysm, vessel
In mycotic aneurysm, the choice of antibiotics walls are more friable and a higher incidence of rebleed
should be guided by the most likely infecting organism is expected.
based on cultures. The optimal duration of antibiotic The normal hemodynamic changes in pregnancy
therapy is uncertain but ideally at least 6 weeks of include increase in cardiac output, plasma volume
antimicrobial therapy is administered. In this patient, and redistribution of cardiac output between various
Ampicillin-Sulbactam was given despite negative culture organs. There is also increase in the levels of estrogen,
studies. progesterone, vascular endothelial growth factor and
Ruptured mycotic aneurysms especially if with mass relaxin, and increased wall tension from intraparenchymal
effect, are generally managed surgically. However, due to artery hypoplasia. Vascular stress is therefore increased
the improving clinical status, a ventriculo-peritoneal shunt during pregnancy. The occurrence of aneurysm affects
was done instead to which the patient initially responded pregnancy in terms of management. Whether ruptured
favorably. Despite aggressive antimicrobial therapy or unruptured, calcium channel blockers are given for
and a seemingly improving neurologic status, multiple 3 weeks to prevent vasospasm and to maintain a low
aneurysms persisted. Unfortunately for this patient, the normal blood pressure to reduce vascular stress. This may
third episode of rupture resulted in a fatal subarachnoid result to decreased venous return leading to decreased
hemorrhage. Remote from term, delivery was not a uteroplacental blood flow.

Volume 41, Number 5, PJOG September-October 2017 31

Figure 1. (A) Plain Cranial CT Scan on day of admission showed Parenchymal hemorrhage (14cc) involving the right frontal lobe with
intraventricular extension, and resultant mild subfalcine herniation. (B) Sixteen days post-ictus, CT angiography revealed an acute to
subacute parenchymal hemorrhage measuring approximately 13cc involving the right frontal lobe with intraventricular extension;
multiple saccular aneurysms were noted. (C) Follow-up CT scan showed decrease in density and amount of the previously noted
hyperdensity due to evolution of the hematoma in the right frontal lobe, now measuring approximately 9.33cc by CT volumetry. A
new hyperdensity was noted posteroinferiorly in relation to the aforementioned hematoma, measuring approximately 8.0cc. (D)
There is almost complete resorption of bleed in right frontal lobe and right ventricle, and marked decrease in the size of ventricles.

SUMMARY/CONCLUSION up of the patient’s valvular heart disease and (3) financial

Mycotic aneurysm in pregnancy is a rare and fatal
complication with no widely accepted treatment guideline.
This distinct group of intracranial aneurysms stands
out from other types of aneurysms due to its infectious
etiology, incidence in relatively young patients and
multiplicity. It usually occurs in the setting of an infective
endocarditis and in this case, the patient was diagnosed
with a valvular heat disease but was not monitored
accordingly. This patient was managed medically with
antibiotics and insertion of a ventriculo-peritoneal shunt.
However, these attempts were unsuccessful in preventing
another episode of rupture.
The specific management of an infected aneurysm
must be individualized and is dependent on the
characteristics of the aneurysm. Administration of
antibiotics should be given for 4-6 weeks to achieve
optimum effect. While a four-vessel angiogram would be
ideal to diagnose an aneurysm accurately, the advent of
CT angiography has provided an opportunity to monitor
the patient non-invasively.
Though there were documented cases of successfully
managed mycotic aneurysms, this patient was given limited
options due to the attempt of preserving the pregnancy
until delivery is acceptable. The patient succumbed after
40 hospital days.
Limitations of this case include (1) insufficient history
taking of early signs of aneurysm, (2) inadequate work-
constraints that hindered timely management from its
onset
In reviewing the management done to this patient
and current literature regarding mycotic aneurysm in
pregnancy, we recommend the following measures to
manage similar cases especially in a low-resource setting.
In a gravidocardiac patient who presents with
neurologic symptoms, we advise that the patient undergo
(1) CT angiogram without delay to confirm the presence of
aneurysm and its characteristics, (2) 2D echocardiogram
to confirm the presence of heart disease and (3) culture
studies to identify the infecting organism.
Our primary strategy is to manage the patient
conservatively with antibiotics. Serial cranial CT
angiogram is advised every 2-3 weeks to monitor the
progress of aneurysm. Fetal growth monitoring every 2-4
weeks, congenital anomaly scan and antepartum fetal
surveillance are likewise recommended for fetal status
monitoring. Delivery should be done as close to term
as possible. Early termination is only advisable if with
favorable fetal survival dependent on the institution,
or if non-reassuring fetal status is noted and patient is
already nearing term. Delivery must be coordinated with
Neurosurgery as immediate neurosurgical procedure
may be necessary if maternal status suddenly. Likewise,
overall management must be carefully planned with the
help of neurologists, internists, anesthesiologists and
pediatricians.

32 Volume 41, Number 5, September-October 2017

REFERENCES
1. Brust J, Dickinson P, Hughes J, Holtzman R. The diagnosis and
treatment of cerebral mycotic aneurysms. Annals of Neurology.
1990;27(3):238-246.
2. Kuo I, Long T, Nguyen N, Chaudry B, Karp M, Sanossian N. Ruptured
Intracranial Mycotic Aneurysm in Infective Endocarditis: A Natural
History. Case Reports in Medicine. 2010;2010:1-7.
3. Oohara K. Infective endocarditis complicated by mycotic cerebral
aneurysm: two case reports of women in the peripartum period.
European Journal of Cardio-Thoracic Surgery. 1998;14(5):533-535.
4. Spelman D. Overview of infected (mycotic) arterial aneurysm
[Internet]. Uptodate.com. 2011 [cited 21 May 2017]. Available
from: http://www.uptodate.com/contents/overview-of-infected-
mycotic-arterial-aneurysm
5. Sun L. Sensitivity of Computed Tomography Angiography vs
Catheter Angiography in the Detection of a Ruptured Intracranial
Infectious Aneurysm in a Pregnant Woman. Archives of Neurology.
2012;69(2):270.
6. Kannoth S, Thomas S, Nair S, Sarma P. Proposed diagnostic criteria
for intracranial infectious aneurysms. Journal of Neurology,
Neurosurgery & Psychiatry. 2008;79(8):943-946.
7. El Gawly R. Ruptured intracranial aneurysm in pregnancy: a case
report and review of the literature. European Journal of Obstetrics
& Gynecology and Reproductive Biology. 1992;46(2-3):150-153.
8. Allen L, Fowler A, Walker C et al. Retrospective Review of Cerebral
Mycotic Aneurysms in 26 Patients: Focus on Treatment in Strongly
Immunocompromised Patients with a Brief Literature Review.
American Journal of Neuroradiology. 2012;34(4):823-827.
9. Lee W, Mossop P, Little A, Fitt G, Vrazas J, Hoang J et. al. Infected
(Mycotic) Aneurysms: Spectrum of Imaging Appearances and
Management. RadioGraphics. 2008;28(7):1853-1868.
10. Barbarite E, Hussain S, Dellarole A, Elhammady M, Peterson E.
The management of intracranial aneurysms during pregnancy: a
systematic review. Turkish Neurosurgery. 2015.
Volume 41, Number 5, PJOG September-October 2017 33
 Spontaneous uterine rupture secondary to pyometra in a
cervical cancer patient: A case report*
By Maria Concepcion D. Cenizal, MD and Leo Francis N. Aquilizan, MD, FPOGS, FSGOP
Department of Obstetrics and Gynecology, St. Luke’s Medical Center - Quezon City

ABSTRACT

Pyometra, an accumulation of pus within the uterine cavity, is a rare gynecologic disease with an incidence of 0.01-0.5%
among all gynecologic patients and 13.6% among elderly gynecologic patients.1 Pyometra in itself is rare, much so is uterine
rupture occurring secondary to it. No local data reporting incidence of ruptured pyometra in the Philippines has been published.
This is a case of a 63-year-old Gravida 5 Para 5 (5-0-0-4), with Cervical Endometrioid Adenocarcinoma Stage IIIB, presented
with abdominal pain. Whole abdominal Computed Tomography scan revealed pneumoperitoneum. Initial assessment was
pneumoperitoneum probably secondary to ruptured viscus. The patient underwent exploratory laparotomy which revealed
ruptured pyometra. Subsequent management included drainage, culture guided antibiotics, radiotherapy and brachytherapy.
Spontaneous rupture of pyometra is a serious medical condition which requires an accurate diagnosis in order to arrive in
appropriate surgical and medical management. However, pre-operative diagnosis is difficult despite the presence of advanced
imaging techniques, hence high level of suspicion is warranted in identifying this condition.

Keywords: uterine rupture, ruptured pyometra, cervical carcinoma

INTRODUCTION The clinical manifestations of pyometra range from

P
yometra is a rare gynecologic occurrence. It
comprises 0.01-0.5% among all gynecologic patients
and 13.6% among elderly gynecologic patients.1
Pyometra in itself is rare, much so is uterine rupture
occurring secondary to it. Lui et al. (2015) conducted
a retrospective review of women diagnosed to have
pyometra from January 2003 to December 2010. There
were 57 patients identified and reviewed. Of the 57, not
a single patient led to spontaneous uterine rupture.3 To
date, there are only approximately 50 cases of ruptured
pyometra that are published in English literature, of which
around 9 cases have a concomitant cervical carcinoma,
our index patient being the 10th reported case. Pyometra
is the accumulation of pus within the uterine cavity which
is commonly caused by a blockage or compromise in the
outflow tract of the uterus. The accumulated pus within
the uterus causes gradual enlargement of the organ
that will lead to thinning of its wall and less frequently,
subsequent spontaneous rupture may follow. This is
usually manifested as generalized peritonitis among most
patients who develop this sequela.9 Among the reported
cases, genital tract malignancies and the consequences
of its management, specifically radiotherapy, has been
shown to be the most common cause of pyometra.3
*Third Place, Philippine Obstetrical and Gynecological Society
(Foundation), Inc. (POGS) Interesting Case Paper Contest,
September 21, 2017, 3rd Floor POGS Building, Quezon City
gynecologic presentation to non-specific symptoms.
In the rare event that pyometra is complicated by
spontaneous rupture, clinical presentation becomes
more non-specific. Once ruptured, abdominal pain and
subsequently, acute abdomen follows. Due to the non-
specific nature of the clinical manifestations of ruptured
pyometra, a vast number of differential diagnoses may be
entertained; this makes accurate pre-operative diagnosis
more difficult. With abdominal pain being the most
common chief complaint, the differential diagnosis would
be based on other causes of a surgical acute abdomen.
Among patients reported to have perforated pyometra
secondary to cervical carcinoma, as much as 60% were
pre-operatively diagnosed with generalized peritonitis,
half of which including the index patient was misdiagnosed
to have ruptured viscus. Only 30% of the reported cases
were correctly diagnosed preoperatively with ruptured
pyometra. Pneumoperitoneum was seen in as much as
40% of the cases, which includes the index patient. This
further poses confusion in diagnosing ruptured pyometra
because 85-90% of cases of pneumoperitoneum
was reported to be associated with gastrointestinal
perforation.17 Because of low index of suspicion and
because of non-specific manifestations similar to other
more common disease entities, in most cases, it is only
intraoperatively that ruptured pyometra is diagnosed.
Due to a challenging preoperative diagnosis of pyometra,
choice of appropriate diagnostic modalities could help in
accurately identifying this catastrophic event. Computed
Tomography of the whole abdomen and Ultrasonography
Volume 41, Number 5, PJOG September-October 2017 43
are some of the diagnostic modalities that can be utilized
in diagnosing ruptured pyometra. However, despite the
presence of advanced imaging techniques, accurate pre-
operative diagnosis of ruptured pyometra remains to
be challenging. Hence, a high index of suspicion among
post-menopausal patients presenting with abdominal
pain and with a history of genital tract occlusion could
aid in diagnosing ruptured pyometra pre-operatively.
Once a diagnosis of acute abdomen is established, an
immediate laparotomy must be performed. The definitive
management of ruptured pyometra is total abdominal
hysterectomy with or without bilateral salpingo-
oophorectomy, thorough peritoneal lavage and drainage,
and prompt antibiotic coverage.15,18 However, total
abdominal hysterectomy is not always possible, especially
in cases that are complicated by malignancy. In such
cases, copious peritoneal lavage and toilette, drainage
and prompt antibiotic coverage should be strictly done.
The success of the management of ruptured pyometra
depends on the clinical presentation of the patient upon
admission, the underlying cause of the rupture and co-
morbidities present in the patient. In the case report
of Saha et al (2008), it was noted that as much as 73%
of cases of ruptured pyometra not associated with any
malignancy had a favorable prognosis for survival while
only 33% of cases associated with malignancy survived.19
Among the cases of ruptured pyometra with associated
cervical carcinoma that underwent peritoneal lavage and
drainage, 75% (3 out of 4, including the index patient) had
a favorable outcome for survival. Among those who were
managed with hysterectomy with or without bilateral
salpingo-oophorectomy, 50% (3) had an unmentioned
outcome, while only 17% (1) had a favorable outcome for
survival.
Review of PubMed/Medline and Herdin using the
keywords uterine rupture + pyometra and hand search
through archives of Philippine Obstetrics and Gynecology
Society yielded no local data discussing pyometra or
its spontaneous rupture in the Philippines. Hence we
present a case of such with the subsequent management
undertaken.
CASE REPORT
This is a case of a 63-year-old Gravida 5 Para
5 (5-0-0-4), menopause for 18 years, who came in
due to abdominal pain that started 2 days prior to
consulting. The patient is a newly diagnosed case of
Cervical Endometrioid Adenocarcinoma Stage IIIB, one
month prior to consultation, initially presented as post-
menopausal bleeding. Internal examination revealed
a cervix converted into a nodular mass with central
excavation, involving the anterior middle third of the
44 Volume 41, Number 5, September-October 2017
vagina, small corpus, with fixed parametria. Cervical
tissue biopsy was done, which revealed endometrioid
adenocarcinoma. The patient underwent Computed
Tomography scan of the whole abdomen, which showed
mild left hydronephrosis (Appendix A). She was undergoing
laboratory examinations as part of her clearance for
a planned radiation therapy when she experienced
generalized abdominal pain, crampy in character, non-
radiating, with increasing severity, from pain score of
5/10 to 10/10, associated with episodes of high-grade
fever and vomiting. No changes in bowel movement nor
urinary symptoms were noted. The patient has no other
co-morbidities nor history of previous surgery. There was
no known history of malignancy or any heredofamilial
illnesses in the family. She is a non-smoker and not an
alcoholic beverage drinker. She had regular monthly
menstruation since the age of 18, using up to 2 pads per
day, lasting for 3 days and experienced menopause at the
age of 45. She had one monogamous sexual partner and
did not have history of oral contraceptive pill use. All of
the five pregnancies were carried to term, delivered by
normal spontaneous delivery with no fetal and maternal
complications.
At the Emergency Department, the patient had
generalized abdominal pain, a pain score of grade 10/10,
with the following vital signs: normotensive at 120/70
mmHg, tachycardic at 120 beats per minute, slightly
tachypneic at 23 cycles per minute and afebrile at 36.8
degree Celsius. Physical examination revealed normal
systemic physical examination findings, the abdomen was
soft but with guarding and generalized direct tenderness.
Diagnosis during that time was acute abdomen.
Work-up for identification of the cause of acute
abdomen was done. Complete blood count showed
hemoglobin of 13.3 g/dl and white blood count of 9,730
mm3 (Appendix B). Blood chemistry showed normal serum
creatinine, blood urea nitrogen, serum electrolytes, lipase
and amylase (Appendix C). Urinalysis showed urinary
tract infection (Appendix D). A scout film of the abdomen
was also performed which showed pneumoperitoneum
(Appendix E). The patient then underwent Computed
Tomography Scan of the whole abdomen with intravenous
contrast which revealed moderate pneumoperitoneum of
indeterminate etiology (Appendix F), for which an initial
assessment of pneumoperitoneum probably secondary to
ruptured viscus was made.
The patient was started on an intravenous antibiotic
(piperacillin-tazobactam) and underwent exploratory
laparotomy by the General Surgery service with an
intraoperative referral to Gynecologic Oncology service.
Intraoperatively, purulent intraperitoneal discharge was
noted, which was evacuated and subsequently sent to
the laboratory for gram stain and culture and sensitivity.
Culture studies of the purulent intraperitoneal discharge
showed few growth of Corynebacterium species
sensitive to azithromycin, benzylpenicillin, clindamycin,
erythromycin, linezolid, cotrimoxazole and tetracycline
(Appendix G). There was a note of the presence of
peritoneal carcinomatosis. Biopsy of the omentum was
done which showed fibrofatty tissues with focal acute
and chronic inflammation, negative for malignancy. Upon
inspection of the pelvic organs, the following findings
were seen: a necrotic ruptured area at the fundus of the
uterus about 2cm in size (Appendix I) with the presence
of intrauterine purulent discharge (pyometra), dilated left
fallopian tube, normal right fallopian tube and bilateral
ovaries, and fixed right parametrium. The intra-operative
diagnosis then was ruptured uterus secondary to pyometra.
With these intra-operative findings, Gynecologic Oncology
service proceeded with peritoneal toilette and drainage.
Total abdominal hysterectomy was not performed due to
fixed parametrium. Intrauterine purulent discharge was
collected and subjected to culture studies which showed
few growth of Extended Spectrum Beta Lactamase positive
Escherichia coli sensitive to amikacin, cefoxitin, colistin,
ertapenem, gentamicin, imipenem and tazobactam-
piperacillin, and carbapenemase positive Pseudomonas
aeruginosa sensitive to amikacin, cefepime, ceftazidime,
ciprofloxacin, colistin and gentamicin (Appendix H).
Peritoneal toilette was done by copious washing of
the peritoneal area. Jackson-Pratt drains were placed
in the subcutaneous layer, subhepatic area, anterior
and posterior uterus and uterine cavity (Appendix J) for
continuous drainage.
Immediately postoperation when results of the
culture studies are not yet available, the patient was
referred to Infectious Disease service who increased the
dose of intravenous piperacillin-tazobactam to 4 grams
every 6 hours and started the patient with intravenous
fluconazole 40 mg once a day and intravenous
metronidazole 500 mg every 8 hours. The patient was
able to tolerate the procedure and was asymptomatic
until day 2 post-operation, she had an episode of dyspnea
and on examination, was tachypneic at 26 breaths per
minute and hypoxemic with an oxygen saturation of 79%.
On auscultation, fine crackles were noted in bilateral
lung fields and on chest x-ray, pulmonary congestion and
hazy opacities on left lower lung were seen, from which
consideration of hospital acquired pneumonia was made.
The patient was then transferred to Intensive Care Unit.
Oxygen saturation subsequently improved to 97% with
oxygen support via nasal canula maintained at 2 liters per
minute and administration of intravenous furosemide. On
the third post-operative day, serosanguinous output was
continued to be drained from the Jackson-Pratt drains, the
highest volume of which coming from the one inserted
in the anterior uterus. Chest ultrasound was also done
which revealed a progression of bilateral pleural effusion,
for which increase in the dosage of furosemide was made,
40 mg every 12 hours. On the day 3 post-operation, a shift
of antibiotic from piperacillin-tazobactam to meropenem
1 gram intravenous every 8 hours was made. Oral
ciprofloxacin 750mg intravenous every 12 hours was also
started. fluconazole and metronidazole were continued.
The patient remained stable and transferred to a regular
room on the fourth post-operative day. There was
continuously decreasing output from the hepatic Jackson-
Pratt drain in the subsequent days, hence it was removed.
On the seventh post-operative day, oral fluconazole and
metronidazole were completed for a 7-day course. The
result of the culture studies of the intrauterine purulent
discharge revealed Extended spectrum beta lactamase
positive Escherichia coli sensitive to ertapenem and
carbapenemase positive Pseudomonas aeruginosa
sensitive to ciprofloxacin, hence intravenous meropenem
(day 5) was shifted to intravenous ertapenem 1 gram
every 24 hours, which was subsequently completed for
a 10-day course. Oral ciprofloxacin was completed for a
14-day course. The remaining Jackson-Pratt drains had
continuously decreasing output, hence were subsequently
removed. The patient was referred to Radiology Oncology
service for radiation therapy which started after the
infection has been resolved. Patient completed 33
sessions of radiotherapy and underwent 3 sessions of
Brachytherapy during admission. She was discharged after
73 hospital days improved with the discharge diagnosis of:
Cervical Endometrioid Adenocarcinoma Stage IIIB, Acute
Abdomen secondary to Pneumoperitoneum secondary
to Ruptured Pyometra, Complicated Intraabdominal
Infection, resolved, Hospital Acquired Pneumonia,
resolved, s/p Cervical Biopsy (March 2016), s/p
Exploratory Laparotomy, Evacuation of Intraabdominal
Abscess, Peritoneal Toilette, Insertion of Uterine and
Peritoneal Drains, Excision Biopsy of Omentum (March
21, 2016), s/p Radiotherapy x 33 sessions (May 2016), s/p
Brachytherapy x 3 sessions (May 2016).
CASE DISCUSSION
With an incidence of 0.01-0.5% among all gynecologic
patients, pyometra is a rare gynecologic disease entity.1
Incidence increases with advancing age, up to 13.6%
among elderly patients.1 In a case report conducted by
Yildizhan et al. (2006), 22 cases of spontaneous uterine
rupture secondary to pyometra from 1980-2004 were
reviewed. Out of the 22 patients, 20 (91%) were of
postmenopausal age.2 Pyometra in itself is rare, much so is
uterine rupture occurring secondary to it. Lui et al. (2015)
conducted a retrospective review of women diagnosed
Volume 41, Number 5, PJOG September-October 2017 45
to have pyometra from January 2003 to December 2010.
There were 57 patients identified and reviewed. Of the 57,
not a single patient led to a spontaneous uterine rupture.3
To date, there are only approximately 50 cases of ruptured
pyometra that are published in English literature, of which
around 9 cases have a concomitant cervical carcinoma,
our index patient being the 10th reported case. Review
of PubMed/Medline and Herdin using the keywords
uterine rupture + pyometra and hand search of journals
in the library of Philippine Obstetrics and Gynecology
Society yielded no local data discussing pyometra or its
spontaneous rupture.
Table 1 summarizes 9 previously reported cases of
ruptured pyometra secondary to cervical carcinoma with
the addition of the index case.4-11 Out of the 10 cases, 9
(90%) are of postmenopausal age (52 to 80 years old) and
only 1 (10%) is of premenopausal age (34 years old). All
of the 10 (100%) cases presented with abdominal pain
as the chief complaint. Only 3 (30%) cases were correctly
diagnosed with ruptured pyometra pre-operatively.
Generalized peritonitis was pre-operatively diagnosed in
6 (60%) of the cases while in 3 (30%) cases, including the
index patient, pre-operative diagnosis of ruptured viscus
was made. Pneumoperitoneum was also seen in 4 (40%)
of the cases, which includes the index patient. The point of
rupture identified in the uterine fundus was seen among
7 (70%) of the reported cases. 1 (10%) case had a point of
rupture in the left cornual area, 1 (10%) in the posterior
uterine wall and the other 1 (10%) in the anterior uterine
wall.
Pyometra is tbhe accumulation of pus within the
uterine cavity which is commonly caused by a blockage or
compromise in the outflow tract of the uterus. Although
abnormalities that interfere with the drainage of the uterus
can result to pyometra, it does not always necessarily
develop secondary to obstruction at the cervical os.12
The accumulated pus within the uterus causes gradual
enlargement of the organ that will lead to thinning of
its wall and less frequently, subsequent spontaneous
rupture may follow. This is usually manifested as
generalized peritonitis among most patients who develop
this sequela.9 Among the reported cases, genital tract
malignancies and the consequences of its management,
specifically radiotherapy, has been shown to be the most
common cause of pyometra.3 As with the index patient
whom on internal examination revealed a cervix that is
converted into a nodular mass, blockage of the genital
outflow tract caused by this cervical carcinoma could have
predisposed the patient in developing pyometra. Aside
from malignancies, benign conditions such as endometrial
polyp and leiomyoma may also cause accumulation of pus
in the uterus. Other causes such as infection, as in senile
cervicitis and endometritis, cervical occlusion after surgery
46 Volume 41, Number 5, September-October 2017
and forgotten intrauterine device have been reported to
be seen among patients with pyometra.13
The clinical manifestations of pyometra range from
gynecologic presentation to non-specific symptoms. The
triad of the disease includes purulent vaginal discharge,
fever, and lower abdominal pain.12 However, up to 50%
of patients with pyometra may also be asymptomatic.14
In the rare event that pyometra is complicated by
spontaneous rupture, clinical presentation becomes
more non-specific. In this sequela, the most predominant
clinical manifestations reported include abdominal pain,
fever and vomiting.15 Once ruptured, abdominal pain and
subsequently, acute abdomen follows. Having non-specific
symptoms contributes to the difficulty of diagnosing
ruptured pyometra pre-operatively. Ou et al. (2010)
conducted a retrospective study of 20 patients diagnosed
with pyometra between 1998-2008, 14 of which have
early-drainage pyometra and 6 have perforated pyometra.
A review of literature was also conducted which yielded
additional 30 cases of perforated pyometra. Of the 20
patients with pyometra, 80% presented with abdominal
pain, 45% with fever and 25% were reported to have
vaginal discharge. Of the 36 with perforated uterus, 97%
had a chief complaint of abdominal pain, 31% had fever
and 10% had vomiting.16 On the report of Yildhizan et al.
(2006) mentioned above, cases of spontaneous rupture
of pyometra included in the report most commonly
presented with abdominal pain (95.5%), vomiting
(41%),nausea (9.1%) and fever (9.1%).2 Referring back to
table 1, all of the reviewed cases of ruptured pyometra
secondary to cervical carcinoma had a chief complaint of
abdominal pain. This includes the index patient, who aside
from abdominal pain also manifested the reported non-
specific symptoms of ruptured pyometra, which are fever
and vomiting.
Less than 10% of the patients with ruptured
pyometra present with gynecologic symptoms such as
vaginal bleeding and vaginal discharge.8 Due to the non-
specific nature of the clinical manifestations of ruptured
pyometra, a vast number of differential diagnoses may be
entertained; this makes accurate pre-operative diagnosis
more difficult. With abdominal pain being the most
common chief complaint, the differential diagnosis would
be based on other causes of a surgical acute abdomen.
Among the 22 cases of ruptured pyometra described in
the report of Yildizhan et al. (2006), the pre-operative
diagnosis that was most commonly made included
generalized peritonitis (47.4%), pneumoperitoneum
(47.4%), and gastrointestinal tract perforation (36.8%).2
Ruptured pyometra was considered in just 3 (15.8%) cases.2
Among patients reported to have perforated pyometra
secondary to cervical carcinoma, as much as 60% were
pre-operatively diagnosed with generalized peritonitis,
Table 1. Cases of Sponataneous Uterine Rupture secondary to Pyometra among Cervical Cancer Patients

CHIEF PRE-OPERATIVE POINT OF

CASE YEAR AGE MANAGEMENT OUTCOME
COMPLAINT DIAGNOSIS RUPTURE
1 1993 67 Abdominal Generalized Peritonitis, Fundus Supravaginal Hysterectomy with Alive 4
Pain + Genital Perforated Pyometra, Bilateral Salpingo-oophorectomy
Bleeding Pneumoperitoneum
2 2000 34 Abdominal Pain Generalized Peritonitis Left cornual region Peritoneal Lavage and Drainage Alive5
3 2000 72 Abdominal Pain Generalized Peritonitis Fundus Peritoneal Lavage and Drainage Expired 5
4 2005 52 Abdominal Pain Generalized Peritonitis Posterior portion of Subtotal Hysterectomy Expired6
uterine segment
5 2006 80 Abdominal Pain Perforated Sigmoid Fundus 1.Repair of rupture with - 14
Diverticulum peritoneal lavage
2.Total Abdominal Hysterectomy
with Bilateral Salpingo-
oophorectomy
6 2007 60 Abdominal Pain Perforated Viscus, Fundus Total Abdominal Hysterectomy -8
Pneumoperitoneum, with Bilateral Salpingo-
Generalized Peritonitis oophorectomy
7 2009 60 Abdominal Pain Perforated Pyometra Fundus Peritoneal Lavage and Drainage Alive 9
8 2013 Postmenopausal Abdominal Pain Perforated Pyometra, Fundus Total Abdominal Hysterectomy -10
Pneumoperitoneum
9 2014 70 Abdominal Pain Generalized Peritonitis Anterior Uterine Wall Total Abdominal Hysterectomy Expired 11
with Bilateral Salpingo-
oophorectomy
10 2016 63 Abdominal Pain Pneumoperitoneum Fundus Peritoneal Lavage and Drainage Alive
(index probably secondary to
patient) ruptured viscus

half of which including the index patient was misdiagnosed
to have ruptured viscus. Only 30% of the reported cases
were correctly diagnosed preoperatively with ruptured
pyometra. Pneumoperitoneum was seen in as much as 40%
of the cases, which includes the index patient. This further
poses confusion in diagnosing ruptured pyometra because
85-90% of cases of pneumoperitoneum was reported to
be associated with gastrointestinal perforation.17 Hence,
the diagnosis of ruptured viscus was initially considered
in the index patient. Pneumoperitoneum may be caused
by gas-forming organisms present in the discharge, such
as Escherichia coli, which grew in the culture studies of
the intrauterine abscess collected from the index patient.
Another possible explanation of the free intrauterine
gas could be from the passage of air through the genital
canal to the peritoneal cavity.18 Because of low index of
suspicion and because of non-specific manifestations
similar to other more common disease entities, in most
cases, it is only intraoperatively that ruptured pyometra is
diagnosed, as what occurred in the index patient.19
Due to a challenging preoperative diagnosis of
pyometra, choice of appropriate diagnostic modalities
could help in accurately identifying this catastrophic event.
Ruptured pyometra commonly mimics clinical presentation
of diseases of gastrointestinal origin, hence imaging
studies are done to identify which among the patients have
surgical acute abdomen. Since the most common site of
uterine perforation in ruptured pyometra is at the fundus,
axial Computed Tomography images may not suffice in
the identification of uterine breach in such location. In
1 of the 3 cervical cancer cases correctly diagnosed with
ruptured pyometra preoperatively, sagittal and coronal
reformats in multi-detector computed tomography was
utilized to identify the site and size of the uterine breach.
This technique was also able to demonstrate the intra-
abdominal collections and was helpful in staging the
cervical cancer of the patient.9 Another imaging that can
be utilized is ultrasonography. Abdominal ultrasonography
has high sensitivity in identifying pyometra, however,
it is not able to demonstrate breach in the uterus in the
event of uterine perforation. In addition, the presence of
pneumoperitoneum causes limited sonographic window,
which further decreases the utilization of abdominal
ultrasonography in such cases.20 However, in a case
reported by Malvadkar et al. (2016), an ultrasonography
accurately diagnosed the patient with uterine perforation
secondary to pyometra. The limitation of the imaging
technique in diagnosing ruptured pyometra was overcome
with the use of Dynamic Transvaginal Ultrasonography,
which demonstrates real-time movement of the

Volume 41, Number 5, PJOG September-October 2017 47

endometrial and peritoneal collections through the defect
in either direction. It was the first and only reported case
of ruptured pyometra that was accurately diagnosed pre-
operatively with the use of a simple Dynamic Transvaginal
Ultrasound.13
In the index patient, an abdominal x-ray was initially
done, which revealed pneumoperitoneum. Multi-detector
Computed Tomography scan of the whole abdomen
was then performed which also identified moderate
pneumoperitoneum, however, of indeterminate etiology.
This led to a pre-operative consideration of ruptured
viscus. This case proves that despite the availability of
advanced imaging facilities, an accurate pre-operative
diagnosis of ruptured pyometra may still be difficult. In the
absence of gynecologic symptoms, it is worth note taking
that gynecologic ultrasonography still plays an important
role in the diagnosis of pyometra and in some extent, its
rupture.
Once a diagnosis of acute abdomen is established,
an immediate laparotomy must be performed. In most
cases, diagnosis of ruptured pyometra is only made
intraoperatively when findings of intraperitoneal purulent
discharge and uterine perforation are observed. The
definitive management of ruptured pyometra is total
abdominal hysterectomy with or without bilateral
salpingo-oophorectomy, thorough peritoneal lavage and
drainage, and prompt antibiotic coverage.15,18 However,
total abdominal hysterectomy is not always possible,
especially in cases that are complicated by malignancy.
In such cases, copious peritoneal lavage and toilette,
drainage and prompt antibiotic coverage should be strictly
done. The aim of peritoneal toilette is to mechanically
remove as many contaminants as possible to reduce the
severity of infection and limit host responses. In the case
report of Yildhizan et al. (2006), 21 out of the 22 cases
of ruptured pyometra reviewed in the report underwent
laparotomy, 1 patient was unstable to undergo the said
procedure. Total abdominal hysterectomy was done to 18
of the cases, while drainage was the management for the
other 4.2 Among the reported cases of ruptured pyometra
with cervical carcinoma reviewed in this case report, 4
(40%) cases underwent peritoneal lavage and drainage,
which includes the index patient, while the other 5 (50%)
underwent hysterectomy. One of the cases reported was
initially managed by repairing the point of rupture and
by doing peritoneal lavage. However, infection was not
controlled and the patient eventually underwent another
operation where a hysterectomy was subsequently
performed. In all of the cases, appropriate antibiotic
coverage was administered.
The index patient underwent laparotomy for
an initial diagnosis of acute abdomen secondary to
pneumoperitoneum probably secondary to ruptured
48 Volume 41, Number 5, September-October 2017
viscus. The service of General Surgery initiated the
procedure and when ruptured pyometra was identified
intraoperatively, Gynecologic Oncology service continued
the procedure. The right parametrium was found to be
fixed, hence, total abdominal hysterectomy was not done.
Instead, evacuation of intraabdominal abscess, peritoneal
toilette, and continuous drainage through an insertion
of uterine and intraperitoneal drains were performed.
Broad spectrum antibiotics were initially started and when
the result of the culture studies of the abscess became
available, medications were shifted to culture-guided
antibiotics. Once the patient was stable and infection
was controlled, the underlying cause of the pyometra
was treated. She completed sessions of radiotherapy and
underwent brachytherapy for her cervical carcinoma.
The success of the management of ruptured pyometra
depends on the clinical presentation of the patient upon
admission, the underlying cause of the rupture and co-
morbidities present in the patient. In the case report of
Saha et al (2008), it was noted that as much as 73% of
cases of ruptured pyometra not associated with any
malignancy had a favorable prognosis for survival while
only 33% of cases associated with malignancy survived.19
Among the cases of ruptured pyometra with associated
cervical carcinoma that underwent peritoneal lavage and
drainage, 75% (3 out of 4, including the index patient) had
a favorable outcome for survival. Among those who were
managed with hysterectomy with or without bilateral
salpingo-oophorectomy, 50% (3) had an unmentioned
outcome, while only 17% (1) had a favorable outcome
for survival. The index patient who was pre-operatively
diagnosed with cervical carcinoma was managed by doing
peritoneal lavage and drainage. Once ruptured pyometra
was managed and infection was controlled, the patient
underwent sessions of radiotherapy and brachytherapy
to address the underlying cause of the pyometra, which
is cervical carcinoma. The patient tolerated both the
procedure for ruptured pyometra and the radiotherapy
and brachytherapy for cervical carcinoma. She was
discharged improved and recovered.
 
SUMMARY AND CONCLUSION
Ruptured pyometra is a rare condition but once
present, can be a catastrophic gynecologic emergency,
wherein prompt and accurate determination is important
in order to provide appropriate management. Incidence
increases among women belonging to postmenopausal
age group. Genital tract malignancies and disorders which
occlude its outflow tract predispose women in acquiring
pyometra. In the rare event that pyometra causes a
spontaneous uterine rupture, non-specific symptoms
follow, abdominal pain being the most common
manifestation. Despite the presence of advanced
imaging techniques, accurate pre-operative diagnosis of
ruptured pyometra remains to be challenging. Hence, a
high index of suspicion among post-menopausal patients
presenting with abdominal pain and with a history of
genital tract occlusion could aid in diagnosing ruptured
pyometra pre-operatively. In the absence of gynecologic
symptoms and presence of high index of suspicion among
this group of patients, note that gynecologic imaging
techniques such as transvaginal ultrasonography could
still play a major role in identifying this disease entity.
Despite the fact that the index patient was only diagnosed
REFERENCES
1. Sawabe M, Takubo K, Esaki Y, Hatano N, Noro T, Nokubi M.
Spontaneous uterine perforation as a serious complication of
pyometra in elderly females. The Australian and New Zealand
Journal of Obstetrics and Gynaecology. 1995;35(1):87–91.
2. Yildizhan B, Uyar E, Sismanoglu A, Gulluoglu G, Kavak Z.
Spontaneous perforation of pyometra. Infectious Diseases in
Obstetrics and Gynecology. 2006;26786.
3. Lui MW, Cheung VY, Pun TC. Clinical significance of pyometra.
Journal of Reproductive Medicine. 2015;60(7-8):329-332.
4. Imachi M, Tanaka S, Ishikawa S, Matsuo K. Spontaneous perforation
of pyometra presenting as generalized peritonitis in a patient with
cervical cancer. Gynecologic Oncology. 1993;50(3):384–388.
5. Chan LY, Yu VS, Ho LC, Lok YH, Hui SK. Spontaneous uterine
perforation of pyometra: a report of three cases. The Journal of
Reproductive Medicine. 2000;45(10):857–860.
6. Zeferino Toquero M, Banuelos Flores J. Secondary peritonitis due
to rupture of pyometra in cervical cancer. Ginecol Obstet Mex.
2005;73(11):618–21.
7. Shahid N, Khan H, Onon TS. Perforation of pyometra leading
to diffuse peritonitis is not necessarily iatrogenic. Journal of
Obstetrics and Gynaecology. 2006;26(1):76-77.
8. Lee SL, Huang LW, Seow KM, Hwang JL. Spontaneous perforation of
a pyometra in a postmenopausal woman with untreated cervical
cancer and forgotten intrauterine device. Taiwanese Journal of
Obstetrics and Gynecology. 2007;46(4):439-441.
9. Vyas S, Kumar A, Prakash M, Kapoor R, Kumar P, Khandelwal
N. Spontaneous perforation of pyometra in a cervical cancer
patient: a case report and literature review. Cancer Imaging 2009.
2009;9(1):12-14.
10. Gonzales-Medrano MG, Uribe-Koch LM, del Estrada-Hernandez
MR, Ojendiz-Nava RC, Perez-Morales A. Spontaneous uterine
perforation secondary to pyometra in a patient with cervicouterine
carcinoma: report of a case. Ginecol Obstet Mex. 2013;81(7)425-
429.
with ruptured pyometra post-operatively, she was still
managed appropriately and was discharged improved
and recovered. This was made possible by the presence
and coordination of the different services attending to
her, namely: Gynecologic Oncology, General Surgery,
Infectious Disease Service, Cardiology, Pulmonology
and Radiologic Oncology. Hence, in addition to a high
index of suspicion leading to an accurate pre-operative
diagnosis of ruptured pyometra, a multi-disciplinary
approach in treating ruptured pyometra, its sequela and
its underlying cause, is necessary to achieve successful
management.
11. Yousefi Z, Sharifi N, Morshedy M. Spontaneous uterine perforation
caused by pyometra: a case report. Iran Red Crescent Med J.
2014;16(9)14491
12. Stosor V, Zembower T. Infectious Complications in Cancer Patients.
Switzerland: Springer International Publishing; 2014.
13. Malvadkar S, Malvadkar M, Domkundwar S, Mohd, S. Spontaneous
rupture of pyometra causing peritonitis in elderly female
diagnosed on dynamic transvaginal ultrasound. Case Reports in
Radiology. 2016;1738521.
14. Jhobta R, Jhobta A. Spontaneous rupture of pyometra a rare cause
of peritonitis. J Pelvic Med Surg. 2006;12:267-268.
15. Shapey IM, Nasser T, Dickens P, Haldar M, Solkar MH.
Spontaneously perforated pyometra: an unusual case of acute
abdomen and pneumoperitoneum. The Anals of the Royal College
of Surgeons of England. 2012;94(8):15-17.
16. Ou YC, Lan KC, Lin H, Tsai CC, ChangChien CC. Clinical characteristics
of perforated pyometra and impending perforation: specific issues
in gynecological emergency. Journal of Obstetrics and Gynecology
Research. 2010;36(3):661-666.
.
17. McGlone FB, Vivion CG, Meir L. Spontaneous pneumoperitoneum.
Gastroenterology 1966; 51: 393–398.
18. Yamada T, Ando N, Shibata N, Suitou M, Takagi H, Matsunami K,
Ichigo Y, Imai A. Spontaneous perforation of pyometra presenting
as acute abdomen and pneumoperitoneum mimicking those of
gastrointestinal origin. Case Reports in Surgery. 2014;548481.
19. Saha P, Gupta P, Mehra R, Goel P, Huria A. Spontaneous rupture of
pyometra presented as acute abdomen: a case report. Medscape
Journal of Medicine. 2008;10 (1):15.
20. H.-S. Jeon, H.-J. Shin, I.-H. Kim, H. Chung, and D.-Y. Chung.
Spontaneous uterine perforation of pyometra presented as an
acute abdomen: a case report. Korean Journal of Obstetrics &
Gynecology. 2012; 55(6):437–440.
Volume 41, Number 5, PJOG September-October 2017 49
 APPENDIX B. Complete Blood Count. March 21, 2016
TEST RESULT UNIT REFERENCE
INTERVAL
Hemoglobin 13.3 g/dl 11.6 - 15.5
Hematocrit 40.4 % 36.0 - 47.0
Red Blood Cell Count 4.46 mil/mm3 4.20 - 5.40
White Blood Cell Count 9,730 mm3 4800 - 10800
Differential Count
Neutrophil(s) 34 % 40 - 74
Lymphocyte(s 14 % 19 - 48
Eosinophil(s) 0 % 0-7
Monocyte(s) 6 % 3-9
Basophil(s) 0 % 0-2
Stabs 34 % 2-6
Myelocyte 4 %
Metamyelocyte 8 %
APPENDIX A Platelet Count 588,000 /mm3 150000 - 400000
Whole Abdominal MCV 91 fl 82 - 98
CT-Scan MCH 30 pg 28 - 33
March 9, 2016 MCHC 33 % 32 - 38
RDW 12.7 % 11.0 - 14.0

A.Axial view cervical level and B. Coronal view cervical level. Marked by
the dotted lines is an enhancing soft tissue mass at the cervical region APPENDIX C. Clinical Chemistry. March 21, 2016
extending into the uterine cavity measuring 3.5 x 3.5 x 5.3 cm likely
representing the patient’s known neoplasm. C. Coronal View. Marked TEST RESULT UNIT REFERENCE
by the blocked arrow is a mild hydronephrosis on the left kidney INTERVAL

FINDINGS: Creatinine 0.99 mg/dL 0.55 - 1.02

There is an enhancing soft tissue mass at the cervical region extending Blood Urea Nitrogen 20 mg/dL 7 - 18
into the uterine cavity measuring 3.5 x 3.5 x 5.3 cm (AP x T x CC). Magnesium 1.9 mg/dL 1.8 - 2.4
Adjacent fat stranding densities are seen. There is narrowing of the Ionized Calcium 1.09 mmol/L 1.00 - 1.30
cervical lumen with retained fluid distending the uterine cavity. There is Lipase 127 u/L 73-393
a enhancing nodule in the LEFT pelvic side wall measuring 2.1 x 1.8cm, Amylase 39 u/L 25/115
likely representing a lymph node.
The posterior urinary bladder wall is seen abutting the cervical mass
with mild wall thickening. The rest of the urinary bladder wall is not
thickened. No filling defects withinthe urinary bladder lumen. APPENDIX D. Urinalysis. March 21, 2016
There are prominent sized to marginally enlarged lymph nodes in both
inguinal regions exhibiting a fatty hilum. The largest measure (short TEST RESULT UNIT
axis diameter) 1.1 cm in the left and 1.2 cm in the right. Subcentimeter MACROSCOPIC/ CHEMICAL
lymph nodes are appreciated in the para-aortic, aortocaval and EXAMINATIONS
mesenteric regions. No enlarged paraaortic and mesenteric lymph
nodes. Color Dark yellow
Transparency Slightly hazy
IMPRESSION: Glucose Negative
ENHANCING SOFT TISSUE MASS IN THE CERVICAL REGION EXTENDING Bile Moderate (2+)
TO THE LOWER UTERINE SEGMENT LIKELY REPRESENTING THE Ketone Trace
PATIENT’S Specific Gravity >/=1.030
KNOWN NEOPLASM WITH ADJACENT INFLAMMATORY / pH (reaction) 5.0 (Acidic)
INFILTRATIVECHANGES Protein 30 mg/dL (1+)
ENLARGED LYMPH NODE, LEFT PELVIC SIDE WALL Urobilinogen 1.0 E.U./dL
FOCAL WALL THICKENING IN THE POSTERIOR URINARY BLADDER Nitrites Negative
ABUTTING Blood Large (3+)
THE CERVICAL MASS Leukocytes Small (1+)
MILD LEFT HYDRONEPHROSIS
PROMINENT TO MARGINALLY ENLARGED INGUINAL LYMPH NODES URINE SEDIMENT ANALYSIS BY
WITH FATTY HILUM MANUAL MICROSCOPY
POST-INFLAMMATORY / INFECTIOUS CALCIFICATION IN THE LIVER Red Blood Cells 5-6 /HPF
MALROTATED LARGE BOWELS; NON-OBSTRUCTIVE BOWEL GAS White Blood Cells 9-10 /HPF
PATTERN Epithelial Cells Occasional
ATHEROSCLEROTIC VESSEL DISEASE Casts 0-1
DEGENERATIVE OSSEOUS AND DISK CHANGES Bacteria Occasional
LIPOMA AT THE RIGHT TENSOR FACIA LATA

50 Volume 41, Number 5, September-October 2017

APPENDIX E. Abdominal X-ray Flat and Upright
March 21, 2016
Findings:
Bowel gas pattern is non-obstructive and nonspecific.
There is no evidence of organomegaly.
Small crescent-shaped lucency is noted at the RIGHT
subdiaphragmatic region seen on the upright view.
Mild degenerative changes of the lumbar spine are seen.
Impression:
SMALL CRESCENT-SHAPED LUCENCY AT THE RIGHT
SUBDIAPHRAGMATIC REGION
IS OF CONCERN FOR PNEUMOPERITONEUM
APPENDIX F. Whole Abdominal CT-Scan with Contrast
March 21, 2016
The RIGHT anterior hip intramuscular lipoma is unchanged.
No bony destruction.
Included lung / chest shows trace posterior gutter effusion.
Impression:
MODERATE PNEUMOPERITONEUM OF INDETERMINATE ETIOLOGY
MODERATE ABDOMINO-PELVIC ASCITES
MINIMAL INTRA-HEPATIC AIR POSSIBLY PERIBILIARY IN ORIGIN DUE TO
ABSENCE OF PNEUMATOSIS
NON-SPECIFIC SMALL AIR COLLECTION ANTERIOR TO THE BILATERAL
EXTERNAL ILIAC VEINS DISTALLY. INTRALUMINAL VESSEL AIR IS NOT
EXCLUDED
SMALLER SIZE OF THE CERVIX
LARGER SIZE OF THE UTERINE BODY; HETEROGENEITY MAY RELATE TO
EDEMA
SMALL BOWEL WALL THICKENING IN THE RIGHT SIDE CAN BE REACTIVE
INFLAMMATION DUE TO THE SURROUNDING ASCITES. PRIMARY
ENTERITIS IS NOT RULED-OUT
SLIGHTLY SMALLER LEFT PELVIC SIDE WALL NODULE / LYMPH NODE
UNCHANGED HEPATIC CALCIFICATIONS AND RIGHT ANTERIOR HIP
INTRAMUSCULAR LIPOMA

APPENDIX G. Culture and Sensitivity: Intraperitoneal Abscess

March 21, 2016
Culture / Organism 1 Corynebacterium species
Few growth

AZITHROMYCIN SENSITIVE
BENZYLPENICILLIN SENSITIVE
CLINDAMYCIN SENSITIVE
ERYTHROMYCIN SENSITIVE
LINEZOLID SENSITIVE
SULFAMETHOXAZOLE TRIMETHOPRIM SENSITIVE
TETRACYCLINE SENSITIVE

APPENDIX H. Culture and Sensitivity: Intrauterine Abscess

March 21, 2016
Culture / Organism 1 Escherichia coli
Few growth
AMIKACIN SENSITIVE
AMOXYCLAV INTERMEDIATE
AMPICILLIN RESISTANT
A.Axial view hepatic level. Marked by the solid arrow are air locules in CEFEPIME RESISTANT
the hepatic area. B. Coronal view external iliac vessel level. Marked by CEFOTAXIME RESISTANT
dotted arrow is a small air collection just anterior to the external iliac CEFOXITIN SENSITIVE
veins distally. C. Axial view uterine level and D. Coronal view uterine CEFTRIAXONE RESISTANT
level. Marked by the solid circle are air locules noted superior to the CEFUROXIME RESISTANT
uterine body.
CIPROFLOXACIN RESISTANT
Findings: COLISTIN SENSITIVE
There is new finding of moderate pneumoperitoneum. Moderate ERTAPENEM SENSITIVE
abdomino-pelvic ascites is likewise seen. GENTAMICIN SENSITIVE
Minimal air is detected at hepatic segments VIII, IV and II. Air locules are IMIPENEM SENSITIVE
further noted in the porta hepatis and in the region of the ligamentum
MEROPENEM RESISTANT
teres. Small air collection is noted just anterior to the bilateral external
iliac veins distally. SULFAMETHOXAZOLE-TRIMETHOPRIM RESISTANT
The size of the cervix is smaller now with axial diameters of 4.0 x 3.3 Culture / Organism 1 Pseudomonas aeruginosa
cm (previously 5.0 x 4.1 cm, re-measured in the prior study using Few growth
approximately the same planes).
The uterine body is larger since the prior study having a craniocaudal AMIKACIN SENSITIVE
diameter of 7.9 cm (previously 5.9 cm). The uterine body is also CEFEPIME SENSITIVE
heterogeneous with air locules superiorly. CEFTAZIDIME SENSITIVE
The colon is mostly collapsed. Appendix is intact. There is wall thickening CIPROFLOXACIN SENSITIVE
of the small bowel in the RIGHT side. No pneumatosis appreciated. COLISTIN SENSITIVE
The LEFT pelvic side wall nodule / lymph node is slightly smaller GENTAMICIN SENSITIVE
measuring 1.8 x 1.7 cm (previously 2.1 x 1.8 cm). The hepatic IMIPENEM RESISTANT
calcifications are unchanged. There are no focal lesions in the kidneys, MEROPENEM RESISTANT
adrenal glands, pancreas, gallbladder and spleen. TAZOBACTAM PIPERACILLIN INTERMEDIATE

Volume 41, Number 5, PJOG September-October 2017 51

APPENDIX I APPENDIX J

Pointed by the block arrow is the point of rupture of the uterus

in the fundal area

Jackson Pratt Drain inserted inside the uterus through its point
of rupture

52 Volume 41, Number 5, September-October 2017

 The Accuracy of the international ovarian tumor analysis
(IOTA) simple rules in predicting malignant ovarian tumors
with biopsy as the reference standard*
By Jediza Jessa B. Balcita, MD and Pherdes E. Galbo, MD, FPOGS, FSGOP
Department of Obstetrics and Gynecology, Chong Hua Hospital

ABSTRACT

Background: The IOTA Simple Rules provide a standardized ultrasound description in order to correctly classify ovarian tumors as
benign or malignant even among non - expert readers. Its high accuracy rate was noted in foreign studies but was never validated
in the local setting.The IOTA inconclusive tumors that were either assumed to be malignant or referred to experts in other studies
were separately addressed in this research.

General Objective: To determine the accuracy of the IOTA Simple Rules to predict malignant ovarian tumors

Materials and Methods: Subjects: Patients with ovarian tumors admitted for surgery with complete ultrasound records done at
Women’s Health Unit and those with histopathologic report from the Department of Pathology. Setting: Department of Obstetrics
and Gynecology in a tertiary hospital from August 2015 to February 2017. Design: Cross-sectional Diagnostic Accuracy Test. Data
Collection: After obtaining approval from the IRB and Office of the Medical Director, the ovarian tumors were tallied and categorized
according to their IOTA classification and final histopathologic diagnoses. The sensitivity, specificity, positive and negative predictive
values, and accuracy were obtained using a 2x2 table. The biopsy reports of the inconclusive tumors were also reviewed and the
sonographic characteristics of those which turned out to be malignant were noted.

Results: A total of 110 adnexal masses were included, with the IOTA Simple Rules applicable in 84.55% of cases. It produced
an accuracy rate of 100%. Among the 17 inconclusive tumors, two proved to be truly malignant with the presence of only one
papillarity in a borderline tumor and the complex appearance of a germ cell tumor.

Conclusion: The IOTA Simple Rules is an accurate preoperative diagnostic tool in predicting ovarian malignancy. Two malignant
tumors were classified as inconclusive and their sonographic characteristic of only one papillarity and the complex appearance of
these tumors may warrant malignancy.

Keywords: Inconclusive, IOTA Simple Rules, Ovarian cancer

INTRODUCTION The evaluation of ovarian masses begins with

A. Background of the Study
Ovarian masses are frequent findings on pelvic
examination and pelvic imaging.1 The task of the clinician
is to determine whether the mass should be removed
or may be managed expectantly.1 Considerations for
removal include the symptoms produced by the mass, the
likelihood of spontaneous resolution and any suspicion
of malignancy. The overall incidence of a symptomatic
ovarian cyst in a premenopausal female being malignant
is approximately 1 in 1000, increasing to 3 in 1000 at the
age of 50 years.2
*First Place, Philippine Obstetrical and Gynecological Society
(Foundation), Inc. (POGS) Research Paper Contest, October 25, 2017,
3rd Floor POGS Building, Quezon City
careful physical examination, including an abdominal
and a bimanual pelvic examination. The size and physical
characteristics of the cyst are as important as the other
laboratory parameters.1 Transvaginal ultrasonography is
the single effective tool in the evaluation of an ovarian
mass and is usually preferable over the transabdominal
route due to its increased sensitivity. Larger masses
and extra-ovarian disease may require a combination
of both routes. Although histopathology remains the
only definitive diagnosis of an ovarian mass, typical
characteristics of ovarian pathology maybe seen on
ultrasonography which help determine whether the mass
is more likely to be benign or malignant.
Prediction models have been developed to aid
clinicians in directing patients toward appropriate
treatment pathways which include morphologic indices,
risk of malignancy indices and mathematical models.

Volume 41, Number 5, PJOG September-October 2017 1

However, the disadvantage of ultrasound-based prediction
models is that it is subjective and is operator dependent.
The International Ovarian Tumor Analysis (IOTA)
Group has developed a list of characteristics for benign
and malignant masses with the aim of producing rules
that may help less experienced examiners replicate the
results of expert sonologists. The IOTA Group simple
rules are defined as benign or B-rules and malignant
or M-rules.2 The benign or B-rules include unilocular
cysts, presence of solid components where the largest
solid component is less than 7 mm, presence of acoustic
shadows, smooth multilocular tumor with largest
diameter of less than 100 mm and a color score of 1. On
the other hand, the malignant or M-rules are as follows:
irregular solid tumor, presence of ascites, at least four
papillary structures, irregular multilocular solid tumor
with largest diameter greater than 100 mm and a color
score of 4 which indicates a strong blood flow (Appendix
A). If one or more M-features apply without the presence
of B-features, the ovarian mass is likely malignant. If
one or more B-features apply without the presence
of M-features, the ovarian mass is likely benign. If no
features present or if both B and M-features apply, the
result is inconclusive.
Preoperative discrimination between benign and
malignant adnexal masses is a crucial step in planning an
individualized therapeutic approach to avoid any delay
in intervention that may lead to disease progression, as
well as avoid unnecessary surgical intervention. Thus, the
use of the IOTA simple rules by a general gynecologist
has the potential to improve the management of women
with adnexal masses. The IOTA Simple Rules have been
validated in a number of foreign studies. However, it has
never been tested for reproducibility in the local setting
particularly in this institution.
B. Significance of the Study
The use of the IOTA Simple Rules by the sonologists
in this institution started in 2015. Although the accuracy of
the use of these simple rules is high in other countries, it
has never been validated in this institution. The findings of
this study compare the accuracy rating of the IOTA simple
rules to the results of previous studies and strengthen its
diagnostic performance as being a reliable preoperative
classification of ovarian masses. Clinical practitioners will
then be given the correct preoperative reading of the
ovarian mass whether it is benign or malignant as well as
be guided in the optimal management for these patients.
And for those read as “inconclusive” by the IOTA, this study
aims to determine the truly malignant tumors among the
inconclusive and discover their most likely sonographic
feature of malignancy. A better understanding of the
2 Volume 41, Number 5, September-October 2017
characteristics of ovarian tumors difficult to classify as
benign or malignant using IOTA will be developed. Thus,
this study provides gynecologists an insight as to the
likelihood of malignancy when these specific sonographic
characteristics will be present.
C. Research Objectives
General Objective
To determine the accuracy of the International
Ovarian Tumor Analysis (IOTA) Simple Rules to predict
malignant ovarian tumors
Specific Objectives
1. To determine the proportion of subjects with
ovarian tumor read as malignant by IOTA Simple
Rules among those confirmed to be malignant by
biopsy (Sensitivity)
2. To determine the proportion of subjects who were
confirmed to be malignant by biopsy among those
screened by IOTA as malignant (Positive Predictive
Value)
3. To determine the proportion of subjects with
ovarian tumor read as benign by IOTA Simple
Rules among those confirmed to be benign by
biopsy (Specificity)
4. To determine the proportion of subjects who were
confirmed to be benign by biopsy among those
screened by IOTA as benign (Negative Predictive
Value)
5. To determine the proportion of malignant ovarian
mass confirmed by biopsy among those tumors
considered to be inconclusive by IOTA
6. To describe the specific sonographic characteristics
of the malignant tumors that were considered
Inconclusive by IOTA Simple Rules
Definition of Terms
1. IOTA Simple Rules - a preoperative classification
system for ovarian tumors, consisting of five features
typical for benign tumors (B-features) and five features
typical for malignant tumors (M- features)
2. IOTA Benign – an ovarian mass with one or more
benign or B - features present without malignant or M -
features
3. IOTA Malignant – an ovarian mass with one or
more malignant or M – features without benign or B -
features
4. IOTA Inconclusive – an ovarian mass with either
the presence of both B and M – features or none at all
5. Two by two table showing the accuracy of IOTA
Simple Rules with Biopsy as reference standard
 carcinoma continues to be a difficult challenge. Since the
Pathologic Diagnosis (Biopsy)
IOTA Simple Rules advent of ultrasound evaluation of the female pelvis, the
Malignant Disease Benign Disease characteristics of the normal and abnormal ovary has
been extensively studied and has improved visualization
Malignant
A B of ovarian function and ovarian tumors. An important
True Positive False Positive goal of ovarian ultrasound evaluation is to determine
C
D the differences between normal physiologic findings,
Benign False Negative inflammatory changes, benign neoplastic processes and
True Negative
ovarian cancer.4 Different scoring systems have been
proposed to standardize ovarian tumor characteristics.
6. Sensitivity – refers to the ability of the test The principal IOTA investigators set out to study
(IOTA Malignant) to correctly identify the true positive a large cohort of patients with a persistent adnexal
(malignancy on histopathology) mass in different clinical centers, using a standardized
Sensitivity = A x 100 ultrasound protocol. The primary aim of the study was
A+C to develop rules and models to characterize ovarian
7. Specificity – refers to the ability of the test (IOTA pathology and subsequently to demonstrate their
Benign) to correctly identify the true negative (Benign on utility by both temporal and external validation in the
histopathology) hands of examiners with different levels of ultrasound
Specificity = D x 100 expertise.5
B+D Several studies done by different investigators
8. Positive Predictive Value – refers to the probability sought to validate the IOTA Simple Rules by calculating
of the presence of disease (malignancy) among those who sensitivity, specificity, positive and negative predictive
had a positive screening test (IOTA Malignant) values. The IOTA simple rules yielded good diagnostic
Positive Predictive Value = A x 100 performance in different institutions including oncology
A+B centers with a high sensitivity of 89%, specificity of 84.7%,
9. Negative Predictive Value – refers to the positive predictive value of 75.4% and negative predictive
probability of the absence of disease (Malignancy) among value of 93.9% as presented by Timmerman et al.5
those who had a negative screening test (IOTA Benign) Likewise, many authors agree that the IOTA simple
Negative Predictive Value = D x 100 rules showed a high - quality reproducibility among non -
C+D expert examiners including residents, fellows and trainee
10. Accuracy – refers to the correctness of the IOTA sonologists. Meta – analysis by Nunes (2014) highlighted
Simple Rules to detect malignant ovarian tumors when IOTA simple rules as an accurate test for discriminating
compared to its histopathologic findings between benign and malignant adnexal lesions in the
Accuracy = A+D x 100 hands of a less experienced reader, applicable in 80% of
A+B+C+D women.14 In the Philippines, Declarador and Pangilinan
(2016) assessed the reliability of these simple rules
Ethical Considerations analyzed by an ultrasound trainee and reported a 100%
accuracy rate in 93% of cases.8
Prior to the conduct of the study, an approval In this institution, though all sonologists are expert
from the Institutional Review Board of the institution was readers, the IOTA Simple Rules is relatively a novel
obtained. The permission to use the data of the patients method to describe ovarian features. This study intends
for the purpose of this research was granted by the Office to validate the predictive accuracy of the IOTA Simple
of the Medical Director. Confidentiality of the patient’s Rules as compared to the histopathologic diagnosis of the
data was observed during the data collection and in the ovarian mass.
writing of the manuscript. In a recently published systematic review and
meta – analysis by Kaijser et al, all tumors designated as
REVIEW OF RELATED LITERATURE inconclusive by the IOTA simple rules were classified in the
malignant group and results of validation studies produced
Ovarian cancer is the second most common the same level of sensitivity but a lower specificity.13 With
malignancy of the lower part of the female genital tract. this in mind, the malignant tumors read as inconclusive is
A major contributing factor to the high death rate from of special interest to the researcher. Thus, this study seeks
the disease stems from its frequent detection after to determine the specific sonographic characteristics of
metastatic spread.1 Thus, early detection of ovarian the malignant tumors classified as IOTA inconclusive.

Volume 41, Number 5, PJOG September-October 2017 3

RESEARCH METHODOLOGY
Study Design: Cross-sectional Diagnostic Accuracy Test
Study Setting: Department of Obstetrics and Gynecology
in a tertiary hospital from August 2015 to February 2017
Study Population: All patients who will fulfill the inclusion
and exclusion criteria will be consecutively evaluated in
the study.
C1. Inclusion Criteria:
1. Transvaginal ultrasound with adnexal or ovarian
mass with an IOTA Simple Rule classification
2. Availability of the histopathologic report
C2. Exclusion Criteria:
1. Surgery beyond 120 days after ultrasound
examination
2. Incomplete records
3. Known diagnosis of adnexal masses such as
ovarian cancers scheduled for second look operation,
or endometrioma diagnosed by previous laparoscopy
C3. Sample Size Calculation:
Sample size calculated was 101, given 95% confidence
level, precision of 0.05 and an assumed proportion of
93% based on a study by Nunes et al.14
Data Collection
After obtaining both the approval from the
Institutional Review Board and the permission from
the Office of the Medical Director, the census of the
Department of Obstetrics and Gynecology were reviewed
as to the patients admitted with ultrasound findings
of ovarian or adnexal mass who underwent surgical
procedure from August 2015 to February 2017. The
surgical treatments include cystectomy and oophorectomy
either by open laparotomy or laparoscopy, and debulking
surgery done within 120 days from the time of ultrasound
examination. The transvaginal or transrectal ultrasound
of the subjects were from the Women’s Health Unit
with complete evaluation of the ovarian or adnexal mass
including the sonographic morphology and color Doppler
study using the advanced ultrasound machines GE Logiq
S6 and Samsung Medison WS80A. The characteristics of
the masses were analyzed according to IOTA simple rules
done by the three IOTA certified obstetric sonologists.
The histopathologic report from the Department of
Pathology were reviewed after the scheduled operation.
The following data were extracted: IOTA classification and
the specific sonographic description of the ovarian mass,
and the final histopathologic report.
Data Analysis
All the adnexal masses were tallied and categorized
into three groups as benign, malignant and inconclusive.
The masses with pathological diagnosis of borderline
4 Volume 41, Number 5, September-October 2017
or low malignant potential tumors were included in the
malignant group. The sensitivity, specificity and predictive
values of the IOTA simple rules in predicting malignancy
were calculated. The adnexal masses categorized under
IOTA Inconclusive were also tallied and followed up on
histopathology whether they were benign or malignant
and reviewed as to which specific characteristic made it
unclassifiable. Descriptive statistics such as proportion
was used to summarize the data.
RESULTS
A total of 110 women with adnexal mass were
included in the study. The IOTA Simple Rules was used
to classify the 110 adnexal masses as benign, malignant
and inconclusive. It was applicable in 84.55% of cases as it
specifically characterized the benign tumors according to
the B – features as well as the malignant tumors according
to the M - features. A summary of the IOTA classification
and corresponding final diagnoses of the cases is shown
in Tables 1 and 2 and findings confirmed all 79 benign
tumors as truly benign and all 14 malignant tumors as
truly malignant by histopathology.
Table 3 shows the IOTA inconclusive tumors and
their final diagnoses by biopsy. Among the 17 tumors that
could not be classified using the IOTA simple rules, 2 cases
proved to be malignant and 15 cases emerged as benign.
Comparison of the results of the IOTA simple rules
and histopathologic findings for the benign and malignant
adnexal masses showed no significant difference as shown
in Table 4. In the 93 masses for which the IOTA simple
rules could be applied, sensitivity was 100%, specificity
100%, positive predictive value 100%, and negative
predictive value 100%. The accuracy of IOTA simple rules
in discriminating adnexal masses as benign or malignant
was 100%.
Among the seventeen inconclusive tumors, no B-rule
or M-rule could be applied in 16 (94.12%) lesions such as in
cases of smooth multiloculated cyst measuring >100 mm,
huge solid mass with no color flow, tumors with minimal
or moderate color flow, and tumors with less than four
papillary like densities or with irregular solid structures
<7 mm. And the remaining 1 (5.88%) case, the lesion
exhibited 2 B-rules and 1 M-rule being a unilocular cyst
measuring <100 mm with absent color flow containing
irregular hyperechoic solid looking components in the cyst
wall.
The sonographic characteristics of the two malignant
tumors classified as IOTA inconclusive are itemized in
Table 6. Both tumors manifested similar features namely
irregular and thick walled, less than 100 mm in size, no solid
densities and no color flow present. However, one tumor
was unilocular and contained medium level echoes with
one papillarity while the other tumor was multilocular,
and complex in appearance.
DISCUSSION
Accurate characterization before surgery of an
ovarian pathology is essential for adequate clinical
decision – making. To date, ultrasound examination has
been largely used to predict ovarian malignancy. Hence,
the advent of the IOTA simple rules in 2008 paved a
simpler way of characterizing benign or malignant adnexal
masses that is equally useful for sonologists both experts
and novices alike. When tested prospectively by the IOTA
group, the simple rules provided conclusive results in 76%
of adnexal masses, with a sensitivity and specificity of 95%
and 91%, respectively. Similarly, Hartman et al in 2012
also reported that the IOTA simple rules was applicable in
82.7% of adnexal tumors resulting in a sensitivity of 90%,
specificity of 87%, positive predictive value of 69% and
negative predictive value of 97%.18

Table 1. Distribution of IOTA Benign Tumors According to Final Histopathological Diagnoses

IOTA
Final Diagnoses Frequency Percentage (%)
Classification
Benign Benign Serous Ovarian Cyst 3 3.8
Tumors Cystic Struma Ovarii 1 1.27
Endometriotic Cyst 12 15.19
Hemorrhagic Corpus Luteum 1 1.27
Hemorrhagic Cystic Follicle 1 1.27
Hemorrhagic Fibrocollagenous Cyst 1 1.27
Hemorrhagic Paratubal Cyst, Paratubal Cyst 6 7.59
Mature Cystic Teratoma 17 21.52
Mucinous Cystadenoma 19 24.05
Multiple Cystic Follicles 1 1.27
Ovarian Inclusion Cyst 1 1.27
Serous Cystadenofibroma 1 1.27
Serous Cystadenoma 14 17.72
Serous Papillary Cystadenoma 1 1.27
Total 79 100

Table 2. Distribution of IOTA Malignant Tumors According to Final Histopathological Diagnoses

IOTA
Final Diagnoses Frequency Percentage (%)
Classification
Malignant Adult Granulosa Cell Tumor 2 14.29
Tumors Clear Cell Carcinoma 2 14.29
Endometrioid Adenocarcinoma 1 7.14
Follicular Carcinoma 1 7.14
Serous Borderline Tumor with Intraepithelial Carcinoma and 1 7.14
Microinvasion
Low Grade Papillary Serous Cystadenocarcinoma 1 7.14
Serous Papillary Adenocarcinoma 1 7.14
Poorly Differentiated Serous Papillary Adenocarcinoma 1 7.14
Mucinous Borderline Tumor 3 21.43
Mucinous Cystadenocarcinoma 1 7.14
Total 14 100

Volume 41, Number 5, PJOG September-October 2017 5

Table 3. Distribution of IOTA Inconclusive Tumors According to Final Histopathological Diagnoses
IOTA
Final Diagnoses Frequency Percentage (%)
Classification
Inconclusive Adult Granulosa Cell Tumor 1 5.88
Tumors Borderline Serous Tumor 1 5.88
Endometriotic Cyst 3 17.65
Fibrothecoma 1 5.88
Mature Cystic Teratoma 1 5.88
Mucinous Cystadenoma 7 41.18
Serous Cystadenoma 1 5.88
Simple Cyst 1 5.88
Ovarian Cyst with Torsion 1 5.88
Total 17 100

Table 4. Diagnostic Indices of IOTA Simple Rules in Predicting Table 5. Distribution of IOTA Inconclusive Tumors and their
Malignant Adnexal Masses features According to Final Histopathologic Diagnoses

Histopathologic Diagnosis Histopathology

IOTA Simple IOTA
Rules Malignant Inconclusive
Benign Disease Total Benign Malignant Total
Disease

Malignant A B 14 Neither B or M Features* 14 2 16

True Positive False Positive With B or M Features 1 0 1
Total 15 2 17
Benign C D 79
* Based on IOTA
False Negative True Negative

Total 14 79
Sensitivity
Specificity
Positive Predictive Value
Negative Predictive Value
Accuracy
In this study, the application of IOTA simple rules
yielded comparable results as it was able to classify
84.55% of cases as benign and malignant. Consequently,
the sensitivity and specificity of the IOTA simple rules
were both 100% which confirmed its ability to precisely
identify the truly benign and truly malignant tumors. In
the same manner, the positive and negative predictive
values increased to 100% which indicate the presence
of ovarian malignancy among the IOTA malignant and its
absence among the IOTA benign tumors, with an overall
accuracy rate of 100%. This finding is rather expected
since sonologists in the study were all IOTA certified and
expert readers.
Despite having obtained a high diagnostic
performance, the application of IOTA Simple Rules by the
original IOTA group had a relatively high rate of inconclusive
results of 20%. In contrast, this study produced a lower
93
rate of inconclusive readings at 15.45%. It can be inferred
= 100% that this study utilized ultrasound machines equipped
= 100% with faster frame rates and powerful data processing
= 100% to provide clearer images and more stable signals, thus
= 100% helping to improve diagnostic accuracy.
= 100%
While some studies assumed these nonclassifiable
tumors to be malignant, others opted not to include them
for data analysis and instead, referred them to expert
readers for pattern recognition. Hartman et al found that
germ cell tumors and serous and mucinous borderline
tumors were the more difficult types to classify.19
Considering that the sonologists in this institution were all
IOTA certified readers, this research focused and analyzed
further the seventeen IOTA inconclusive tumors. Upon
follow - up of their respective histopathologic results,
two turned out to be malignant. Both tumors were 70-80
mm in size and had thick and irregular cyst walls. Striking
differences were noted between malignant neoplasms,
the presence of only one papillarity in the borderline
serous tumor and the complex appearance of the adult
granulosa cell tumor.
Pattern recognition among expert sonologists
is considered superior in large multicenter studies in
establishing a confident diagnosis of common ovarian

6 Volume 41, Number 5, September-October 2017

Table 6. Distribution of Malignant Tumors Classified as IOTA Inconclusive According to Sonographic Characteristics

IOTA Inconclusive Malignant Tumor

Sonographic characteristics
N (%) N (%)

Cyst wall Smooth 8 47.1 0 0

Irregular 9 52.9 2 100

Cyst wall thickness Thin walled 5 29.4 0 0

Thick walled 12 70.6 2 100

Locularity Unilocular 5 29.4 1 50

Multilocular 12 70.6 1 50

Internal contents Anechoic 3 17.6 0 0

Low level 7 41.2 0 0
Medium level 1 5.9 1 50
High level 1 5.9 0 0
Mixed 2 11.8 0 0
Complex 1 5.9 1 50
Solid 2 11.8 0 0

Presence of Solid Density None 9 52.9 2 100

1 4 23.5 0 0
2 1 5.9 0 0
3 1 5.9 0 0
4 1 5.9 0 0
5 or more 1 5.9 0 0

Presence of Papillarity None 14 82.4 1 50

1 3 17.6 1 50
2 0 0 0 0
3 0 0 0 0
4 or more 0 0 0 0

Size <100 mm 10 58.8 2 100

>100 mm 7 41.2 0 0

Color flow No color 9 52.9 2 100

Minimal 7 41.2 0 0
Moderate 1 5.9 0 0
Marked 0 0 0 0

masses. Findings of a large size greater than 70 mm,
presence of septations and nodularities, papillary
projections or frank solid masses, and lesions with
irregular and thick walls greater than 3 mm, all increase
the likelihood of a neoplastic nature. Moreover, the color
content of the tumor reflects both the number and size of
tumor vessels and malignancies often exhibit increased
flow signals. In pattern recognition, papillarity is a
characteristic of borderline tumors and stage I primary
invasive epithelial ovarian cancers. Also, the “complex”
appearance of an ovarian mass is a sonographic
description prevalent among germ cell tumors because
it contain various type of tissues. The above definitions
are evident in this study. Even though only one case
was noted per sonographic characteristic, the presence
of one papillarity may clinically signify an early stage of
the disease such as in a low malignant potential tumor.
Similarly, the complex appearance of the tumor may
warn the clinician of a probable germ cell malignancy.
CONCLUSION
The International Ovarian Tumor Analysis (IOTA)
Simple Rules is an accurate diagnostic tool in predicting
ovarian malignancy before surgery. In this institution,
it has a sensitivity, specificity, positive and negative
Volume 41, Number 5, PJOG September-October 2017 7
predictive values of 100%, resulting in an overall accuracy
of 100%. Along with its excellent diagnostic performance,
a lesser number of inconclusive tumors were identified
in this study at 15.45%, with two tumors diagnosed to be
truly malignant. Their specific sonographic characteristics
showed irregular and thick cyst walls with presence of
only one papillarity in a low malignant potential tumor
and the description of complex appearance in a germ cell
tumor even with the absence of color flow. These two
findings when present in any ovarian pathology warrants
a high suspicion of malignancy.
LIMITATION
All the transvaginal ultrasound readings and IOTA
classification of ovarian masses were done by IOTA
certified and expert sonologists in this institution. During
the data analysis, only the IOTA classification of the
ovarian mass and the final histopathologic diagnoses were
included irregardless of patient related characteristics and
presence of symptoms.
REFERENCES
1. Lobo RA, Gershenson DM, Lentz GM, Valea FL. Neoplastic
Diseases of the Ovary. Coleman RL, Ramirez PT, Gershenson
DM. Comprehensive Gynecology, 7th ed, Philadelphia: Elsevier.,
2017.
2. Yeoh M. Investigation and Management of an Ovarian Mass. The
Royal Australian College of General Practitioners. 2015 Jan-Feb;
44 (1):48-52.
3. Kaloo PD, Louden KA, Khazali S, Hoy D, Sadoon S. Management
of Suspected Ovarian Masses in Premenopausal Women. RCOG/
BSGE Joint Green-top Guideline No.62 2011 Nov.
4. Kaijser J, Bourne T, Valentin L, et al. Improving Strategies for
Diagnosing Ovarian Cancer: A Summary of the International
Ovarian Tumor Analysis (IOTA) studies. Ultrasound Obstet Gynecol.
2013 Jan; 41(1):9-20.
5. Timmerman D, Van Calster B, Testa A, et al. Predicting the Risk of
Malignancy in Adnexal Masses based on the Simple Rules from the
International Ovarian Tumor Analysis group. Am J Obstet Gynecol.
2016 Apr; 214(4):424-37.
6. Alcázar JL, Pascual MÁ, Olartecoechea B, et al. IOTA Simple Rules
for Discriminating between Benign and Malignant Adnexal Masses:
Prospective External Validation. Ultrasound Obstet Gynecol. 2013
Oct; 42(4):467-71.
7. Alcazar J, Sanchez-Go ́mez P, Pineda L, Juez L, Utrilla-Layna J.
Offline Reproducibility Assessment of IOTA Simple Rules by OB/
GYN Trainees. Ultrasound Obstet Gynecol. 2013; 42(1):113-179.
8 Volume 41, Number 5, September-October 2017
RECOMMENDATION
Further prospective studies using the IOTA Simple
Rules in classifiying ovarian masses with the analysis
done by an ultrasound rotator resident physician in the
local setting with a larger population is recommended.
This is to test its applicability with a less experienced
examiner. This research also serves as a benchmark for
future studies to investigate on the specific sonographic
characteristics of the IOTA inconclusive tumors as well as
establish the probability of malignancy when cyst walls
are irregular and thick, presence of only one papillarity
or when the ovarian mass is described to be complex
in appearance. This is to create an improved scoring
system based on the results of patterns identified among
inconclusive tumors.
8. Declarador CV, Pangilinan NP. Validation of the IOTA Simple Rules
for Discriminating between Benign and Malignant Adnexal Masses
as performed by a Trainee Sonologist. Ultrasound in Obstet
Gynecol. 2016 Sept; 48(1):204.
9. Rama P, Llanos L, Ferrer S, Zambrano A, Mendoza M, Díaz N.
Simple descriptors and simple rules of the International Ovarian
Tumor Analysis (IOTA) Group: A Prospective Study of Combined
Use for the Description of Adnexal Masses. Eur J Obstet Gynecol
Reprod Biol. 2015 Dec; 195:7-11.
10. Tinnangwattana D, Vichak-Ururote L, Tontivuthikul P, Charoenratana
C, Lerthiranwong T, Tongsong T. IOTA Simple Rules in Differentiating
between Benign and Malignant Adnexal Masses by Non-expert
Examiners. Asian Pac J Cancer Prev. 2015; 16(9): 3835-3838.
11. Timmerman D, Valentin L, Bourne TH, Collins PW, Verrelst H,
Vergote I. Terms, Definitions and Measurements to Describe the
Sonographic Features of Adnexal Tumors: A Consensus Opinion
from the International Ovarian Tumor Analysis (IOTA) group.
Ultrasound Obstet Gynecol. 2000; 16:500-505.
12. Valentin L. Gray Scale Sonography, Subjective Evaluation of the
Color Doppler Image and Measurement of Blood Flow Velocity for
Distinguishing Benign and Malignant Tumors of Suspected Adnexal
Origin. Eur J Obstet Gynecol Reprod Biol. 1997; 72:63-7211.
13. Kaijser J, Sayasneh A, Van Hoorde K, et al. Presurgical Diagnosis of
Adnexal Tumors using Mathematical models and Scoring systems:
A Systematic Review and Meta-analysis. Hum Reprod Update.
2014; 20(3):449-462.
14. Nunes N, Ambler G, Foo X, Naftalin J, Widschwendter M, Jurkovic
D. Use of IOTA simple rules for Diagnosis of Ovarian Cancer: Meta-
analysis. Ultrasound Obstet Gynecol. 2014 Nov; 44(5):503-514.
15. Timmerman D, Testa A, Bourne T, et al. Simple ultrasound-based
rules for the diagnosis of ovarian cancer. Ultrasound Obstet
Gynecol. 2008; 31:681-690.
16. Di Legge A, Testa A, Ameye L, et al. Lesion size affects diagnostic
performance of IOTA logistic regression models, IOTA simple rules
and risk of malignancy index in discriminating between benign
and malignant adnexal masses. Ultrasound Obstet Gynecol. 2012;
40:345-354.
17. Kaijser J, Bourne T, Valentin L, et al. Improving strategies for
diagnosing ovarian cancer: a summary of the International Ovarian
Tumor Analysis (IOTA) studies. Ultrasound Obstet Gynecol. 2013;
41:9-20.
18. Ameye L, Timmerman D, Valentin L, et al. Clinically oriented three-
step strategy for assessment of adnexal pathology. Ultrasound
Obstet Gynecol. 2012; 40:582-591.
19. Hartman C, Juliato C, Sarian L, et al. Ultrasound criteria and CA 125
as predictive variables of ovarian cancer in women with adnexal
tumors. Ultrasound Obstet Gynecol. 2012; 40:360-366.
20. Alcazar J, Pascual M, Olartecoechea B, et al. IOTA simple rules for
discriminating between benign and malignant adnexal masses:
Prospective external validation. Ultrasound Obstet Gynecol. 2013;
42:467-471.
21. Tantipalakorn C, Wanapirak C, Khunamornpong S, Sukpan K,
Tongsong T. IOTA Simple Rules in Differentiating between Benign
and Malignant Ovarian Tumors. Asian Pac J Cancer Prev. 2014; 15
(13):5123-512.
Volume 41, Number 5, PJOG September-October 2017 9
 CASE REPORTS
Philippine Journal Of Otolaryngology-Head And Neck Surgery
Diane Clarice D. Magbuhat, MD
Jeannette Marie S. Matsuo, MD
Rhodieleen Anne R. de la Cruz, MD
Department of Otorhinolaryngology
University of the Philippines- Philippine General Hospital
Correspondence: Dr. Jeannette Marie S. Matsuo
Department of Otorhinolaryngology
Ward 10, Philippine General Hospital
University of the Philippines Manila
Taft Avenue, Ermita, Manila 1000
Philippines
Phone: (632) 554 8400 local 2152
Email: orl.up.pgh@gmail.com
The authors declared that this represents original material
that is not being considered for publication or has not been
published or accepted for publication elsewhere, in full or in
part, in print or electronic media; that the manuscript has been
read and approved by all the authors, that the requirements
for authorship have been met by each author, and that each
author believes that the manuscript represents honest work.
Disclosures: The authors signed disclosures that there are no
financial or other (including personal) relationships, intellectual
passion, political or religious beliefs, and institutional affiliations
that might lead to a conflict of interest.
Presented at the Philippine Society of Otolaryngology Head
and Neck Surgery Interesting Case Contest (2nd Place). April 8,
2017. Plaza del Norte Hotel & Convention Center, Ilocos Norte.
Creative Commons (CC BY-NC-ND 4.0)
Attribution - NonCommercial - NoDerivatives 4.0 International
38 Philippine Journal Of Otolaryngology-Head And Neck Surgery
Vol. 32 No. 2 July– December 2017
Basal Cell Carcinoma, Odontogenic Cysts,
Brain and Skeletal Abnormalities (Gorlin Goltz
Syndrome) in a 46-Year-Old Woman
ABSTRACT
Objective: To present the case of a 46-year-old woman with basal cell carcinoma, odontogenic
cysts, brain anomalies and skeletal abnormalities.
Methods:
Design: Case Report
Setting: Tertiary National University Hospital
Patient: One
Results: A 46-year-old woman consulted for a non-healing, necrotic left orbital ulcer that started
as a skin-colored, papilla-like lesion on the upper eyelid. There were also hyperpigmented lesions
with ill-defined borders over both paranasal areas. Tissue biopsies revealed basal cell carcinoma.
Radiologic imaging showed cystic lesions in the mandible, straightening of cervical vertebrae
and calcifications of the falx cerebri, tentorium cerebelli, pineal gland and choroid plexus. Based
on established major and minor clinical and radiologic criteria, we arrived at a diagnosis of Gorlin
Goltz Syndrome or Nevoid Basal Cell Carcinoma Syndrome (NBCCS). She underwent wide excision
of the left orbital mass with exenteration, excision of left and right paranasal masses, left total
parotidectomy with facial nerve preservation, enucleation of mandibular cyst and cervicofacial
reconstruction with skin grafts of the left orbital area and ala.
Conclusions: NBCCS is a rare autosomal dominant disorder with a high tendency for neoplasms
and developmental anomalies. Diagnosis can easily be missed if the physician is unaware of its
classic but bizarre presentation. Early recognition and prompt specialist referral is very important
in order to prevent complications and provide better prognosis. Patients should be reminded of
the importance of follow-up as other presentations of the syndrome may manifest later in life
and family genetic screening and counseling should be undertaken.
Keywords: Gorlin Goltz Syndrome; Nevoid Basal Cell Carcinoma Syndrome; odontogenic keratocyst
Physicians are all too familiar with compartmentalization of knowledge – even Ear Nose
Throat (ENT) Surgeons divide the head and neck into subspecialties. Beyond our realm the patient
is likewise deconstructed-- bent spines are a job for orthopedic spine surgeons, eye problems
must be seen by ophthalmologists and brain problems are left to neuroscientists. This effective
“divide and conquer” strategy allows for more rapid advancement in each of our fields. But it can
also make us lose sight of the larger picture and cause us to miss a rare, more complex entity. We
present one such case.
Philipp J Otolaryngol Head Neck Surg 2017; 32 (2): 38-42 c Philippine Society of Otolaryngology – Head and Neck Surgery, Inc.
 CASE REPORTS
Philippine Journal Of Otolaryngology-Head And Neck Surgery Vol. 32 No. 2 July– December 2017

CASE REPORT Incision biopsies of the orbital and paranasal lesions revealed Basal
A 46-year-old woman from Zamboanga del Norte, Philippines Cell Carcinoma. Contrast-enhanced cranial, facial and orbital CT Scans
consulted with a chief complaint of a non-healing, necrotic ulcer over revealed an enhancing soft tissue density in the superior and lateral
the left orbital region. Her condition started 10 years prior when a skin- left intraorbital region measuring approximately 2.9 x 1.9 x 1.2 cm,
colored, non-pruritic, non-painful papilla-like lesion appeared on her with extensive ulceration involving the left eyelids and surrounding
left upper eyelid. She manually removed the lesion and since noted that soft tissues. (Figure 2) There were dense coarse calcifications in the
the wound had not healed and had changed its appearance, becoming falx cerebri and tentorium cerebelli (Figure 3) as well as at the pineal
hyperpigmented with raised borders and beginning ulcer formation. It gland and choroid plexus. The cortical sulci and lateral fissures were
continuously enlarged, occupying the left periorbital area, with areas of prominent with dilatation of the third and fourth ventricles. There were
necrosis, occasional bleeding and yellowish discharge. expansile lytic lesions involving the right hemimandible measuring 6.6
Two years prior to consult, she developed anorexia, easy x 1.6 x 3.0 cm and symphyseal area measuring 2.5 x 2 x 1 cm. (Figure
fatigability and weight loss. She also noted progressive blurring of 4) There were lymphadenopathies in the left parotid region. A skeletal
vision. Consequently, two hyperpigmented papules appeared over survey revealed straightened cervical vertebra with spurs and sclerosis
her paranasal area. She consulted at a local hospital where she was on endplates and decreased intervertebral space between C4 and C5. A
advised surgery. However, due to financial constraints, she eventually small cystic lesion was seen in the left distal radius. (Figure 5)
transferred to our institution for further workup and management.
A housewife with seven children, she never smoked or drank alcohol.
She had no family history of cancer or chronic sun exposure.
She presented with a 9 x 7 x 3 cm non-tender, non-pruritic ulcer with
raised, rolled up border areas of necrosis and crusting occupying the
left orbital region. (Figure 1) There were also hyperpigmented, raised
lesions with ill-defined borders at the left nasolabial fold and right
paranasal area measuring 1 x 1 x 0.5 cm. A 1.5 x 1.5 x 0.5 cm firm non-
tender, non-erythematous, movable mass was palpated at the left pre-
auricular area. The left upper and lower eyelids were absent and the left
globe was deformed but still with light perception. The right eye was
grossly normal with 20/20 vision. The rest of the ear, nose, throat, head
and neck exam was normal.
A

B
Figure 2. Contrast-enhanced cranial CT scans (April 2016) A. coronal
Figure 1. Mass with necrotic areas occupying the left periorbital region and and B. axial views showing an enhancing soft tissue density involving
smaller hyperpigmented lesions involving both paranasal areas. the left intraorbital region (arrows).

Philippine Journal Of Otolaryngology-Head And Neck Surgery 39

 CASE REPORTS
Philippine Journal Of Otolaryngology-Head And Neck Surgery Vol. 32 No. 2 July– December 2017

Our search for a multisystemic syndrome with Basal Cell Carcinoma,

odontogenic cysts, brain abnormalities and skeletal anomalies led us to
diagnose Gorlin Goltz Syndrome.
Our patient underwent wide excision of the left orbital mass with
exenteration, excision of both paranasal masses and the alar mass,
left total parotidectomy with facial nerve preservation, enucleation
of mandibular cyst, and cervicofacial reconstruction with left orbital
split thickness skin graft and left ala full thickness skin graft. (Figure
6) She was discharged after one week but poor graft take was noted
two weeks after surgery and application of Silver Sulfadiazine cream
was initiated to hasten granulation. (Figure 7A) Three weeks after
surgery, she followed up at our clinic and granulation tissue formation
was already noted on the defect. (Figure 7B) She has been unable to
physically follow-up since as she lives in a remote village on a distant A
island.

B
Figure 3. Contrast-enhanced cranial CT scans (April 2016), A. axial and
B. sagittal views, showing calcification of falx cerebi and tentorium
cerebelli (arrows).
C
Figure 4. Contrast-enhanced CT scans (April 2016), A. B. axial and C.
coronal bone window views showing an expansile lytic lesion involving
the right hemimandible and symphysis (arrows).

40 Philippine Journal Of Otolaryngology-Head And Neck Surgery


Philippine Journal Of Otolaryngology-Head And Neck Surgery
Figure 5. X-Ray of the left forearm (April 2016) showing a small cystic
lesion at the left distal radius (arrow).
B W. Goltz established the classical triad of odontogenic cyst, basal cell
Figure 6. Intraoperative A. after orbital exenteration and total
parotidectomy with facial nerve preservation B. cervicofacial flap and
STSG.
Philippine Journal Of Otolaryngology-Head And Neck Surgery 41
CASE REPORTS
Vol. 32 No. 2 July– December 2017
B
Figure 7. Post-operative A. poor graft take over the orbital region
2 weeks after surgery B. granulation tissue forming on the surgical
wound 3 weeks post surgery.
DISCUSSION
Gorlin Goltz Syndrome, also known as Nevoid Basal Cell Carcinoma
Syndrome (NBCCS), is a rare autosomal dominant disorder with a high
degree of penetrance and phenotype expressiveness.1 It may present
with cutaneous, dental, craniofacial, skeletal, cardiac, ophthalmologic,
neurological and sexual anomalies.2,3 This condition is also called Gorlin
Syndrome, Multiple Nevoid Basal Cell Epithelioma, Jaw Cyst Bifid Rib
Syndrome or Multiple Nevoid BCC Syndrome.4
In 1894, Jarish and White first reported cases of this syndrome
highlighting the multiple basocellular carcinomas present in patients.5,6
However, it was not until the 1960s that Robert J. Gorlin and Robert
carcinoma and bifid rib.6 This triad was later modified by Rayner et al.
who added findings of calcification of falx cerebri or palmar and plantar
 CASE REPORTS
Philippine Journal Of Otolaryngology-Head And Neck Surgery
pits as parts of the criteria in the diagnosis of this syndrome.7
The usual age of presentation of NBCCS is 10-30 years old with
females being more affected than males.8 Its prevalence is quite
variable. A study in England showed a prevalence of 1 out of 55,600.9 In
Italy, it is 1 out of 256,000; in Australia, 1 out of 164,000; while in Japan,
the prevalence is 1 out of 235,800.9 In the Philippines, an incidence
rate has not been established but there was one case report on NBCCS
published in a dermatology journal in 2009.10
The pathogenesis of NBCCS is attributed to mutations in the patched
tumor suppressor gene (PTCH) on chromosome 9q21-23 where an
abnormality in the Hedgehog signaling pathway results in neoplasm
formation.11 However, mutations in other genes such as Patched 2 (PTCH
2), Smoothened (SMO) and Sonic hedgehog (SHH) have been noted in
some isolated cases.11
The diagnostic criteria for NBCCS have undergone several changes
over the past years-- initially established by Evans et al.,12 modified by
Kimmons et al.,13 reviewed by Manfredi et al.2 and recently reviewed
again at the first international conference on Basal Cell Nevus Syndrome
in 2011.14 From this meeting, the official list of major and minor criteria
for diagnosis of NBCCS was established. Major criteria include Basal
Cell Carcinoma prior to 20 years old or excessive number of BCC out
of proportion to prior sun exposure and skin type, odontogenic
keratocyst of jaw prior to 20 years old, palmar and plantar pitting,
REFERENCES
1. Jawa DS, Sircar K, Somani R, Grover N, Jaidka S, Singh S. Gorlin Goltz syndrome. J Oral Maxillofac
Pathol.  2009 Jul;13(2):89–92. DOI: 10.4103/0973-029X.57677; Pubmed PMID: 21887009;
PubMed Central PMCID: PMC3162868.
2. Manfredi M, Vescovi P, Bonanini M, Porter S. Nevoid basal cell carcinoma syndrome: a review of
the literature. Int J Oral Maxillofac Surg. 2004 Mar; 33(2):117–24. DOI: 10.1054/ijom.2003.0435;
PubMed PMID: 15050066.
3. Gorlin RJ, Goltz RW. Multiple nevoid basal-cell epithelioma, jaw cyst and bifid rib: A syndrome.
N Engl J Med. 1960 May 5; 262:908-12. DOI: 10.1056/NEJM196005052621803; PubMed PMID:
13851319.
4. Lo ML. Orphanet Encyclopedia. 2002. pp. 166–69. [retrieved 2016 Feb 13]. Available from
http://www.orpha.net/data/patho/GB/uk-gorlin.pdf
5. Jarisch W. On Doctrine of skin tumors. Archiv of Dermatology and Syphilis. 1894; 28:163–222.
6. White JC. Multiple benign cystic ephiteliomata. J Cutan Dis. 1894; 12:477–81.
7. Rayner CR, Towers JF, Wilson JS. What is Gorlin’s syndrome? The diagnosis and management of
the basal cell naevus syndrome, based on a study of thirty-seven patients. Br J Plast Surg. 1977
Jan; 30(1):62–7. PubMed PMID: 836983.
8. Woolgar JA, Rippen JW, Browne RM. The odontogenic keratocyst and its occurrence in the
nevoid basal cell carcinoma syndrome. Oral Surg Oral Med Oral Pathol. 1987 Dec; 64(6):727–30.
42 Philippine Journal Of Otolaryngology-Head And Neck Surgery
Vol. 32 No. 2 July– December 2017
lamellar calcification of the falx cerebri, medulloblastoma, typically
desmoplastic and first degree relative with NBCCS. Minor criteria are
as follows: rib anomalies, macrocephaly, skeletal malformation and
radiologic changes (i.e., vertebral anomalies, kyphoscoliosis, short
fourth metacarpals, cleft lip/palate, ovarian or cardiac fibroma and
ocular abnormalities (strabismus, hypertelorism, congenital cataract,
glaucoma, coloboma).14 The presence of one major criterion and a
molecular confirmation or two major criteria or one major and two
minor criteria is necessary for the diagnosis.14 Our patient satisfied
3 Major Criteria (basal cell carcinoma, odontogenic keratocyst and
calcified falx cerebri) and 1 Minor Criterion (skeletal malformations).
As demonstrated by our case, the management of NBCCS requires
specific treatment for each clinical condition and should involve a
multidisciplinary team. Because of its aggressiveness and high rate of
recurrence, it is advisable that the patient follows up every 6 months
for the first 5 years and every year thereafter.12 This becomes a major
issue in low- and middle-income countries such as ours where people
in remote island villages have poor access to health care. Since this is
an autosomal dominant condition, family members should undergo
genetic screening and be monitored as well, and educated about the
disease- its presentation, course, prognosis and the importance of
prompt consult – again, an ideal that is easier said than done.
PubMed PMID: 3480489.
9. Thalakoti S, Geller T. Basal Cellevus Syndrome or Gorlin Syndrome. Handbook of Clinical
Neurology Vol 132 (3rd series) Neurocutaneous Syndromes. 2015; 119-127.
10. Nicolas ME, Gonzales-Carait PK. A case of Goltz Syndrome. Indian J Paediatr Dermatol.
2015;16(3);170-172.
11. Joshi PS, Deshmukh V, Golgire S. Gorlin Goltz syndrome. Dent Res J (Isfahan). 2012 Jan-Mar; 9(1):
100–106. DOI: 10.4103/1735-3327.92963; PubMed PMID: 22363371; PubMed Central PMCID:
PMC3283966.
12. Evans DG, Ladusans EJ, Rimmer S, Burnell LD, Thakker N, Farndon PA. Complications of the
naevoid basal cell carcinoma syndrome: results of a population based study. J Med Genet. 1993
Jun;30(6):460–4. Pubmed PMID: 8326488; PubMed PMCID: PMC1016416.
13. Kimonis VE, Goldstein AM, Pastakia B, Yang ML, Kase R, DiGiovanna JJ, et al. Clinical
manifestations in 105 persons with nevoid basal cell carcinoma syndrome. Am J Med Genet.
1997 Mar 31; 69(3):299–308. PubMed PMID: 9096761.
14. Bree AF, Shah MR. BCNS Colloquium Group. Consensus statement from the first international
colloquium on basal cell nevus syndrome (BCNS). Am J Med Genet A. 2011 Sep; 155A(9):2091-7.
DOI: 10.1002/ajmg.a.34128; PubMed PMID: 21834049.

Philippine Journal Of Otolaryngology-Head And Neck Surgery
Daniel Jose C. Mendoza, MD
Cristina S. Nieves, MD
Samantha S. Castañeda, MD
Department of Otorhinolaryngology
Head and Neck Surgery
Jose R. Reyes Memorial Medical Center
Correspondence: Dr. Cristina S. Nieves
Department of Otorhinolaryngology - Head and Neck Surgery
Jose R. Reyes Memorial Medical Center
San Lazaro Compound, Rizal Avenue
Sta. Cruz, Manila 1003
Philippines
Phone: (632) 743 6921; (632) 711 9491 local 320
Email: chienieves_md@yahoo.com
The authors declared that this represents original material
that is not being considered for publication or has not been
published or accepted for publication elsewhere, in full or
in part, in print or electronic media; that the manuscript has
been read and approved by the authors, that the requirements
for authorship have been met by each author, and that each
author believes that the manuscript represents honest work.
Disclosures: The authors signed disclosures that there are no
financial or other (including personal) relationships, intellectual
passion, political or religious beliefs, and institutional affiliations
that might lead to a conflict of interest.
Creative Commons (CC BY-NC-ND 4.0)
Attribution - NonCommercial - NoDerivatives 4.0 International
Philippine Journal Of Otolaryngology-Head And Neck Surgery 47
CASE REPORTS
Vol. 32 No. 2 July– December 2017
Late-onset Anterolateral Thigh Free Flap Failure
in Buccal Carcinoma Reconstruction
ABSTRACT
Objective: To report a case of late-onset anterolateral thigh free flap failure in reconstruction of a
defect from excision of buccal carcinoma.
Methods:
Design: Case Report
Setting: Tertiary Government Training Hospital
Patient: One
Results: A 57-year-old man with well-differentiated buccal squamous cell carcinoma underwent
wide excision with segmental mandibulectomy, bilateral neck dissection and anterolateral thigh
free flap reconstruction. Complete failure of the anterolateral thigh free flap was documented on
the 29th post-operative day.
Conclusion: Late-onset flap failure is mainly non-vascular in etiology. However, flap failure is more
likely multifactorial. Frequent follow-up after hospital discharge is recommended to monitor flap
viability.
 Keywords: free flap, anterolateral thigh flap, flap failure, microvascular surgery, head and neck
reconstruction
Free tissue transfer has become the gold standard in reconstruction of many head and neck
defects.1 Success rates are more than 90%.2-3 However, failures and complications still occur. Late-
onset flap failure is defined as failure occurring 7 days post-operatively or on follow-up visits after
hospital discharge.4
We present a case of a 57-year-old man with a complete, late-onset anterolateral thigh (ALT)
free flap failure in reconstructing the defect from excision of a buccal carcinoma.
Philipp J Otolaryngol Head Neck Surg 2017; 32 (2): 47-50 c Philippine Society of Otolaryngology – Head and Neck Surgery, Inc.
 CASE REPORTS
Philippine Journal Of Otolaryngology-Head And Neck Surgery Vol. 32 No. 2 July– December 2017

CASE REPORT
A 57-year-old man was seen at the outpatient department with an
enlarging left buccal mass for six months which started as ulcers, now
accompanied by pain and occasional bleeding. (Figure 1) He did not
complain of dysphagia, dyspnea, trismus or weight loss. He was a 37-
pack-year smoker and consumed 1 bottle of beer 3-4 times per week.
He did not have hypertension, diabetes mellitus or radiation exposure
and denied any heredofamilial diseases such as cancer.
Physical examination showed an ulcerated mass over the buccal
mucosa extending to adjacent structures such as the left soft palate,
retromolar trigone and mandibular alveolar ridge. A 1 x 1cm level
Figure 1. Squamous cell carcinoma of left buccal mucosa with extension to the
1B lymph node was palpable on the left. Contrast computerized lower alveolar ridge, hard and soft palate, and retromolar trigone
tomography scan of the oral cavity showed the buccal mass encasing
the ramus of the left mandible with osteolytic changes and necrotic
changes in the left masticator space. Biopsy revealed well-differentiated
squamous cell carcinoma. Chest radiograph and liver ultrasonogram
were unremarkable. He was staged T4aN1M0, Stage IVA based on the
American Joint Committee on Cancer (AJCC) Staging, 7th edition for oral
cavity cancer.
He underwent tracheostomy, modified radical neck dissection on
the left, selective neck dissection (levels I-III) on the right, wide excision
with segmental mandibulectomy from left body to left ascending A
ramus via lip-split approach, and reconstruction using ALT flap under
general anesthesia. (Figures 2 and 3)
The left ALT fasciocutaneous flap measuring 18 x 6 cm was
harvested by elevating the medial portion down to the subfascial
layer by cutting the tensor fascia above the rectus femoris muscle. Two
musculocutaneous perforators passing through the vastus lateralis
and emerging from the pedicle, the descending branch of the lateral
circumflex femoral artery (LCFA) and 2 venae comitantes, were identified
and dissected. The lateral portion of the flap was cut to complete
dissection of the flap. Recipient vessels in the neck were first identified B
before dividing the pedicle and harvesting the ALT flap. Figure 2. A. Actual defect after excision of mass; and B. mandibular reconstruction
using titanium plates and screws; a. Body of mandible; b. hard palate; and c.
Partial flap inset with horizontal mattress suturing using absorbable tongue
polygalactin suture was done. Using an operating microscope,
microvascular anastomosis was done to reestablish perfusion of the hourly for the first 48 hours, every 4 hours from the 3rd to 5th post-
flap using nylon 9-0 sutures. The descending branch of the LCFA was operative days, and once daily thereafter while admitted. There were no
anastomosed to the left facial artery and the venae comitantes were post-operative complications and he was decannulated after 1 week.
anastomosed to tributaries of the left external jugular vein. After He was discharged after 10-hospital days without flap dehiscence or
anastomosis, there was immediate perfusion of the flap evidenced discoloration such as bluish or pale flap color.
by presence of bright-red bleeding of the flap edges. Complete flap Follow-up was on a weekly basis. On the 17th post-operative day,
inset, lip and neck closure and primary closure of the donor site were minimal salivary discharge was noticed from the neck incision site.
done. Blood loss was 1500 mL and 2 units of fresh whole blood were Conservative management with acetic acid gargle thrice a day was
transfused. Surgery lasted 17.25 hours. started. Partial dehiscence of the flap was noted on the 24th post-
Flap monitoring using visual inspection and pin prick was done operative day and removal of necrotic tissue and resuturing were done.

48 Philippine Journal Of Otolaryngology-Head And Neck Surgery


Philippine Journal Of Otolaryngology-Head And Neck Surgery
A
B In head and neck reconstruction, wound infection is usually caused by
Figure 3. A. Left ALT flap design measuring 18 x 6 cm; and B. flap inset
Figure 4. Complete flap necrosis on 29th post-operative day. a. ALT flap, b. hard
and soft palate, c. buccal mucosa, and d. tongue.
Complete flap failure was seen on the 29th post-operative day and
removal was done under local anesthesia. (Figure 4) Granulation and
mucosa formation was seen on the bed of the recipient site without
plate exposure. The neck fistula spontaneously closed and no additional
surgery was done. Adjuvant chemotherapy and radiation were advised
but he was not able to comply. Recurrence in the buccal area was seen
a year after surgery.
Philippine Journal Of Otolaryngology-Head And Neck Surgery 49
CASE REPORTS
Vol. 32 No. 2 July– December 2017
DISCUSSION
The ALT flap is an extremely versatile flap for head and neck
reconstruction providing excellent tissue quality and quantity as well as
low donor site morbidity.5 The large tissue defect created after removal
of buccal carcinoma in our patient was the main reason for choosing an
ALT flap over other available free flaps.
Vascular occlusion remains the primary reason for flap loss with
venous thrombosis being more common than arterial occlusion and
majority of flap failures occur within the first 48 hours.1 Rarely do flaps
fail in the late post-operative period. It is not well understood why free
flaps can fail after 7 post-operative days.4
Wax and Rosenthal reported median time of necrosis at 21 (range
7-90) days.4 However, none of the 13 patients reported had an ALT
free flap. Flap necrosis in our patient was within range but was longer
compared to the median time on the 29th post-operative day.
Late flap failures were most often due to infection or mechanical
stress around anastomosis rather than technical or vascular etiology.1,4,6
fistula formation or wound dehiscence 4 or 5 days after surgery.6 Kubo
et al. found that disruption of anastomosed vessels can occur with high
frequency after infection ranging from 3-14 days post-operatively and
salivary fistula formation is one of the causes of infection reported.7
Small intraoral dehiscence exposes the vascular pedicle of the flap
and can cause saliva to leak into the neck where the anastomosis site
is located. Saliva carries potential pathogens which may not be part
of the normal oral flora.7 Wound infection causes edema and necrosis
promoting thrombus formation.6 It is one of the possible causes of flap
failure in our patient. However, Huang et al. showed that postoperative
salivary fistulas do not appear to be strongly associated with flap failure
in head and neck reconstruction.8
The condition and quality of the recipient site also play a large
role in flap survival. Young demonstrated that neovascularization
develops within 7 to 10 days.9 However, the flap edges lose contact
with skin edges and base of recipient site once fistula or wound
dehiscence occurs, delaying revascularization.6 Thus, wound infection
due to salivary fistula may damage anastomosed vessels and delay
revascularization leading to flap failure.6-7
Blood loss and transfusion may indirectly contribute to flap failure
of our patient. Although flap survival was not significantly different
comparing patients who were transfused and not transfused with
blood, wound dehiscence was significantly increased in patients with
transfusion. Fistula formation and wound infection tended to be higher
in transfused patients.10 The blood loss of our patient was 1500mL,
which was 3 times more than their findings(499.41+/-163.64),10
requiring blood transfusion. Animal studies indicate that transfusion
 CASE REPORTS
Philippine Journal Of Otolaryngology-Head And Neck Surgery Vol. 32 No. 2 July– December 2017

triggers release of inflammatory cytokines such as interleukin-8 which

impair wound healing.­11 This may have affected normal wound healing
of our patient causing fistula formation and poor revascularization of
the ALT flap.
Our patient presented with late-onset ALT fasciocutaneous free
flap failure on the 29th post-operative day. Wound dehiscence causing
salivary fistula may be the cause of flap failure. It may have damaged
the anastomosed vessels and delayed revascularization of the flap.
Blood loss and transfusion may also have contributed to poor wound
healing. Possibly, free flap failure in this case was multifactorial and not
due to a single cause.
In conclusion, late-onset flap failures are mostly non-vascular in
origin. The presence of a salivary fistula should alert surgeons to the
possibility of flap failure. Extensive pre-operative planning, meticulous
intraoperative dissection and hemostasis, and timely intervention are
necessary to prevent and minimize free flap loss. It is also important to
reiterate the importance of frequent follow-up to monitor flap viability
and status even after hospital discharge, among patients who undergo
free flap reconstruction.

REFERENCES

1. Novakovic D, Patel RS, Goldstein DP, Gullane PJ. Salvage of failed free flaps used in head and
neck reconstruction. Head Neck Oncol. 2009 Aug 21; 1:33. DOI: 10.1186/1758-3284-1-33; PMID:
19698095 PMCID: PMC2749848.
2. Klosterman T, Siu E, Tatum S. Free flap reconstruction experience and outcomes at a low-
volume institution over 20 years. Otolaryngol Head Neck Surg. 2015 May;152(5):832-7. DOI:
10.1177/0194599815573726; PMID: 25953911.
3. Disa JJ, Hu QY, Hidalgo DA. Retrospective review of 400 consecutive free flap reconstructions for
oncologic surgical defects. Ann Surg Oncol. 1997 Dec;4(8):663-9. PMID: 9416415.
4. Wax MK, Rosenthal E. Etiology of late free flap failures occurring after hospital discharge.
Laryngoscope. 2007 Nov;117(11):1961-3. DOI:10.1097/MLG.0b013e31812e017a; PMID:
17828052.
5. Park CW, Miles BA. The expanding role of the anterolateral thigh free flap in head and
neck reconstruction. Curr Opin Head Neck Surg. 2011 Aug.;19(4):263-8. DOI: 10.1097/
MOO.0b013e328347f845; PMID: 21900855.
6. Kadota H, Sakuraba M, Kimata Y, Yano T, Hayashi R. Analysis of thrombosis on postoperative
day 5 or later after microvascular reconstruction for head and neck cancers. Head Neck. 2009
May;31(5):635-41. DOI:10.1002/hed.21021; PMID: 19260134.
7. Kubo T, Matsuda K, Kiya K, Hosokawa K. Behavior of anastomozed vessels and transferred flaps
after anastomosed site infection in head and neck microsurgical reconstruction. Microsurgery.
2016 Nov; 36(8): 658-663. DOI:10.1002/micr.30025; PMID: 26790991.
8. Huang RY, Sercarz JA, Smith J, Blackwell KE. Effect of salivary fistulas on free flap failure: a
laboratory and clinical investigation. Laryngoscope. 2005 Mar;115(3):517-21. DOI: 10.1097/01.
mlg.0000157827.92884.c5; PMID: 15744169.
9. Young CM. The revascularization of pedicle skin flaps in pigs: a functional and morphologic
study. Plast Reconstr Surg. 1982 Oct;70(4):455-64. PMID: 6287512.
10. Puram SV, Yarlagadda BB, Sethi R, Muralidhar V, Chambers KJ, Emerick KS, et al. Transfusion in
head and neck free flap patients: practice patterns and a comparative analysis by flap type.
Otolaryngol Head Neck Surg. 2015 Mar;152(3):449-57. DOI:10.1177/0194599814567107; PMID:
25628368.
11. Okano T, Ohwada S, Sato Y, Sato M, Toyama Y, Nakanose Y, et al. Blood transfusions impair
anastomotic wound healing, reduce luminol-dependent chemiluminescence, and increase
interleukin-8. Hepatogastroenterology. 2001 Nov-Dec;48(42):1669-74. PMID: 11813598.

50 Philippine Journal Of Otolaryngology-Head And Neck Surgery


Philippine Journal Of Otolaryngology-Head And Neck Surgery
Ann Christie P. Lluisma, MD
Cagayan de Oro Consortium of Otorhinolaryngology
Head and Neck Surgery
Correspondence: Dr. Ann Christie P. Lluisma
Cagayan de Oro Consortium of Otorhinolaryngology
Head and Neck Surgery
Northern Mindanao Medical Center
Capitol Compound, Cagayan de Oro City 9000
Philippines
Phone: (6388) 726362 local 636
Email: anners.alovera@gmail.com
The author declares that this represents original material, that
the manuscript has been read and approved by the author, that
the requirements for authorship have been met by the author,
and that the author believes that the manuscript represents
honest work.
Disclosures: The author signed a disclosure that there are no
financial or other (including personal) relationships, intellectual
passion, political or religious beliefs, and institutional affiliations
that might lead to a conflict of interest.
Presented at the Philippine Society of Otolaryngology Head
and Neck Surgery Interesting Case Contest. June 30, 2016.
Unilab Bayanihan Center, Pasig City.
Creative Commons (CC BY-NC-ND 4.0)
Attribution - NonCommercial - NoDerivatives 4.0 International
Philippine Journal Of Otolaryngology-Head And Neck Surgery 51
CASE REPORTS
Vol. 32 No. 2 July– December 2017
Supernumerary Nostril in a 15-Year-Old Girl
ABSTRACT
Objectives: To describe a rare case of a supernumerary nostril and its management and to
discuss the different theories pertaining to this type of deformity.
Methods:
Design: Case Report
Setting: Tertiary Government Hospital
Patient: One
Results: A 15-year-old girl was born with one extra nasal opening. Nasal endoscopy after 15 years
revealed a mucosa-lined cavity that ended blindly. Computed tomography scan showed a small
opening lateral to the right nasal ala which did not communicate with the right nasal cavity. A
crescent incision was made along the inner circumference of the supernumerary nostril and the
blind ending nasal tract was excised. A portion of the ala was removed and a Z-plasty repair was
performed.
Conclusion: Treatment has to be tailored as to the presentation of a supernumerary nostril and
any other associated deformity. Though various surgical interventions exist, the goal of repair is
to create a functioning and normal-appearing nose.
 Keywords: Supernumerary Nostril, Accessory Nostril
A supernumerary nostril is a congenital malformation characterized by an accessory nasal
cavity that usually manifests as a small nasal orifice with surrounding redundant soft tissue.1 The
accessory nostril is similar to a normal nostril which has vibrissae and an intranasal opening,
can be unilateral or bilateral and may have a communication with the ipsilateral nostril.2 The
first reported case was published in 1906 by Lindsay who described a patient with bilateral
supernumerary nostrils.2 In the English literature, there have been about 40 reported cases of
supernumerary nostrils.2-12 To the best of our knowledge based on a search of HERDIN using the
keywords “supernumerary” “accessory” and “ nostril,” there has been no locally-reported case of a
supernumerary nostril.
Philipp J Otolaryngol Head Neck Surg 2017; 32 (2): 51-54 c Philippine Society of Otolaryngology – Head and Neck Surgery, Inc.
 CASE REPORTS
Philippine Journal Of Otolaryngology-Head And Neck Surgery
We describe a rare case of a supernumerary nostril and its
management and discuss the different theories pertaining to this type
of deformity.
CASE REPORT
A 15-year-old girl presented to the Ear Nose Throat (ENT) outpatient
department due to an accessory nostril on the right side of her nose
since birth. (Figure 1) There was no history of bleeding or discharge
(although she reported recurrent yellowish discharge from the other
nostrils). She had no previous medical consultations due to financial
constraints. She was vaginally born to a then 22-year-old gravida 1
mother. The prenatal history was unremarkable with no history of
exposure to alcohol, drugs or ionizing radiation. There was no history
of consanguineous marriage or family history of birth defects and the
antenatal and neonatal history were also uneventful.
Figure 1. Preoperative frontal and basal view (published in full with permission)
Figure 2. Small blind mucous membrane-lined pocket with vibrissae located lateral to and at the
same level as the right nostril
52 Philippine Journal Of Otolaryngology-Head And Neck Surgery
Vol. 32 No. 2 July– December 2017
On physical examination, the left nasal opening was wider compared
to the right with two nasal openings. The smaller supernumerary nostril
had an internal diameter of about 5 mm located lateral to and at the same
level as the right nostril. (Figure 2) Anterior rhinoscopy revealed that the
accessory nostril was lined with hair follicles. The septum between the
right and left nasal cavities was midline. The inferior turbinates were not
congested. However, there was yellowish discharge in both right and
left nostrils. Nasal endoscopy revealed no communication between
the normal and accessory nasal cavity which ended blindly and was
lined by mucous membrane. A polypoid mass was noted within the left
middle meatus.
Computed tomography scans of the paranasal sinuses revealed
soft tissue thickening of the right nasal ala with a small opening
laterally. There were no bony or cartilaginous abnormalities. There were
opacifications seen in the left frontal sinus, left anterior ethmoid, both
maxillary sinuses and mucosal thickening of the right sphenoid sinus.
(Figure 3)
The patient was admitted with an impression of right unilateral
supernumerary nostril and chronic rhinosinusitis with left nasal polyp
and underwent surgery under general anesthesia. A crescent incision
A B
C D
Figure 3. Paranasal Sinus CT scans. A. Coronal and B. Axial cut show a small opening lateral to the
right nasal ala that does not communicate with the right nasal cavity. C. and D. Axial cuts reveal
opacifications in the left frontal sinus, left anterior ethmoid, both maxillary sinuses and mucosal
thickening of the right sphenoid sinus with deviated nasal septum to the right.

Philippine Journal Of Otolaryngology-Head And Neck Surgery
was made along the inner circumference of the supernumerary nostril
and the blind ending nasal tract was excised. The result was a medial
nostril and untouched ala with dead space in between. A portion of the
ala was removed and a Z plasty was designed. Through-and-through
sutures were placed to obliterate dead space. (Figure 4) Endoscopic sinus
Figure 4. Intraoperative photos A. crescent incision B. blind ending nasal tract excised C. z-plasty
and D. closure
Figure 5. Postoperative frontal and basal view (published in full with permission)
surgery was performed to remove the left nasal polyp and establish a
functional osteomeatal complex.
The post-operative period was uneventful and she was discharged
after 2 days with a slightly swollen right nostril. Results at 2 months
showed improvement in the contour of the right nostril. (Figure 5)
Philippine Journal Of Otolaryngology-Head And Neck Surgery 53
CASE REPORTS
Vol. 32 No. 2 July– December 2017
DISCUSSION
Supernumerary nostrils are rare congenital anomalies with unclear
etiology. A review of literature reveals that there are about 40 published
cases since 1906.2-12 Of these 40 cases, 23 were isolated supernumerary
nostrils and 15 had associated anomalies; more than half of the reported
cases were from the Asian continent of which 10 were from India.2-12
There is no known exact mechanism and stage of embryological
development at which the error occurs and because of its rarity,
different speculative theories exist related to its embryogenesis.11
According to Erich, Lindsay described a case of bilateral supernumerary
nostrils and proposed the theory of dichotomy by atavism or parallel
evolution in 1906.2 In biology, “an atavism is an evolutionary throwback,
such as traits reappearing which had disappeared generations before…
that can occur in several ways. One way is when genes for previously
existing phenotypical features are preserved in DNA, and these become
expressed through a mutation that either knock out the overriding
genes for the new traits or make the old traits override the new one.”13
In 1962, Erich reported a case of a patient with two noses and
explained the development of that deformity and the accompanying
four nostrils by the appearance of four nasal pits instead of two,
horizontally, each forming a nasal sac.2 He hypothesized that “the
medial sacs are interposed between the nasal laminae, preventing their
fusion into one septum and resulting in a double nose and suggested
that when the accessory nasal pit is located too laterally, the fusion of
the laminae is not disturbed and one nose with a supernumerary nostril
is formed.”2
Nakamura and Onizuka advanced a new theory when they reported
a case of supernumerary nostril in 1987.3 They suggested that “the
supernumerary nostrils resulted from a localized abnormality of the
lateral nasal process, with a fissure appearing accidentally and dividing
the lateral nasal process in two, resulting in two nostrils on one side of
the nose.”3 Also in 1987, Reddy and Rao reported a case of triple nostrils
and assumed that the “deformity developed as a result of an accessory
olfactory pit appearing either above or below the normal location of
the placode.”4
As for treatment, there is no generally accepted method of surgical
repair. The goal of repair is to create a functioning and normal-appearing
nose with minimal deformity.5 My review of literature revealed a
systematic classification of supernumerary nostril by Saiga and Matsua
and its corresponding surgical technique.6 The classification is based on
the shape of the nasus externus. (Figure 8) Based on this classification,
our patient belongs to Type 1 where the inner nostril is sufficiently large
and symmetry with the unaffected side can be obtained. In this case,
the suggested surgical technique is resection of the outer nostril.
 CASE REPORTS
Philippine Journal Of Otolaryngology-Head And Neck Surgery Vol. 32 No. 2 July– December 2017

Although various types and techniques exist for the management

of a supernumerary nostril, most of the authors advocated the
circumferential excision of the accessory cavity and resection of the
entire fistulous tract.2,5-8,11-12 As to the timing of surgery, it is advisable
to operate in early childhood to prevent deformity of normal nostrils.4
For adult patients, surgical treatment should be planned in stages to
achieve a good outcome.
Because of the rarity of this congenital anomaly, the etiology
and mechanism of developmental error remain hypothetical. An
observation of a high incidence in the Asian continent calls for further
investigation to identify common factors in this geographical region
that contribute to the deformity.7 As mentioned by Rout and Lath,
there is no cookbook for the correction of this defect.7 Treatment has
to be tailored as to the presentation of a supernumerary nostril and any
other associated deformity. Though various surgical interventions exist,
the goal of repair is to create a functioning and normal-appearing nose
essential for normal psycho-social development.

ACKNOWLEDGEMENTS
I would like to thank Dr. Vincent Mark Jardin who handled the case with me and who never
get tired of pushing me to write this case report; Dr. Stephanie E. Jacutin for the help in doing the
nasal endoscopy and documentation; and all the consultants and residents of the Cagayan de Oro
Consortium of ORL-HNS for their inputs and comments.

REFERENCES
1. Elluru RG. “Cogenital Malformations of the Nose and Nasopharynx”. In: Flint PW, Haughey BH,
Robbins KT, Thomas JR, Niparko JK, et al. (editors). Cummings Otolaryngology Head and Neck
Surgery, 6th ed, Vol. 3, Canada: Elsevier Saunders 2015. p.2950.
2. Erich JB. Nasal duplication: case report of a patient with two noses. Plast Reconstr Surg Transplant
Bull. 1962 Feb; 29:159-66. PMID: 13890550.
3. Nakamura K, Onizuka T. A case of supernumerary nostrils. Plast Reconstr Surg. 1987 Sep;
80(3):436-41. PMID: 3306743.
4. Reddy KA, Rao AK. Triple nostrils: a case report and review. Br J Plast Surg. 1987 Nov; 40(6): 651-
652. PMID: 3318987.
5. Shaye DA, Tibesar RJ. Repair of supernumerary nostril. J Craniofac Surg. 2014 May; 25(3): 978-9.
DOI: 10.1097/SCS.0000000000000549; PMID: 24699105.
6. Saiga A, Mitsukawa N. Case of supernumerary nostril. J Plast Reconstr Aesthet Surg. 2013 Jan;
66(1): 126-128. DOI: 10.1016/j.bjps.2012.05.014; PMID: 22687717.
7. Rout SK, Lath MK. Supernumerary nostril. J Craniofac Surg. 2013 Jan; 24(1): e13-5. DOI: 10.1097/
SCS.0b013e3182668b14; PMID: 23348320.
8. Uppal SK, Garg R, Gupta A, Pannu DS. Supernumerary nostril: A rare congenital anomaly. Ann
Maxillofac Surg. 2011 Jul; 1(2): 169-171. DOI: 10.4103/2231-0746.92788; PMID: 23483576 PMCID:
PMC3591022.
9. upernumerary nostril: An extremely rare case. Int J Pediatr Otorhinolaryngol. 2012 Mar; 7(2):
89-91. https://doi.org/10.1016/j.pedex.2012.02.001.
10. Kashyap SK, Khan MA. Supernumerary nostril: A case report and review. Int J Morphol. 2009;
27(1): 39-41. http://dx.doi.org/10.4067/S0717-95022009000100007.
11. Sah BP, Bhandary S, Pokharel A, Shilpakar SL, Chettri ST, Paudel D. A supernumerary nostril
associated with dermoid cyst: A rare case report and review of literature. American Journal of
Medical Case Reports. 2014; 2(3): 52-54. DOI: 10.12691/ajmcr-2-3-3.
12. Krishna NR, Kumar BR, Srinivas K, Akurati L. A rare congenital anomaly of accessory nose: Case
report. Indian J Otolaryngol Head Neck Surg. 2006 Oct; 58(4): 389-391. DOI: 10.1007/BF03049606;
PMID: 23120359 PMCID: PMC3450355.
13. Hall BK. Atavisms and atavistic mutations. Nat Genet. 1995 Jun; 10(2): 126-127. DOI: 10.1038/
ng0695-126; PMID: 7663504.

54 Philippine Journal Of Otolaryngology-Head And Neck Surgery

 CASE REPORTS
Philippine Journal Of Otolaryngology-Head And Neck Surgery Vol. 32 No. 2 July– December 2017

John Emmanuel L. Ong, MD1

Emmanuel Tadeus S. Cruz, MD1,2
Unilateral Tonsilar Hypertrophy
Clydine Maria Antonette G. Barrientos, MD1,3 in a 4-Year-Old Girl with Focal Dermal Hypoplasia
1
Department of Otorhinolaryngology (Goltz Syndrome)
Head and Neck Surgery
Manila Central University – Filemon D. Tanchoco Medical
Foundation Hospital

2
Department of Otorhinolaryngology
Head and Neck Surgery
Quezon City General Hospital
ABSTRACT
3
Department of Otorhinolaryngology Objective: To report a case of unilateral tonsillar hypertrophy resulting in severe Obstructive Sleep
Head and Neck Surgery
Makati Medical Center Apnea in a 4-year-old girl with focal dermal hypoplasia (FDH, Goltz or Goltz-Gorlin) Syndrome.

Methods:
Design: Case Report
Setting: Tertiary Private Teaching Hospital
Patient: One

Correspondence: Dr. Emmanuel Tadeus S. Cruz Results: A 4-year-old girl with Goltz Syndrome (classical features of cutaneous and osteopathic
Department of Otorhinolaryngology – Head and Neck Surgery
Manila Central University – Filemon D. Tanchoco Medical disorders since birth) and unilateral tonsillar hypertrophy manifested with snoring and apneic
Foundation Hospital
Epifanio de los Santos Ave., Caloocan City 1400
episodes at two years of age. Polysomnography revealed severe Obstructive Sleep Apnea
Philippines and Arterial Blood Gases revealed metabolic acidosis with hypoxemia. A tonsillectomy and
Phone: (632) 367 2031 loc 1212
Email: orlhns_mcu@yahoo.com adenoidectomy improved breathing, appetite and sleep with resolution of snoring and apneic
The authors declared that this represents original material
spells and final tonsil histopathology revealed lymphoepithelial polyp.
that is not being considered for publication or has not been
published or accepted for publication elsewhere, in full or
in part, in print or electronic media; that the manuscript has Conclusion: A 4-year-old child with Goltz syndrome who developed severe obstructive sleep
been read and approved by all authors, that the requirements
for authorship have been met by each author, and that each
apnea due to tonsillar hypertrophy was presented. Otolaryngologists should be aware of this
author believes that the manuscript represents honest work. syndrome which may manifest with oral and mucosal lesions. Although rare, Goltz syndrome may
Disclosures: The authors signed disclosures that there are no be considered in the differential diagnosis of tonsillar hypertrophy especially in the presence of
financial or other (including personal) relationships, intellectual
passion, political or religious beliefs, and institutional affiliations
the inherent clinical features. Physicians should educate patients and address the co-morbidities
that might lead to a conflict of interest. associated with it through individualized treatment.
Presented at the 35th Residents’ Interesting Case Presentation
Contest (1st place), March 30, 2016. MCU-FDTMF Hospital Keywords: Focal Dermal Hypoplasia, Unilateral Tonsillar Hypertrophy, Goltz Syndrome, Goltz-Gorlin
Presented at the North East Otolaryngologists Consortium Syndrome
Interesting Case Presentation Contest (1st place), April 6, 2016.
Quirino Memorial Medical Center.
Focal dermal hypoplasia (FDH), popularly known as Goltz or Goltz-Gorlin syndrome is a rare
Presented at the Philippine Society of Otolaryngology Head
and Neck Surgery Interesting Case Contest. June 30, 2016. multisystem disorder first described by Goltz et al. in 1962 in a case report of 3 female patients
Unilab Bayanihan Center, Pasig City.
who presented with similar cutaneous and skeletal abnormalities.1,2,3 This syndrome is registered
under the National Organization for Rare Disorders and in a recent study done by Nicolas in

Creative Commons (CC BY-NC-ND 4.0)

Attribution - NonCommercial - NoDerivatives 4.0 International Philipp J Otolaryngol Head Neck Surg 2017; 32 (2): 43-46 c Philippine Society of Otolaryngology – Head and Neck Surgery, Inc.

Philippine Journal Of Otolaryngology-Head And Neck Surgery 43

 CASE REPORTS
Philippine Journal Of Otolaryngology-Head And Neck Surgery Vol. 32 No. 2 July– December 2017

2015, around 300 cases are registered in literature.5 To the best of our
knowledge, other than a case of a 12-year-old girl with Goltz syndrome
in the Philippine General Hospital by Nicholas in 2015, there is paucity
of reports in Philippine literature.5 A keyword search using “focal dermal
hypoplasia,”“Goltz syndrome” and “Goltz-Gorlin syndrome” in the Health
Research and Development Information Network (HERDIN) database
yielded negative results.
We present a case of unilateral tonsillar hypertrophy resulting in
severe obstructive sleep apnea in a child with Focal Dermal Hypoplasia
(FDH, Goltz or Goltz-Gorlin) Syndrome.

CASE REPORT A B
A 4-year-old Filipino girl born to non-consanguinous parents was Figure 1. A. facial asymmetry, left eyelid ptosis, low-set ears, sparse eye brows and scalp hair
the product of a 41-42 week gestation in a 28-year-old Gravida 3, Para B. a patch of parieto-occipital alopecia. (photos published in full, with permission)

1 (0110) mother whose first pregnancy ended with early fetal loss at
7 months and whose second pregnancy terminated at 4 months,
necessitating dilatation and curettage in both instances. Maintained
on Progesterone and tocolytics for the entire duration of her third
pregnancy, the mother had episodes of urinary tract infections in the
5th -7th months of gestation treated with vaginal suppositories. The girl
was delivered via emergency low transverse caesarian section due to A B
non-reassuring fetal status, and confined in the neonatal ICU for 5 days Figure 2. A. Right tonsillar hypertrophy with polypoid extension (arrow), prominent tongue
on antibiotics for meconium staining. There was no family history of papillae and slight clefting of the tip of the tongue B. Dental notching of maxillary incisors and
mandibular canine and incisors (arrows) and left lower lip mass (dashed arrow).
congenital anomalies.
At birth, the child had atrophic skin lesions streaking over the
forearms, chest and abdomen as well as ptosis of the left eyelid, low-set
ears, dermal hypoplasia, nail dystrophy, and syndactyly of the 2nd and
3rd digit of the left foot, but no consults or interventions were made.
Around 2 years of age, she was noted to have increased snoring with
A B C
apneic episodes. At 4 years of age, she was finally brought to us by her
Figure 3. A. Cutaneous examination showed multiple hypo and hyper-pigmented macules
mother for a progressively enlarging right tonsillar mass associated over the chest and abdomen B. slightly dysplastic nails of the 1st, 2nd and 3rd digits (arrows) C.
with snoring and frequent apneic spells. Syndactyly affecting the 2nd and 3rd digit of the left foot.

Physical examination revealed short stature and thin build with

X ray revealed dental notching, deciduous teeth and appropriate
height and weight measurements falling below Z score -2. There was
dentition for age while 2D echocardiography findings were normal
ptosis of the left eyelid, sparse hair and a patch of parieto-occipital
with an ejection fraction of 76%. Polysomnography resulted in a
alopecia. (Figure 1) Oral cavity examination revealed complete
diagnosis of severe Obstructive Sleep Apnea and behavioral insomnia
dentition for age with notching and multiple dental caries and a 0.5
of childhood. Arterial blood gases revealed metabolic acidosis with
cm erythematous left lower lip mass. The right tonsil was hypertrophic,
hypoxemia, while chest x-ray showed pneumonia and primary Koch’s
pinkish with a polypoid growth extending beyond midline while the
infection, which were treated. Unable to afford continuous positive
left tonsil was unremarkable and confined within the anterior and
airway pressure (CPAP) to alleviate chronic hypoxemia, she was
posterior pillars. (Figure 2) Nasal endoscopic findings showed adenoid
eventually cleared to undergo tonsillectomy for removal of the tonsillar
hypertrophy. Cutaneous lesions included hypo- and hyperpigmented
mass and adenoidectomy. Intraoperative findings confirmed the initial
macules on the forearms, chest and abdomen. There was also syndactyly
examination findings. (Figure 4)
of the 2nd and 3rd digit of the left foot. (Figure 3)
She tolerated the procedure well with no postoperative
Karyotyping yielded normal genetic constitution (46XX). Panoramic

44 Philippine Journal Of Otolaryngology-Head And Neck Surgery

 CASE REPORTS
Philippine Journal Of Otolaryngology-Head And Neck Surgery Vol. 32 No. 2 July– December 2017

A B C
Figure 4. A. Intraoperative findings of a hypertrophic right tonsil with a polypoid growth extending beyond the midline B. right tonsil with polyp (arrow)
C. left tonsil

(Hematoxylin – Eosin , 4X) (Hematoxylin – Eosin , 4X) (Hematoxylin – Eosin , 4X)

A B C
Figure 5. Histopathologic slide, scanning view (4x magnification), H&E stain, showing A. lymphoepithelial polyp and subepithelial lymphoid nodules with
active germinal centers (arrows) B. right tonsil with normal histology C. lower lip mass consistent with squamous papilloma.

complications. Her breathing, appetite and sleep pattern improved
with resolution of snoring and apneic spells. The final histopathologic
report revealed a lymphoepithelial polyp and subepithelial lymphoid
nodules with active germinal centers, lower lip mass findings were
consistent with squamous papilloma. (Figure 5)
DISCUSSION
FDH or Goltz-Gorlin syndrome should not be confused with Gorlin-
Goltz syndrome which presents as multiple odontogenic keratocysts
associated with Nevoid Basal Cell Carcinoma Syndrome.6 The genetic
defect of Goltz syndrome lies in mutations of the porcupine homolog
(PORCN) gene on the X chromosome, with probable locus at Xp11.23.4
-9
This mutation manifests as defects that can involve all 3 dermal
layers-- ectoderm (skin, eyes), mesoderm (bones, teeth) and endoderm
(various mucosa). 7 8 The mnemonic FOCAL can be used to identify
the key features of Goltz Syndrome: Female Sex; Osteopathy, striata;
Coloboma; Absent ectodermis, mesodermis and neurodermis-derived
elements; and Lobster claw deformity.6
The severity of defects is variable ranging from mild to mutilating
manifestations.6 Women are predominantly affected and diagnosed
90% of the time primarily due to in-utero lethality in males.7 The
variability is said to be due to random X-chromosome inactivation or
lyonization within cells, hence females who have two X chromosomes
are spared.7 Males do present with the disease in 10% of cases and
this can be attributed to somatic mosaicism or due to a sporadic new
mutation.7
There is no specific criteria to diagnose Goltz syndrome but the
presence of skin lesions is considered essential followed by skeletal
defects seen in 80% of patients.8 PORCN gene mutations causes defects
in the WNT signaling pathway which is important in normal embryonic
development of skin, bones, teeth and eyes.5 Hence, this would explain
the primary features of Goltz syndrome: dermal hypoplasia that follows
Blaschko lines which represent pathways of epidermal cell migration
and proliferation during the development of the fetus, syndactyly,
dental abnormalities and ptosis, which were present in our patient.5
However, due to polymorphism, not all features may be present in
every individual affected by the syndrome.8
According to Jain et al., differential diagnoses for Goltz syndrome
are: “(1) MIDAS (microphthalmia, dermal aplasia, sclerocornea), (2)
Incontinentia Pigmenti, and (3) Rothmund Thomson syndrome.”7
MIDAS syndrome usually shows “dermal atrophy typically limited to
the upper half of the body and does not present with skeletal and
extremity abnormalities”7 in contrast to our patient who presented with
syndactyly and ptosis. Incontinentia pigmenti happens in stages which
includes “a blistering rash at birth or early childhood, development of
grey or brown skin patches of hyperpigmentation, which in adulthood

Philippine Journal Of Otolaryngology-Head And Neck Surgery 45

 CASE REPORTS
Philippine Journal Of Otolaryngology-Head And Neck Surgery
fades with time leaving lines of hypopigmentation.”7 Finally, Rothmund
Thomson syndrome generally “presents after 3 months of age with
initial redness on the cheeks between ages 3 months and 6 months and
then the rash spreads to the arms and legs with non-linear lesions.”7
These 2 entities were ruled out because of the absence of their clinical
manifestations in our patient.
As for the oral cavity findings, various authors have cited the
occurrence of single to multiple raspberry papillomas which are usually
not present at birth but develop with age and are typically found on skin
and mucosal surfaces including the anus and vagina.4-6, 9-14 Ghosh et al.
reported that 6 out of 8 patients (75%) with Goltz syndrome presented
with the characteristic raspberry papillomas around the mouth.10
Ogunbiyi stated that these could also occur in the “larynx, eyelid
margins, mouth, pharynx, tonsils, palate, gums, tongue and lips.”15 The
usual histology would show a “fibrovascular stalk covered with a layer
of acanthotic stratified squamous epithelium resembling epidermis
with extensive papillary folds.”15 In our case, a lymphoepithelial polyp
was attached to the right hypertrophic tonsil, and a lower lip mass was
also excised with histopathology consistent with squamous papilloma.
In addition, DiSalvo et al. reported the case of a 38-year-old man
with Goltz syndrome who presented with exophytic papillomatous
masses from the right tongue base, left anterior tonsillar pillar, soft
palate and small lesions on the upper and lower lips, which revealed
papillary lymphoid hyperplasia following excision.16 Ogunbiyi reported
a final histopathology of squamous papilloma in a 14-year-old girl
with skeletal and cutaneous lesions who underwent tonsillectomy
for kissing tonsils with obstructive sleep apnea.15 Nicolas reported on
a 12-year-old girl with tonsillar hypertrophy occluding the pharynx
coinciding with the syndrome but no surgical intervention was done.5
Indeed, oral and mucosal lesions may be apparent in Goltz syndrome
and may compromise and obstruct the upper airway which may
require tonsillectomy such as in our case.
Ancilliaries such as genetic studies and skin biopsy may be helpful
but not essential in establishing Goltz syndrome since it is often
diagnosed clinically. In our patient, chromosomal analysis revealed
normal karyotype (46XX) while gene analysis used to detect mutations
in the PORCN gene was not done.4 Skin biopsy would reveal dermal
atrophy with disordered connective tissue and decreased collagen
bundles and nests of adipose tissue extending into the upper dermis.5
Hence, clinical diagnosis in this case was established by the presence of
skin, hair, oral cavity and extremity findings.
Patients with Goltz syndrome usually lead normal lives with normal
to near normal intelligence.7 Management maybe individualized and
may require multi-specialty care.5,7
In summary, we presented the case of a 4-year-old child with Goltz
46 Philippine Journal Of Otolaryngology-Head And Neck Surgery
Vol. 32 No. 2 July– December 2017
syndrome who developed severe obstructive sleep apnea due to
adenotonsillar hypertrophy. Otolaryngologists should be aware of this
syndrome which may manifest with oral and mucosal lesions. Although
rare, Goltz syndrome may be considered in the differential diagnosis of
tonsillar hypertrophy especially in the presence of the inherent clinical
features. Physicians should educate patients with the condition and
address the co-morbidities associated with it through individualized
treatment.
ACKNOWLEDGEMENTS
The authors would like to thank Dr. Lyra Veloro from the Department of Otorhinolaryngology,
Section of Pediatrics, Philippines Children’s Medical Center and Dr. Eva Maria C. Cutiongco-dela Paz,
from the Department of Pediatrics, College of Medicine, Philippine General Hospital, University of the
Philippines and Institute of Human Genetics, National Institute of Health, University of the Philippines
for assisting in the diagnosis.
REFERENCES
1. Goltz RW, Petersone WC, Gorlin RJ, Ravits HG. Focal dermal hypoplasia. Arch Dermatol. 1962
Dec; 86:708-17. PMID: 13948891.
2. Goltz RW, Henderson RR, Hitch JM, Ott JE. Focal dermal hypoplasia syndrome. Arch Dermatol.
1970 Jan; 101(1):1-11. PMID: 5416790.
3. Goltz RW. Focal dermal hypoplasia syndrome: An update. Arch Dermatol. 1992 Aug; 128(8):
1108-11. PMID: 1497368.
4. Bundra K, Sutton VR. National Organization for Rare Disorders. [Last update: 2013; Accessed
2016 Jan 28]. Available at: http://rarediseases.org/rare-diseases/focal-dermal-hyoplasia.
5. Nicolas ME, Gonzales-Carait PK. A case of Goltz syndrome. Indian J Paediatr Dermatol. 2015; 16
(3): 170-172. DOI: 10.4103/2319-7250.160664.
6. Soccio LC, Butler DF, Chan EF, Elston DM, Goltz RW, Lee W. Medscape: Focal Dermal Hypoplasia
Syndrome. [Last update: 2014; accessed 2016 Jan 28]. Available at: http://emedicine.medscape.
com/article/1110936-overview.
7. Jain A, Chander R, Garg T, Nikita, Shetty GS. A rare multisystem disorder: Goltz syndrome – Case
report and brief overview. Dermatol Online J. 2010 Jun 15; 16(6): 2. PMID: 20579457.
8. Bharani S, Thakkar S. A case report of focal dermal hypoplasia-Goltz syndrome. Indian Dermatol
Online J. 2013 Jul-Sep; 4(3): 241-243. DOI: 10.4103/2229-5178.115535; PMID: 23984248 PMCID:
PMC3752490.
9. Sarkar S, Patra C, Das A, Roy S. Goltz syndrome: A newborn with ectrodactyly and skin lesions.
Indian J Dermatol. 2015 Mar-Apr; 60 (2): 215. DOI: 10.4103/0019-5154.152608; PMID: 25814752
PMCID: PMC4372956.
10. Ghosh SK, Dutta A, Sarkar S, Nag SS, Biswas SK, Mandal P. Focal dermal hypoplasia (Goltz
syndrome): A cross-sectional study from Eastern India. Indian J Dermatol. 2017; 62 (5): 498 –
504. DOI: 10.4103/ijd.IJD_317_17.
11. Gammaz H, Amer A, Adly A, Mohsen A. Focal dermal hypoplasia (Goltz syndrome): A case report
and review of literature. Egyptian Dermatology Online Journal. 2010 Jun; 6 (1): 13.
12. Riyaz N, Riyaz A, Chandran R, Rakesh SV. Focal dermal hypoplasia (Goltz syndrome). Indian J
Dermatol Venereol Leprol. 2005 Jul-Aug; 71 (4); 279 -281. PMID: 16394441.
13. Kadyan R, Al-Abdulrazzaq A, Najem N. Focal dermal hypoplasia (Goltz syndrome). The Gulf
Journal of Dermatology and Venereology. 2010 Oct; 17 (2): 58 – 60.
14. Braun-Falco O, Plewig G, Wolff HH, Burgdoff WHC. Malformations and Genetic Disorders: Focal
Dermal Hypoplasia. 2nd Ed. Revised. Dermatology. Berlin Heidelberg New York: Springer. 2000. P
833. DOI: 10.1007/978-3-642-97931-6.
15. Ogunbiyi AO, Adewole IO, Ogunleye O, Ogunbiyi JO, Ogunseinde OO, Baiyeroju-Agbeja A, et
al. Focal dermal hypoplasia: a case report and review of literature. West Afr J Med. 2004 Mar:
346-349. PMID: 15008304.
16. DiSalvo DS, Oberman BS, Warrick JI, Goldenberg D. Pharyngeal presentation of Goltz syndrome:
A case report with review of literature. Head Neck Pathol. 2016 Jun; 10 (2): 188-191. DOI: 10.1007/
s12105-015-0667-4; PMID: 26577212 PMCID: PMC4838964.

Philippine Journal Of Otolaryngology-Head And Neck Surgery
Ann Bernadette G. Sunga, MD
Samantha S. Castañeda, MD
Department of Otorhinolaryngology
Head and Neck Surgery
Rizal Medical Center
Correspondence: Dr. Samantha S. Castañeda
Department of Otorhinolaryngology - Head and Neck Surgery
Rizal Medical Center
Barangay Pineda, Shaw Boulevard, Pasig City 1600
Philippines
Phone: (632) 865 8400 local 207
Email: ent.hns_rmc@yahoo.com
The authors declare that this represents original material, that
the manuscript has been read and approved by all the authors,
that the requirements for authorship have been met by each
author, and that each author believes that the manuscript
represents honest work.
Disclosures: The authors signed disclosures that there are no
financial or other (including personal) relationships, intellectual
passion, political or religious beliefs, and institutional affiliations
that might lead to a conflict of interest
Presented at the Philippine Society of Otolaryngology Head
and Neck Surgery Inter Hospital Grand Rounds. August 30,
2017. Saint Luke’s Medical Center, Quezon City.
Creative Commons (CC BY-NC-ND 4.0)
Attribution - NonCommercial - NoDerivatives 4.0 International
Philippine Journal Of Otolaryngology-Head And Neck Surgery 55
FEATURED GRAND ROUNDS
Vol. 32 No. 2 July– December 2017
A Second Branchial Cleft Cyst Presenting as a
Dumbbell-Shaped Anterior Neck Mass
Branchial cleft anomalies are among the most common causes of congenital anterior neck
masses in the pediatric population. They present as epithelial-lined, single cysts.1,2 The definitive
management is surgical excision.3 However, failure to remove the entire cyst and tract may lead
to recurrence of the mass.3
Unusual presentations of this condition may lead to incomplete excision if inadequately
evaluated. There is a scarcity of material documenting atypical presentations of branchial cleft
anomalies-- in particular, presentation as 2 distinct cysts in one region. In our literature search of
PubMed, Google Scholar and HERDIN using the terms: “congenital mass,” “branchial cleft cyst,”
and “multiple cysts,” only 3 similar cases were found.
We report a case of a second branchial cleft anomaly presenting as a dumbbell-shaped mass
(two cystic structures, connected by a tubular structure) in the right lateral neck, the subsequent
management and outcomes.
CASE REPORT
A 2-year-old girl presented with a 0.5 cm x 0.5 cm right anterior neck mass since birth which
was soft, non-tender and movable with no other associated complaints. They consulted at a
government institution where the parents were reassured that the mass was “excess fat.” No
further investigations were done.
Three months prior to consult, after a bout of upper respiratory tract infection (URTI), the
caregivers noted an increase in size of the mass to approximately 4 x 4 cm which was still soft
but tender and erythematous with a central draining sinus. She was seen at our clinic and
was diagnosed with an infected branchial cleft cyst type II, right. She was admitted and given
appropriate antibiotics. Physical examination showed the mass located at the level of the thyroid
notch, anterior to the medial border of the sternocleidomastoid (SCM) muscle, immediately
superior to the right clavicular head. (Figure 1)
Contrast enhanced computed tomography (CT) scans of the neck showed thin-walled, sharply
circumscribed, minimally enhancing cystic masses at the right upper jugular region, anterior
to the sternocleidomastoid muscle, 1.5 x 2.4 x 1.8 cm (Figure 2A), mid jugular region along the
anterior margin of sternocleidomastoid muscle measuring, 0.6 x 1.2 x 0.8cm, and in the lower
jugular region anterior to the thyroid gland measuring 2.0 x 3.1 x 2.2 cm. (Figure 2B) The cystic
Philipp J Otolaryngol Head Neck Surg 2017; 32 (2): 55-57 c Philippine Society of Otolaryngology – Head and Neck Surgery, Inc.
 FEATURED GRAND ROUNDS
Philippine Journal Of Otolaryngology-Head And Neck Surgery
Figure 1. Right anterior neck mass with a draining sinus
A encasement of the vessels and cervical trachea or evident invasion of
B
Figure 2. Contrast- enhanced CT-scan of the neck, axial view showing thin-
walled, minimally enhancing cystic structures, A. Upper jugular region B.
Lower jugular region
56 Philippine Journal Of Otolaryngology-Head And Neck Surgery
Vol. 32 No. 2 July– December 2017
Figure 3. Intraoperative findings: superficial cyst, anterior to the sternocleidomastoid
muscle (SCM) connected by a tract to a second cyst, deep into the SCM
Figure 4. Excised mass
masses showed no obvious communications with each other and
with the pyriform sinus and laryngeal ventricle. There was no tumoral
vascular structures.
A month after resolution of the infection, the patient underwent
surgery. Intraoperatively, there were 2 masses observed, the first
mass more superficial located anterior to the SCM and upon further
exploration there was a bottle-neck narrowing and another cystic
structure located deep to the right SCM. (Figure 3) The excised mass
was composed of 2 cystic structures attached to one another that still
appeared to have different compartments. (Figure 4) The second cyst
was followed superiorly until the upper jugular region at the level of
the body of the mandible ending in a blind sac. No further exploration
was done and no dye was infiltrated into the cyst or tract.
Histopathologic studies showed a cyst wall lined with squamous
cells. (Figure 5) Higher magnification showed the inner lining with
lymphoid aggregates and possible chronic inflammation as evidenced
by infiltration of mononuclear cells. (Figure 6)
On latest follow-up 1 month post-operatively, the patient had good
wound healing with no persistent draining sinus.

Philippine Journal Of Otolaryngology-Head And Neck Surgery
(Hematoxylin – Eosin , 40X)
Figure 5. Scanner view of the excised mass under H & E staining, showing
an epithelium-lined cyst
DISCUSSION
Branchial cleft anomalies are congenital epithelium-lined cysts
theorized to result from entrapment of elements of the cervical sinus
of His.1 Clinically, they can present as a non-painful, fluctuant and single
mass identified at birth or as late as adulthood when the mass becomes
infected and forms an abscess during episodes of URTI.1,4 These factors
were noted to be consistent with our patient’s case where the reason
for consult was an abrupt increase in mass size due to an infection.
There are four known types of this condition, the second branchial
cleft anomaly being the most common4 comprising more than 90% of
all branchial cleft anomalies.3 On physical examination, they appear
as masses located anterior to the SCM at the below the mandible.4
The fistulous forms of this type extend from an external opening in
the anterior neck coursing superiorly in between the in between the
internal and external carotid arteries then travels up the level of the
tonsillar fossa.5
Radiologic evaluation of this condition includes ultrasonography,
CT scans and magnetic resonance imaging (MRI).1 The contrast-
enhanced CT scan of our patient identified 2 separate cystic masses.
Histopathologic studies that showed epithilium-lined cysts are also
consistent with the diagnosis.
Our patient presented with an infected second branchial cleft cyst.
Recommended management consists of initial antibiotics followed
by definitive surgery. The entire tract must be explored and removed
to prevent recurrences.3 On surgical excision the mass was noted to
have a dumbbell-shaped appearance with two (2) cystic structures
connected by a tubular structure. Three other studies also reported
similar presentations-- a double second branchial cleft cyst by Muñoz-
Fernández et al.,6 a dumbbell - shaped 4th branchial cleft cyst by Kim et
al.7 and two more cases of multiple branchial clefts reported in a study
of 284 cases by Hu et al.8
The definitive treatment for branchial cleft anomalies is surgical
excision ideally up to the level of the tonsillar fossa.3,9 A fistulogram
Philippine Journal Of Otolaryngology-Head And Neck Surgery 57
FEATURED GRAND ROUNDS
Vol. 32 No. 2 July– December 2017
(Hematoxylin – Eosin , 400X)
Figure 6. High power magnification of the excised mass under H & E
staining, showing the inner lining with lymphoid aggregates, and infiltration
with mononuclear cells which represents chronic inflammation
can be used to follow the tract but is not absolutely necessary.10 Other
methods may be used to follow the tract such as injecting methylene
blue dye placing a catheter or using a wire probe on the external
opening.11
Our patient presented with a cyst that ended in a blind pouch at
the level of the mandible and a tract could no longer be appreciated.
Unusual presentations of such conditions may pose intraoperative
surgical challenges and good preoperative evaluation as well as
detailed imaging is necessary to ensure the complete and safe removal
of this congenital mass.
ACKNOWLEDGEMENTS
We would like to thank Dr. Mark Jansen D.G. Austria for the details of the case and intraoperative
pictures and Dr. Ivan De Guzman for interpreting the slides.
REFERENCES
1. Rizzi MD, Wetmore RF, Potsic WP. Differential Diagnosis of Neck Masses. In: Flint PW, Haughey
BH, Lund VJ, Niparko JK, Robbins KT, Thomas JR, et al. (editors). Cummings Otolaryngology. 6th
edition. Philadelphia, PA: Elsevier, Saunders. 2015. p. 3057.
2. Ahuja AT, King AD, Metreweli C. Second branchial cleft cysts: variability of sonographic
appearances in adult cases. Am J Neuroradiol. 2000 Feb; 21(2): 315-319. PMID: 10696015.
3. Myers EN. Branchial Cleft Cyst and Sinuses. In: Myers EN, Carrau RL (editors). Operative
Otolaryngology. Saint Louis: Elsevier Health Sciences. 2008. p.5-7.
4. Emerick K. Differential diagnosis of a neck mass. In Deschler DG, Sullivan DJ (editors). UpToDate.
[Last Updated 2016 May 16; Retrieved 2017 August 1]. Available from: https://www.uptodate.
com/contents/differential-diagnosis-of-a-neck-mass.
5. Chen EY, Sie KCY. Developmental Anatomy. In: Flint PW, Haughey BH, Lund VJ, Niparko JK,
Robbins KT, Thomas JR, et.al. (editors). Cummings Otolaryngology. 6th edition. Philadelphia,
PA: Elsevier, Saunders. 2015. p. 2823-28.
6. Muñoz-Fernández N, Mallea-Cañizares I, Fernández-Julián E, De La Fuente-Arjona L, Marco-
Algarra J. Double second branchial cleft anomaly. Acta Otorrinolaringol Esp. (English Edition).
2011 Jan-Feb; 62(1): 68-70. DOI: 10.1016/j.otorri.2010.01.008; PMID: 20236623.
7. Kim JY, Yoo YS, Choi JH, Cho KR. A Case of Non-Communicating Dumbbell Shaped Fourth
Branchial Cleft Cyst. Korean Journal of Otolaryngology-Head and Neck Surgery. 2009; 52(2):
189-192. DOI: https://doi.org/10.3342/kjorl-hns.2009.52.2.189. [Korean], [Abstract available in
english].
8. Hu YJ, Li YD, Qu XZ, Wang LZ, Zhong LP, Liu L, Zhang CP. [Clinical analysis of branchial cleft
cyst (fistula): report of 284 cases]. Shanghai Kou Qiang Yi Xue. 2008 Oct; 17(5): 461-464. PMID:
18989583.
9. Fagan J. Resecting Branchial Fistulae, Sinuses and Cysts. The Open Access Atlas of Otolaryngology,
Head & Neck Operative Surgery. [Retrieved 2017 Oct 11]. Available from: https://vula.uct.ac.za/
access/content/group/ba5fb1bd-be95-48e5-81be-586fbaeba29d/Resecting%20branchial%20
cysts%2C%20fistulae%20and%20sinuses.pdf.
10. Rattan KN, Rattan S, Parihar D, Gulia JS, Yadav SP. Second branchial cleft fistula: is fistulogram
necessary for complete excision. Int J Pediatr Otorhinolaryngol. 2006 Jun; 70(6); 1027-1030. DOI:
10.1016/j.ijporl.2005.10.014; PMID: 16343647.
11. Houck J. Excision of Branchial Cysts. Operative Techniques in Otolaryngology. 2005; 16: 213-222.
 FROM THE VIEWBOX
Philippine Journal Of Otolaryngology-Head And Neck Surgery Vol. 32 No. 2 July– December 2017

Nathaniel W. Yang, MD
Unilateral Horizontal Semicircular Canal
Department of Otorhinolaryngology Malformation Causing Recurrent Vertigo
College of Medicine – Philippine General Hospital
University of the Philippines Manila

Department of Otolaryngology Head and Neck Surgery

Far Eastern University - Nicanor Reyes Medical
Foundation Institute of Medicine

A 62-year-old man consulted for recurrent episodes of vertigo lasting from seconds to several
minutes. The vertigo was variably described as spinning, lateral swaying and a feeling of being
“unsure of his position in space.” These episodes were noted to have begun when the patient
was still in his 20’s. Standard pure tone audiometry revealed a mild-to-moderate downsloping
mixed hearing loss in the left ear. Bithermal caloric testing indicated the presence of a significant
left-sided peripheral vestibular loss. Due to the fact that the vertigo episodes presented relatively
early in life, the possibility of a congenital inner ear malformation was considered as a cause for
his symptoms. Computerized tomographic (CT) imaging of the temporal bone was performed.
This clearly showed the left horizontal semicircular canal lacking a central bony island. (Figure 1
and 2) The cochlea, superior and posterior semicircular canals, vestibular and cochlear aqueducts
and ossicular chain were grossly normal.

Correspondence: Dr. Nathaniel W. Yang

Department of Otorhinolaryngology
Ward 10, Philippine General Hospital
University of the Philippines Manila
Taft Avenue, Ermita, Manila 1000
Philippines
Phone: (632) 526 4360
Fax: (632) 525 5444
Email: nwyang@gmx.net

The author declared that this represents original material, that

the manuscript has been read and approved by the author, that
the requirements for authorship have been met by the author,
and that the author believes that the manuscript represents
honest work.

Disclosures: The author signed a disclosure that there are no

financial or other (including personal) relationships, intellectual Figure 1. Computerized tomographic imaging of the temporal bone in the axial view at the level of the horizontal semicircular
passion, political or religious beliefs, and institutional affiliations canal. The arrow points to the left horizontal semicircular canal which lacks a central bony island and has a cystic appearance.
that might lead to a conflict of interest. In comparison, the right horizontal semicircular canal has the classic “signet ring” appearance.

Creative Commons (CC BY-NC-ND 4.0)

Philipp J Otolaryngol Head Neck Surg 2017; 32 (2): 58-59 c Philippine Society of Otolaryngology – Head and Neck Surgery, Inc.
Attribution - NonCommercial - NoDerivatives 4.0 International

58 Philippine Journal Of Otolaryngology-Head And Neck Surgery

 FROM THE VIEWBOX
Philippine Journal Of Otolaryngology-Head And Neck Surgery Vol. 32 No. 2 July– December 2017

Figure 2. Computerized tomographic imaging of the temporal bone in the coronal view showing the horizontal semicircular canals at two different
levels. A. is at the level of the ampullated end of the canal, where the canals look similar (white arrows). B. is at the midpoint of the canal where
the right side shows a small ovoid lumen separated from the vestibule by bone; whereas the left side shows an enlarged lumen representing the
combined vestibule and semicircular canal without any intervening bone (angled white arrows). These images illustrate the difficulty in identifying
the abnormality on coronal view as compared to the axial view.

A malformation of the horizontal or lateral semicircular canal is
one of the most common inner ear malformations since it is the last
vestibular structure to be formed during inner ear embryogenesis.
As such, it may occur in isolation or may be associated with other
vestibular, cochlear, or middle ear malformations.1,2 Although vertigo
and dizziness are symptoms to be expected in such a condition,
existing data indicates that it may be totally asymptomatic or it may
also present as a sensorineural, conductive or mixed type of hearing
loss.1,3 Radiologic imaging is of prime importance in diagnosing such
conditions especially when auditory and/or vestibular symptoms
manifest early in life. This case perfectly illustrates the need for such
studies as the patient went undiagnosed for more than forty years!
No definitive statements can be gleaned from existing medical
literature with respect to treatment. However, in patients with
debilitating vestibular symptoms, management with modalities that
selectively target the vestibular system, but spare the auditory system,
such as vestibular neurectomy and trans-tympanic aminoglycoside
therapy appear to be reasonable options.

REFERENCES
1. Johnson J, Lalwani AK. Sensorineural and conductive hearing loss associated with
lateral semicircular canal malformation. Laryngoscope 2000 Oct;110(10):1673–1679.
DOI:10.1097/00005537-200010000-00019 PMID: 11037823
2. Casselman JW, Delanote J, Kuhweide R, van Dinther J, De Foer B, Offeciers EF. Congenital
malformations of the temporal bone. In: Lemmerling M, De Foer B, editors. Temporal bone
imaging. Berlin Heidelberg: Springer-Verlag; 2015, pp. 120-154.
3. Kim CH, Shin JE, Lee YJ, Park HJ. Clinical characteristics of 7 patients with lateral semicircular
canal dysplasia. Res Vestib Sci 2012;11(2):64-68.

Philippine Journal Of Otolaryngology-Head And Neck Surgery 59

 LETTER TO THE EDITOR
Philippine Journal Of Otolaryngology-Head And Neck Surgery
Cesar V. Villafuerte Jr., MD, MHA
Department of Otorhinolaryngology
College of Medicine – Philippine General Hospital
University of the Philippines Manila
Correspondence: Dr. Cesar V. Villafuerte, Jr.
Department of Otorhinolaryngology
Ward 10, Philippine General Hospital
University of the Philippines Manila
Taft Avenue, Ermita, Manila 1000
Philippines
Phone: (632) 554 8467; (632) 554 8400 local 2152
Email address: cvillafuertemd@gmail.com
The author declared that this represents original material
that is not being considered for publication or has not been
published or accepted for publication elsewhere in full or in
part, in print or electronic media; that the manuscript has been
read and approved by the author, that the requirements for
authorship have been met by the author, and that the author
believe that the manuscript represents honest work.
Disclosures: The author signed a disclosure that there are no
financial or other (including personal) relationships, intellectual
passion, political or religious beliefs, and institutional affiliations
that might lead to a conflict of interest.
Creative Commons (CC BY-NC-ND 4.0)
Attribution - NonCommercial - NoDerivatives 4.0 International
62 Philippine Journal Of Otolaryngology-Head And Neck Surgery
Vol. 32 No. 2 July– December 2017
Total Thyroidectomy From a Patient’s Perspective
Dear Editor,
Thyroidectomy is a common surgical procedure performed by us otolaryngologists on our
patients. Quite often, we make our post-operative rounds on them, not knowing that the patient
may have a lot of concerns regarding his or her operation that we somehow take lightly or worse,
do not take seriously. I would like to share with other Ear Nose Throat (ENT) surgeons how it was
to be a patient who underwent total thyroidectomy.
My journey began in the mid-1990’s with an incidental finding of thyroid nodules when I
underwent a Magnetic Resonance Imaging (MRI) of the cervical spine. It was then when I
started medical suppression and yearly thyroid ultrasound examinations. However as the years
passed, the nodules became more numerous involving both lobes and enlarging. It was last July
when ultrasonography revealed that 2 of the nodules were solid and large. I then underwent
ultrasound guided Fine Needle Aspiration Biopsy of the thyroid nodules for which the result was
Bethesda 1 (the biopsy was non-diagnostic or unsatisfactory). It was unanimously decided by
the endocrinologist and my ENT surgeons, Dr. Alfredo Pontejos, Jr. and Dr. Arsensio Cabungcal,
that I would undergo total thyroidectomy.
I had myself admitted at the Manila Doctors Hospital (MDH) on September 18, 2017 and
underwent the surgical procedure on September 19. Pre-operatively, I told the ENT chief
resident, Dr. Catherine Oseña my special “bilins”: 1) that I had a cervical spine problem so I could
not hyperextend the neck; 2) that I was allergic to Penicillin; 3) that I had ceased antiplatelets
(Clopidogrel, Aspirin) and fish oil omega for one week; 4) I had allergies to some non-steroidal
anti-inflammatory drugs (NSAIDs); 5) if possible the suturing be subcuticular so that there
wouldn’t be any need to remove any stitches post-op; and 6) the superior thyroid artery be ligated
twice and the end of the stump sealed by harmonic scalpel. I had some anxieties regarding the
surgery: losing my voice, undergoing tracheostomy for bilateral abductor paralysis since both
thyroid lobes would be removed, having a malignant histopathologic result and hypocalcemia.
DAY 0: “This is it”, I said to myself, when the nurse fetched me from my room at 6 am to be
brought to the operating room (OR) for my 7 am schedule. At the OR everybody who saw me
greeted me with phrases such as “Ikaw pala ang pasyente, kaya mo yan,” “Good luck” and “God
bless.” Here I saw one of my surgeons, Dr. Cabungcal enter the OR suite. It was then when I saw
my anesthesiologists, Dr. Ariel la Rosa and Dr. Greg Macasaet. The last memory I had pre-op was
that of Dr. La Rosa inserting an intravenous (IV) line in my right wrist and that was the last thing
I remembered.
Philipp J Otolaryngol Head Neck Surg 2012; 27 (2): 62-64 c Philippine Society of Otolaryngology – Head and Neck Surgery, Inc.

Philippine Journal Of Otolaryngology-Head And Neck Surgery
I woke up, already in the Post-Anesthesia Care Unit (PACU) or
Recovery Room (RR) when I felt severe pain in my neck (surgical area). I
also wanted to fix the pillow at the back of my head but I did not want
to cause any strain on my anterior neck. It was also here when I was
very happy to hear my own voice. It was then I said that the surgeons
preserved my voice. “Whataguys!” I said to my self, “Thank God.” It was
very painful then, I remember the PACU nurse injecting something thru
my I.V. line. I felt the medication run thru the I.V. line towards my arm
and throughout my body and this made me sleep again (later I found
out that it was nalbuphine). I recognize seeing my wife Lil, my son Vinci
and the ENT resident, Dr. Dindo Retreta at the PACU. The medication I
was given made me sleep again. I woke up again and heard that I was
being wheeled out of the PACU to be brought to my room. I only learned
later that I slept about an hour after the nalbuphine was given.
In my hospital room, the pain in the neck was really painful (9/10)
and I had difficulty expelling the phlegm from my trachea. Each
time I swallowed my saliva, I could feel my trachea move up with
accompanying pain. When the resident-on-duty (ROD) visited, I was
given N-acetylcysteine effervescent tablet BID (Ed: bis in die; twice a
day) that was very helpful as it made my expectoration easier. I could
feel the pressure dressing over my neck which was now stiff due to
dried blood.
I had my first meal at around 4 pm. I remember it was a tuna
sandwich and cold water which I drank using a straw from the hospital
plastic cup. Every bite and swallow was painful in the neck and throat. I
could not detect whether the pain was coming from the throat or from
the surgical site. My antibiotic was given I.V. and so was the pain reliever
parecoxib, paracetamol and tranexamic acid. I still did not resume the
blood thinners to prevent any post-op bleeding.
I tried to get up after dinner to walk around but warm serosnguinous
fluid came out of the drain soaking my hospital gown. I then had the
Philippine Journal Of Otolaryngology-Head And Neck Surgery 63
LETTER TO THE EDITOR
Vol. 32 No. 2 July– December 2017
nurse call the ENT ROD to change my thyroid dressing. In a few minutes,
a new fluffy gauze pressure dressing was applied by the ROD and my
hospital gown was replaced. I had a good sleep with some pain still at
the surgical site and throat.
DAY 1: The day started with Holy Communion in my room, a good
breakfast and my usual morning breakfast pills (thyroxine, nevibolol
and folic acid). The residents came and changed the dressing. The
resident “milked” the neck trying to see if there was any accumulated
blood or serum at the surgical site. This was the most painful of the
whole surgical experience (10/10) and it was good news that there was
no hematoma in the operative site. They then mobilized the drain by a
few centimeters. The dressing was still replaced with less fluffy dressing.
I have allergic rhinitis, and the act of sneezing caused recurrent pain
in the surgical site so I asked for an antihistamine tablet. My neck and
throat were still painful on Day 1 (8/10) but relieved every time the I.V.
analgesic was given. In the afternoon, I had a sponge bath given by the
nurse on duty with me lying in bed. I still had throat phlegm but thanks
to the acetylcysteine effervescent tablet it was easier to expectorate.
Every time the ROD made rounds, he checked for hypocalcemia--
fortunately I did not have it.
DAY 2: The day again started with Holy Communion and breakfast
in my hospital room. My main attending surgeon, Dr. Pontejos made
his rounds late morning and he changed the dressing and removed
the drain. I was here that I realized that the superior and inferior flaps
including the incision were all numb. There was no pain on drain
removal as well as on tying of the standby suture to close the drain site.
They were all numb. At this point, I realized that in all our patients, this
removal of the drain and the tying the standby suture were painless.
After a bath in the mid-afternoon before discharge, I was then feeling
better but the pain was still there (7/10). On the way home, I bought
some sterile gauze, plaster, mupirocin ointment and hydrogen peroxide
(H2O2) for my neck wound dressing at home.
 LETTER TO THE EDITOR
Philippine Journal Of Otolaryngology-Head And Neck Surgery Vol. 32 No. 2 July– December 2017

DAY 3. The pain was less (5/10) and I did not have to take any analgesic from hereon. Bathing became a problem but I devised a way to bathe
that I adopted for the following days. In the shower, I first shampooed by hair with my head and face facing down with my wife holding the
telephone shower and focusing it where it was needed. After this I dried my head and hair with a clean towel then bathed the rest of the body in
standing position with the telephone shower targeting the area needing to be rinsed. I did this method of bathing for a week until I decided that
I could now bathe without my head looking down. I was at rest at home for 2 weeks.

DAY 6: It was one of the best days of my life when the chief resident told me that the histopathologic result was multinodular goiter and no
malignancy. Yehey! Thanks to God! God is really good!

To summarize some of the things I want to share with other thyroid surgeons:

1) I didn’t realize that the post-op pain was really painful, so I can now understand my patients if they experience pain post-operatively.

2) It was difficult to expel throat phlegm and the N-acetylcysteine effervescent tablet was a big help in liquefying the phlegm.

3) The whole area is numb (superior and inferior flaps), thus the removal of the drain and sutures would not cause any pain on the patient.

4) The “milking” of the site was painful and this procedure should be gently done.

5) If the patient has nasal allergy, cover the patient with an antihistamine to prevent sneezing and unnecessary pain.

6) Teach your patient the way I bathed and order a sponge bath on Day 1 and 2.

I hope this sharing of experience will benefit all your patients who will undergo the same procedure- thyroidectomy.

I would like to thank my surgeons (Dr. Alfredo Pontejos, Jr. and Dr. Arsenio Cabungcal), the anesthesiologists (Dr. Ariel la Rosa and Dr. Greg
Macasaet), the surgical assistants (MDH ORL residents – Drs. Catherine Elise Oseña and Dindo Retreta), my endocrinologist Dr. Roberto Mirasol and
my cardiologist Dr. Rogelio Tangco, for the excellent job, well done.

I would like to thank my family – Lil my wife, Vinci, Ericka and Raymond for their love and support and for taking care of me.

I would like to thank the MDH ORL Residents for taking care of me and for a job well done as well. I would also like to thank all the nursing staff
at the MDH tower 1 and the OR, PACU nurses for taking care of me as well.

Sincerely yours,
Cesar V. Villafuerte, Jr., MD, MHA

64 Philippine Journal Of Otolaryngology-Head And Neck Surgery


Philippine Journal Of Otolaryngology-Head And Neck Surgery
Rhoda Zyra M. Padilla-Baraoidan, MD
Maria Jocelyn Capuli-Isidro, MD
Beinjerinck Ivan B. Cudal, MD
Ayezl A. Embestro-Pontillas, MD
Department of Medicine
Section of Endocrinology
Diabetes, and Metabolism
Makati Medical Center
Correspondence: Dr. Rhoda Zyra M. Padilla-Baraoidan
Department of Medicine - Section of Endocrinology,
Diabetes and Metabolism
Makati Medical Center
#2 Amorsolo St., Legaspi Village, Makati City 1229
Philippines
Phone: +63-917-598-2520
Email: rzpadillamd@gmail.com
The authors declared that this represents original material
that is not being considered for publication or has not been
published or accepted for publication elsewhere, in full or in
part, in print or electronic media; that the manuscript has been
read and approved by all the authors, that the requirements
for authorship have been met by each author, and that each
author believes that the manuscript represents honest work.
Disclosures: The authors signed disclosures that there are no
financial or other (including personal) relationships, intellectual
passion, political or religious beliefs, and institutional affiliations
that might lead to a conflict of interest.
Presented at PSEDM 17th Endocrine Fellows Research Forum at
Innogen Office, February 16, 2017. Brgy. Sacred Heart, Quezon
City, Philippines
Presented at Makati Medical Center Annual Fellows’ Scientific
Paper Presentation. June 1, 2017. Legaspi Village, Makati City,
Philippines
Creative Commons (CC BY-NC-ND 4.0)
Attribution - NonCommercial - NoDerivatives 4.0 International
Philippine Journal Of Otolaryngology-Head And Neck Surgery 11
ORIGINAL ARTICLES
Vol. 32 No. 2 July– December 2017
Hungry Bone Syndrome (HBS) in Patients
Operated for Primary Hyperparathyroidism
(PHPT): A Six-Year Experience
ABSTRACT
Objective: To review cases of adult patients who develop Hungry Bone Syndrome (HBS) after
parathyroidectomy for Primary Hyperparathyroidism (PHPT) in a tertiary care center in the
Philippines and describe the clinical features, pre-operative preventive measures done and risk
factors for HBS.
Methods:
Design: Retrospective Case Note Review
Setting: Tertiary Private Hospital
Participants: Chart review of adult Filipino patients who underwent
parathyroidectomy for PHPT at Makati Medical Center from January 2011 to December 2016 was
conducted and evaluated according to the inclusion and exclusion criteria. Medical information
obtained included clinical parameters, biochemical results, operation performed, pathology,
length of hospital stay and complications if with any.
Results: From among 20 adult Filipino patients (mean age 55 years; 13, 65% female) who
underwent parathyroidectomy for PHPT, HBS was found in 7 (35%). Most common pre-operative
symptoms of hypercalcemia were musculoskeletal complaints. To prevent HBS, all were hydrated
prior to surgery while some were given bisphosphonates and diuretics. The most common
parathyroid gland imaging used for pre-procedure localization was Tc 99m Sestamibi scan with
single photon emission computed tomography (SPECT) and 19 (95%) had parathyroid adenoma
on post-operative histopathologic report. Among biochemical and clinical factors that may be
risk factors for HBS, those with HBS had significantly lower pre-operative 25-hydroxyvitamin D,
higher BUN, phosphate and alkaline phosphatase (ALP) than those without HBS. Of these, only
ALP showed significant association with HBS (OR = 107.17, p = <0.0001). Length of hospital stay
was longer among those with HBS although not statistically significant.
Conclusion: Knowledge on post-parathyroidectomy HBS for PHPT may aid clinicians on pre-
operative prevention and post-operative monitoring. Thirty-five percent (7) of our patients
presented with HBS post-parathyroidectomy for PHPT from 2011 to 2016. An abnormal ALP level
pre-operatively may be a risk factor in developing HBS post-parathyroidectomy for PHPT.
Philipp J Otolaryngol Head Neck Surg 2017; 32 (2): 11-16 c Philippine Society of Otolaryngology – Head and Neck Surgery, Inc.
 ORIGINAL ARTICLES
Philippine Journal Of Otolaryngology-Head And Neck Surgery
Keywords: primary hyperparathyroidism, hungry bone syndrome,
Philippines
Primary hyperparathyroidism (PHPT) is the most common
etiology of hypercalcemia with a reported prevalence of 21 per 100,000
in Minnesota between 1999 – 2001.1 It is caused by excessive and
uncontrolled secretion of parathyroid hormone (PTH) by an abnormal
parathyroid gland. Parathyroidectomy remains the treatment of
choice for PHPT but it is not without risks.1 One common complication
of parathyroid surgery is the development of hypocalcemia post-
operatively.2 When hypocalcemia is severe, defined as serum total
calcium concentration below 2.1 mmol/L and lasts for more than 4 days
post-parathyroidectomy, patients are deemed to have Hungry Bone
Syndrome (HBS).3 A 2016 study in Turkey noted the incidence of HBS
post parathyroidectomy for PHPT was 13.4%.2 Another 2012 study in
Thailand reported the HBS incidence post-parathyroidectomy for PHPT
was 22%.4 Identified risk factors for the development of HBS include
parathyroid hyperplasia and presence of osteoporosis. Identified
biochemical predictors for HBS were higher preoperative PTH, ALP and
BUN values. Moreover, HBS was more common in patients who had
thyroidectomy together with parathyroidectomy.2 The General Endocrine Cases census from the Annual Reports of
A search of local (HERDIN) and international databases (PubMed
- MEDLINE, Google Scholar and ScienceDirect) using the following
keywords: hungry bone syndrome, primary hyperparathyroidism
and Philippines revealed only one reported case in 2010 of PHPT
with classic and severe skeletal involvement who underwent
parathyroidectomy and developed HBS 7 days post-operatively5
but yielded no other articles on the incidence and risk factors of
HBS post parathyroidectomy for PHPT in our country. Increasing
identification of hypercalcemia from primary hyperparathyroidism
and the importance of equipping clinicians with knowledge on pre-
operative prevention and post-operative monitoring of HBS after
parathyroidectomy prompted this study. nonspecific symptoms. Chemistry findings included pre-operative and
Our aim was to review the cases of adult patients who developed
HBS after parathyroidectomy for PHPT in a tertiary care center in
the Philippines and to describe the clinical features, pre-operative
preventive measures done and risk factors for HBS.
Methods
Study Design and Subjects
This retrospective case note review considered Filipino adults
18-years-old and above, admitted under or referred to the Section
of Endocrinology, Diabetes and Metabolism of the Makati Medical
Center in the Philippines between January 2011 to December 2016
12 Philippine Journal Of Otolaryngology-Head And Neck Surgery
Vol. 32 No. 2 July– December 2017
who underwent parathyroidectomy for primary hyperparathyroidism.
Primary hyperparathyroidism was defined as a primary abnormality
of parathyroid tissue that leads to inappropriately high serum
concentration of PTH with hypercalcemia, hypophosphatemia, loss
of cortical bone and hypercalciuria. Discharge diagnoses in the chart
included all possible terms that could include parathyroidectomy
in our institution, coded as either primary hyperparathyroidism,
neck exploration, parathyroidectomy or parathyroid biopsy. Patients
diagnosed to have secondary hyperparathyroidism due to end-stage
renal disease, sarcoidosis, familial hypocalciuric hypercalcemia, tertiary
hyperparathyroidism or recurrent or persistent hyperparathyroidism
after parathyroidectomy (as these patients would have been previously
diagnosed with PHPT and may have undergone parathyroidectomy but
have persistently elevated post-operative calcium and PTH levels and
re-operation increases their risk for permanent hypocalcemia and not
just HBS) were excluded.
This study was approved by the Institutional Review Board of the
Makati Medical Center (protocol number MMCIRB 2016-109).
Data Collection
2011-2016 of the Section of Endocrinology, Diabetes and Metabolism
of Makati Medical Center were retrieved. All related medical information
were obtained including the following: demographic data, clinical
presentation, comorbidities, method of localization used to identify
the abnormal parathyroid gland, preoperative medications given to
prevent HBS, preoperative and postoperative blood chemistry results,
operation performed with operative findings, pathology, length of
hospital stay and post-operative complications, if any. Demographic
data consisted of gender, age, and other comorbidities. Clinical
presentation was divided into the effect of calcium on the organ systems:
skeletal, renal, neuromuscular, neuropsychiatric, gastrointestinal, and
post-operative serum calcium (total or ionized), albumin, magnesium,
phosphate, alkaline phosphatase (ALP), intact parathyroid hormone
(iPTH), BUN, creatinine and serum 25-hydroxyvitamin D. Postoperative
blood chemistry was recorded until discharge. Imaging modalities for
localization was accounted for and its volume was computed using the
ellipsoid model formula (length x width x height x 0.52).
Normal range of the laboratory parameters were established as
follows: iPTH: 15-65 pg/mL, Total Calcium: 8.6 – 10.2 mg/dL, Ionized
Calcium: 1.12 – 1.32 meq/L, phosphorus: 2.75 – 4.5 mg/dL, albumin: 3.5
– 5.2 g/dL, magnesium: 1.6 – 2.6 mg/dL, Alkaline Phosphatase: 30 – 130
IU/L, BUN: 6 – 20 mg/dL, TSH: 0.27 – 4.2 uIU/mL, fT4: 12 – 22 pmol/L, 25-
 ORIGINAL ARTICLES
Philippine Journal Of Otolaryngology-Head And Neck Surgery Vol. 32 No. 2 July– December 2017

OHD: 30 – 100 ng/mL, TSH-IRMA (nuclear medicine): 0.27 – 3.75 uIU/mL,

fT4-RIA (nuclear medicine): 8.8 – 33 pmol/L.
Calcium levels were calculated with the corrected calcium formula
based on the patient’s albumin levels if with abnormal albumin results.
The formula used was as follows: Corrected Calcium (mg/dL) = [0.8 x
(4 – patient’s albumin)] + Serum Calcium level.

Statistical Analysis
Data encoding, processing and analysis were performed using
Microsoft Excel for Mac 2015 version 15.13.3 (Microsoft Corporation,
Washington, USA). Continuous data were presented as means and
standard deviation (SD) while categorical data were presented as
frequencies and SD or 95% confidence intervals (CIs) as appropriate. Figure 1. Pre-operative symptoms of hypercalcemia among included patients
Fisher exact test was used for assessment of association of categorical
data and Student t-test for two-group comparison of continuous
variables. Risk factors associated with hungry bone syndrome were
determined with exact logistic regression analysis using the software
Stata 15 (StataCorp LLC, Texas, USA). Significance level was set at 5%.

Results
Out of 20 adult Filipino patients who underwent parathyroidectomy
for primary hyperparathyroidism at the Makati Medical Center from
January 2011 to December 2016, seven (35%) were found to have
Hungry Bone Syndrome (HBS).
The 20 participants included in this study had a mean age of 55-
years-old with a range of 36 to 69 years and female predominance of
2:1. The most common pre-operative symptoms of hypercalcemia were
renal calculi, osteoporosis, myalgia, neck mass, pathologic fracture
Figure 2. Medications given pre-operatively for hypercalcemia management and HBS prevention
and constipation. (Figure 1) The most common co-morbidities by
frequency of mention were hypertension (15; 70%), diabetes mellitus
type 2 (8; 40%) and myocardial infarction (5; 25%). To prevent HBS, all
were hydrated preoperatively, 7 (35%) were given bisphosphonates
and 6 (30%) were given diuretics. A few were given calcitonin (3; 15%)
calcimimetics (3; 15%) and vitamin D (3; 15%). (Figure 2) The most
common parathyroid gland imaging used for pre-procedure localization
was Tc99m Sestamibi scan with single photon emission computed
tomography (SPECT). (Figure 3) All patients with PHPT underwent
parathyroidectomy involving removal of only one culprit parathyroid
gland. Ninety-five percent (19/20) were found to have parathyroid
gland adenoma on post-operative histopathology report. Sixty-percent
(12/20) of patients had a concomitant subtotal (3; 15%) or total (9; 45%)
thyroidectomy for a separate thyroid pathologic indication. Of the 12
patients that underwent thyroidectomy, 2 had papillary thyroid cancer
and the rest had multinodular goiter. None had abnormal thyroid Figure 3. Distribution of pre-operative parathyroid gland localization imaging study used in patients
Included in the study

Philippine Journal Of Otolaryngology-Head And Neck Surgery 13

 ORIGINAL ARTICLES
Philippine Journal Of Otolaryngology-Head And Neck Surgery Vol. 32 No. 2 July– December 2017

function tests pre-operatively. Table 1. Pre-operative biochemical and clinical risk factors of HBS after parathyroidectomy for
Table 1 compares values of selected pre-surgical biochemical and PHPT
clinical risk factors of HBS. From among these factors, only 4 variables Risk Factors* (-) HBS (+) HBS p Value
showed significant association with HBS at the 95% confidence level (p N = 13 N=7
<0.05): 25-hydroxyvitamin D, BUN, phosphate and ALP. Those with HBS Thyroid
Stimulating
had significantly lower pre-operative 25-hydroxyvitamin D, higher BUN, Hormone (TSH) 1.66 + 1.12 1.65 + 0.85 0.992
phosphate and ALP than those without HBS. (uIU/ml), Mean,
SD
To determine independent risk factors for HBS, we employed exact
Free Thyroxine
binary logistic regression for small sample sized data sets. The four (fT4) (pmol/L), 16.55 + 3.21 18.18 +3.32 0.299
variables which showed significant p values from the bivariate analysis Mean, SD
were included in logistic regression analysis. Calcium (mg/ 10.81 + 1.04 10.73 + 0.87 0.859
Full model exact binary logistic regression using continuous data dL), Mean, SD
did not produce viable estimates. When only ALP was placed in the Parathyroid
Hormone (PTH) 175.19 + 132.03 441.61 + 603.35 0.136
model, the analysis showed significant results (p <0.0001). Considering (pg/mL), Mean,
only this model, it was found that the odds of having HBS increased by SD
9% with every unit increase in ALP. (Table 2A) 25-hydroxy
Vitamin D(ng/ 24.15 + 7.81 11.39 + 2.36 0.00057 (S)
Table 2A shows that viable estimates for ALP were produced when mL), Mean, SD
only categorical variables were used. If the full model is considered, the Blood Urea
association between HBS and ALP status is shown to be insignificant (p Nitrogen (BUN) 14.95 +4.36 43.84 + 23.00 0.00029 (S)
(mg/dL), Mean,
= 0.08). Understandably, when each variable is taken out of the model
SD
one by one, the odds ratio (OR) increased. When placed in a model Phosphorous
with HBS, ALP showed a significant association with the said outcome (mg/dL), Mean, 2.79 + 0. 89 4.03 + 1.71 0.04110 (S)
variable (p <0.0001). Odds ratio was 107.17, which means HBS was SD
107.17 times more likely to occur given an abnormal level of ALP than Magnesium
(mg/dL), Mean, 2.01 + 0.29 1.99 + 0.46 0.882
with a normal level. (Table 2B) SD
The length of hospital stay in days was longer among those with Creatinine (mg/ 0.94 + 0.32 2.29 + 2.52 0.067
HBS with a mean of 10.86 ± 6.15 vs. 6.77 ± 3.98 although the value did dL), Mean, SD
not reach statistical significance (p = 0.085). Alkaline
phosphatase 79.77 + 24.96 161.86 + 17.37 <0.0001 (S)
(IU/L), Mean, SD
Discussion Parathyroid
Primary hyperparathyroidism (PHPT) is an endocrine disorder gland adenoma 1.34 + 0.92 3.18 + 3.66 0.097
volume (cm3),
characterized by autonomous production of parathyroid hormone.
Mean, SD
In the United States of America, the estimated incidence of PHPT With
between 1998-2010 was approximately 50 per 100,000 person years thyroidectomy, 7 (54%) 5(71%) 0.642
in the general population.6 The increase in PTH secretion in primary N (%)
hyperparathyroidism is hypothesized to be secondary to an elevation *Student’s t-test for test of association of continuous variables (i.e. those with means and
in set-point with a documented variable shift to the right in the slope SDs); Fischer’s exact test for categorical data (i.e. those with frequency count)
(S): significant p value (p <0.05) at 95% confidence interval
of the calcium – PTH curve due to relative non-suppressibility of PTH
secretion. The increase in the set-point is the primary determinant of that effects abrupt discontinuation of excessive osteoclastic activity
the degree of hypercalcemia.1 from the hyperparathyroid state.
Parathyroidectomy is the definitive management for PHPT with the With the advent of wide availability and utilization of biochemical
aim of removing the culprit abnormal parathyroid gland, however, post- tests performed even among asymptomatic patients, hypercalcemia
operative severe and prolonged hypocalcemia (HBS) may occur. This is from PHPT is now identified with increasing frequency. In our
a consequence of the sudden withdrawal of PTH signal post surgery institution, it was noted that there has been a steady increase in the

14 Philippine Journal Of Otolaryngology-Head And Neck Surgery


Philippine Journal Of Otolaryngology-Head And Neck Surgery
Table 2A. Results of exact binary logistic regression to determine independent risk factors of
HBS pre-operatively using continuous variables
Risk Factors* Odds Ratio Sufficient Suff.2* 95% CI
(OR) Pr(Suff)
Alk 1.09* 1133 0.0000 1.03 - +Inf
Phosphatase
(ALP)
*median unbiased estimates (MUE)
number of performed parathyroidectomies per year from 2 cases in
2011 to 8 cases in 2016.
In this investigation, 35% (7/20) of patients who underwent
parathyroidectomy for PHPT in our institution from 2011 to 2016 were
found to have HBS. The mean age was in the fifth decade of life with
females comprising the majority at 65% (13/20). These findings are
comparable with the results of several authors. One study in 2016
reported an incidence of HBS post-parathyroidectomy for PHPT at
13.4%.2 Yeh et al. in 2013 noted that majority of cases occured in patients
over the age of 50-65 years with women being affected twice as often
as men.7 Among Asians in Thailand, the reported HBS incidence post-
parathyroidectomy for PHPT was 22%. The subjects had a median age
of 49 years (range 15 to 89 years) with female predominance at 3:1.4
In terms of clinical pre-operative symptoms of hypercalcemia,
since calcium homeostasis is important to normal cellular function,
the manifestations of PHPT may present as musculoskeletal,
renal, gastrointestinal, cardiovascular, neuromuscular and
neuropsychiatric symptoms.1 The abnormalities directly associated
with hyperparathyroidism are nephrolithiasis and bone disease due to
prolonged PTH excess. Among our patients included in this study, the
most common presenting symptoms were renal, musculoskeletal and
gastrointestinal in nature.
PHPT diagnosis is made by biochemical testing. Localization studies
are only recommended if the patient will undergo surgery. Commonly
used and available imaging methods include neck ultrasound, Tc99m
Sestamibi scintigraphy with SPECT or subtraction thyroid scan and
MRI of the neck. Sestamibi scintigraphy combined with SPECT has the
highest positive predictive value of the available imaging techniques.8
In our institution, the practice was at par with the recommendations for
pre-operative parathyroid gland localization as majority of the patients
were likewise subjected to Tc99m Sestamibi scan with SPECT. Even
the findings of the parathyroid gland histopathology post-operatively
among our patients were consistent with the literature that single
adenomas account for up to 80 – 85% of cases of PHPT and mostly
consist of parathyroid chief cells.1
In a 2013 meta-analysis on measures that can be instituted pre-
Philippine Journal Of Otolaryngology-Head And Neck Surger 15
ORIGINAL ARTICLES
Vol. 32 No. 2 July– December 2017
Table 2B. Results of exact binary logistic regression to determine independent risk factors of
HBS pre-operatively using binary variables (normal/abnormal)
Variable Odds Ratio Sufficient Suff.2* 95% CI
Pr(Suff)
Alk 107.17* 7 0.0000 9.91 - +Inf
Phosphatase
(ALP)
*median unbiased estimates (MUE)
operatively to prevent HBS, it was recommended to supplement
vitamin D pre-parathyroidectomy to normalize levels as depleted
vitamin D has been postulated as a risk factor for the development
of HBS. Other agents that may be used with good level of evidence
are bisphosphonates that best address bone resorption. Intravenous
pamidronate given 2 days pre-operatively decreased serum
calcium pre-surgery and decreased calcium requirements post-
procedure while intravenous zoledronate lowered HBS frequency
post-operatively by as much as 4%.3 On one end of the spectrum,
preparation for parathyroidectomy in patients is not limited to
prevention of HBS but also involves controlling elevated calcium
levels to prevent occurrence of hypercalcemic crisis pre-operatively.
In 2011, a study enumerated the treatment needed in the correction
of hypercalcemia which includes adequate hydration, stimulation of
calcium excretion by forced diuresis, inhibition of osteoclast effect
on bone resorption through bisphosphonates or calcitonin and use
of estrogens in menopausal women or calcimimetics like calcitonin.9
These were the rationale for the pre-operative preparation of our
patients wherein most received hydration, diuretics, anti-resorptive
agents, vitamin D and calcimimetics.
Several authors investigated possible risk factors for the
development of HBS post-parathyroidectomy for PHPT and in 2016,
the following were identified: histopathologic finding of parathyroid
hyperplasia and presence of osteoporosis pre-operatively. The HBS
biochemical predictors were higher pre-surgery PTH, ALP and BUN
values. In addition, HBS was more common in patients who had
parathyroidectomy concomitantly with thyroidectomy.2 Another article
presented the following risk factors: older age at the time of surgery,
higher pre-operative levels of serum calcium, PTH, ALP, decreased
serum levels of magnesium and albumin and depleted vitamin D
status.3 Radiographic evidence of PHPT-associated bone pathology
was likewise deemed to be a risk factor for HBS development. It was
also reported that the volume and weight of the removed parathyroid
adenomas were higher among patients who had HBS than those
who had an uncomplicated post-operative course.3 Apart from the
documented increased risk of HBS if parathyroidectomy is performed
 ORIGINAL ARTICLES
Philippine Journal Of Otolaryngology-Head And Neck Surgery
with thyroidectomy, it is prudent to include thyroid function tests in the
biochemical investigation prior to parathyroidectomy as concomitant
Graves’ disease or hyperthyroidism can exacerbate the increased bone
turnover state in PHPT.10
In our investigation, there were 4 identified possible biochemical
risk factors that may predict HBS pre-operatively: 25-hydroxyvitamin
D, BUN, phosphate and ALP. However, only abnormal ALP showed a
significant association with HBS after further analysis.
Serum ALP levels can serve as a marker of bone remineralization.
Preoperative serum ALP levels thereby reflect bone turnover status
and directly relates to the osteoclastic activity and degree of bone
resorption.2,3 As for the other three risk factors identified but that
did not show significant results after exact logistic regression tests,
a possible theoretical explanation could be that low vitamin D
levels in PHPT could mean more advanced disease reflecting higher
bone resorption, reduced bone mineral density, post-operative
hypocalcemia and higher PTH levels.11 Moreover, low serum levels of
25-hydroxyvitamin D cause decreased fractional calcium absorption
leading to suboptimal bone mineralization.3 In HBS, the elevated
BUN as a risk factor can develop due to the advanced age of patients
and the effects of hypercalcemia on renal blood flow and renal
tubular function.2 While an increased PTH level would theoretically
inhibit proximal tubule reabsorption of phosphate leading to
hypophosphatemia, the elevated pre-operative levels of phosphate in
patients who developed HBS post-parathyroidectomy for PHPT in our
cases could be secondary to the effect of high PTH on the bones that
influences higher bone turnover releasing calcium and phosphate
from the bone matrix into the circulation.1
This study has several limitations. The retrospective design did
not give the researchers the opportunity to validate the symptoms
of hypercalcemia pre-operatively or the hungry bone syndrome
manifestations post-operatively. The sample size of 96 that was
needed to show accurate estimates of incidence and identify
significant predictors was not achieved in this study and potential
significant associations among variables could have been masked.
Future researchers may consider a prospective study on the outcomes
of patients undergoing parathyroidectomy for PHPT or extend the
study period to achieve the target sample size. The establishment
of a multicenter case registry may provide a means for collaboration
among different centers in the country for a more accurate estimate
of epidemiology and better understanding of the clinical features of
HBS post-parathyroidectomy for PHPT.
In conclusion, our study found that thirty-five percent (7/20)
of our patients developed HBS post-parathyroidectomy for PHPT
between 2011 and 2016. Our findings suggest that an abnormal ALP
16 Philippine Journal Of Otolaryngology-Head And Neck Surgery
Vol. 32 No. 2 July– December 2017
level pre-operatively may be a risk factor for developing HBS post-
parathyroidectomy for PHPT. Knowledge of post-parathyroidectomy
HBS for PHPT may aid clinicians in pre-operative prevention and post-
operative monitoring.
REFERENCES
1. Melmed S, Polonsky KS, Larsen PR, Krokenberg H, editors. Williams Textbook of Endocrinology.
13thed. Philadelphia: Elsevier, Inc. 2016.
2. Kaya C, Tam AA, Dirikoc A, Kilicyazgan A, Kilic M, Turkolmez S, Ersoy R, Cakir B. Hypocalcemia
development in patients operated for primary hyperparathyroidism: Can it be predicted
preoperatively? Arch Endocrinol Metab. 2016 Oct; 60 (5): 465-471. DOI: 10.1590/2359-
3997000000207. Epub 2016 Oct 10. PMID: 27737322.
3. Witteveen JE, van Thiel S, Romjin JA, Hamdy NA. Hungry bone syndrome: still a challenge in the
post-operative management of primary hyperparathyroidism: a systematic review of literature.
Eur J Endocrinol. 2013 Feb 20; 168(3): R45-R53. DOI: 10.1530/EJE-12-0528. PMID: 23152439.
4. Prasarttong-Osoth P, Wathanaoran P, Imruetaicharoenchoke W, Rojananin S. Primary
hyperparathyroidism: 11-year experience in a single institute in Thailand. Int J Endocrinol. 2012;
2012: 952426. DOI: 10.1155/2012/952426. PMID: 22701120 PMCID: PMC3369527.
5. Sandoval MA, Paz-Pacheco E. Primary hyperparathyroidism with classic and severe skeletal
involvement. BMJ Case Rep. 2010 Aug 26; 2010. DOI: 10.1136/bcr.04.2010.2929. PMID: 22767476.
PMCID: PMC3028290.
6. Griebeler ML, Keams AE, Ryu E, Hathcock MA, Melton LJ, Wermers RA. Secular trends in the
incidence of primary hyperparathyroidism over five decades (1965 – 2010). Bone. 2015 Apr;
73: 1 – 7. DOI: 10.1016/j.bone.2014.12.003. Epub 2014 Dec 11. PMID: 25497786; PMCID:
PMC4445941.
7. Yeh MW, Ituarte PH, Zhou HC, Nishimoto S, Liu IL, Harari A, et al. Incidence and prevalence of
primary hyperparathyroidism in a racially mixed population. J Clin Endocrinol Metab. 2013 Mar;
98 (3): 1122-1129. DOI: 10.1210/jc.2012-4022. PMID: 23418315. PMCID: PMC3590475.
8. Eslamy HK, Ziessman HA. Parathyroid scintigraphy in patients with primary hyperparathyroidism:
99mTc sestamibi SPECT and SPECT/CT. Radiographics. 2008 Sep-Oct; 28 (5): 1461 – 76. DOI:
10.1148/rg.285075055. PMID: 18794320.
9. Zivaljevic V, Kalezic N, Jovanovic D, Sabljak V, Diklic A, Paunovi I. Preoperative preparation of
patients with hyperparathyroidism as comorbidity. Acta Chir Iugosl. 2011; 58 (2): 109-115. DOI:
10.2298/ACI1102109Z. PMID: 21879659.
10. Tachibana S, Sato S, Yokoi T, Nagaishi R, Akehi Y, Yanase T, et al. Severe hypocalcemia complicated
by postsurgical hypoparathyroidism and hungry bone syndrome in a patient with primary
hyperparathyroidism, Graves’ disease, and acromegaly. Intern Med. 2012; 51 (14): 1896 – 1873.
Epub 2012 Jul 15. DOI: 10.2169/internalmedicine.51.7102. PMID: 22821103.
11. Rolighed L, Rejnmark L, Sikjaer T, Heickendorff L, Vestergaard P, Mosekilde L, et al. Vitamin
D treatment in primary hyperparathyroidism: a randomized placebo controlled trial. J Clin
Endocrinol Metab. 2014 Mar; 99 (3): 1072 – 1080. Epub 2014 Jan 13. DOI: 10.1210/jc.2013-3978.
PMID: 24423366.
 ORIGINAL ARTICLES
Philippine Journal Of Otolaryngology-Head And Neck Surgery Vol. 32 No. 2 July– December 2017

Rodolfo U. Fernandez III, MD

An Initial Overview of Management
Department of Otorhinolaryngology and Treatment Outcomes
Philippine General Hospital
University of the Philippines Manila for Head and Neck Hemangiomas

ABSTRACT
Objectives: To provide an initial overview of the outcomes of different treatment modalities
used for hemangiomas.

Methods:
Design: Case Series
Setting: Tertiary National University Hospital
Participants: Records of 21 patients diagnosed with head and neck hemangiomas
in the Philippine General Hospital Department of Otorhinolaryngology from 2009 to 2014 were
reviewed.

Results: Majority of the patients were female (61.9%) and in the pediatric age group (57.1%).
Of the 21 patients, 6 underwent medical management, 13 had surgical management, 1 had
both medical and surgical management and 1 opted to observe the lesion. All patients treated
with propranolol observed a decrease in the size of the lesion. Seven out of the 13 patients had
radiofrequency ablation; all had gross residual lesion. Six of the 13 underwent excision with
complete excision being achieved in 5 of 6 cases.
Correspondence: Dr. Rodolfo U. Fernandez III
Department of Otorhinolaryngology
Ward 10, Philippine General Hospital
Taft Avenue, Ermita, Manila 1000
Conclusion: Treatment response of patients in this series with hemangiomas of the head and neck
Philippines to propranolol at a dose of 1 to 2 mg/kg/day may reflect international data. Outcomes analysis for
Phone (632) 554 8467
Email: rufernandez.iii@gmail.com radiofrequency ablation and surgical excision requires a longer duration of follow-up.
The author declared that this represents original material
that is not being considered for publication or has not been  Keywords: propranolol hydrochloride, prednisone, pulsed radiofrequency treatment, capillary
published or accepted for publication elsewhere in full or in
part, in print or electronic media; that the manuscript has been hemangioma, vascular tissue neoplasms
read and approved by the author, that the requirements for
authorship have been met by the author, and that the author
believe that the manuscript represents honest work. Hemangiomas are the most common benign vascular tumors in infancy (but may also involve
The author signed disclosures that there are no financial or adults) and most commonly affect the head and neck region.1 Unlike other vascular tumors,
other (including personal) relationships, intellectual passion,
political or religious beliefs, and institutional affiliations that
hemangiomas have a characteristic natural course-- they rapidly proliferate during infancy and
might lead to a conflict of interest. gradually involute over the next few years of life. However, a small proportion of hemangiomas
Presented at the Philippine Society of Otolaryngology Head require intervention. Indications for intervention include function-threatening hemangiomas
and Neck Surgery Descriptive Research Contest, October 6,
2016. Natrapharm, The Patriot Bldg. Parañaque City.
(e.g. ocular, ear, nasal tip and genitalia), life-threatening hemangiomas (e.g. airway lesion),
disfiguring large hemifacial hemangiomas, ulcerated hemangiomas and those with associated
systemic involvement.1
Creative Commons (CC BY-NC-ND 4.0)
Philipp J Otolaryngol Head Neck Surg 2017; 32 (2): 30-33 c Philippine Society of Otolaryngology – Head and Neck Surgery, Inc.
Attribution - NonCommercial - NoDerivatives 4.0 International

30 Philippine Journal Of Otolaryngology-Head And Neck Surgery

 ORIGINAL ARTICLES
Philippine Journal Of Otolaryngology-Head And Neck Surgery Vol. 32 No. 2 July– December 2017

Systemic corticosteroids (e.g. prednisone at a dose of 2-4 mg/kg/ Table 1. Medical Management Group
day) have been used as the first line treatment for hemangiomas for Dura-
many years but long-term side effects of systemic steroids have been Location Size of Dose tion
a recurring problem.1 Recently, non-selective beta-blockers such as Patient Age/ of lesion Drug (mg/ of Out-
Code Sex lesion (cm) kg/ treat come
propranolol and timolol have emerged as safer and more promising day) ment
treatment modalities.1 Other treatment options include the use (months)
of intralesional triamcinolone, topical steroids such as clobetasol M1 8/M lip 1x1x oral 1.25 12 decrease
propionate, topical imiquimod and pulse dye laser.1-3 With the failure of 0.5 propranolol in size
medical management, surgical modalities come into play. M2 9 oral 1 3 no change
mo buccal 8 x 6 x 2 prednisone
In the Philippine General Hospital, hemangiomas are independently s/F oral 2 6 decrease
managed by different units which include Pediatrics, Plastic Surgery, propranolol in size
Dermatology and Otorhinolaryngology. The objective of this study is M3 8/F lip 5x2x1 oral 1 1.5 no change
prednisone
to provide an initial overview of the outcomes of different treatment
intralesional 1.5 q1 3 decrease
modalities for patients with hemangiomas of the head and neck of the methyl month in size
Department of Otorhinolaryngology from 2009 to 2014. M4 4/F nasal 1 x 1 x prednisolone
0.5 oral 2 20 decrease
METHODS propranolol in size
M5 6/F temporal 4.5 x 5 oral 2 2 decrease
With Institutional Review Board approval, this case series purposively
x 1 propranolol in size
identified patients diagnosed with head and neck hemangiomas M6 4/F tongue 10 x 8 oral 1 6 decrease
between January 2009 to December 2014 from outpatient, in patient, x 8 propranolol in size
and emergency room censuses of the Philippine General Hospital
(PGH) Department of Otorhinolaryngology, and retrieved their medical
records for review. surgical management, and 1 patient opted to observe the lesion.
Excluded were records of patients with a post-treatment follow- All 5 patients who underwent medical management with
up of less than 6 months or who were lost to follow-up before or after propranolol doses ranging from 1 to 2 mg/kg/day for at least 2 months
treatment, those who did not comply with the medical treatment were reported to have a decrease in size of their hemangiomas. Of
regimen, and those whose records were incomplete or missing. the 5, one (M2) was initially treated with oral prednisone (without
Demographic data, location and size of lesion were extracted response) and another (M4) received intralesional methylprednisolone
from the records. For patients treated medically, the following were (with decrease in size) prior to propranolol therapy. Another patient
determined: drug used, method of delivery, dose, duration of treatment, (M3) who underwent treatment with oral prednisone alone exhibited
and treatment outcome (complete resolution, no change, decrease or no change in hemangioma size. (Table 1)
increase in size, change in color). For patients treated surgically, the Of the 13 surgical patients, 7 underwent radiofrequency ablation: 4
following were determined: type of surgery and outcome (complete for lip lesions and one each for the chin, cheek and nasolabial area. Two
resection, partial resection with gross residual). Information was of these patients (S5, S7) had prior surgeries. All 7 had gross residual
anonymized, recorded and tabulated using Microsoft® Excel for Mac lesions after the procedure. Of the six patients that underwent excision,
2015 Version 15.13.3 (150815) (Microsoft Corp., Redmond, WA, USA) complete excision was claimed in 5 of 6 cases while 1 case had gross
and descriptive statistics were computed. intracranial residual tumor. (Table 2)
The one patient who underwent both medical and surgical
RESULTS management was a 30-year-old man with a hemangioma in the right
Out of 41 identified patients from the databases, only 21 fulfilled buccal area that was surgically excised. Due to recurrence, he underwent
inclusion and exclusion criteria, 8 males (38.1%) and 13 females (61.9%). medical management with Nebivolol at a dose of 0.5 mg/kg/day for 24
The age range was 0.75 to 66 years and a mean age of 18.1 years (SD months. A decrease in size of the lesion was reported after 2 years. The
= 17.2). Twelve (57.1%) belonged to the pediatric age group (0 to 17 one patient who opted to observe the lesion (a 3-year old female with
years) while 9 (42.8%) were adults. Six patients underwent medical a right pre-auricular hemangioma) was reported to have spontaneous
management, 13 had surgical management, 1 had both medical and resolution of her lesion after 4 years.

Philippine Journal Of Otolaryngology-Head And Neck Surgery 31

 ORIGINAL ARTICLES
Philippine Journal Of Otolaryngology-Head And Neck Surgery Vol. 32 No. 2 July– December 2017

Table 2. Surgical Management Group majority of infantile hemangiomas undergo spontaneous resolution
and that only 10 to 20% of patients require treatment.1 If such is the
Patient Age/ Location Size of Surgery Prior Out-
Code Sex of lesion done Surgery come case, why treat infantile hemangiomas with propranolol to begin with?
lesion (cm) Why not wait for spontaneous resolution (which should happen in most
S1 18/F chin 5x5x2 RF ablation none gross cases) and treat only those that do not resolve? The decision to treat
residual
an infantile hemangioma or wait for spontaneous resolution depends
S2 18/F cheek 4x4x RF ablation none gross
0.5 residual on the indication for intervention which includes function-threatening
S3 66/M nasolabial 2 x 2.5 x RF ablation none gross hemangiomas (e.g. ocular, ear, nasal tip and genitalia), life-threatening
0.5 residual hemangiomas (e.g. airway lesion), disfiguring large hemifacial
S4 11/F lip 3x3x RF ablation none gross hemangiomas and ulcerated hemangiomas.1 It must also be noted
2.5 residual that the use of oral propranolol therapy for infantile hemangiomas
1x1x RF gross
has contraindications (e.g. sinus bradycardia, bronchial asthma, heart
S5 3/M lip 0.5 RF ablation ablation residual
x2 failure) and is associated with several adverse effects (e.g. bradycardia,
S6 4/F lip 2x2x1 RF ablation none gross hypotension, hyperkalemia, hypoglycemia, bronchospasm) therefore,
residual the decision to treat is highly individualized.4 The possible risks and
S7 20/M lip 5x4x1 RF ablation excision gross adverse effects should be weighed against the potential benefits of
residual
intervention before starting treatment.4
S8 15/M temporal 10 x 8 x 7 excision none complete
excision The target dose of propranolol of 1-3 mg/kg/day has been
S9 20/M intranasal 5x5x3 excision none complete recommended with a mean duration of treatment varying from 6 to 10
via lateral excision months.4 A meta-analysis by Marqueling et al. showed that the overall
rhinotomy
response rate is 98% with a range of 82 to 100%.5 The 2 patients who
S10 21/M gingivo- 2.5 x 2.5 excision none complete
buccal x2 excision took Prednisone with a dose of 1 mg/kg/day with a mean duration of
S11 37/F intranasal 1x1x1 endoscopic none complete 2.25 months (range of 1.5 to 3 months) had no response and this may
excision excision be attributed to an insufficient dose (recommended dose ranges from
excision with 2-5 mg/kg/day). For Prednisone, the recommended dose is 2-4 mg/kg/
S12 26/M lip and buccal 6 x 5 x 4 deltopectoral none complete
flap excision day.6 In a study by Benett et al., a dose of 2-4 mg/kg/day resulted in 75%
reconstruction response, >3 mg/kg/day showed 94% response but with greater side
wide effects while a lesser dose of <2 mg/kg/day resulted in poor response
excision via and rebound phenomenon in 70% of cases.6 Sawa et al. found excellent
S13 58/F temporal with 10 x 8 x 5 transtemporal none gross
intracranial approach with residual treatment response to both propranolol and prednisone for infantile
extension trapezius flap (intracranial) hemangiomas, at a median dose of 5 mg/kg/day for prednisone (n = 11)
reconstruction
and 2 mg/kg/day for propranolol (n = 7).7 The difference between the
two drugs was significantly longer treatment duration for propranolol
with a mean duration of 372 days.7 Side effects of corticosteroid
DISCUSSION
treatment noted were increase in body-mass index (BMI) and systolic
All patients who underwent treatment with oral propranolol in this
blood pressure.7
series were reported to have had a decrease in size in their lesions while
Propranolol is well documented as an effective treatment
those who underwent treatment with oral prednisone had no change
modality for infantile hemangiomas.1,4,5,7 Its mechanism of action in
in their lesions. The propranolol treatment group had a treatment dose
hemangiomas is related to its beta-2 inhibitory effect which decreases
ranging from 1-2 mg/kg/day and a mean duration of 9.3 months (range
the release of vasodilators such as nitric oxide. Vasoconstriction of the
of 2 to 20 months).
feeding capillaries results for the early visible changes in the color
The lesion observed in one patient that was reported to
of the lesion.1 Furthermore, propranolol down-regulates vascular
spontaneously resolve after 4 years may be explained by the natural
endothelial growth factors and basic fibroblast growth factors,
history of infantile hemangiomas-- a rapid proliferative phase followed
inhibiting the proangiogenic cascade and angiogenesis. This results
by a slower phase of involution.1,4 It is important to note that the
in apoptosis and regression of hemangiomas.1

32 Philippine Journal Of Otolaryngology-Head And Neck Surgery

 ORIGINAL ARTICLES
Philippine Journal Of Otolaryngology-Head And Neck Surgery Vol. 32 No. 2 July– December 2017

Complete removal of lesions through radiofrequency ablation

is difficult to achieve, hence it is done multiple times per patient.
However, it has been proven a safe and effective surgical modality for
the treatment of hemangiomas because incisions are not required
with pain and bleeding kept at a minimum.8 In this series, 7 patients
underwent radiofrequency ablation, all with gross residual lesions post-
treatment. Among these patients, 5 lesions involved the lip. It may be
surmised that the location of the hemangioma may influence the type
of surgical intervention. Six patients underwent surgical excision with
5 of 6 cases claimed to have achieved complete excision.
A major limitation of this study is that as a review of case records,
outcome observations of propranolol and prednisone therapy were
made by multiple observers and recorded observations could not
be verified. The variables of measure were neither standardized nor
quantified. Future prospective studies should include photographic
documentation and standardized measurements of tumor volume. The
failure to serially analyze outcomes of radiofrequency ablation patients
who had prior surgeries, as well as the short duration of follow-up for
patients who underwent radiofrequency ablation and surgical excision
are further limitations of this study. It is recommended that a longer
follow-up for this subset of hemangioma patients be performed in order
to adequately analyze the outcomes of each radiofrequency ablation
procedure and to document any recurrences after surgical excision.
In conclusion, the treatment response of patients in this series
with hemangiomas of the head and neck to propranolol at a dose of
1 to 2 mg/kg/day may reflect international data. Outcomes analysis
for radiofrequency ablation and surgical excision requires a longer
duration of follow-up.
ACKNOWLEDGEMENTS
I would like to acknowledge my adviser, Dr. Cesar V. Villafuerte, Jr. for his guidance in the execution
and writing of this research paper. Also, I would like to acknowledge Dr. Precious Eunice R. Grullo for
her invaluable assistance in revising this paper.

REFERENCES
1. Sethuraman G, Yenamandra VK, Gupta V. Management of infantile hemangiomas: current
trends. J Cutan Aesthet Surg. 2014 Apr;7(2):75-85. DOI: 10.4103/0974-2077.138324; PubMed
PMID: 25136206 PMCID: PMC4134656.
2. Couto J, Greene A. Management of problematic infantile hemangioma using intralesional
triamcinolone: efficacy and safety in 100 infants. J Plast Reconstr Aesthet Surg. 2014 Nov;
67(11):1469-1474. DOI: 10.1016/j.bjps.2014.07.009; PMID: 25104131.
3. Garzon MC, Lucky AW, Hawrot A, Frieden IJ. Ultrapotent topical corticosteroid treatment
of hemangiomas of infancy. J Am Acad Dermatol. 2005 Feb; 52(2):281-286. DOI: 10.1016/j.
jaad.2004.09.004; PMID: 15692474.
4. Drolet BA, Frommelt PC, Chamlin SL, Haggstrom A, Bauman NM, Chiu YE, et al. Initiation and
use of propranolol for infantile hemangioma: report of a consensus conference. Pediatrics. 2013
Jan;131(1):128-140. DOI: 10.1542/peds.2012-1691; PMID: 23266923; PMCID: PMC3529954.
5. Marqueling AL, Oza V, Frieden IJ, Puttgen KB. Propranolol and infantile hemangiomas four
years later: a systematic review. Pediatr Dermatol. 2013 Mar-Apr; 30(2):182-191. DOI: 10.1111/
pde.12089; PMID: 23405852.
6. Bennett ML, Fleischer AB Jr, Chamlin SL, Frieden IJ. Oral corticosteroid use is effective for
cutaneous hemangiomas: an evidence-based evaluation. Arch Dermatol. 2001 Sep; 137(9):
1208-13. PMID: 11559219.
7. Sawa K, Yazdani A, Rieder MJ, Filler G. Propranolol therapy for infantile hemangioma is less
toxic but longer in duration than corticosteroid therapy. Plast Surg. 2014 Winter; 22(4): 233-236.
PMID: 25535459; PMCID: PMC4271750.
8. Bozan N, Gur MH, Kiroglu AF, Cankaya H, Garca MF. Tongue Hemangioma: A Case Report. Van
Tip Dergisi. 2014; 21 (2): 120-122.

Philippine Journal Of Otolaryngology-Head And Neck Surgery 33

 ORIGINAL ARTICLES
Philippine Journal Of Otolaryngology-Head And Neck Surgery
Gerardo Aniano C. Dimaguila, MD, MPH
Emmanuel S. Samson, MD
Department of Otolaryngology
Head and Neck Surgery
Pamantasan ng Lungsod ng Maynila
Ospital ng Maynila Medical Center
Correspondence: Dr. Emmanuel S. Samson
Department of Otolaryngology Head and Neck Surgery
Pamantasan ng Lungsod ng Maynila
Ospital ng Maynila Medical Center
Quirino cor. Harrison Blvd., Malate, Manila 1004
Philippines
Phone: (632) 524 6061 local 220
Telefax: (632) 523 6681
Email: ommc_enthns@yahoo.com
The authors declared that this represents original material
that is not being considered for publication or has not been
published or accepted for publication elsewhere, in full or
in part, in print or in electronic media; that the manuscript
has been read and approved by all the authors, that the
requirements for authorship have been met by each author,
and that each author believes that the manuscript represents
honest work.
Disclosures: The authors signed disclosures that there are no
financial or other (including personal) relationships, intellectual
passion, political or religious beliefs, and institutional affiliations
that might lead to a conflict of interest.
Creative Commons (CC BY-NC-ND 4.0)
Attribution - NonCommercial - NoDerivatives 4.0 International
34 Philippine Journal Of Otolaryngology-Head And Neck Surgery
Vol. 32 No. 2 July– December 2017
Oral Propranolol Therapy for Benign Capillary
Hemangiomas in a Series of Adult
and Pediatric Patients
ABSTRACT
Objective: To describe outcomes of oral propranolol therapy in a series of adult and pediatric
patients diagnosed with benign capillary hemangioma of the head and neck.
Methods:
Design: Prospective Case Series
Setting: Tertiary Government Teaching Hospital
Participants: Ten (10) patients representing all patients clinically diagnosed with
benign capillary hemangioma of the head and neck enrolled in the study from 2012 to 2015.
Results: Two (2) adults and eight (8) children were enrolled in the study. Although a decrease in
lesion size was observed in half of the participants starting at three months, only one (1) attained
complete resolution of the lesion-- a 12-year-old girl with hemangioma of the right parotid gland
that attained clinical resolution of symptoms after four months of treatment. The remaining nine
out of ten (9/10) participants did not attain complete clinical resolution; but there was a decrease
in lesion size in four (4) of these participants. For the remaining five (5) participants, there was
neither a decrease nor an increase in lesion size. Altogether, of the two adult participants, only
one responded to therapy while only 4 out of 8 pediatric participants responded to therapy.
There were no noticeable differences between adult and pediatric patients in terms of resolution
and plateau. Aside from mild bradycardia expected with propranolol, no adverse reactions were
observed during the course of treatment.
Conclusions: Although half of our participants responded to oral propranolol therapy whether
these observations may be attributable to oral propranolol alone cannot be concluded.
Keywords: hemangioma, capillary; hemangioma; propranolol administration, oral; propranolol
Benign capillary hemangiomas are one of the most common benign tumors of childhood
with an incidence at birth of 1-2 % in white Caucasians, Asians and Blacks reaching almost 10%
in the former but significantly lower in the latter two by the end of the first year.1 The incidence is
higher in preterm infants less than 1 kg reaching nearly 30%.1
Several trials have demonstrated the efficacy of oral propranolol therapy in treating infantile
hemangiomas.2-6 However, despite its anecdotal use, we were not aware of evidence supporting
the use of oral propranolol for treating hemangiomas in older children and adults with negative
results from a search of PubMED, HERDIN and Google Scholar using the keywords “hemangioma
Philipp J Otolaryngol Head Neck Surg 2017; 32 (2): 34-37 c Philippine Society of Otolaryngology – Head and Neck Surgery, Inc.

Philippine Journal Of Otolaryngology-Head And Neck Surgery
capillary” “hemangioma” “propranolol administration oral” and
“propranolol.”
With the question; “will oral propranolol still be effective in treating
hemangiomas in older children and adults,” this study aims to describe
outcomes in a series of adult and pediatric patients with benign capillary
hemangioma of the head and neck.
METHODS
With institutional review board approval, this prospective case
series considered all patients seen at the out-patient or emergency
department of our tertiary government hospital, who were clinically
diagnosed with benign capillary hemangioma of the head and neck
from 2012 to 2015. To be excluded were patients clinically diagnosed
with capillary hemangioma who had undergone other forms of
treatment such as, but not limited to use of intralesional sclerosing
agents, oral or topical corticosteroids, or recurrence after prior surgical
intervention; patients or patients parents/ guardians who would not
consent to undergo oral propranolol therapy; and patients in whom
oral propranolol therapy was contraindicated or in whom the adverse
effects of oral propranolol would greatly outweigh the benefits such as
those suffering from asthma.
With written informed consent (and assent, where applicable),
propranolol 40mg and 10mg tablets were used. For adult patients,
propranolol was administered orally in three (3) divided doses daily
with reassessment planned weekly for the first month followed by
2-month intervals for a year. For pediatric patients, paper tablets- finely
ground powder that can be dissolved in liquid were used. A written
prescription with instructions to the pharmacist to prepare propranolol
paper tablets in the computed dose was given to the patient’s parent/
relative/guardian so that they could purchase this at the pharmacy.
Oral propranolol was given at a dose of 2mg/kg/day in three (3) divided
doses daily with reassessment planned weekly for the first month
followed by 2-month intervals for a year.
Prior to initiation of therapy, each patient was evaluated by a
cardiologist to obtain baseline data and to ascertain that there were no
contraindications to the proposed therapy. Patients were observed in
the emergency room for 24 hours at the start of therapy with heart rate
and blood pressure monitored by the hour. After the first 24 hours, the
patients were then discharged and instructed to take propranolol orally
every 8 hours with daily visits for the first week followed by weekly visits
thereafter.
On each follow-up visit, either author evaluated the lesion, focusing
on such gross features as size and boundaries, color, induration and
consistency. Measurements were taken using a Vernier caliper 150mm
(Acosta, Taiwan) and cloth tape measure (Goldfish, China) and findings
Philippine Journal Of Otolaryngology-Head And Neck Surgery 35
ORIGINAL ARTICLES
Vol. 32 No. 2 July– December 2017
were manually recorded with pen and paper. Photographs were taken
using a 2007 Sony Ericsson W960 3-Mega Pixel Auto Focus LED Flash
Camera (Sony Ericsson, China).
Qualitative final assessments regarding decrease in lesion size and
boundaries, change in color and change in consistency and induration
were subjectively classified “yes” or “no” by both authors in consensus
based on the recorded measurements and photographs.
RESULTS
A total of 10 patients, two (2) adults (aged 23 and 31, respectively)
and eight (8) pediatric patients (aged 3 months to 13 years) were
enrolled in the study with none excluded. Only one (1) attained
complete resolution of the lesion; a 12-year-old female diagnosed with
hemangioma of the right parotid gland that attained clinical resolution
of symptoms after four months of treatment. (Figure 1) Including this
girl, five of the patients were lost to follow up less than six (6) months
after initiating treatment (two at the 2nd month, one at the 3rd month
and two at the 4th month, respectively).
Although the remaining nine out of ten (9/10) patients did not
attain complete clinical resolution, there was a decrease in lesion size in
four (4) participants starting at three months.
One of these, a 31-year-old woman with multiple small capillary
hemangiomas of the dorsum of the tongue was observed until the 8th
month of therapy. There was marked decrease in the size and number
of lesions since the start of the therapy prominently noticed around the
3rd month with markedly less discoloration surrounding the lesions.
However, there was no noticeable change in the size of the lesions after
the 5th month. (Figure 2)
Another, a four-year-old girl with a lesion of the anterior third of
the tongue was observed to have a decrease in lesion size by the 12th
month of therapy with plateau occurring by the end of the 15th month.
She was initially seen when she was still a year old and presented with
a purplish red lesion involving almost the entire dorsum of the tongue.
After 12 months of therapy, the lesion started to shrink with areas that
started sloughing off. It assumed a wrinkled, prune-like appearance
and showed signs of resolving. However by the 15th month, the lesion
regained its purplish color and remained unchanged until the patient
was last seen at age 4. There were no reported difficulties in speech and
feeding. (Figure 3)
Also included in this group was an 8-year-old boy with capillary
hemangioma of the right cheek and upper lip. The patient’s lesion
showed signs of regression after four months of therapy. The most
noticeable change was a decrease in discoloration around the right
cheek as well as a decrease in the swelling around the right upper lip
after 6 months of treatment. (Figure 4)
 ORIGINAL ARTICLES
Philippine Journal Of Otolaryngology-Head And Neck Surgery Vol. 32 No. 2 July– December 2017

The last patient to show a decrease in lesion size was an 11-year-old

girl with hemangioma of the right cheek and upper lip with involvement
of the buccal mucosa noted around the 3rd month of therapy. Also
noteworthy was the clearing up of the buccal mucosa involvement
to almost near-normal. However, rapid plateau was attained with no
decrease in lesion size after the 5th month. She was on continued oral
propranolol therapy for 12 months before being lost to follow up. A B
(Figures 5 and 6)
Altogether, of the two adult participants, only one responded
to therapy while only 4 out of 8 pediatric participants responded to
therapy. There were no noticeable differences between adult and
pediatric patients in terms of resolution and plateau. Aside from mild
bradycardia expected with propranolol, no adverse reactions were
observed during the course of treatment. C D
Figure 3. A. Patient on day 0 of therapy B. on day 450 (15 months) of therapy; C. After 720 days (24
Table 1. Summarizes our findings months); D. There was almost no change in size of the lesion from 15 months to 24 months except for
some areas which had sloughed off.
Duration of Decrease Change
Patient participation/ in Lesion Change in
Age/ Sex duration of oral Size/ in Color? Consistency
propranolol therapy Boundaries? (Yes/No) Induration
(months) (Yes/No) (Yes/No)
23/F 2 months No No No
13/F 2 months No No No
6 mos/M 3 months No No No
1/M 4 months No No No A B
12/F 4 months Yes Yes Yes Figure 4. A. Day 0 of therapy B. Day 120 (4th month) of therapy; note the decrease in discoloration
of the right cheek and hemiface.
3 mos/F 6 months No No No
8/M 6 months Yes Yes Yes
31/F 8 months Yes Yes Yes
11/F 12 months Yes Yes Yes
1/F 36 months Yes Yes Yes

A B
Figure 5. A. Day 0 of therapy B. At approximately 120 days of therapy (4th month).

A B C

Figure 1. A. Patient on day 1 of oral propranolol therapy B. Day 78 (end of 2nd month) C. Day 121
(end of 4th month).

A B
A B C
Figure 2. A. Patient on day 1 of therapy B. after the 64th day of therapy (2 months) and C. after 150 Figure 6. A. Buccal mucosa involvement of our patient depicted above at day 0 B. Day 120 (4 months).
days of therapy (5 months). Note little change in the size of the lesion in figures B and C. Notice the decrease in the small maculo-papular lesions to near normal mucosa by the 4th month.

36 Philippine Journal Of Otolaryngology-Head And Neck Surgery


Philippine Journal Of Otolaryngology-Head And Neck Surgery
DISCUSSION
Out of the ten (10) patients who were enrolled in the study, only half
or five (5) showed a decrease in the size of the lesion-- one (1) adult and
four (4) children. The remaining half did not show any changes in the
size of the lesion. Given the number of reports on the success of oral
propranolol therapy in infantile hemangiomas,2-6 we were expecting a
high rate of resolution among older children and adults as well. As our
results show though, only half of the patients responded (and most,
only partly) to oral propranolol therapy. Getting to the bottom of the
whys and why nots entail taking a look at how propranolol acts on
infantile hemangiomas.
The exact mechanism of hemangioma growth and regression is not
clearly understood. Hemangiomas are a mixture of clonal endothelial
cells, pericytes, dendritic cells and mast cells.7 Proangiogenic
factors such as basic fibroblast growth factor (bFGF) and vascular
endothelial growth factor (VEGF) have been theorized to play a role
in the proliferation and growth of hemangiomas.7 Factors that affect
involution are downregulation of angiogenesis and upregulation of
angiogenesis inhibitors,7,9 the mechanism proposed by some for the
success of beta blockers in triggering involution.8 These studies have
demonstrated a triggered apoptosis of capillary endothelial cells in
adult rat lung tissue with the use of propranolol and documented a
decrease in locally produced VEGF-1 in hemangiomas upon initiation
of propranolol.8 Since VEGF-1 is a proangiogenic factor, its inhibition
results in involution. Based on these studies, we thought oral
propranolol therapy should work on hemangiomas whether infantile
among older children or among adults. Yet, only half of the patients in
our study responded to therapy.
An important limitation of our study may have been our failure to
distinguish ‘true’ infantile hemangiomas from other vascular anomalies
and malformations.7,11 Other studies that have employed oral propranolol
therapy would not recommend using it on other vascular anomalies.10
These anomalies behave differently from infantile hemangiomas in
that they are not affected by angiogenic factors and can be affected by
other factors such as trauma, infection and hormones.7 In retrospect,
we could have been dealing with other forms of vascular anomalies
in those patients who did not respond to oral propranolol therapy.
We recommend that more attention be given to correctly diagnosing
infantile hemangiomas in distinction from other vascular anomalies.
As for the participants who did respond to therapy, we must
consider whether the resolution was indeed due to propranolol
therapy or to spontaneous involution. It is well documented that
90% of hemangiomas involute by age 10 years while those that do
not involute beyond 10 years have a greater chance of persisting
throughout adulthood.7 Five (5) of our patients presented with a
Philippine Journal Of Otolaryngology-Head And Neck Surgery 37
ORIGINAL ARTICLES
Vol. 32 No. 2 July– December 2017
hemangioma persisting beyond the 10th year of life and the probability
of spontaneous involution coinciding with the initiation of propranolol
therapy seems slim. In these cases, it would be tempting to consider
that the resolution and/or diminution of our patients’ lesions was an
effect of propranolol therapy. However, our small sample with cursory
documentation and observer bias and no comparator group (inherent
to the design of a case series) are limitations that do not allow us to jump
to any such conclusions. Future, better-designed studies may avoid
these limitations and possibly shed light on our research question.
Our experience with these ten (10) patients has not answered
the question of whether oral propranolol therapy will have a good
outcome on older children and adults. Although half of our participants
responded to oral propranolol therapy whether these observations
may be attributable to oral propranolol alone cannot be concluded.
REFERENCES
1. Antaya RJ. Infantile Hemangioma. In James WD, Wells MJ, Perry V (editors). Medscape.
[updated 2017 Oct 02; cited 2017 Oct 4] Available from: http://emedicine.medscape.com/
article/1083849-overview#showall.
2. Leaute-Labreze C, Dumas de la Roque E, Hubiche T, Boralevi F, Thambo JB, Taieb A. Propranolol
for Severe Hemangiomas of Infancy. Letters to the Editor. N Engl J Med. 2008 Jun 12; 358(24):
2649-51. [updated 2008 Jun 12; cited 2012 Aug 20] Available from: http:// authors.nejm.org/
nengljmed358;24. DOI: 10.1056/NEJMc0708819; PMID: 18550886.
3. Zvulunov A, McCuaig C, Frieden IJ, Mancini AJ, Puttgen KB, Dohil M, et al. Oral propranolol
therapy for infantile hemangiomas beyond the proliferation phase: A multicenter retrospective
study. Pediatr Dermatol. 2011 Mar-Apr; 28(2): 94-98. DOI: 10.1111/j.1525-1470.2010.01379.x;
PMID: 21362031.
4. Celik A, Tiryaki S, Musayev A, Kismali E, Levent E, Erqun O. Propranolol as the first line therapy
for infantile hemangiomas: Preliminary results of two centers. J Drugs Dermatol. 2012 Jul;
11(7):808-11. PMID: 22777220.
5. Schupp CJ, Kleber JB, Gunther P, Holland-Cunz S. Propranolol therapy in 55 infants with infantile
hemangioma: dosage, duration, adverse effects and outcome. Pediatr Dermatol. 2011 Nov-Dec;
28 (6):640-4. DOI: 10.1111/j.1525-1470.2011.01569.x; PMID: 21995836.
6. Al Dhaybi R, Superstein R, Milet A, Powell J, Dubois J, McCuaig C, Codere F. Treatment of
periocular infantile hemangiomas with propranolol: case series of 18 children. Ophthalmology.
2011 Jun; 118(6): 1184-8. DOI: 10.1016/j.ophtha.2010.10.031; PMID: 21292326.
7. Darrow DH, Greene AK, Mancini AJ, Nopper AJ. Diagnosis and Management of Infantile
Hemangioma. Pediatrics. 2015 Oct; 136(4): e1060-e1104. [cited 2017 Oct 4]. Available from:
http://pediatrics.aappublications.org/content/136/4/e1060. DOI: 10.1542/peds.2015-2485.
8. Sommers-Smith S, Smith DM. Beta blockade induces apoptosis in cultured capillary endothelial
cells. In Vitro Cell Dev Biol Anim. 2002 May; 38(5):298-304. DOI: 10.1290/1071-2690(2002)038<0
298:BBIAIC>2.0.CO;2; PMID: 12418927.
9. Zimmerman AP, Wiegand S, Werner JA, Eivazi B. Propranolol therapy for infantile hemangiomas:
review of the literature. Int J Pediatr Otorhinolaryngol. 2010 Apr; 74(4):338-42. DOI: 10.1016/j.
ijporl.2010.01.001; PMID: 20117846.
10. Popoiu CM, Stanciulescu C, Popoiu A, Nyiredi A, RE Iacob PC, David VL, et. al., Treatment of
Vascular Anomalies in Children: Pros and Cons. Jurnalul Pediatrului. 2014 Jul-Dec; XVII (67-68)
37-41. [cited 2017 Oct]. Available from: http://www.jurnalulpediatrului.ro/pages/arhiva/67-
68/67-68-08.pdf
11. Richter GT, Friedman AB. Hemangiomas and Vascular Malformations: Current Theory
and Management. International Journal of Pediatrics. Volume 2012 (2012): Article ID
645678. 10 pages. [cited 2017 Oct 4]. Available from: https://www.hindawi.com/journals/
ijpedi/2012/645678/. DOI: http://dx.doi.org/10.1155/2012/645678.
 ORIGINAL ARTICLES
Philippine Journal Of Otolaryngology-Head And Neck Surgery Vol. 32 No. 2 July– December 2017

Kimberly Mae C. Ong, MD

Teresa Luisa G. Cruz, MD, MHPEd Prevalence and Reasons for Non-Follow-Up
of Newborns with “Refer” Results
Precious Eunice R. Grullo, MD, MPH

Department of Otorhinolaryngology
Philippine General Hospital
on Initial Hearing Screening

ABSTRACT
Objective: To determine the prevalence rate of follow-up among infants who had a “refer” result
on initial newborn hearing screening and to identify reasons for default by parents or guardians.

Methods:
Design: Cross-Sectional Study
Setting: Tertiary National University Hospital
Participants: 79 parents or guardians whose newborns obtained a “refer” result on
initial hearing screening were interviewed over the phone.

Results: Among those babies who had a “refer” result on initial hearing screening, 51% followed
up for repeat testing. The most common reasons for non-follow up by parents or guardians
Correspondence: Dr. Teresa Luisa G. Cruz
Department of Otorhinolaryngology include being busy, distance from the hospital and baby’s health condition.
Ward 10, Philippine General Hospital
University of the Philippines Manila
Taft Avenue, Ermita, Manila 1000 Conclusions: The follow-up rate in this study is higher compared to previous figures (27%), but is
Philippines
Phone: (632) 554 8400 local 2152 still below target. The reasons for non-follow-up obtained suggest problems may exist on all levels
Email: orl.up.pgh@yahoo.com of the healthcare system. Appropriate solutions to address these problems should be explored.
The authors declare that this represents original material, that
the manuscript has been read and approved by all the authors,
that the requirements for authorship have been met by each Keywords: neonatal screening, hearing loss, infant, newborn, hearing tests, otoacoustic emissions
author, and that each author believes that the manuscript
represents honest work.
Republic Act 9709 also known as the Universal Newborn Hearing Screening and Intervention
Disclosures: The authors signed disclosures that there are no
financial or other (including personal) relationships, intellectual Act was signed into law in 2009 with the primary aim of ensuring that every newborn be given
passion, political or religious beliefs, and institutional affiliations access to hearing screening examination and early intervention services.1 Local published data
that might lead to a conflict of interest.
documenting screening rates and follow-up rates in different Newborn Hearing Screening
Presented at the UP-PGH Department of ORL Descriptive
Case Presentation, June 2, 2017. Ward 10 Conference Room, Centers in the Philippines have been limited. A 3-month screening of “995 babies or 75% of all
Philippine General Hospital, Manila. (1,327) newborns at the Philippine General Hospital” in 2007 yielded a 10.6% ‘refer’ result, but “of
Presented at the Philippine Society of Otolaryngology – Head
and Neck Surgery Descriptive Research Contest (2nd place). 104 babies, only 27% followed up.”2 A similar study at the St. Luke’s Medical Center in 2004 also
August 10, 2017. Natrapharm, The Patriot Bldg., Parañaque
City. revealed a follow up rate of 27.7% in patients who did not pass the initial OAE.3 These rates are
dismal considering that in the Year 2000 Position Statement released by the Joint Committee of
Infant Hearing, the ideal return-for-follow up rate of infants should at least be 70%.4
Creative Commons (CC BY-NC-ND 4.0)
Philipp J Otolaryngol Head Neck Surg 2017; 32 (2): 17-21 c Philippine Society of Otolaryngology – Head and Neck Surgery, Inc.
Attribution - NonCommercial - NoDerivatives 4.0 International

Philippine Journal Of Otolaryngology-Head And Neck Surgery 17

 ORIGINAL ARTICLES
Philippine Journal Of Otolaryngology-Head And Neck Surgery
Low follow-up rates pose a significant barrier to proper diagnosis
and are lost opportunities for potential early intervention for patients
confirmed to have hearing impairment. Implementation of any health
program can only be considered effective if it involves a significant
percentage of the population for which the program was intended.
This study aims to determine the prevalence rate of follow-up
among infants who had a “refer” result in initial hearing screening
and to identify the reasons for non-follow-up of hearing screening by
parents or guardians whose newborn was found to have a “refer” result
on initial OAE test at the Philippine General Hospital (PGH). Identifying
these factors can help policymakers and stakeholders revisit existing
protocols and guidelines to ensure better follow up for these patients in
line with the overall aim of improving implementation of the Universal
Newborn Hearing Screening Program.
METHODS
With Institutional Review Board approval, this cross-sectional study
considered infants who had their hearing screening performed at the
PGH Ear Unit between November 2014 and December 2016, but did
not follow up for a repeat hearing screening within 3 months after a
“refer” result on initial screening. Parents or guardians of the target
infants were recruited and informed consent was obtained and those
who did not consent to an interview, or who retracted consent anytime
between the interview and writing of the manuscript were excluded.
The sample size was obtained using the formula n= 1.962 p (1-p)
DEFF/ d2, where p was the expected proportion (27%2,3), DEFF was the
estimated design effect (1.0), and d was the desired level of absolute
precision (0.1), computed at 95% confidence interval. A minimum
number of 76 parents or guardians interviewed was needed (level
of significance 0.05, prevalence of 50%). Convenience sampling was
employed.
A review of records at the Ear Unit was performed. Those who did
not follow up at the Ear Unit within 3 months from the time of the initial
screen were considered “default.” The contact numbers of their parents
or guardians were obtained from their records at the Ear Unit.
Informed consent was obtained and recorded over the phone by
the investigators prior to conducting interviews. The Total Recall call
and voice note recorder version 2.0.42 (Killer Mobile® Software LLC,
Henderson, NV, USA), a phone application that allows users to record
phone conversations was used with permission of interviewees to
document consent. An open-ended questionnaire with a sample
checklist of common reasons for not following up (based on our review
of literature), was used as a coding guide to interview the parents or
guardians. All interviews were conducted by one author (KMCO).
All patient information was anonymized and kept confidential. Data
18 Philippine Journal Of Otolaryngology-Head And Neck Surgery
Vol. 32 No. 2 July– December 2017
was simultaneously encoded by two authors (KMCO and PERG) using
Microsoft Excel v2013 (Microsoft Corp., Redmond, WA, USA), and
analyzed by all three authors using frequencies, percentages, Chi
Square and content analysis.
RESULTS
A total of 3,517 babies were screened at the Ear Unit using
otoacoustic emissions between November 2014 and December 2016.
These included both well-babies and those that required admission
at the neonatal intensive care unit. Out of these, 384 (11%) babies
obtained a “refer” result either unilaterally or bilaterally. Fifty one
percent (195/384) of these babies followed up within 3 months from
initial screening.
Of the 49% (189/384 babies) who defaulted, only 79 (42%) parents
or guardians were successfully contacted. The rest of the given contacts
were either “unavailable,” “unattended or out of coverage area” or
invalid. Six (7.6%) of the 79 had repeat screenings elsewhere while 13
(16.5%) had repeat screenings in our institution beyond 3 months from
initial screening. The rest did not have a repeat screening at the time of
interview. Table 1 summarizes the demographic profile of these infants
as well as information on their parents or guardians.
Respondents showed various levels of understanding regarding
the reason for needing a repeat test. Some attributed the “refer” result
to the baby’s incessant crying and movement. Others were told that
there might still be fluid in the ear that could be obstructing the ear
canal or because the baby’s ear is still not fully developed. Still others
believed that a repeat hearing test was needed because the baby failed
the initial screening, had hearing impairment, or there was a problem
with the functioning of the machine.
Table 2 shows the reasons for failing to follow up. The most common
reason given (35%) was that parents were busy or had other obligations.
Many of the parents who gave this reason are part of the workforce and
expressed an inability to follow up either because they could not take
time off work or their free time did not coincide with Ear Unit opening
hours. Under this busy cluster were parents who also had other children
that needed their attention. Less common reasons under this cluster
involved consecutive deaths in the family, and calamity in the locale.
The second most common reasons given were location and the
baby’s health condition. Fifteen of the 60 (25%) said that our institution
was far from where they lived. Interestingly, however, there was no
significant association between place of residence and citing location
as a reason (Fisher’s probability, 2-tailed, = 0.19), such that there was an
almost equal number of respondents who lived within Metro Manila and
who lived within the Luzon area (Cavite, Tarlac, Quezon) among those
who cited this as reason. Only one respondent lived in Mindanao, who
 ORIGINAL ARTICLES
Philippine Journal Of Otolaryngology-Head And Neck Surgery Vol. 32 No. 2 July– December 2017

also cited distance as a reason. Fifteen of the 60 (25%) also mentioned repeat screening (6 of 13 respondents). According to these parents,
their baby’s health condition as a reason for not being able to follow they were notified of the need to repeat the hearing test more than
up. Being “sick” ranged from the relatively simple upper respiratory 3 months after the initial screening was performed, via phone short
tract infection to more serious medical conditions requiring prolonged message service (SMS).
hospitalization such as seizure disorder, pneumonia and sepsis. In Possible factors that could affect the decision to follow-up were
fact, 5 of the babies had already expired at the time of interview due analyzed using Chi Square test, comparing those that followed up
to various serious illnesses. On the other hand, we also interviewed within 3 months and those that did not, between November 2014 and
one parent who opted to prioritize vaccination of his prematurely born September 2016. Laterality of “refer” result (unilateral or bilateral) and
baby. Fourteen (23%) of the respondents said that they were not aware admission to private or public services (used as a surrogate marker
of the results of their baby’s hearing exam or were not told that they for financial capacity) were the factors explored. Neither factor had a
had to repeat the test. significant relationship with decision to follow up. (Table 3)
Distance was the most commonly given reason for not having a
repeat screening at our institution among those who opted to have Table 2. Reasons for failure to follow up. Categories listed are not mutually exclusive
them done elsewhere (5 of 6 respondents). On the other hand, late Reasons for Failure to Follow Up % (n=60)
notification was the most commonly given reason for the delay in Busy 35
Distance 25
Table 1. Summary of infants and parent/guardian profiles
Baby’s health condition 25
Factor Category Frequency (n=79) Unaware of results 23
Sex of Infant Male 40 (50.6%) Patient is not deaf 18
Female 39 (49.3%) Lack of transportation 10
Laterality of Unilateral 45 (57%) Parents forgot 8
Affected Ear Bilateral 34 (43%) Lack of companion 8
0 37 (46.8%) Pediatrician said no 5
Number of Siblings 1 21 (26.6%) Notified late 2
2 11 (13.9%)
3 or more 2 (2.5%) Table 3. Relationship of laterality and admission type to status of follow- up
Admission Public 41 (51.9%)
Factor Categories With No Chi Square p value*
Private 37 (46.8%)
Follow Up Follow Up
Monthly Income <15,000 24 (30.4%)
Laterality Unilateral 101 103 0.14 .71
(PhP) <30,000 12 (15.2%)
Bilateral 65 72
<50,000 5 (6.3%)
Admission Public 72 91 2.54 .11
≥50,000 7 (8.9%)
Private 94 84
≤ age 2
21 to 25 15 * level of significance =0.05
Age of Parent 26 to 30 16
31 to 35 21 DISCUSSION
36 to 40 10 The prevalence rate for follow up obtained in this study was 51%.
≥ 40 5 The top three most common reasons for failing to follow up include:
Metro Manila 38 (48.1%) parents were busy or had other obligations, distance and baby’s health
Place of residence Luzon 37 (46.8%) condition. Distance was the most common reason for not having a
Outside Luzon 1 (1.3%) repeat screening at our institution while late notification was the most
High School 13 (16.5%) common reason for delay in repeat screening. Laterality of result and
Educational College Undergraduate 9 (11.4%)
Attainment financial capacity were not significantly associated with decision to
College graduate 33 (41.8%) follow up.
Vocational 12 (15.2%)
The 51% follow-up rate in this study is lower than the ideal return-

Philippine Journal Of Otolaryngology-Head And Neck Surgery 19

 ORIGINAL ARTICLES
Philippine Journal Of Otolaryngology-Head And Neck Surgery Vol. 32 No. 2 July– December 2017

for-follow up rate of infants set by the Joint Committee of Infant The first two levels are self-explanatory—factors relating to the
Hearing in 2000 which was set at a minimum of 70%.4 Nevertheless, patient, his/her family and to healthcare providers. Reid et al. described
this reflects a significant increase from 20072 where only 27% followed organization, the third level, as the one that “provides infrastructure and
up (X2 = 18.77, α= 0.05, p< .0001). Moreover, if we were to consider other complementary resources to support the work and development
including the 6 respondents who followed up elsewhere and the 13 of care teams and microsystems.”5 It allows for the coordination of
who had repeat screenings beyond three months, the actual follow-up multiple care teams and the management of allocation of human,
rate improves to 56%. material and financial resources. It is at this level where referral systems
A 2004 study at the St. Luke’s Medical Center in Quezon City revealed between hearing screening units may be established and used to
that reasons for noncompliance with repeat testing included “the improve service, especially in our setting where distance between
patient was seen responding well to sound,” “the test was seen as an residence and hospital is a factor. Finally, the priorities of the Filipino
unnecessary expense,” and “some patients were transferred to another family can be influenced significantly by the political and economic
pediatrician, to another city or to another province.”3 Others were environment. These include “regulatory, financial and payment regimes
also “advised by pediatricians that repeat testing was not necessary.”3 and entities that influence the structure and performance of healthcare
However, this study did not mention how many respondents identified organizations directly and through them all other levels of the system”.5
each of these factors as their reasons for noncompliance. In our setting, this involves coverage and/or reimbursement schemes
Our results revealed themes similar to the aforementioned study. by the Philippine Health Insurance System (PhilHealth) and other
But in contrast, our study found other parental obligations to be the insurance companies, as well as government policies on compensation
most common reason for default followed by distance and the baby’s and incentives for hearing screening.
health. Since this study delved into reasons for default as perceived by
The reasons for lack of follow-up may be categorized according parents, it does not come as a surprise that most of the reasons elicited
to a four-level model of the healthcare system adapted from Reid et were more personal and may be categorized under the first two levels.
al.5 (Figure 1) The model may help us determine what level of action is However, it is also relevant to note that some factors go across levels
required to address a problem. For example, problems at the patient of the healthcare system. The reason “busy” suggests that following up
or healthcare provider level might be deemed more manageable to for repeat hearing tests would require certain sacrifices that parents or
address than problems at the environment level which require policy guardians were not willing to make—income, employment, time and
changes and involvement of regulatory agencies. the welfare of their other children. Hearing screening does not seem
to be a priority for some Filipino families, and this must be addressed
if follow up rates are to improve especially since this is the most
commonly-cited reason for lack of follow-up—addressing this issue
might require the efforts of the healthcare provider as well as higher
levels of the healthcare system. Interviews with the respondents have
PATIENT
Factors relating to the
ENVIRONMENT shown that some lack understanding regarding the need for newborn
Factors relating to the
patient or his/her family political and economic hearing screening as well as the need to have it repeated. This might
• Busy/ other parental conditions (e.g.
obligations regulatory, financial,
payment regimes),
have contributed to down-prioritizing their baby’s hearing screening.
• Baby’s health
under which

•
condition
Distance from PGH organizations, care Healthcare providers such as physicians (otorhinolaryngologists,
HEALTH CARE ORGANIZATION providers, and patients
•
•
Baby is not deaf
Lack of budget for PROVIDER Factors relating to the operate pediatricians and family physicians), audiologists and staff of the
transportation Factors relating to the infrastructure/resources
• Lack of companion health care professionals (e.g. hospitals, clinics) • Busy/ other parental
obligation
ear unit giving results to parents or guardians should emphasize the
• Parents forgot (e.g. physicians, that can support the
• Distance from PGH
• Number unattended audiologists, etc.) development and work of importance of a repeat OAE despite their busy schedule. However,
the health care provider
•

Busy/ other parental
obligations • Distance from PGH
there were respondents who showed adequate understanding of the
• Unaware of results
• No or delayed need to repeat their baby’s hearing screening yet made the decision
notification
• Baby is not deaf not to follow up to prioritize other obligations. In such situations,
• Pediatrician said no
need higher levels of the healthcare system might play a role since it would
Figure 1. Four-level model of the health care system adapted and reproduced with permission from be difficult to expect this subset of parents to stop working even for
Building a Better Delivery System: A New Engineering/Health Care Partnership, 2005 by the National
Academy of Sciences, Courtesy of the National Academies Press, Washington, DC. Reasons for default a day. Perhaps better incentives and appropriate compensation may
categorized according to levels.

20 Philippine Journal Of Otolaryngology-Head And Neck Surgery


Philippine Journal Of Otolaryngology-Head And Neck Surgery
ensure better compliance-- which is why we considered this reason
under environment as well.
Parents and caregivers must have access to the necessary
information they will need to make informed decisions regarding
their baby’s hearing screening. Healthcare providers must also be
given access to updated information so they may be sufficiently
equipped to educate patients. The reason “baby is not deaf” might not
simply be an issue of parental perception but may also reflect a lack of
information given by healthcare providers. In fact, some pediatricians
actually advised that hearing screening was not necessary.
Healthcare providers, especially physicians, are in the best position to
encourage patient participation in the program as they are deemed
the experts and should have developed trusting relationships with
patients. Communication between healthcare providers and parents/
caregivers remains vital to overall improvement of the newborn
hearing screening program.
Distance as a reason for non-follow up may not be just an issue
of transportation for the family, but may also reflect a lack of referral
systems and coordination among hearing screening centers. Taking
into consideration that a good percentage of our participants live within
and just outside Metro Manila, as well as the dismal traffic situation in
the area, perhaps the true reason for lack of follow up might actually
be the potential time wasted stuck in traffic, instead of actual distance.
These issues should also be addressed, and we must recognize that for
any program to be effective, it must be made convenient and efficient
for the patient.
A major limitation in this study was its reliance on contacting
potential participants using phone numbers they disclosed during
initial testing. A significant percentage of these phone numbers were
unreachable which proved to be a major hindrance both for conducting
the interview as well as reminding them to follow up. Home visits may
be done in future studies to aid in research delving on this topic and
to encourage follow up. Nevertheless, results of this study will greatly
impact follow up protocols at the Ear Unit. They may also have impact
on policies that can improve implementation of the Universal Newborn
Hearing Screening Program. Further research may be done comparing
follow up rates, reasons for default and factors affecting decision to
follow up across multiple hearing screening centers in the country.
It might also be worthwhile to compare the profiles of those who
defaulted against those who followed up.
Another limitation is that the reasons for non-follow up were not
mutually exclusive, as each participant was allowed to enumerate all
possible reasons they had. However, these reasons were only tallied
and analyzed as individual frequencies and percentages without
accounting for overlaps. Although certain trends and relationships
Philippine Journal Of Otolaryngology-Head And Neck Surgery 21
ORIGINAL ARTICLES
Vol. 32 No. 2 July– December 2017
between reasons were discussed, the data was not subjected to
statistical treatment to determine presence of significant interaction
between reasons. It would be interesting for future studies to examine
the combinations of reasons given for default.
In conclusion, the reasons for poor follow-up given by our
respondents suggest problems on all levels of the healthcare system.
Improving implementation of the universal newborn hearing screening
program will require efforts from families and healthcare providers
as well as policy makers. We should explore appropriate solutions to
address these problems.
REFERENCES
1. Chiong CM, Abes GT, Reyes-Quintos MRT, Ricalde RR, Llanes EGDV, Acuin JM, et al. Universal
Newborn Hearing Screening and Intervention Act of 2009: Manual of Operations for Republict
Act 9709. 2009.
2. Santos-Cortez RL, Chiong C. Cost-Analysis of Universal Newborn Hearing Screening in the
Philippines. Acta Medica Philippina. 2014 [cited 2016 January 12] . Available fromhttp://
actamedicaphilippina.com.ph/content/cost-analysis-universal-newborn-hearing-screening-
philippines-0.
3. Tan-Bumanlag RA, Romualdez JA. Initial outcome of the universal newborn hearing
screening program at St. Luke’s Medical Center. Philipp J Pediatr. 2005 Jan-Mar. 54(1), 31-
37. [cited 2016 January 12]. Available from: http://www.herdin.ph/index.php/component/
herdin/?view=research&cid=329.
4. Joint Committee on Infant Hearing, American Academy of Audiology, American Academy
of Pediatrics, American Speech-Language-Hearing Association and Directors of Speech and
Hearing Programs in State Health and Welfare Agencies. Year 2000 Position Statement: Principles
and Guidelines for Early Hearing Detection and Intervention Programs. Pediatrics. 2000 Oct;
106(4): 798-817. [cited 2016 January 12]. Available from http://pediatrics.aappublications.org/
content/106/4/798..info.
5. Reid PP, Compton WD, Grossman JH, Fanjiang GA. Framework for a Systems Approach to Health
Care Delivery. In Reid PP, Compton WD, Grossman JH, Fanjiang G (editors). Building a Better
Delivery System: A New Engineering/Health Care Partnership Washington, DC, USA: National
Academies Press.; 2005. p. 19-22. [cited 2016 January 12]. Available from https://www.ncbi.nlm.
nih.gov/books/NBK22878/.
 ORIGINAL ARTICLES
Philippine Journal Of Otolaryngology-Head And Neck Surgery Vol. 32 No. 2 July– December 2017

Jonel Donn Leo S. Gloria, MD, MOH

Alfredo Quintin Y. Pontejos, Jr., MD Risk Factors for Recurrent
Papillary Thyroid Carcinoma
Precious Eunice R. Grullo, MD, MPH

Department of Otorhinolaryngology
University of the Philippines – Philippine General Hospital

ABSTRACT
Objective: To identify risk factors associated with disease recurrence among Filipinos with
papillary thyroid carcinoma (PTC).

Methods:
Design: Retrospective Cohort Study
Setting: Tertiary National University Hospital
Participants: 76 patients diagnosed with papillary thyroid carcinoma, classified as
low and low-to-intermediate risk (2015 ATA classification) that underwent total thyroidectomy
with or without neck dissection from 2010-2014 and were followed up from 10 months to 5
years. Log rank and Cox regression analyses were used to determine significant risk factors for
recurrence.

Results: 29 (38.15%) had recurrence. On univariate analysis, age, tumor size, multifocality,
extrathyroidal extension, presence of lateral neck nodes and RAI therapy were statistically
Correspondence: Dr. Alfredo Quintin Y. Pontejos, Jr. associated with recurrence. However, on multivariate analysis, no clinicopathologic factor was
Department of Otorhinolaryngology
Ward 10, Philippine General Hospital statistically associated with recurrence.
University of the Philippines, Manila
Taft Avenue, Ermita, Manila 1000
Philippines Conclusion: Age of >45 years, female sex, tumor size of >2 cm, multifocality, presence of
Phone: (632) 554 8400 local 2152
Email: docpontejosjr@yahoo.com microscopic extrathyroidal extension and lymph node metastasis might contribute to the
The authors declare that this represents original material, that recurrence of papillary thyroid cancer while post-operative radioactive ablation may have some
the manuscript has been read and approved by all the authors, protective effect. However, this study suggests that other factors must be included in the model
that the requirements for authorship have been met by each
author, and that each author believes that the manuscript to better understand the relationship between these factors and recurrence.
represents honest work.

Disclosures: The authors signed disclosures that there are no Keywords: papillary thyroid cancer, thyroid neoplasm, recurrence
financial or other (including personal) relationships, intellectual
passion, political or religious beliefs, and institutional affiliations
that might lead to a conflict of interest
Thyroid cancer was the most frequent head and neck cancer in the Philippines in 20121 and
Presented at the Philippine Society of Otolaryngology Head continues to rank among the most common reasons for admission at the Philippine General
and Neck Surgery Analytical Research Contest (1st Place),
November 17, 2016. Bella Ibarra, Quezon Avenue, Quezon City. Hospital-Department of Otorhinolaryngology (PGH-ORL). A review of all thyroid cases admitted at
the PGH-ORL from January 2006 to December 2010 revealed 415 thyroid malignancies managed,
of which 82.9% were papillary thyroid carcinoma (PTC).2
Creative Commons (CC BY-NC-ND 4.0)
Attribution - NonCommercial - NoDerivatives 4.0 International Philipp J Otolaryngol Head Neck Surg 2017; 32 (2): 25-29 c Philippine Society of Otolaryngology – Head and Neck Surgery, Inc.

Philippine Journal Of Otolaryngology-Head And Neck Surgery 25

 ORIGINAL ARTICLES
Philippine Journal Of Otolaryngology-Head And Neck Surgery
The primary treatment of PTC is still surgery (thyroidectomy) and
when appropriate, a neck dissection.3,4,5 In our setting, a considerable
subset of PTC tends to become more aggressive and recurs even with
adequate surgical and medical management. While local and regional
recurrences of PTC after surgery have ranged from 5-10%,6 a 2010 study
among Filipinos with thyroid cancer claimed recurrence rates as high as
25%.7 Recurrences may be local (primary site and adjacent structures),
regional (cervical lymph nodes) or distant and impact negatively on
patients’ quality of life with increased morbidity.
The extent of surgery and need for adjuvant treatment depend on
several prognostic factors that influence risk stratification of patients
in terms of recurrence and survival. Several studies have identified
clinicopathologic factors predictive of increased risk of recurrence
among patients with PTC, including age, sex, tumor size, cervical lymph
node metastasis, extrathyroidal invasion, bilaterality/multifocality and
post-operative RAI therapy.8 -17
In order to determine specific patient- and disease-related factors
associated with PTC recurrence among our patient population that are
essential for developing initial treatment and follow-up schemes and
establishing the need for adjuvant treatment in our setting, this study
aims to determine factors that are associated with recurrence of PTC
among patients admitted at PGH-ORL in terms of age during initial
surgery, sex, tumor size, multifocality, extrathyroidal extension, lymph
node metastasis and post-operative RAI therapy.
METHODS
With institutional review board approval, this retrospective cohort
study reviewed the records of 86 patients diagnosed with papillary
thyroid carcinoma that underwent total thyroidectomy with or without
neck dissection at the PGH-ORL from January 2010 to December 2014
and followed up for at least 10 months. Papillary thyroid carcinoma
recurrence was defined as the reappearance of PTC after a period of at
least 10 months from initial surgery including both local and regional
recurrences.7
Medical records (including operative records and histopathology
results) were reviewed for the following data: age (years) at the time of
initial surgery, sex, tumor size, multifocality, extrathyroidal extension,
lymph node metastasis, post-operative RAI therapy and length of
follow-up. Considered for inclusion were records of patients with
Papillary Thyroid Cancer on histopathologic result and low and low-
to-intermediate risk 2015 ATA classification. Excluded were records
of cases with no definite histopathologic result and high-risk 2015
American Thyroid Association (ATA) classification (residual disease,
26 Philippine Journal Of Otolaryngology-Head And Neck Surgery
Vol. 32 No. 2 July– December 2017
gross extrathyroidal extension, distant metastasis) as these patients
had high risk of recurrence.18
Data was tabulated using Microsoft Excel version 2013 (Microsoft,
Chicago, USA) and means and proportions were obtained. Univariate
analysis was performed using log-rank test. The outcome of interest
was recurrence, established by imaging (ultrasonography or
computed tomography), thyroglobulin levels, thyroid scintigraphy,
or histopathology. Variables with p < .25 on univariate analysis were
included in the multivariate analysis using Cox regression. Kaplan-
Meier curves were obtained. Data were analyzed using STATA version
13.1 (StataCorp, TX, USA).
RESULTS
Records of 76 patients (21 males, 55 females) were included in this
series. The mean age of the patients was 44 ± 2 years (range 15-77
years). The average tumor size was 3.96 ± 0.29 cm (range 0.3 to 14.5 cm).
29 (38.15%) had recurrences while 47 had no observed recurrence on
the cut-off date. The sites of recurrences follows: 3, thyroid bed only; 17,
lateral neck (16 unilateral and 1 bilateral); 9, both thyroid bed and lateral
neck (6 in the thyroid bed and unilateral neck and 3 in the thyroid bed
and bilateral neck). The 10 excluded records were those of 2 patients
that had no definite histopathologic result and 8 cases with high risk
2015 ATA classification. Table 1 summarizes the clinicopathologic
profiles of the patients included in the series.
With cut-off p < .25, age (p = .01), tumor size (p = .2), multifocality (p
= .04), extrathyroidal extension (p = .02), presence of lateral neck nodes
(p = .03) and RAI therapy (p = .2) were included in multivariate analysis
on which no clinicopathologic factor was statistically associated with
recurrence. This indicates that other factors affecting recurrence are
missing in the model (R2=0.3776). Table 2 summarizes the results (p
values, hazards ratios and confidence intervals) of both univariate and
multivariate logistic regression analyses on the factors studied.
In this study, those with age > 45 years old had 1.93 times higher risk
of having a recurrence than those </= 45 years old . Tumor size of >2 to 4
cm and >4 cm had 59% and 74% increased risk of recurrence compared
to tumors <2 cm in size, respectively. The presence of multifocality
increased the risk of recurrence by 69%. The risk of recurrence was 1.31
times higher if extrathyroidal extension was present. Unilateral neck
nodes and bilateral neck nodes increased the risk of recurrence 2.06
times and 1.47 times, respectively. RAI therapy decreased the risk of
recurrence by 51%. Figure 1 shows the Kaplan-Meier curve analysis for
each clinicopathologic factor studied. The estimated 5-year recurrence-
free estimate is 32.87%.
 ORIGINAL ARTICLES
Philippine Journal Of Otolaryngology-Head And Neck Surgery Vol. 32 No. 2 July– December 2017

Table 1. Clinicopathologic profile of the patients

Clinicopathologic factors Without With
recurrence recurrence
n = 47 n = 29
Age (years) ≤ 45 28 (60%) 11 (38%)
> 45 19 (40%) 18 (62%)
Sex male 14 (30%) 7 (24%)
female 33 (70%) 22 (76%)
Tumor Size (cm) ≤2 17 (36%) 7 (24%)
> 2 to 4 16 (34%) 6 (21%)
>4 14 (30%) 16 (55%)
Multifocality absent 32 (68%) 12 (41%)
present 15 (32%) 17 (59%)
Extrathyroidal absent 38 (81%) 11 (38%) A
extension present 9 (19%) 18 (62%)
Central neck absent 33 (70%) 21 (72%)
nodes present 14 (30%) 8 (28%)
Lateral neck absent 32 (68%) 14 (48%)
nodes unilateral 12 (41%)
14 (30%)
bilateral 1 (2%) 3 (11%)
RAI therapy absent 20 (43%) 19 (66%)
present 27 (57%) 10 (34%)
Follow-up time 30 (sd:3) 32 (sd:4)
(months)

Table 2. Univariate and multivariate analyses of the factors associated with PTC recurrence
Clinicopathologic Factors Univariate Multivariate Analysis
Analysis B
p HR CI p
Age ≤ 45 .01 1.93 0.78-4.80 .10
Sex female .27
Tumor Size > 2 to 4 .20 1.59 0.49-5.24 .44
>4 1.74 0.68-4.48 .25
Multifocality present .04 1.69 0.71-4.04 .25
Extrathyroidal present .02 1.31 0.56-3.1 .53
extension
Central neck present .74
nodes
Lateral neck unilateral .03 2.06 0.83-5.1 .12
nodes bilateral 1.47 0.33-6.47 .61
RAI therapy present .20 0.49 0.21-1.15 .10

Note: Blacked out cells are not included in the multivariate analysis; cut-off p<0.25

Philippine Journal Of Otolaryngology-Head And Neck Surgery 27

 ORIGINAL ARTICLES
Philippine Journal Of Otolaryngology-Head And Neck Surgery Vol. 32 No. 2 July– December 2017

D G

Figure 1. Kaplan-Meier disease-free estimate curves of clinicopathologic factors for papillary thyroid
cancer recurrence. A. Age. Note that age >45 (dash) has a lower recurrence-free estimate than
younger patients B. Sex. Males (solid line) have a lower recurrence free estimate than females but not
statistically significant. C. Tumor size. Tumor size of 2-4 cm (dash) and more than 4 cm (dotted line)
have a lower recurrence free estimate than size less than 2 cm (solid). D. Extrathyroidal extension.
Recurrence free estimate is lower when microscopic extrathyroidal extension is present (dash). E.
Presence of central neck node. The presence of central neck node metastasis (dash) has a higher
recurrence-free estimate compared to its absence but only during the early periods of observation.
F. Presence of lateral neck node. Those without lateral neck node (solid) have a significantly higher
recurrence free estimate compared to unilateral (dash) and bilateral (dotted) neck node metastasis. G.
Postsurgical radio¬active iodine (RAI) ablation. The use of post-op RAI (dash) has higher recurrence-
free estimate compared to cases without post-op RAI although not statistically significant.

DISCUSSION
This study suggests that age of >45 years, female sex, tumor size of
>2 cm, multifocality, presence of extrathyroidal extension and lymph
node metastasis may increase the risk of papillary thyroid recurrence
E although the associations did not reach statistical significance. Post-
operative RAI ablation may decrease the risk of recurrence although
this also did not reach statistical significance. (Table 2) These factors are
similar to reports in other populations.11,16
The 45-year-old age cut-off by the National Comprehensive Cancer
Network Clinical Practice Guidelines in Oncology was also shown to be
a risk factor for papillary thyroid cancer recurrence among Filipi­nos in
this study.4 In this study, PTC patients with multifocal disease had higher
risk of developing recurrence than those with unifocal disease. This
echoes the findings of Qu et al.19 that increasing number of tumor foci
of PTC are associated with a tendency toward more aggressive features,
shorter recurrence-free survival and may be a possible indicator of
cancer death. The number of tumor foci might also represent the
tumor burden in PTC patients,19 consistent with another study by
Lin et al. where 52.9% of recurrent multicentric PTC patients were
diagnosed within the first year of thyroidectomy.20 This study showed
F
that extrathyroidal extension carries an increased risk of developing
recurrence. In comparison, Arora et al. found a 6.4-fold increased risk

28 Philippine Journal Of Otolaryngology-Head And Neck Surgery


Philippine Journal Of Otolaryngology-Head And Neck Surgery
of recurrence and significantly decreased disease-free survival in
PTC patients with macroscopic extrathyroidal extension21 and nodal
metastasis has been reported to increase the risk of recurrence.19, 21
The use of post-operative RAI therapy based on our results is
protective with an HR of 0.49. Unlike in high risk patients where the
evidence for the benefits of RAI are strong, the ATA 2015 guideline
reported that there are conflicting observational data in the use of post-
op RAI among low and low-to intermediate risk patients.18 According to
the UP-PGH Revised Clinical Practice Guidelines for the Management of
Well-Differentiated Thyroid Carcinoma of Follicular Cell Origin in 2012,
the use of adjuvant RAI treatment in well-differentiated thyroid cancer
has been shown to significantly decrease disease recurrence and cause-
specific mortality.5 Our study supports this recommendation.
There are several limitations of this study. First is the potential for
selection bias in a retrospective study. In this study, it was assumed
that all tumors were resected if no residual tumor was indicated
in the operative technique or no positive margins were noted on
histopathologic result. Initial thyroglobulin levels were not available
REFERENCES
1. World Health Organization. GLOBOCAN 2012: Estimated cancer incidence, mortality and
prevalence worldwide in 2012. [cited 2014 Jan 12]. Available from: : http://globocan.iarc.fr/
Pages/fact_sheets_cancer.aspx.
2. Holgado J, Gloria J, Pontejos A. Epidemiologic study of thyroid lesions treated in the Philippine
General Hospital – Department of Otorhinolaryngology: A 5-year experience. In press 2012.
3. Pontejos A, Caparas M, Cabungcal A, Hardillo J, Hernandez J, Hernandez M, et al. Manual for the
Management of Head and Neck Malignancies, 2nd Edition. 2012, p 59-65.
4. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology,
Head and Neck Cancers, Version 1.2015. [accessed 2015 Jan 13]. Available from: http://
oralcancerfoundation.org/wp-content/uploads/2015/09/head-and-neck.pdf.
5. Sison CM, Obaldo J, Matsuo J, Uy GM, Jaring C. University of the Philippines – Philippine General
Hospital Revised Clinical Practice Guidelines for the Management of Well-Differentiated Thyroid
Carcinoma of Follicular Cell Origin. Journal of the ASEAN Federation of Endocrine Societies.
2012 May; 27(1):49-61. DOI: https://doi.org/10.15605/jafes.027.01.08.
6. Schlumberger M. Papillary thyroid carcinoma. Orphanet encyclopedia. 2004. [cited 2014 Feb
2]. Available from: http://www.orpha.net/data/patho/GB/uk-PTC.pdf.
7. Kus L, Shah M, Eski S, Walfish P, Freeman J. Thyroid cancer outcomes in Filipino patients. 2010.
[cited 2014 Jan 23]. Available from: http://archotol.jamanetwork.com.
8. Popadich A, Levin O, Lee JC, Smooke-Praw S, Ro K, Fazel M, et al. A multicenter cohort study of
total thyroidectomy and routine central lymph node dissection for cN0 papillary thyroid cancer.
Surgery. 2011 Dec;150(6): 1048-57. DOI: 10.1016/j.surg.2011.09.003; PMID: 22136820.
9. Hartl D, Mamelle E, Borget I, Leboulleux S, Mirghani H, Schlumberger M. Influence of prophylactic
neck dissection on rate of retreatment for papillary thyroid carcinoma. World J Surg. 2013 Aug;
37(8):1951-8. DOI: 10.1007/s00268-013-2089-3; PMID: 23677562.
10. Zhu J, Wang X, Zhang X, Li P, Hou H. Clinicopathological features of recurrent papillary thyroid
cancer. Diagn Pathol. 2015 Jul 14; 10: 96. DOI: 10.1186/s13000-015-0346-5; PMID: 26168921;
PMCID: PMC4501206.
11. Liu FH, Kuo SF, Hsueh C, Chao TC, Lin JD, et al. Postoperative recurrence of papillary thyroid
carcinoma with lymph node metastasis. J Surg Oncol. 2015 Aug; 112(2): 149-54. DOI: 10.1002/
jso.23967; PMID: 26175314; PMCID: PMC5034820.
Philippine Journal Of Otolaryngology-Head And Neck Surgery 29
ORIGINAL ARTICLES
Vol. 32 No. 2 July– December 2017
for all patients. Second, the timing of recurrence is relative. For some
patients, recurrence was detected due to regular determination of
thyroglobulin. For some, imaging was done after a neck mass was
noted. In effect, the diagnosis of recurrence might be later than it
really is. This could decrease the possible relationship of recurrence
to the variables studied. Third, the variables measured in this study
were limited to age (years) at the time of initial surgery, sex, tumor
size, multifocality, microscopic extrathyroidal extension, lymph node
metastasis and post-operative RAI therapy. Other variables that could
affect recurrence like molecular mutation status and timeliness of RAI
therapy were not measured.
In conclusion, age of >45 years, female sex, tumor size of >2 cm,
multifocality, presence of microscopic extrathyroidal extension and
lymph node metastasis might contribute to the recurrence of papillary
thyroid cancer while post-operative radioactive ablation may have some
protective effect. However, the findings in this study suggest that other
factors must be included in the model in order to better understand the
relationship between these factors and recurrence.
12. Yang J, Gong Y, Yan S, Shi Q, Zhu J, Li Z, et al. Comparison of the clinicopathological behavior of
the follicular variant of papillary thyroid carcinoma and classical papillary thyroid carcinoma:
A systematic review and meta-analysis. Mol Clin Oncol.  2015 Jul;3(4):753-764. DOI: 10.3892/
mco.2015.540; PMID: 26171175; PMCID: PMC4487034.
13. Rapoport A, Curioni OA, Amar A, Dedivitis RA. Review of survival rates 20-years after conservative
surgery for  papillary thyroid carcinoma. Braz J Otorhinolaryngol.  2015 Jul-Aug; 81(4):389-93.
DOI: 10.1016/j.bjorl.2014.08.020; PMID: 26120098.
14. Jin BJ, Kim MK, Ji YB, Song CM, Park JH, Tae K. Characteristics and significance of minimal
and maximal extrathyroidal extension in  papillary thyroid carcinoma. Oral Oncol. 2015
Aug;51(8):759-63. DOI: 10.1016/j.oraloncology.2015.05.010; PMID: 26093388.
15. Scerrino G, Attard A, Melfa GI, Raspanti C, DI Giovanni S, Attard M, et al. Role of prophylactic
central neck dissection in CN0-papillary thyroid carcinoma: results from a high-prevalence area.
Minerva Chir. 2016 Jun; 159-67. PMID: 26046958.
16. Suh YJ, Kwon H, Kim SJ, Choi JY, Lee KE, Park YJ, et al. Factors affecting the locoregional recurrence of
conventional papillary thyroid carcinoma after surgery: a retrospective analysis of 3381 patients.
Ann Surg Oncol. 2015 Oct; 22(11): 3543-9. DOI: 10.1245/s10434-015-4448-9; PMID: 25743326.
17. Kim HJ, Sohn SY, Jang HW, Kim SW, Chung JH. Multifocality, but not bilaterality, is a predictor of
disease recurrence/persistence of papillary thyroid carcinoma. World J Surg. 2013 Feb;37(2):376-
84. DOI: 10.1007/s00268-012-1835-2; PMID: 23135422.
18. Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE. 2015 American Thyroid
Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated
Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules
and Differentiated Thyroid Cancer. Thyroid. 2015. DOI: 10.1089/thy.2015.0020.
19.Qu N, Zhang L, Ji Q, Zhu Y, Wang Z, Shen Q, et al. Number of tumor foci predicts prognosis in
papillary thyroid cancer. BMC Cancer. 2014; 14:914. [cited 2014 Feb 12]. Available from: http://
www.biomedcentral.com/content/pdf/1471-2407-14-914.pdf
20. Lin JD, Chao TC, Hsueh C, Kuo SF. High recurrent rate of multicentric papillary thyroid carcinoma.
Ann Surg Oncol. 2009 Sep;16(9):2609–2616. DOI: 10.1245/s10434-009-0565-7; PMID: 19533244.
21. Arora N, Turbendian H, Scognamiglio T, Wagner P, Goldsmith S, Zarnegar R, et al. Extrathyroidal
extension is not all equal: Implications of macroscopic versus microscopic extent in papillary
thyroid carcinoma. Surgery. 2008 Dec;144(6):942-7.
 ORIGINAL ARTICLES
Philippine Journal Of Otolaryngology-Head And Neck Surgery Vol. 32 No. 2 July– December 2017

Maria Concepcion F. Vitamog, MD

Samantha S. Castañeda, MD
Thyroid Gland Invasion in Laryngeal Carcinoma
Department of Otorhinolaryngology
Head and Neck Surgery
Jose R. Reyes Memorial Medical Center
ABSTRACT
Objective: To determine the prevalence of, and describe transglottic cancer with thyroid
cartilage invasion as a possible risk for, thyroid gland invasion in a series of patients with laryngeal
carcinoma who underwent total laryngectomy with thyroidectomy.

Methods:
Design: Retrospective Case Series
Setting: Tertiary Government Training Hospital
Participants: 61 laryngeal carcinoma patients who underwent total laryngectomy
with hemi- or total thyroidectomy from January 2010 to August 2017.

Results: Out of 61 patients with laryngeal carcinoma, 11 patients had supraglottic, 11 glottic,
2 subglottic and 37 had transglottic involvement. Eleven had thyroid cartilage invasion, all of
whom had transglottic tumors. Of these 11 patients, only 1 had thyroid gland invasion. This was
a case of a 78 year-old male patient with poorly differentiated SCC stage IVa transglottic tumor
with thyroid cartilage invasion.

Correspondence: Dr. Maria Concepcion F. Vitamog Conclusion: Thyroid gland invasion was uncommon in our sample of laryngeal carcinoma
Department of Otorhinolaryngology - Head and Neck Surgery
Jose R. Reyes Memorial Medical Center patients who underwent laryngectomy and thyroidectomy. Although transglottic involvement
San Lazaro Compound, Rizal Avenue
Sta. Cruz, Manila 1003 with thyroid cartilage invasion may increase the risk of thyroid gland invasion, it could not
Philippines be confirmed by our series. Perhaps thyroidectomy should not be routinely performed on all
Phone: (632) 743 6921; (632) 711 9491 local 320
Email: entjrrmmc@yahoo.com patients with laryngeal carcinoma who undergo total laryngectomy but more rigorous studies
The authors declared that this represents original material are needed to establish this.
that is not being considered for publication or has not been
published or accepted for publication elsewhere, in full or
in part, in print or in electronic media; that the manuscript Keywords: laryngeal carcinoma, transglottic, thyroid cartilage invasion, thyroid gland invasion,
has been read and approved by all the authors, that the
requirements for authorship have been met by each author, thyroidectomy
and that each author believes that the manuscript represents
honest work.
Total laryngectomy is the standard of care for operable squamous cell carcinoma (SCC) of
Disclosures: The authors signed disclosures that there are no
financial or other (including personal) relationships, intellectual the larynx.1-2 SCC of the larynx can spread to adjacent structures like the trachea, esophagus
passion, political or religious beliefs, and institutional affiliations and thyroid gland.3 Invasion of the thyroid gland can be contiguous or non-contiguous via
that might lead to a conflict of interest.
lymphovascular spread.4 The incidence of thyroid gland involvement in laryngo-pharyngeal
Presented at the Philippine Society of Otolaryngology Head
and Neck Surgery Descriptive Research Contest (3rd Place). cancer ranges from 0-23%.5-6
October 6, 2016. Natrapharm, The Patriot Bldg. Parañaque City. The need for thyroidectomy during total laryngectomy is controversial as thyroid gland
invasion is rare and thyroidectomy is associated with long term morbidities.7-8 A meta-analysis by
Mendelson et al. advised hemithyroidectomy in transglottic tumors, subglottic tumors and tumors
Creative Commons (CC BY-NC-ND 4.0)
Attribution - NonCommercial - NoDerivatives 4.0 International Philipp J Otolaryngol Head Neck Surg 2017; 32 (2): 22-24 c Philippine Society of Otolaryngology – Head and Neck Surgery, Inc.

22 Philippine Journal Of Otolaryngology-Head And Neck Surgery


Philippine Journal Of Otolaryngology-Head And Neck Surgery
with subglottic extension more than 10 mm.9 Other indications for
thyroidectomy are palpable nodule,10 T3 and T4 lesion,5,9-13 transglottic
growth,9-13 subglottic disease or extension more than 10 mm9-12,14-16
anterior commissure involvement5,12 and thyroid cartilage invasion.11
A local study revealed that extralaryngeal spread, tracheostomal
involvement and tracheal extension were associated with thyroid
gland invasion.17 However, despite all these studies, thyroidectomy
is still routinely done for laryngectomy cases in our institution. The
NCCN 2017 Guideline for laryngeal cancer states that for glottic and
supraglottic T3 tumors requiring (amenable) to total laryngectomy
can undergo the procedure with ipsilateral thyroidectomy. For patients
with glottic and supraglottic T4a tumors, the standard approach is total
laryngectomy with thyroidectomy and neck dissection as indicated
(depending on node involevement) followed by adjuvant treatment.18
Studies in the local setting may change prevailing guidelines about the
need for thyroidectomy in laryngectomy.
Our study aims to determine the prevalence of, and describe
transglottic cancer with thyroid cartilage invasion as a possible risk for,
thyroid gland invasion in a series of patients with laryngeal carcinoma
who underwent total laryngectomy with thyroidectomy.
METHODS
With institutional Ethical Review Board approval, we retrieved
records of all patients who underwent laryngectomy with thyroidectomy
of any type at our institution from January 2010 to August 2017.
Excluded were incomplete records and those of laryngectomy without
histopathologically-documented thyroidectomy.
Demographics such as age and sex of the patients were obtained.
The laryngeal tumor extent, type of thyroidectomy and thyroid gland
involvement were recorded based on reported histological analysis of
pathological specimens by different pathologists. Data were tabulated
using MS Word for Mac 2011 version 14.0.0 (100825) (Microsoft
Corporation, Redmond, WA, USA). Data were analyzed using Epi Info
2017 Version 7 (Centers for Disease Control and Prevention, Atlanta,
GA, USA). A descriptive analysis was performed using frequency and
proportion for each subsite of laryngeal carcinoma that was treated
with total laryngectomy with or without thyroid cartilage involvement
and with or without thyroid gland invasion and results evaluated in the
light of the reviewed literature.
RESULTS
Records of 64 patients were initially considered but only 61 met
the inclusion criteria. Of the 3 records excluded from the study, 2
were incomplete while 1 reported a total laryngectomy without
thyroidectomy. Of the 61 patients included in the study, 58 (95.1%)
Philippine Journal Of Otolaryngology-Head And Neck Surgery 23
ORIGINAL ARTICLES
Vol. 32 No. 2 July– December 2017
were males and 3 (4.9%) were females. Their mean age was 62 years
(range 48 to 78 years).
Twenty-seven patients underwent hemithyroidectomy (with
isthmusectomy) while 34 had total thyroidectomy. Eleven had
supraglottic involvement, 11 glottic, 2 subglottic and 37 transglottic.
Out of the 37 transglottic cases, 11 had histopathologic thyroid
cartilage invasion. Of these 11 transglottic cancers with thyroid cartilage
involvement, only 1 (1.6%) had histopathologically-confirmed thyroid
gland invasion.
DISCUSSION
Our study had a 1.6% prevalence of thyroid gland invasion among
patients who underwent total laryngectomy with thyroidectomy
for laryngeal SCC. Previous studies show prevalences ranging from
1-11%,1,11,14,15,17 supportive of our findings that suggest thyroid gland
invasion is uncommon in patients undergoing total laryngectomy for
laryngeal SCC. Given the varied sample sizes and clinical scenarios of
these studies, there seems to be no significant geographical difference
in the incidence rate of thyroid gland invasion.
We were also interested in transglottic involvement with thyroid
cartilage invasion as a possible risk for thyroid gland invasion. In our
study, the prevalence of thyroid gland invasion increases to 2.7% if we
consider only transglottic tumors (or 1 out of 37 patients). The lesion
has to invade through thyroid cartilage, cricoid cartilage or cricothyroid
membrane to reach the extralaryngeal soft tissue.1 A retrospective study
by Iype et al. showed 30% increase in thyroid gland invasion among
patients with pre-operative findings of thyroid cartilage erosion by CT
scan.16 In our study, there were 11 cases with thyroid cartilage invasion
confirmed through histopathology, all of which were transglottic
tumors. Among these, only one had positive thyroid gland invasion,
increasing the risk to 9.1% or 1 out of 11.
Laryngeal cancer is 4 times more common in males and 90% more
common in patients more than 40 years old.9 Our patient with thyroid
gland invasion was a 78 year-old male. It may be conjectured that he
might have had ossified thyroid lamina that were more vulnerable to
tumor invasion. Ossified portions of cartilage are potentially at higher
risk for invasion because of vascular channel penetration, whereas
intact perichondrium that surrounds avascular unossified cartilage
resists tumor encroachment.19 Having said that, a meta-analysis by
Mendelson et al. found that cartilaginous invasion by tumor was not a
significant predictor of thyroid gland invasion.9
One drawback of the study is the limited number of cases with
concomitant thyroid gland invasion. A multi- institutional study can be
conducted to increase the number of cases. Another limitation is that it
focused only on the subsite involved and presence of thyroid cartilage
 ORIGINAL ARTICLES
Philippine Journal Of Otolaryngology-Head And Neck Surgery
invasion as possible risk factors for having thyroid gland invasion. Other
parameters such as size of mass, presence of palpable lymph nodes and
involvement of anterior commissure as possible risk factors for having
thyroid gland invasion can be included in future studies. The quality
and reliability of second-hand data retrieved from patient records add
another limitation to our study. For instance, our study design cannot
account for variability in qualifications and competence among the
different pathology residents and pathologists who evaluated and cut
the gross specimens, read the slides and issued final histopathology
REFERENCES
1. Nayak SP, Singh V, Dan A, Bhownik A, Jadhav TS, Ashraf M. et al. Mechanism of thyroid gland
invasion in laryngeal cancer and indications for thyroidectomy. Indian J Otolaryngol Head
Neck Surg. 2013 Jul; 65(1): S69-S73. DOI: 10.1007/s12070-012-0530-9; PMID:24427619 PMCID:
PMC3718952.
2. Armstrong W, Vokes D, Maisel R. Malignant tumors of the larynx. In: Flint P, Haughey B, Lund V,
Niparko J, Richardson M, Robbins KT et al (editors). Cummings Otolaryngology Head and Neck
Surgery. 5th ed. Philadelphia: Mosby Elsevier. 2010.p. 1482.
3. Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A. AJCC cancer staging manual 7th
edition. Chapter 5 Larynx. New York: Springer; 2010.p. 58.
4. Gilbert RW, Cullen RJ, van Nostrand AW, Bryce DP, Harwood AR. Prognostic significance of
thyroid gland involvement in laryngeal carcinoma. Arch Otolaryngology Head Neck Surg. 1986
Aug; 112(8):856–859. PMID: 3718691.
5. Kim JW, Han GS, Byun SS, Lee DY, Cho BH, Kim YM. Management of thyroid gland invasion
in laryngopharyngeal cancer. Auris Nasus Larynx. 2008 Jun; 35 (2):209-12 . DOI:10.1016/j.
anl.2007.07.003; PMID: 17851001.
6. Croce A, Moretti A, Bianchedi M. Thyroid gland involvement in cancer of the larynx. Acta
Otorhinolaryngoly Ital. 1991 Jul-Aug;11(4):429-35. PMID: 1792897.
7. Sinard RJ, Tobin EJ, Mazzaferri EL, Hodgson SE, Young DC, Kunz AL, et al. Hypothyroidism
after treatment of non-thyroid head and neck cancer. Arch Otolarygol Head Neck Surg. 2000
May;126(5):652-57.
 PMID:10807335.
8. Ho AC, Ho WK, Lam PK, Yeun AP, Wei WI. Thyroid dysfunction in laryngectomies – 10 years after
treatment. Head Neck. 2008 Mar;30(3):336-40. DOI10.1002/hed.20693; PMID: 17636544.
9. Mendelson AA, Al-Khatib TA, Julien M, Payne RJ, Black MJ, Hier MP. Thyroid gland management
in total laryngectomy: meta-analysis and surgical recommendations. Otolaryngol Head Neck
Surg 2009 Mar; 140(3): 298–305. DOI: 10.1016/j.otohns.2008.10.031; PMID: 19248932.
10. Biel MA, Maisel RH. Indications for performing hemi- thyroidectomy for tumours requiring total
laryngectomy. Am J Surg. 1985 Oct; 150:435–439. PMID: 4051106.
24 Philippine Journal Of Otolaryngology-Head And Neck Surgery
Vol. 32 No. 2 July– December 2017
reports. Future, controlled studies may address these issues.
Despite these considerations, thyroid gland invasion was
uncommon in our sample of laryngeal carcinoma patients who
underwent laryngectomy and thyroidectomy. Although transglottic
involvement with thyroid cartilage invasion may increase the risk of
thyroid gland invasion, it could not be confirmed by our series. Perhaps
thyroidectomy should not be routinely performed on all patients
with laryngeal carcinoma who undergo total laryngectomy but more
rigorous studies are needed to establish this.
11. Dadas B, Uslu B, Cakir B, Ozdogan HC, Calis AB, Turgut S. Intraoperative management of
the thyroid gland in laryngeal cancer surgery. J Otolaryngol. 2001 Jun; 30(3):179–183.
PMID:11771049.
12. Brennan JA, Meyers AD, Jafek BW. The intraoperative management of the thyroid gland during
laryngectomy. Laryngoscope. 1991 Sep;101(9):929–934. DOI:10.1288/00005537-199109000-
00003; PMID: 1886441.
13. Gallegos-Hernandez JF, Minauro-Munoz G, Hernandez DM, Flores-Carranza A, Hernandez-
Sanjuan M, Resendiz-Colosia JA. Thyroidectomy associated with laryngectomy in laryngeal
cancer treatment. Is it routinely necessary? Cir. 2005 Jan-Feb; 73(1):3–6. PMID: 15888262.
14. Al-Khatib T, Mendelson AA, Kost K, Zeitouni A, Black M, Payne R, et al. Routine thyroidectomy
in total laryngectomy: is it really indicated? J Otolaryngoly Head Neck Surg. 2009 Oct; 38(5):564–
567. PMID: 19769827.
15. Kumar R, Drinnan M, Robinson M, Meikle D, Stafford F, Welch A et al. Thyroid gland invasion in
total laryngectomy and total laryngopharyngectomy: a systematic review and meta-analysis of
the English literature. Clin Otolaryngol. 2013 Oct; 38(5): 372-8. DOI: 10.1111/coa.12165; PMID:
23998197.
16. Iype EM, Jagad V, Nochikattil SK, Varghese BT, Sebastian P. Thyroid gland involvement in
carcinoma of larynx and hypopharynx- predictive factors and prognostic significance. J Clin
Diagn Res. 2016 Feb; 10(2): XCO5-XCO7. DOI: 10.7860/JCDR/2016/15225.7310; PMID: 27042568
PMCID: PMC4800634.
17. Holgado J, Grullo P, Gloria J, Pontejos A. Thyroid gland involvement in advanced laryngeal
squamous cell carcinoma. Acta Medica Philippina. 2017 Jan; 51 (1): p. 11-13.
18. Pfister D, Spencer S, Adelstein D, Adkins D, Brizel D, Burtness B, et al. National Comprehensive
Cancer Network Clinical Practice Guidelines in Oncology Version 1. 2017. [accessed 2017 Feb 6].
Available from: https://www.nccn.org/.
19. Parsons M, Stachecki R, Wippold F. Diagnostic imaging of the larynx. In: Flint P, Haughey B,
Robbins K, Thomas J, Niparko J, Lund VJ et al (editors). Cummings Otolaryngology Head and
Neck Surgery. 6th ed. Philadelphia: Saunders. 2015.p. 1592.
 ORIGINAL ARTICLES
Philippine Journal Of Otolaryngology-Head And Neck Surgery
Fatima Angela C. Umali, MD
Antonio H. Chua, MD
Department of Otorhinolaryngology
Head and Neck Surgery
Jose R. Reyes Memorial Medical Center
Correspondence: Dr. Antonio H. Chua
Department of Otorhinolaryngology – Head and Neck Surgery
4th Floor, Jose R. Reyes Memorial Medical Center
Rizal Avenue, Sta. Cruz, Manila 1003
Philippines
Phone: (+632) 711 9491 local 320
Email: entjrrmmc@yahoo.com
The authors declared that this represents original material
that is not being considered for publication or has not been
published or accepted for publication elsewhere in full or in
part, in print or electronic media; that the requirements for
authorship have been met by all the authors, and that each
author believes that the manuscript represents honest work.
Disclosures: The authors signed a disclosure that there are no
financial or other (including personal) relationships, intellectual
passion, political or religious beliefs, and institutional affiliations
that might lead to a conflict of interest.
Presented at the Philippine Society of Otolaryngology Head
and Neck Surgery Analytical Research Contest (3rd Place),
November 17, 2016, Bella Ibarra, Quezon Avenue, Quezon City.
Creative Commons (CC BY-NC-ND 4.0)
Attribution - NonCommercial - NoDerivatives 4.0 International
6 Philippine Journal Of Otolaryngology-Head And Neck Surgery
Vol. 32 No. 2 July– December 2017
Ehretia Microphylla (Tsaang Gubat) versus
Loratadine as Treatment for Allergic Rhinitis: A
Randomized Controlled Trial
ABSTRACT
Objective: To determine if Ehretia microphylla (Tsaang Gubat) decoction tea and placebo can
improve the symptoms of mild intermittent allergic rhinitis in comparison to loratadine and
control tea.
Methods:
Design: Double-Blind, Randomized Controlled Trial
Setting: Tertiary-Government Training Hospital
Participants: Twenty-four patients diagnosed with mild intermittent allergic rhinitis
from October 2015 to July 2016 were randomly divided into a treatment group given Ehretia
microphylla (Tsaang Gubat) decoction tea and placebo, and a control group given control tea and
loratadine, both taken for 7 days. Patients underwent pre– and post–intervention evaluation by
anterior rhinoscopy, Sino-nasal Outcome Test 22 (SNOT 22) Questionnaire and 10-point Visual
Analog Scale (VAS). Data were encoded and subjected to statistical analysis using Mann Whitney
U test and Wilcoxon Signed Rank test.
Results: Age and gender of the treatment and control group participants were comparable. Prior
to intervention, no differences in symptoms were noted between both groups on SNOT 22 and
VAS scores. After intervention, no differences in symptoms were noted between the 2 groups on
SNOT 22 and VAS scores either. Comparison of pre- (30.4 ± 17.3) and post- (7.2 ± 6.5) intervention
mean SNOT 22 scores of the loratadine control group with pre- (32.5 ± 23.7) and post- (7.8 ± 10.4)
intervention mean SNOT 22 scores of the Ehretia Microphylla treatment group showed significant
improvement of symptoms in both groups. Likewise, comparison of pre- and post-intervention
mean VAS scores of the loratadine control group and pre- and post-intervention mean VAS scores
of the Ehretia Microphylla treatment group based on symptoms of sneezing, rhinorrhea, nasal
congestion and pruritus showed significant improvement of symptoms in both groups (p-values
of < .001).
Conclusion: Ehretia microphylla (Tsaang Gubat) decoction tea may improve symptoms of allergic
rhinitis (sneezing, rhinorrhea, pruritus and nasal congestion) and be taken as an alternative to
loratadine in patients with mild intermittent allergic rhinitis. Further clinical trials with more
participants may provide stronger evidence for this conclusion.
Keywords: Allergic rhinitis, tsaang gubat, ehretia microphylla, loratadine
Philipp J Otolaryngol Head Neck Surg 2017; 32 (2): 6-10 c Philippine Society of Otolaryngology – Head and Neck Surgery, Inc.

Philippine Journal Of Otolaryngology-Head And Neck Surgery
Allergic rhinitis is a common health problem affecting all ages
with prevalence of 20% among Filipino adults.1 Patients present with
symptoms of sneezing, rhinorrhea, nasal congestion and pruritus.
These symptoms result from the inflammatory reaction caused by
the interplay of inflammatory cells and mediators due to exposure to
allergens. Current treatment guidelines include recommendations for
environmental modifications, antihistamines, decongestants, intranasal
cromolyn, intranasal anti-cholinergics, intranasal corticosteroids and
immunotherapy.2 Allergic rhinitis carries the burden of impaired quality
of life and enormous cost implications.3 Thus, treatment goals focus
on alleviating troublesome symptoms of allergic rhinitis at a viable
economical cost.
Ehretia microphylla (Tsaang Gubat) is 1 of the 10 medicinal plants
approved by the Republic of the Philippines Department of Health to
treat different ailments.4 The leaves are traditionally used for medicinal
purposes as an anti-spasmodic, mouthwash and body cleanser,
attributed to the effects of different components (phenolic acids,
flavonoids, benzoquinones, cyanogenetic glycosides, and fatty acids).5
It also contains rosmarinic acid and nitrile glucosides which are anti-
allergic substances that counter histamine release from mast cells that
cause type-1 reactions.5,6 Unfortunately, to the best of our knowledge,
there is still no study detailing the use of this herbal medicine for
allergic rhinitis. A PubMED, EMBASE and HERDIN search of the English
literature using the keywords “allergic rhinitis,” “tsaang gubat,” “ehretia
microphylla,” and “loratadine” did not yield any study on the use of
Ehretia microphylla for allergic rhinitis.
This study aims to determine if Ehretia microphylla (Tsaang Gubat)
decoction tea and placebo can improve the symptoms of allergic
rhinitis in comparison to loratadine and control tea.
METHODS
With Institutional Review Board approval, this double blind,
randomized controlled trial was conducted at the Ear, Nose, Throat
– Head and Neck Surgery (ENT-HNS) Out-Patient Department of the
Jose R. Reyes Memorial Medical Center, a tertiary government training
hospital from October 2015 to July 2016.
Participants
The target population were patients aged 18 years old and above
who complained of sneezing, rhinorrhea, nasal congestion and pruritus;
with pale, edematous, boggy mucosa on anterior rhinoscopy; clinically
diagnosed with mild intermittent allergic rhinitis (symptoms <4 times
per week or for <4 weeks, with normal sleep, and no impairment in
daily activities, sport, leisure, work or school). Excluded were patients
with nasal mass, polyp and nasal trauma, those with history, symptoms
Philippine Journal Of Otolaryngology-Head And Neck Surgery 7
ORIGINAL ARTICLES
Vol. 32 No. 2 July– December 2017
or signs of Ehretia microphylla allergy, and those who could not tolerate
ingestion of the tea decoction.
Preparation of Ehretia microphylla (Tsaang Gubat) decoction tea7
Fresh leaves were gathered from Baliuag, Bulacan and authenticated
at the University of Santo Tomas – Research Center for Natural and
Applied Sciences Herbarium. After washing the leaves thoroughly in
running water, one cup (200 ml) of leaves was chopped and boiled per
2 cups (400 ml) of water for 15 to 20 minutes under low heat. The boiled
leaves were drained, cooled, transferred to clean plastic containers and
refrigerated. The Ehretia Microphylla tea was given to participants in 1L
bottles that were refilled every 2 days during the study.
Preparation of control tea
One (1) teabag of Lipton® Yellow Label Tea (Uniliver, Manila) was
soaked per 2 cups (400 ml) of water just off the boil for 3 to 5 minutes.
The teabag was removed and the tea preparation cooled, transferred
to clean plastic containers and refrigerated. The control tea was given
to participants in 1L bottles that were refilled every 2 days during the
study.
Procedure
Clinical histories were obtained and physical examinations,
including anterior rhinoscopy were performed by ENT-HNS resident
physicians on duty. Each patient was asked to answer the Allergic
Rhinitis Questionnaire2 as guide for fulfilling inclusion criteria. After
obtaining informed consent 24 participants fulfilling these criteria were
considered for inclusion in the study. Subjects were assigned to either
of the 2 groups via electronic randomizer using Microsoft Excel for Mac
2011, Version 14.5.6 (150930) (Microsoft Corp., Redwood CA, USA).
The treatment group was given Ehretia microphylla tea taken by
cupful (200 ml) every 4 hours when awake and placebo (flour dummy
pill) taken once nightly, for 7 days. The control group was given
loratadine 10 mg / tablet taken once nightly and control tea taken by
cupful (200 ml) every 4 hours when awake, also for 7 days.
The Sino-nasal Outcome Test 22 (SNOT22) Questionnaire
(Washington University, St. Louis, Missouri) and 10-point Visual
Analog Scale (VAS) scores per symptom of sneezing, rhinorrhea, nasal
congestion and pruritus were obtained before and after intervention by
the blinded outpatient resident physician on duty. Data were encoded
and tallied in SPSS version 24 (IBM, 64 bit edition). Statistical analysis of
different variables, mean and standard deviation were computed and
analyzed using Mann Whitney U test, and Wilcoxon Signed Rank test,
and p-values were set with 95% confidence interval.
 ORIGINAL ARTICLES
Philippine Journal Of Otolaryngology-Head And Neck Surgery Vol. 32 No. 2 July– December 2017

RESULTS
Twenty four participants, 11 males (45.8%) and 13 females (54.2%)
with mean age of 44 years (range 18-77) were randomly assigned
to two groups of 12 persons each and completed the study with no
adverse events reported. There were no significant differences in age
and gender between treatment and control groups.
Comparison of scores of individual SNOT 22 items between groups
showed that there were no significant differences in symptoms before
and after intervention. (Table 1, 2)
Comparison of mean SNOT 22 scores pre- (30.4 ± 17.3) and post-
intervention (7.2 ± 6.5) in the loratadine control group with mean SNOT
22 scores pre- (32.5 ± 23.7) and post- (7.8 ± 10.4) intervention in the
Ehretia Microphylla treatment group showed significant improvement
of symptoms in both groups (p = .002 and p = .017, respectively) as
shown in Table 3.
There were no significant differences in the pre–intervention VAS
scores of both groups specifically for symptoms of sneezing, rhinorrhea,
nasal congestion and pruritus as shown in Table 4. Likewise, there were
no significant differences in the post-intervention VAS scores of both
groups. There was significant improvement noted in the pre- and
post-intervention VAS scores (p = .002 and p = .003) for both groups as
shown in Table 5.

Table 1. Comparison of the Pre-Intervention SNOT 22 Between the Two Groups Table 2. Comparison of the Post-Intervention SNOT 22 Between the Two Groups
PRE-INTERVENTION POST-INTERVENTION
SNOT 22 Control Group Treatment Group p-value SNOT 22 Control Group Treatment Group p-value
(n=12) (n=12) (n=12) (n=12)
1. Need to blow nose 2 2 .68 (NS) 1. Need to blow nose 0 0 .95 (NS)
2. Sneezing 4 4 1.00 (NS) 2. Sneezing 1 1 .57 (NS)
3. Runny nose 3.5 4 .44 (NS) 3. Runny nose 1 0 .18 (NS)
4. Cough 1 1.5 .56 (NS) 4. Cough 1 1 1.00 (NS)
5. Post-nasal 1 1 .88 (NS) 5. Post-nasal 0 0 .89 (NS)
discharge discharge
6. Thick nasal 0.5 1 .69 (NS) 6. Thick nasal 0 0 .69 (NS)
discharge discharge
7. Ear fullness 1 1 .86 (NS) 7. Ear fullness 0 0 .91 (NS)
8. Dizziness 1 1 .74 (NS) 8. Dizziness 0 0 1.00 (NS)
9. Ear pain/pressure 0.5 0.5 .78 (NS) 9. Ear pain/pressure 0 0 .62 (NS)
10. Facial pain/pressure 0.5 0.5 .98 (NS) 10. Facial pain/pressure 0 0 .91 (NS)
11. Difficulty falling 1 1 .90 (NS) 11. Difficulty falling 0 0 .32 (NS)
asleep asleep
12. Wake up at night 0 1 .44 (NS) 12. Wake up at night 0 0 .57 (NS)
13. Lack of a good 0 1 .65 (NS) 13. Lack of a good 0 0 .93 (NS)
night’s sleep night’s sleep
14. Wake up tired 0 0 .78 (NS) 14. Wake up tired 0 0 .93 (NS)
15. Fatigue during the 0 0.5 .66 (NS) 15. Fatigue during the 0 0 1.00 (NS)
day day
16. Reduced 0 0.5 .73 (NS) 16. Reduced 0 0 .58 (NS)
productivity productivity
17. Reduced 0 0 .71 (NS) 17. Reduced 0 0 1.00 (NS)
concentration concentration
18. Frustrated/restless/ 1 0.5 .44 (NS) 18. Frustrated/restless/ 0 0 .44 (NS)
irritable irritable
19. Sad 1 0.5 .44 (NS) 19. Sad 0 0 .91 (NS)
20. Embarrassed 0.5 0 .55 (NS) 20. Embarrassed 0 0 .51 (NS)
21. Sense of smell/taste 0 0 .97 (NS) 21. Sense of smell/taste 0 0 .95 (NS)
22. Congestion/ 3 4 .54 (NS) 22. Congestion/ 1 1 .65 (NS)
Obstruction of nose Obstruction of nose

8 Philippine Journal Of Otolaryngology-Head And Neck Surgery

 ORIGINAL ARTICLES
Philippine Journal Of Otolaryngology-Head And Neck Surgery Vol. 32 No. 2 July– December 2017

Table 3. Comparison of the Pre- and Post-Intervention SNOT 22 Mean Scores Table 5. Comparison of the Pre- and Post-Intervention VAS Mean Scores
Mean SNOT 22 Mean VAS
Control Group Treatment Group Control Group Treatment Group
(n=12) (n=12) (n=12) (n=12)
Mean SD Mean SD p-value Mean SD Mean SD p-value
Pre 30.4 17.3 32.5 23.7 .843 (NS) Pre 2.6 1.6 2.8 2.1 .713 (NS)
Post 7.2 6.5 7.8 10.4 .671 (NS) Post 0.5 0.5 0.5 0.7 .514 (NS)
p-value .002 (S) .017 (S) p-value .002 (S) .003 (S)

Table 4. Comparison of Pre- and Post-Intervention VAS Scores per Symptom of Allergic Rhinitis DISCUSSION
A. Sneezing In this randomized controlled trial, both Ehretia microphylla (Tsaang
Control Group Treatment Group Gubat) decoction tea (plus placebo) and loratadine (plus control tea)
(n=12) (n=12) improved the symptoms of allergic rhinitis. Comparison of the SNOT22
VAS Mean SD Mean SD Mann-Whitney p-value and VAS scores before and after the intervention both for the loratadine
Pre 7.8 1.8 7.9 1.6 68.0 0.843 (NS) control group and Ehretia microphylla treatment group showed
Post 1.1 0.9 1.0 1.0 65.0 0.713 (NS)
improvement in sneezing, rhinorrhea, nasal congestion and pruritus.
Wilcoxon 3.075 3.078
The leaves of Ehretia microphylla (Tsaang Gubat) have been
P-value .002 (S) .002 (S)
investigated for their anti-inflammatory property. The active
B. Rhinorrhea components, rosmarinic acid and nitrile glucosides5,6 are claimed to
Control Group Treatment Group be anti-allergic substances that counter histamine release from mast
(n=12) (n=12) cells, rosmarinic acid being one of the particularly active principles.
VAS Mean SD Mean SD Mann-Whitney p-value Ehretia microphylla has been found useful in the treatment of different
Pre 6.8 1.4 7.2 1.2 58.5 .443 (NS) inflammatory ailments.7
Post 1.0 1.0 0.4 0.5 46.5 .143 (NS) Rosmarinic acid is a strong anti-inflammatory agent according to
Wilcoxon 3.089 3.140 several studies.5,8 A study by Osakabe et al., found a significant increase
P-value .002 (S) .002 (S) in responder rates for itchy nose, watery eyes and total symptoms in
C. Nasal Congestion patients with seasonal allergic rhinoconjunctivities supplemented
Control Group Treatment Group with rosmarinic acid.9 A decrease in the number of neutrophils and
(n=12) (n=12) eosinophils in the lavage fluid from the same patients was noted with
VAS Mean SD Mean SD Mann-Whitney p-value no adverse events recorded.9
Pre 6.1 2.5 6.7 2.3 61.5 .551 (NS) Improvement of symptoms of sneezing, rhinorrhea, nasal
Post 1.2 1.0 1.1 1.2 68.5 .843 (NS) congestion and pruritus in allergic rhinitis may be attributed to the
Wilcoxon 3.108 3.077 anti-inflammatory effect of rosmarinic acid, by inhibition of histamine
P-value .002 (S) .002 (S) release and inhibition of adhesion molecule, chemokine and eicosnoid
D. Pruritus synthesis.6,9 In a study by Oh, rosmarinic acid inhibited IgE production,
histamine release, inflammatory cytokine production and COX-2
Control Group Treatment Group
(n=12) (n=12) expression.10
VAS Mean SD Mean SD Mann-Whitney p-value This study has several limitations. Since tsaang gubat was not
Pre 6.4 1.2 7.4 1.0 38.0 .052 (NS) compared with loratadine alone (loratadine was combined with a tea),
Post 1.0 0.7 1.3 0.8 54.0 .319 (NS) possible interactions of tea with loratadine and effects of tea on allergic
Wilcoxon 3.084 3.072 rhinitis itself were not accounted for in this study. Moreover, tsaang
P-value .002 (S) .002 (S) gubat can be prepared in various concentrations and administered in
various forms, none of which were accounted for in this trial. Tsaang

Philippine Journal Of Otolaryngology-Head And Neck Surgery 9

 ORIGINAL ARTICLES
Philippine Journal Of Otolaryngology-Head And Neck Surgery Vol. 32 No. 2 July– December 2017

gubat itself may vary in effect depending on where it is sourced (studies

have shown such variation for other herbals). It is important to note that
the possible active ingredient(s) in tsaang gubat that have anti allergic
and anti inflammatory properties were not isolated and may be present
in varying concentrations as well.
In conclusion, Ehretia microphylla (Tsaang Gubat) decoction tea
may improve symptoms of allergic rhinitis (sneezing, rhinorrhea, nasal
congestion and pruritus) and be taken as an alternative to loratadine
in patients with mild intermittent allergic rhinitis. Further clinical
trials with more participants may provide stronger evidence for this
recommendation.

ACKNOWLEDGEMENTS
The authors would like to thank Dr. Samantha S. Castañeda, the research coordinator who pre-
reviewed this paper, Mr. Fercy B. Cavan for the statistical analysis of data, and the JRRMMC ENT-HNS
residents who helped in data gathering.

REFERENCES
1. Abong JM, Kwong SL, Alava HD, Castor MA, De Leon JC. Prevalence of allergic rhinitis in
Filipino adults based on the National Nutrition and Health Survey 2008. Asia Pac Allergy. 2012
Apr;2(2):129-135. DOI: 10.5415/apallergy.2012.2.2.129. PMID: 22701863 PMCID: PMC3345326.
2. Bousquet J, Reid J, van Weel C, Baena Cagnani C, Canonica GW, Demoly P, et al. Allergic rhinitis
management pocket reference 2008. Allergy. 2008 Aug;63(8):990-996. DOI: 10.1111/j.1398-
9995.2008.01642.x. PMID: 18691301.
3. Green RJ, Davis G. The burden of allergic rhinitis. J Allergy Clin Immunol Current Allergy & Clinical
Immunology. 2005 Nov;18(4):176-178.
4. Ammakiw C, Odiem M. Availability, preparation, and uses of herbal plants in Kalinga, Philippines.
Eur Sci J. 2013; 4:1857.
5. Simpol LR, Otsuka H, Ohtani K, Kasai R, Yamasaki K. Nitrile glucosides and rosmarinic acid, the
histamine inhibitor from Ehretia philippinensis. Phytochemistry. 1994;36(1):91-95.
6. Yamamura S, Simpol LR, Ozawa K, Ohtani K, Otsuka H, Kasai R, et al. Antiallergic dimeric
prenylbenzoquinones from Ehretia microphylla. Phytochemistry. 1995 May;39(1):105-110.
PMID: 7786482.
7. Alvarez, AA. Tsaang Gubat or Wild Tea (Ehretia microphylla Lam.). [Retrieved 2015 Mar 6]
Available from: http://www.philippineherbalmedicine.org/tsaang_gubat.htm.
8. Sanbongi C, Takano H, Osakabe N, Sasa N, Natsume M, Yanagisawa R, et al. Rosmarinic acid
inhibits lung injury induced by diesel exhaust particles. Free Radic Biol Med. 2003 Apr 15;
34(8):1060–1069. PMID: 12684091.
9. Osakabe N, Takano H, Sanbongi C, Yasuda A, Yanagisawa R, Inoue K, et al. Anti-inflammatory
and anti-allergic effect of rosmarinic acid (RA); inhibition of seasonal allergic rhinoconjunctivitis
(SARS) and its mechanism. Biofactors. 2004;21(1-4):127-131. PMID: 15630183.
10. Oh HA, Park CS, Ahn HJ, Park YS, Kim HM. Effect of Perilla frutescens var. acuta Kudo and
rosmarinic acid on allergic inflammatory reactions. Exp Biol Med. 2011 Jan; 236(1): 99-106. DOI:
10.1258/ebm.2010.010252. PMID: 21239739.
11. Farnsworth NR, Akerele O, Bingel AS, Soejarto DD, Guo Z. Medicinal plants in therapy. Bull World
Health Organ. 1985;63(6): 965–981.

10 Philippine Journal Of Otolaryngology-Head And Neck Surgery

 UNDER THE MICROSCOPE
Philippine Journal Of Otolaryngology-Head And Neck Surgery Vol. 32 No. 2 July– December 2017

Jonathan P. Rivera, MD1

Jose M. Carnate, Jr., MD2 Sinonasal Tract Meningioma
1
Department of Laboratories
Philippine General Hospital
University of the Philippines Manila A 63-year-old Filipino female presented with epistaxis of undisclosed duration. Examination
showed a vascular, pulsating, rubbery intranasal mass involving both nasal cavities. The clinical
2
Department of Pathology
College of Medicine impression was that of a nasal hemangioma. She underwent excision of the tumor and the
University of the Philippines Manila specimen was sent for histopathologic evaluation.
The specimen consisted of several tan-brown irregular tissue fragments with an aggregate
diameter of 2 cm. Microscopic examination showed a cellular spindle cell tumor underneath the
respiratory mucosa. (Figure 1) The tumor cells formed a syncytial pattern arranged in whorls that
were separated by thin fibrovascular bands. (Figure 2) The cells had round to oval nuclei with
nuclear clearing and moderate amount of syncytial cytoplasm compatible with a meningothelial
derivation. (Figure 3) There was absence of nuclear atypia, significant mitotic activity and necrosis.
Immunohistochemistry studies showed positivity for Epithelial Membrane Antigen (EMA) and
Progesterone Receptors (PR) and absence of reaction for Smooth Muscle Actin (SMA) and CD34.
(Figure 4) Our diagnosis was sinonasal tract meningioma.

(Hematoxylin – Eosin , 40X)

Correspondence: Dr. Jose M. Carnate, Jr.

Department of Pathology
College of Medicine, University of the Philippines Manila
547 Pedro Gil St. Ermita, Manila 1000
Philippines
Phone (632) 526 4450
Telefax (632) 400 3638
Email: jmcjpath@gmail.com

The authors declared that this represents original material
that is not being considered for publication or has not been
published or accepted for publication elsewhere, in full or in
part, in print or electronic media; that the manuscript has been
read and approved by the authors, that the requirements for
authorship have been met by each author, and that the authors
believe that the manuscript represents honest work.
Disclosures: The authors signed a disclosure that there are no
financial or other (including personal) relationships, intellectual
passion, political or religious beliefs, and institutional affiliations
that might lead to conflict of interest.
Figure 1. Cellular spindle cell tumor underneath the respiratory mucosa (Hematoxylin-eosin, 40X
magnification)
Primary extracranial meningioma of the sinonasal cavity is rare and thus secondary extension
from a primary intracranial tumor should be ruled out. It involves a wide age range with no
striking gender predilection.1,2 Most common symptoms include nasal obstruction, epistaxis,
exophthalmos and a mass. Etiogenesis is not completely established and is postulated to arise
from meningocytes that are entrapped during closure of midline structures very similar to the
development of meningoceles.3

Creative Commons (CC BY-NC-ND 4.0)

Philipp J Otolaryngol Head Neck Surg 2017; 32 (2): 60-61 c Philippine Society of Otolaryngology – Head and Neck Surgery, Inc.
Attribution - NonCommercial - NoDerivatives 4.0 International

60 Philippine Journal Of Otolaryngology-Head And Neck Surgery


Philippine Journal Of Otolaryngology-Head And Neck Surgery
Histopathologic examination discloses a spindle cell tumor arranged
predominantly in whorls composed of cells showing meningothelial
differentiation. Most are histologically grade 1 tumors. Grade 2 and 3
sinonasal tract meningiomas are rare.4 Histologic differential diagnoses
include a glomangiopericytoma, leiomyosarcoma and a solitary
fibrous tumor/hemangiopericytoma. Close histologic evaluation
with appropriate immunohistochemistry studies point to the correct
diagnosis. Meningioma shows strong diffuse positivity with EMA and PR,
and is usually negative for other immunohistochemistry markers such
(Hematoxylin – Eosin , 100X)
Figure 2. Cellular whorls of tumor cells with occasional intervening fibrovascular bands (Hematoxylin-
eosin, 100X magnification)
(Hematoxylin – Eosin , 400X)
Figure 3. Whorled pattern with cellular features indicative of a meningothelial differentiation
(Hematoxylin-eosin, 400X magnification)
Philippine Journal Of Otolaryngology-Head And Neck Surgery 61
UNDER THE MICROSCOPE
Vol. 32 No. 2 July– December 2017
as muscle actins (for glomangiopericytoma and leiomyosarcoma), and
CD34 (for solitary fibrous tumor/hemangiopericytoma).1,3 A diagnosis
of primary sinonasal meningioma should not be made if an intracranial
mass is identified.4
Sinonasal meningiomas are benign tumors with no documented
distant metastases.1,2 Although recurrences occur in about 30% (mostly
due to incomplete excision), metastasis and malignant transformation
has not been reported.4
(Hematoxylin – Eosin , 400X)
Figure 4. Immunohistochemistry showing Epithelial Membrane Antigen (EMA) and Progesterone
Receptors (PR) positivity, and Smooth Muscle Actin (SMA) and CD34 non-reactivity (Horseradish
peroxidase method, 400X magnification)
REFERENCES
1. Gnepp DR. Diagnostic Surgical Pathology of the Head and Neck . 2nd Edition. Philadelphia : PA:
Saunders/Elsevier, 2009. p. 167.
2. Thompson LD, Gyure KA. Extracranial sinonasal tract meningiomas: a clinicopathologic study
of 30 cases with a review of the literature. Am J Surg Pathol. 2000 May: 24(5):640-50. PMID:
10800982.
3. Aiyer RG, Prashanth V, Ambani K, Bhat VS, Soni GB. Primary extracranial meningioma of
paranasal sinuses. Indian J Otolaryngol Head Neck Surg. 2013 Aug: 65(Suppl 2): 384–387. DOI:
10.1007/s12070-012-0565-y; PMID: 24427682 PMCID: PMC3738789.
4. Ro JY, Bell D, Nicolai P, Thompson LDR. Meningioma. In: El-Naggar AK, Chan JKC, Grandis JR,
Takata T, Slootweg PJ (editors). World Health Organization Classification of Head and Neck
Tumours. Lyon: IARC Press. 2017. p. 50-51.
 CASE REPORTS
Philippine Journal Of Otolaryngology-Head And Neck Surgery Vol. 32 No. 1 January – June 2017

Soraya N. Joson, MD
Natividad A. Almazan, MD
An Impacted Live Fish in the Oropharynx
Melanie Grace Y. Cruz, MD
of an 8-Year-Old Child
Department of Otorhinolaryngology
Head and Neck Surgery
East Avenue Medical Center

ABSTRACT
Objective: To present an atypical case of a live fish lodged in the throat of a pediatric patient and
discuss its management.

Methods:
Design: Case Report
Setting: Tertiary Government Hospital
Patient: One

Result: An 8-year-old girl swallowed a live fish when she accidentally fell in a body of water.
Failed attempts to remove the live fish prompted consult in the emergency room of our hospital,
where removal of the foreign body was successfully done using Mixter right angle forceps assisted
with a gloved finger. Transient cyanosis and unresponsiveness during extraction was overcome
with oxygen by mask and she regained consciousness. She was allowed to go home as no other
untoward events or complications were observed.

Correspondence: Dr. Melanie Grace Y. Cruz

Department of Otorhinolaryngology
Conclusion: All ingested foreign bodies particularly in children require immediate attention.
Head and Neck Surgery The survival of patients with upper aerodigestive and airway foreign bodies depends on early
6th Floor, East Avenue Medical Center
East Avenue, Diliman, Quezon City 1100 recognition and prompt multidisciplinary management.
Philippines
Phone: (632) 928 0611 local 324
Fax: (632) 435 6988  Keywords: Foreign body, endoscopy, foreign body ingestion, impaction, oropharynx
Email: eamc_enthns@yahoo.com

The authors declared that this represents original material

that is not being considered for publication or has not been
While swimming in the river, a person can accidentally swallow water. But how often do we
published or accepted for publication elsewhere in full or in see a fish enter the mouth and get lodged in the oropharyngeal inlet? We report a rare case of live
part, in print or electronic media; that the manuscript has been
read and approved by all the authors, that the requirements fish impaction in the oropharynx of a pediatric patient and discuss its removal.
for authorship have been met by each author, and that each
author believes that the manuscript represents honest work.
CASE REPORT
Disclosures: The authors signed disclosures that there are no
financial or other (including personal) relationships, intellectual An 8-year-old girl was brought to the emergency room of our hospital with severe throat
passion, political or religious beliefs, and institutional affiliations
that might lead to a conflict of interest.
discomfort. Her parents claimed that she was walking along the banks of a river in Bulacan in
central Luzon, Philippines, when she slipped and accidently fell into the water. A live fish swam
Presented at the Philippine Society of Otolaryngology Head
and Neck Surgery Interesting Case Contest (3rd Place), June 30, towards her and accidentally entered her mouth. Attempts to remove the fish from her mouth
2016. Unilab Bayanihan Center, Pasig City
were unsuccessful and she was rushed to our hospital where she arrived approximately 8 hours
after the incident.

Creative Commons (CC BY-NC-ND 4.0)

Philipp J Otolaryngol Head Neck Surg 2017; 32 (1): 44-46 c Philippine Society of Otolaryngology – Head and Neck Surgery, Inc.
Attribution - NonCommercial - NoDerivatives 4.0 International

44 Philippine Journal Of Otolaryngology-Head And Neck Surgery


Philippine Journal Of Otolaryngology-Head And Neck Surgery
She was received conscious and was able to follow commands
but noted to have dysphagia, odynophagia, drooling of saliva and a
muffled voice. Oral examination revealed abrasions and hyperemia
over the soft palate, with the dark-colored fin of the fish visible in the
oropharynx. (Figure 1) This was better visualized with depression of
the tongue. Extraction of the foreign body was initially planned under
sedation, but the anesthesiologist was concerned about the risk of
Figure 1. Abrasions over the soft palate with the fish’s tail seen in the
oropharynx.
Figure 2. Application of Jennings retractor, and depression of the tongue with
a gloved finger reveals more of the fish.
Figure 3. 8 x 5 cm fish. A part of the tail was detached during initial extraction
attempts.
Philippine Journal Of Otolaryngology-Head And Neck Surgery 45
CASE REPORTS
Vol. 32 No. 1 January – June 2017
complete airway obstruction from the tongue falling back against the
already-obstructed airway in our patient who was becoming cyanotic
and lethergic. Consent was obtained to remove it while she was awake
and a Jennings mouth gag was applied to hold her mouth open. (Figure
2) Initial attempts to remove the fish using Mixter right-angle forceps
were unsuccessful, as were subsequent attempts made by palpating
the fish with a gloved finger. The fish was eventually grasped mid-body
using Mixter right-angle forceps assisted by a gloved finger and finally
extracted, measuring 8 x 5 cm. (Figure 3) Immediately prior to extraction
of the foreign body, the child became cyanotic and unresponsive.
Oxygen was administered by mask and she immediately regained
consciousness. There was no bleeding noted in the oropharynx. They
declined admission for observation, and were eventually allowed to go
home, as there were no other untoward events or complications.
DISCUSSION
Foreign body ingestion among children is not uncommon in the
emergency room. Majority of these were ingested accidentally among
children aged between six months and six years.1,2 Foreign bodies
may be aspirated or impacted. Common sites of impaction include
the tonsils, base of the tongue, piriform fossae and the cricopharynx.3
However, a bigger foreign body in the throat may block both the
trachea and esophagus and result in death. With impaction, our patient
had dysphagia, odynophagia, drooling of saliva and muffling of the
voice. In most cases of foreign bodies in children, diagnosis may be
difficult because a clear history cannot be obtained due to the lack of
characteristic clinical features and radiologic findings.3 It was different
in our patient. Oral examination revealed a large fish obstructing the
entire oropharynx. Impaction of live fish in the laryngopharynx has
been previously reported in adults and in children,4,5 but to the best of
our knowledge not in our institution.
An impacted foreign body in the oropharynx should be immediately
removed as the chance of spontaneous passage is less likely. A delay
in the procedure causes edema of the mucosa which lodges the
object more firmly, making later manipulation extremely difficult.6
More serious and potential life-threatening complications include
esophageal perforation, mediastinitis, cervical or mediastinal abscess,
emphysema, esophageal-tracheal fistula and septic complications.2
Removal should be performed promptly as no foreign body should
remain in the aerodigestive tract beyond 24 hours after presentation.7
Most importantly, the procedure should be performed under conditions
of maximum safety and minimum trauma.6
Live fish entering the pharynx while bathing in a stream of water is
not commonly reported. In a search of HERDIN, PubMed and Google
Scholar using the keywords “foreign body,” “impaction,” “oropharynx,”
 CASE REPORTS
Philippine Journal Of Otolaryngology-Head And Neck Surgery
“hypopharynx,” “esophagus,” and “fish” the authors did not find any
similar cases reported in the Philippines. However, live fish impaction
in the hypopharynx in both children and adults have been reported
elsewhere.4,5 Most notable was the report of a live fish successfully
removed in toto from the hypopharynx of a 7-month-old child.4
Removal was done under general anesthesia inside the operating room.
Although we operated under less-controlled circumstances, we also
obtained a successful outcome. Ideally, patients should be relaxed, well
ventilated and unconscious as these factors afford the best prospects for
the successful removal of the foreign body. Our decision to remove the
foreign body promptly in the emergency room was further necessitated
because the patient was becoming cyanotic and lethargic. The possible
46 Philippine Journal Of Otolaryngology-Head And Neck Surgery
Vol. 32 No. 1 January – June 2017
complications of awake foreign body removal in this case were deemed
to outweigh the risk of her possible impending demise.
This interesting rare case of impacted live fish in the oropharynx
was, to the best of our knowledge, the first in our institution and the first
reported in the Philippines. The decision to extract the fish was urgent
and straightforward because of the risk of total airway obstruction. All
ingested foreign bodies, particularly in children, require immediate
attention, and impacted oropharyngeal foreign bodies in particular
should be removed. The survival of patients with upper aerodigestive
and airway foreign bodies depends on early recognition and prompt
multidisciplinary management.
REFERENCES
1. Mevio E, Mevio N. Unusual esophageal foreign body: A table fork.  Case Rep Otolaryngol.
[Internet]. 2013; 2013:987504: 1-20 [cited 2015 Dec 15]. Available from: https://www.hindawi.
com/journals/criot/2013/987504/. DOI: 10.1155/2013/987504; PMID: 23634316; PMCID:
PMC3619629.
2. Sardana P, Bais AS, Singh VP, Arora M. Unusual foreign bodies of the aerodigestive tract.
Indian J Otolarygol Head Neck Surg. 2002 Apr; 54(2): 123-126. DOI: 10.1007/BF02968730; PMID:
23119872; PMCID: PMC3450538.
3. Vadhera R, Gulati SP, Garg A, Goyal R, Ghai A. Extraluminal hypopharyngeal foreign body. Indian
J Otolarygol Head Neck Surg. 2009 Mar; 61(1):76-78. DOI: 10.1007/s12070-009-0039-z; PMID:
23120609; PMCID: PMC3450132.
4. Aggarwal MK, Singh GB, Dhawan R, Tiwari A. An unusual case of live fish impaction in
hypopharynx in an infant. Int J Pediatr Otorhinolaryngol. 2006 Jun; 1(2): 154–156.
5. Senthilkumaran S, Sweni S, Ganapathysubramanian, Suresh P, Thirumalaikolundusubramnian P.
Live fish impaction in hypopharynx in an elderly patient. Int J Gerontol. 2011 Dec; 5(4): 225-226.
DOI:: http://dx.doi.org/10.1016/j.ijge.2011.12.003.
6. Murty P, Ingle VS, Ramakrishna S, Shah FA, Varghese P. Foreign bodies in the upper aero-digestive
tract. J Sci Res Med Sci. 2001 Oct; 3(2): 117-120. PMID: 24019718; PMCID: PMC3174712.
7. Loh KS, Tan LK, Smith JD, Yeoh KH, Dong F. Complications of foreign bodies in the esophagus.
Otolaryngol Head Neck Surg. 2000 Nov; 123(5):613–616. DOI: 10.1067/mhn.2000.110616; PMID:
11077351.
 CASE REPORTS
Philippine Journal Of Otolaryngology-Head And Neck Surgery Vol. 32 No. 1 January – June 2017

Jose Z. Fernando III, MD

Rosario R. Ricalde, MD Capillary Hemangioma of the Temporal Bone
Department of Otorhinolaryngology
Head and Neck Surgery
Quirino Memorial Medical Center

ABSTRACT
Objectives: To discuss a rare case of temporal bone capillary hemangioma and its diagnosis and
management.

Methods:
Design: Case Report
Setting: Tertiary Government Hospital
Patient: One

Results: A 44-year-old woman with a history of on-and-off right ear discharge, tinnitus and
decreased hearing, and a pinkish, smooth-surfaced, non-friable, non-pulsating mass occluding
the right external auditory canal, was initially treated for chronic suppurative otitis media with
aural polyp. A punch biopsy due to persistence of disease despite medical treatment revealed
capillary hemangioma. She underwent canal wall down mastoidectomy with obliteration to
completely resect the tumor.
Correspondence: Dr. Rosario R. Ricalde
Department of Otorhinolaryngology
Head and Neck Surgery Conclusion: Capillary hemangiomas of the temporal bone are benign lesions that may lead
Quirino Memorial Medical Center
Katipunan Road Ext., Project 4, Quezon City 1108
to complications such as bone erosion, hearing loss, recurrent infection and bleeding if left
Philippines untreated. Surgery remains the ideal treatment and recurrence is rare and the prognosis is good
Phone: (632) 421 2250 local 117
Email: quirino_orlhns@yahoo.com if resection is complete.
The authors declared that this represents original material
that is not being considered for publication or has not been  Keywords: Hemangioma, capillary hemangioma, temporal bone, middle ear
published or accepted for publication elsewhere in full or in
part, in print or electronic media; that the manuscript has been
read and approved by all the authors, that the requirements
for authorship have been met by each author, and that each
Hemangiomas in the head and neck are common accounting for more than 60 percent of
author believes that the manuscript represents honest work. all hemangiomas.1 They are vascular anomalies commonly seen in children and young adults

Disclosures: The authors signed disclosures that there are no that usually grow intermittently throughout the first year of life, go through a quiescent period
financial or other (including personal) relationships, intellectual
passion, political or religious beliefs, and institutional affiliations
then spontaneously involute by 5 or 6 years old.1 They are exceptionally reported in the middle
that might lead to a conflict of interest. ear.1 When located in the temporal bone they are commonly seen in adults such as in this case.
Presented at the Philippine Society of Otolaryngology-Head This case was initially treated as a case of chronic supportive otitis media with aural polyp, a
and Neck Surgery, Interesting Case Contest. June 2, 2015.
Menarini Office, 4/F W Building, BGC Taguig City.
protracted treatment period that may have led to progression of the disease and complications.

Creative Commons (CC BY-NC-ND 4.0)

Philipp J Otolaryngol Head Neck Surg 2017; 32 (1): 37-40 c Philippine Society of Otolaryngology – Head and Neck Surgery, Inc.
Attribution - NonCommercial - NoDerivatives 4.0 International

Philippine Journal Of Otolaryngology-Head And Neck Surgery 37

 CASE REPORTS
Philippine Journal Of Otolaryngology-Head And Neck Surgery Vol. 32 No. 1 January – June 2017

The majority of intraosseous hemangiomas arising from the skull subcutaneous tissues, lips, liver and spleen or kidneys.1 Cavernous
base are cavernous and only few are capillary.2 Capillary hemangiomas hemangiomas often appear in the skin, mucosal surfaces and internal
arise predominantly in the area of the geniculate ganglion and the organs.1 Histologically, capillary hemangiomas consist of closely
internal auditory canal.2, 3 According to Singh et al., only 18 cases have arranged capillary like channels.1 This case of capillary hemangioma
been reported in English literature, with 8 cases confined to the middle showed proliferation of well-circumscribed mature formed dilated
ear and 9 cases confined to the external auditory canal, plus a case with capillaries.
involvement of the mastoid, middle ear and external ear canal.4 The The symptoms encountered by patients with hemangiomas of the
patient was initially diagnosed as chronic suppurative otitis media with ear include hearing loss, pulsating tinnitus, aural bleeding, facial nerve
aural polyp until biopsy and subsequent surgery discredited the initial dysfunction, ear pain and recurrent ear infection and ear discharge.2-5
diagnosis with an impression of capillary hemangioma. We present a Our patient also experienced on-and-off ear discharge, hearing loss and
similar case. non-pulsatile tinnitus without facial nerve dysfunction. The types of
hearing loss of patients with hemangioma of the ear can be conductive
CASE REPORT or mixed;4,6-8 our patient had conductive hearing loss.
A 44-year-old woman presented with a history of on-and-off right A diagnostic CT-scan of the temporal bone is important to localize
ear discharge of 8 years duration. She also noted tinnitus and decreased the lesion and to determine bony erosion and involvement of the
hearing after 3 years and reported right aural bleeding and post- ossicular chain.7,9 Hemangiomas are enhancing soft tissue masses
auricular swelling and discharge. No facial asymmetry was observed.
She was treated for chronic suppurative otitis media with aural polyp
without relief.
The patient was seen 8 years after the onset of symptoms. On
examination, a pinkish, smooth-surfaced, non-friable, non-pulsating
mass occluded the right external auditory canal. A draining post-
auricular sinus was surrounded by a hypertrophic scar. (Figure 1)
Temporal bone computed tomography showed a heterogenous
mass with enhancement in the right external ear canal with canal
erosions extending to the right temporo-mandibular joint and space
behind the right parotid gland. (Figure 2) Pure Tone Audiometry
revealed conductive hearing loss on the right. A punch biopsy revealed
capillary hemangioma. Mild bleeding was observed during the biopsy,
easily controlled by packing. A B
The patient underwent canal wall down mastoidectomy with
mastoid obliteration using abdominal fat and temporalis muscle
and blind sac closure. Intra-operatively, a friable mass surrounded
by granulation tissue occupied the epitympanum, middle ear cavity
and external auditory canal eroding the mallues, incus and stapes
suprastructure. The stapes foot plate was fixed. (Figure 3) Histopathology
showed proliferation of well-circumscribed mature formed dilated
capillaries without anastomoses and cellular atypia consistent with
capillary hemangioma. (Figure 4)

DISCUSSION Figure 1. A. Right ear showing mass

Hemangiomas are benign vascular tumors that can be classified
as capillary or cavernous. The former consist of closely arranged
capillary-like channels while the latter are composed of cavernous
vascular spaces.4 Capillary hemangiomas typically occur in the skin,
extruding out of the right external ear canal
B. Closer view of right external ear canal with
C mass C. Hypertrophic scar in the right post-
auricular area.

38 Philippine Journal Of Otolaryngology-Head And Neck Surgery

 CASE REPORTS
Philippine Journal Of Otolaryngology-Head And Neck Surgery Vol. 32 No. 1 January – June 2017

A B

C
Figure 2. Temporal bone CT scan A. Axial section bone window, showing soft tissue density inside the external auditory canal and middle ear cavity with bone
erosion of the anterior and posterior canal wall of the right ear. B. Axial section with contrast showing the same mass on the right ear which is heterogeneously
enhancing C. Coronal section, bone window, showing erosion of the ossicles of the right ear.

Anterior

Superior Inferior

Figure 3. Intra-operative view of

capillary hemangioma occupying
the middle ear and external auditory
Posterior canal (arrow).

Philippine Journal Of Otolaryngology-Head And Neck Surgery 39

 CASE REPORTS
Philippine Journal Of Otolaryngology-Head And Neck Surgery
(Hematoxylin – Eosin , 10X)
Figure 4. Histopathologic Low-power view (10X), Hematoxylin-Eosin
stain, showing proliferation of well-circumscribed mature formed dilated
capillaries (Arrow pointing at a mature formed dilated capillary).
as seen in the contrast CT-scan of our patient.4 Some cases reported
in literature had no bony erosion or involvement of ossicular chain
because they were either limited to the external auditory canal or
early intervention was done.1-10 Our patient had erosion of both the
posterior and anterior auditory ear canal walls and all ossicles. On
Magnetic Resonance Imaging (MRI), T1 weighted images show a lesion
of moderate intensity and T2 weighted images show high intensity
while the tumor is clearly enhanced.6 Angiography can be helpful
in identifying feeding vessels for embolization prior to surgery.1,6
Hemangioma has been described as a vascular blush on arteriography.8
Our patient did not undergo pre-operative embolization due to
financial constraints. However, we only sustained a total 900 ml blood
loss out of an allowable blood loss of 1,095 ml.
The surgical approach for capillary hemangioma of the ear depends
on the involved area and extent. The procedure can be done transcanal
if there is only external ear involvement or transmastoid with middle
ear involvement.1,4,8-10 In our patient, a transmastoid approach was
done for both middle ear and external auditory canal involvement.
Compared to other cases where middle ear structures like the ossicles
were not involved,1-10 our patient had erosion of the ossicles with
ossification of the stapes footplate. This may have been caused by
overlapping infection from manipulation and disease progression.
Our case may suggest that such hemangiomas can become extensive
and present with complications if no intervention is made.
Since there was a post-auricular sinus and a large mastoid cavity
with multiple small bleeders from the bone bed despite aggressive
hemostasis after excision of the hemangioma, surrounding granulation
and fibrosis, we decided to completely obliterate the mastoid with
40 Philippine Journal Of Otolaryngology-Head And Neck Surgery
Vol. 32 No. 1 January – June 2017
abdominal fat and temporalis muscle and perform blind sac closure
of the external auditory canal. The stapes footplate was also fixed, so
hearing rehabilitation surgery as a second stage procedure would most
likely not result in better hearing. Post-operatively, she was offered
the use of a bone anchored hearing aid (BAHA) or a bone conducting
hearing aid to address the conductive hearing loss on the right side.
The prognosis of capillary hemangioma is good and recurrence is
rare after complete resection.1,4,6-8 However, it is associated with a high
recurrence rate of 43.5 % if resection is incomplete.2
Capillary hemangiomas of the middle ear are benign lesions of
the temporal bone. However, left untreated, they may lead to disease
progression and complications such as bone erosion, hearing loss,
recurrent infection and bleeding. Surgery remains the ideal treatment,
and prognosis is good, and the chance of recurrence is rare for complete
resection.
REFERENCES
1. Martines F, Bentivegna D, Maira E, Marasa S, Ferrara S. Cavernous haemangioma of the external
auditory canal: clinical case and review of the literature. Acta Otorhinolaryngol Ital. 2012 Feb;
32(1):54-57. PMID: 22500069; PMCID: PMC3324958.
2. Yang G, Li C, Chen X, Liu Y, Han D, Gao X, et al. Large capillary hemangioma of the temporal
bone with a dural tail sign: A case report. Oncol Lett. 2014 Jul; 8(1):183-186. DOI: 10.3892/
ol.2014.2143; PMID: 24959241; PMCID: PMC4063632.
3. Fierek O, Laskawi R, Kunze E. Large intraosseous hemangioma of the temporal bone in a child.
Ann Otol Rhinol Laryngol. 2004 May; 113(5):394-8. DOI: 10.1177/000348940411300510; PMID:
15174768.
4. Singh RK, Bhandary S, Tiwary A,Karki S. Capillary Hemangioma of Tympanic Cleft. Online J Health
Allied Sci. 2008; 7(4):8. [cited 2014 Jul 28]. Available from: http://www.ojhas.org/issue28/2008-
4-8.htm.
5. Hartwein JH, Raschke DT. Hemangioma of the middle ear. Laryngol Rhinol Otol (Stuttg). 1987
May; 66(5):280-2. PMID: 3613779.
6. Pistorio V, De Stefano A, Petrucci AG, Achilli V. Capillary haemangioma of the middle ear: a rare
lesion difficult to evaluate. Acta Otorhinolaryngol Ital. 2011 Apr; 31(2):109-112. PMID: 22064794;
PMCID: PMC3203740.
7. Alvarez-BuyllaBlanco M, Vazquez Barro JC, Lopez Amado M, Santiago Freijanes MP, Martinez
Vidal J. Capillary hemangioma of middle ear a case report. Acta Otorrinolaringol Esp. 2011 Jan-
Feb; 62 (1):74-76. DOI: 10.1016/j.otorri.2010.02.001; PMID: 20347430
8. Nouri H, Harkani A, EloualiIdrissi M, Rochdi Y, Aderdour L, Oussehal A, Raji A, et al. Capillary
hemangioma of the middle ear: one case report and review of the literature. Case Rep
Otolaryngol.2012; 2012:305172. DOI: 10.1155/2012/305172; PMID: 22953107; PMCID:
PMC3420627.
9. Neto JFL, Miura MS, Saleh C, de Andrade M, Assmann M. Hemangioma as mass of external ear
canal. Intl Arch Otorhinolaryngol. 2007; 11(4): 498-500.
10. Yasar H, Ozkul H, Somay A. A rare vascular tumor of the external auditory canal: the capillary
hemangioma. Kulak Burun Bogaz Ihtis Derg. 2009 Jul-Aug; 19 (4):212-5. PMID: 19860637.

Philippine Journal Of Otolaryngology-Head And Neck Surgery
Laurence Michael N. Vera Cruz, MD
Gil M. Vicente, MD
Department of Otorhinolaryngology
Head and Neck Surgery
Jose R. Reyes Memorial Medical Center
Correspondence: Dr. Gil M. Vicente
Department of Otorhinolaryngology
Head and Neck Surgery
Jose R. Reyes Memorial Medical Center
San Lazaro Compound, Rizal Avenue
Sta. Cruz, Manila 1003
Philippines
Phone: (632) 711-9491 local 320
E-mail: drgmvicente@yahoo.com
The authors declared that this represents original material
that is not being considered for publication or has not been
published or accepted for publication elsewhere, in full or in
part, in print or electronic media; that the manuscript has been
read and approved by all the authors, that the requirements
for authorship have been met by each author, and that each
author believes that the manuscript represents honest work.
Disclosures: The authors signed disclosures that there are no
financial or other (including personal) relationships, intellectual
passion, political or religious beliefs, and institutional affiliations
that might lead to a conflict of interest.
Presented at the Philippine Society of Otolaryngology Head
and Neck Surgery Interesting Case Contest (1st Place). April 8,
2017. Plaza del Norte Hotel & Convention Center, Ilocos Norte.
Creative Commons (CC BY-NC-ND 4.0)
Attribution - NonCommercial - NoDerivatives 4.0 International
Philippine Journal Of Otolaryngology-Head And Neck Surgery 41
CASE REPORTS
Vol. 32 No. 1 January – June 2017
Proboscis Lateralis with Rhinosinusitis
ABSTRACT
Objective: This report aims to describe unique manifestations of proboscis lateralis and highlight
the importance of a multidisciplinary approach to address the problems that arise from this rare
congenital anomaly.
Methods:
Design: Case Report
Setting: Tertiary Government Hospital
Patient: One
Results: A 13-year-old girl diagnosed with proboscis lateralis presented with a trunk-like
appendage projecting from the surface of the right supramedial canthal area. She also had
clear nasal discharge, nasal congestion, mouth-breathing and snoring since birth. Paranasal
Sinus (PNS) CT scan with 3D reconstruction showed agenesis of the right paranasal sinuses and
expansile aeration of the left paranasal sinuses. Due to her condition, the drainage system of the
paranasal sinuses was obstructed causing chronic rhinosinusitis (CRS). This hindered plans for
reconstructive surgery despite medical management, hence, the patient underwent Endoscopic
Sinus Surgery (ESS).
Conclusions: Proboscis lateralis is a rare congenital anomaly that results in aesthetic problems
as well as airway concerns such as rhinosinusitis and obstructive sleep apnea syndrome (OSAS).
Management entails a multidisciplinary approach to address functional and aesthetic problems
of the patient.
Keywords: proboscis lateralis, chronic rhinosinusitis, obstructive sleep apnea, endoscopic sinus
surgery, multidisciplinary approach, plastic surgery, reconstructive surgery
Proboscis lateralis is a rare congenital anomaly of the craniofacial anatomy with an incidence
of 1:1,000,000 to 1:100,000 caused by abnormal embryonic nasal development that results in a
trunk-like appendage from the facial surface projecting frequently from the region of the medial
canthus.1
This report aims to describe the unique manifestations of proboscis lateralis associated with
chronic rhinosinusitis (CRS) and obstructive sleep apnea syndrome (OSAS), which, to the best
of our knowledge, have not been previously described in the English literature. It also aims to
highlight the importance of a multidisciplinary approach to address functional and aesthetic
problems that arise from this rare condition.
Philipp J Otolaryngol Head Neck Surg 2017; 32 (1): 41-43 c Philippine Society of Otolaryngology – Head and Neck Surgery, Inc.
 CASE REPORTS
Philippine Journal Of Otolaryngology-Head And Neck Surgery
CASE REPORT
This is the case of a 13-year-old girl who presented with a trunk-
like appendage projecting from the surface of the right supramedial
canthal area and was born preterm at 32 weeks age of gestation via
normal spontaneous delivery to a 30 year-old primigravid. Her mother
had fever followed by threatened abortion at the sixth week age of
gestation and was managed successfully with Isoxsuprine. Her mother
denied exposure to teratogens.
Since birth, the patient had also been manifesting with clear nasal
discharge, nasal congestion, mouth-breathing and snoring. She was
referred to a tertiary hospital for reconstructive surgery of the aesthetic
anomaly. However, repeated attempts at reconstructive surgery were
deferred due to persistent nasal discharge despite aggressive medical
management. This caused her to be quiet and socially withdrawn with
low self-esteem.
Three years prior to admission, the patient was seen at our institution
by the plastic surgery service but surgery was deferred again due to
persistent nasal discharge and sinus infection which could result in
failure of the reconstructive surgery.
A few months prior to admission, she was referred to our
otorhinolaryngology service for management of chronic nasal
discharge and congestion. She had severe manifestations with a Visual
Analog Score (VAS) of 9 for CRS. On physical examination, she had
hypertelorism and a nasal appendage located at the right supramedial
canthal area. (Figure 1)
Figure 1. Preoperative photographs of the patient (published in full with permission)
Paranasal Sinus (PNS) CT scan with 3D reconstruction revealed a
rudimentary right nasal structure attached at the right supramedial
canthal area with agenesis of frontal, maxillary, ethmoid and sphenoid
sinuses on the right. The left sphenoid and maxillary sinuses had
expansile aeration with deviation towards the contralateral side. The
left anterior ethmoid cells were aerated. (Figure 2)
Because of the combination of CRS, OSAS, hypertelorism and possible
depression arising from the aesthetic problem, a multidisciplinary team
42 Philippine Journal Of Otolaryngology-Head And Neck Surgery
Vol. 32 No. 1 January – June 2017
Figure 2. A. Coronal view using 16-slice helical CT scan B. Three-dimensional CT scan
reconstruction
approach was necessary. The patient was referred to the snoring clinic to
explore treatment of the OSAS and to the ophthalmology department
to assess what can be done for the hypertelorism. The ophthalmology
service also evaluated the patient’s hypertelorism, weighed risks and
benefits and leaned towards conservative management since the
condition was not visually disturbing. The patient was likewise referred
to the psychiatry department to ensure that the dynamics of a normal
growing child in the adolescent stage were evaluated and addressed
properly. The pediatrics service addressed the patient’s general health,
and developmental pediatrics also played a role in counselling. The
otorhinolaryngology, plastic surgery, and anesthesia teams collaborated
to plan surgical interventions. The teams on board carefully weighed
risks of possible complications of surgery against possible outcomes on
the future of a growing child if surgery was delayed or not done.
She first underwent endoscopic sinus surgery. Nasal videoendoscopy
showed the clear nasal discharge from the left nasal cavity and from
the rudimentary nasal appendage. The endoscope could not be
inserted further into the nasopharynx through the left nasal cavity due
to the distorted nasal anatomy. (Figure 3) Intraoperatively, the nasal
turbinates, uncinate process, and ethmoid air cells were identifiable
but were noted to have abnormal structures. Uncinectomy, antrostomy,
anterior ethmoidectomy and frontal sinusotomy were performed
endoscopically.
Significant clinical improvement was noted on follow-up 9 weeks
after the procedure. The patient reported improved nasal airflow,
resolution of snoring and decrease in amount and frequency of
rhinorrhea. Visual Analog Score (VAS) for CRS decreased from the
preoperative score of 9 (severe) to 2 (mild). No complications were
noted. In addition to functional improvement, there was also an
improvement in self-esteem. With otorhinolaryngology, pediatrics,
and anesthesia on board, she successfully underwent initial
reconstruction by the plastic surgery service. (Figure 4) Future plans
are directed towards a second stage reconstructive surgery after the
pubertal growth spurt which occurs at around 16-18 years of age.2

Philippine Journal Of Otolaryngology-Head And Neck Surgery
Figure 3. Preoperative Nasal Videoendoscopy showing obstruction of the nasal cavity. A. Nasal
Septum. B. Lateral nasal wall. C. Inferior turbinate. D. Nasal septum. E. Uncinate process. F. Middle
turbinate.
Figure 4. Before and after photographs (published in full with permission)
DISCUSSION
Under the Revised Sakomoto Grouping System,3 this case of
proboscis lateralis with hypertelorism, nasal defect but no cleft lip
or palate is classified under group III. Proboscis lateralis is commonly
associated with median facial clefts which cause hypoplasia or agenesis
of one side of the nose.4,5 This was consistent with the findings in this
patient with agenesis of the right side of the nose and nasal sinuses.
However, to the best of our knowledge, there are no published
reports in the English literature of proboscis lateralis complicated by
the presence of CRS and OSAS. This case showed that proboscis lateralis
may be associated with anatomical defects that obstruct drainage of
the developed contralateral paranasal sinuses, leading to chronic
rhinosinusitis. The patient’s chronic and non-resolving sinusitis was due
to obstruction of the ostiomeatal unit. The abnormal nasal anatomy
caused an obstruction of the left ostiomeatal unit which then resulted
in obstruction of drainage of the left paranasal sinuses.
Computed tomography and magnetic resonance imaging have
been used as the imaging modalities for preoperative evaluation of
patients with this anomaly.4,5,7-10 In this case, PNS CT scan was crucial for
planning the surgical management of the functional airway problem.
Previous reports largely focused on the successful outcomes of
reconstructive surgery4,7,9,11,12 but for this case, CRS had to be addressed
first. Endoscopic sinus surgery addressed this functional problem by
removing the ostiomeatal unit obstruction.
Philippine Journal Of Otolaryngology-Head And Neck Surgery 43
CASE REPORTS
Vol. 32 No. 1 January – June 2017
Significant clinical improvement was noted on follow-up. A literature
review of eleven studies on the outcomes of ESS in children with CRS
showed that success rate ranged from 82 to 100%. Safety profile was
excellent with rate of complications as low as 1.4%.11 However, none of
the subjects had congenital anomalies of the nasal cavity. To the best of
our knowledge, this is the first report of the successful treatment with
ESS of CRS related to proboscis lateralis.
Proboscis lateralis presents with aesthetic and functional
problems. ESS played a pivotal role in addressing the functional
problems and in paving the way towards definitive reconstruction.
The first stage of reconstruction aimed to restore the external
anatomy and promote normal development and growth of the
nose. Future management includes secondary surgical repair after
complete facial growth. However, due to the complex nature of this
malformation, achieving a favorable result is often a challenge.13
Because of this, it is important to have different services working
together for holistic and optimal management.
In summary, this paper described the unique manifestations of
proboscis lateralis that resulted in chronic rhinosinusitis and OSAS. A
multidisciplinary approach involving the otorhinolaryngology, plastic
surgery, anesthesiology, pediatrics, psychiatry, and ophthalmology
services was essential for the successful management of functional
and aesthetic problems arising from proboscis lateralis. The patient is a
living testimony to this successful cooperation.
REFERENCES
1. Martin S, Hogan E, Sorenson EP, Cohen-Gadol AA, Tubbs RS, Loukas M. Proboscis lateralis. Childs
Nerv Syst. 2013 Jun; 29(6): 885-91. DOI: 10.1007/s00381-012-1989-0; PMID: 23354442.
2. Bhatt YC, Bakshi HS, Vyas KA, Ambat GS, Laad H, Panse NS. Complete cleft of the upper limb:
A very rare anomaly. Indian J Plast Surg. 2008 Jul;41(2):195-9. DOI: 10.4103/0970-0358.44842;
PMID: 19753263; PMCID: PMC2740503.
3. Chauhan DS, Guruprasad Y. Proboscis lateralis. J Maxillofac Oral Surg. 2010 Jun; 9(2):162-5. DOI:
10.1007/s12663-010-0046-3; PMID: 22190778; PMCID: PMC3244101.
4. Vaid S, Shah D, Rawat S, Shukla R. Proboscis lateralis with ipsilateral sinonasal and olfactory
pathway aplasia. J Pediatr Surg. 2010 Feb; 45(2):453-6. DOI: 10.1016/j.jpedsurg.2009.10.044;
PMID: 20152374.
5. Sakamoto Y, Miyamoto J, Nakajima H, Kishi K. New classification scheme of proboscis lateralis
based on a review of 50 cases. Cleft Palate Craniofac J. 2012 Mar; 49(2):201-7. DOI: 10.1597/10-
127.1; PMID: 21219222.
6. Verma P, Pal M, Goel A, Singh I, Bansal V. Proboscis lateralis: case report and overview. Indian J
Otolaryngol Head Neck Surg. 2011 Jul; 63(Suppl 1):36-7. DOI: 10.1007/s12070-011-0182-1; PMID:
22754832; PMCID: PMC3146664.
7. Magadum SB, Khairnar P, Hirugade S, Kassa V. Proboscis lateralis of nose-a case report. Indian
J Surg. 2012 Apr; 74(2):181-3. DOI: 10.1007/s12262-011-0279-5; PMID: 23543614; PMCID:
PMC3309082.
8. Mohsen N, Mehdi B. Proboscis lateralis: a unique case with choanal atresia and bilateral
ophthalmopathy. Otolaryngology. 2015 Jan; 5: 183. DOI:10.4172/2161-119X.1000183.
9. Franco D, Medeiros J, Faveret P, Franco T. Supernumerary nostril: case report and review of the
literature. J Plast Reconstr Aesthet Surg. 2008; 61(4): 442-446. DOI: 10.1016/j.bjps.2006.04.007;
PMID: 18358435.
10. da Silva Freitas R, Alonso N, de Freitas Azzolini T, Busato L, Dall’Oglio Tolazzi AR, Azor de Oliveira
E Cruz G, et al. The surgical repair of half-nose. J Plast Reconstr Aesthet Surg. 2010 Jan; 63(1): 15-
21. DOI: 10.1016/j.bjps.2008.08.040; PMID: 19046661.
11. Johns Hopkins Medicine [homepage on the Internet]. Endoscopic Sinus Surgery.
Otolaryngology-Head and Neck Surgery. [cited 2015 Dec 07]. Available from: http://www.
hopkinsmedicine.org/otolaryngology/specialty_areas/sinus_center/procedures/endoscopic_
sinus_surgery.html.
12. Kapocheva-Barsova G, Nikolovski N. Justification for Rhinoseptoplasty in Children–Our 10
Years Overview. Open Access Maced J Med Sci. 2016 Sep 15; 4(3): 397–403. DOI: 10.3889/
oamjms.2016.080; PMID: 27703562; PMCID: PMC5042622.
13. Bircher A. Proboscis Lateralis. [homepage on the Internet] The Fetus.net. [cited 2017 Feb 09].
Available from: https://sonoworld.com/Fetus/page.aspx?id=2370.

Philippine Journal Of Otolaryngology-Head And Neck Surgery
Elmer F. Fabito, Jr., MD
Mary Jane Tipayno-Lubos, MD
Felixberto D. Ayahao, MD
Department of Ear Nose Throat – Head and Neck Surgery
Baguio General Hospital and Medical Center
Correspondence: Dr. Felixberto D. Ayahao
Department of Otorhinolaryngology
Head and Neck Surgery
Baguio General Hospital and Medical Center
Governor Pack Road, Baguio City, Benguet 2600
Philippines
Telefax: (074) 444 4176
Email: entbaguio@yahoo.com
The authors declared that this represents original material
that is not being considered for publication or has not been
published or accepted for publication elsewhere, in full or
in part, in print or electronic media; that the manuscript has
been read and approved by the authors, that the requirements
for authorship have been met by each author, and that each
author believes that the manuscript represents honest work.
Disclosures: The authors signed disclosures that there are no
financial or other (including personal) relationships, intellectual
passion, political or religious beliefs, and institutional affiliations
that might lead to a conflict of interest.
Presented at the Philippine Society of Otolaryngology-Head
and Neck Surgery, Interesting Case Contest. June 2, 2015.
Menarini Office, 4/F W Building, BGC Taguig City.
Creative Commons (CC BY-NC-ND 4.0)
Attribution - NonCommercial - NoDerivatives 4.0 International
Philippine Journal Of Otolaryngology-Head And Neck Surgery 47
CASE REPORTS
Vol. 32 No. 1 January – June 2017
Tuberculosis of the Thyroid
ABSTRACT
Objective: To present a case of thyroid tuberculosis and to discuss its clinical presentation,
differential diagnoses and management.
Methods:
Design: Case Report
Setting: Tertiary Government Hospital
Patient: One
Results: A 55-year-old farmer presented with an 8-month progressively enlarging anterior neck
mass, and fine needle aspiration biopsy yielded grossly turbid straw-colored aspirate admixed
with blood with microscopy showing scattered inflammatory cells and macrophages set against
a colloid background. After total thyroidectomy, hispathology revealed parenchymal infiltration
by multiple aggregates of plump spindled to epitheloid cells forming granulomas with
interspersed multinucleated giant cells, central caseation necrosis and surrounding fibrosis with
chronic inflammatory infiltrates. The nodal masses also showed prominent germinal centers with
interspersed epitheloid cells and foamy macrophages. Final diagnosis was chronic granulomatous
inflammation consistent with tuberculosis.
Conclusion: Tuberculosis (TB) of the thyroid is a rare occurrence that can present as inflammation,
infection or tumor formation of the thyroid gland. Diagnosis depends on identification of the
tubercle from tissues and aspirates by acid fast staining and TB culture. Treatment consists of
multiple drug therapy for tuberculosis but thyroidectomy may be an option if the thyroid gland
is severely diseased.
Keywords: tuberculosis, endocrine; thyroid disease
Tuberculosis (TB) is one of the leading causes of morbidity and mortality affecting one-third of
the world’s population.1 It has been reported to occur in many parts of the human body but thyroid
gland involvement is extremely rare and its true incidence is unknown.1 Thyroid tuberculosis is rare
even in countries in which tuberculosis constitutes an endemic disorder, barely 200 cases have
been reported in the world literature.2 Tuberculosis of the thyroid can present as inflammation,
infection or tumor formation of the thyroid gland. Bacteriological studies are needed to make a
specific diagnosis.2
Philipp J Otolaryngol Head Neck Surg 2017; 32 (1): 47-50 c Philippine Society of Otolaryngology – Head and Neck Surgery, Inc.
 CASE REPORTS
Philippine Journal Of Otolaryngology-Head And Neck Surgery Vol. 32 No. 1 January – June 2017

CASE REPORT lymphatic and vascular supply, well developed capsule, high iodine
A 55-year-old male farmer from Pangasinan, Philippines was content of the gland and bactericidal effect of the colloid and iodine.5-9
admitted on February 12, 2014 with a chief complaint of anterior neck Iodine can interact on the outermost layer of microbial cells producing
mass. He was apparently in good general condition until 8 months prior significant effect on their viability. In most cases, although dysphagia,
to admission when he noticed a non-tender, soft, approximately golf dyspnea and more rarely dysphonia are the main symptoms of the
ball sized mass in the anterior neck over the left lobe of the thyroid with disease, the patient may be asymptomatic as our patient was.10 In
no associated dysphagia, dyspnea, palpitations or tremors. Despite two thyroid tuberculosis, the duration of presenting symptoms varies from
unrecalled medications and regular follow-up with a private physician, 2 weeks to more than a year and there is no relationship with age or
the mass persistently enlarged.
He consulted in our institution 2 months prior to admission. Thyroid
hormone test results were normal but neck ultrasonography revealed Medium Power Objective (100 x)
bilaterally enlarged thyroid lobes with cystic mass lesions measuring 30
x 23 x 11 mm and 40 x 38 x 32 mm in the right and left lobe, respectively.
The cysts exhibited internal comet tail signs reflective of benign colloid
lesions. Fine needle aspiration biopsy on the left anterolateral neck
mass yielded grossly turbid straw-colored aspirate admixed with blood.
Microscopy showed scattered inflammatory cells and macrophages set
against a colloid background. Cell block revealed few inflammatory cells
scattered in fibrinous background consistent with benign cystic fluid.
The patient was admitted for total thyroidectomy with a clinical
impression of multinodular non-toxic goiter. Intraoperative findings
revealed a multinodular thyroid gland with approximate combined size Figure 1. Fine Needle Aspiration cytologic smear, polychromatic stain,
of 5 x 5 x 2 cm with firm yellow nodules in both lobes and isthmus with medium power objective (100 x), arrow pointing at a macrophage.

the largest nodule on the left lobe measuring approximately 3 x 2 x 3

cm. The rest of the cut specimen showed a meaty surface. The post-
operative course was unremarkable.
Hispathology revealed the left thyroid lobe parenchyma to be
infiltrated by multiple aggregates of plump spindled to epitheloid
cells forming granulomas with interspersed multinucleated giant
cells, central caseation necrosis and surrounding fibrosis with chronic
inflammatory infiltrates. The nodal masses attached to the isthmus
and right thyroid lobe also showed prominent germinal centers with
interspersed epitheloid cells and foamy macrophages. Microsection of
the right thyroid lobe revealed varisized, well circumscribed nodules of
small to cystically dilated follicles containing scant to abundant colloid
and lined by flattened to cuboidal lining cells. The isthmus appeared
histologically unremarkable. The final histopathologic diagnosis was
chronic granulomatous inflammation consistent with tuberculosis, left
thyroid lobe and lymph nodes attached to the right thyroid lobe and
isthmus; nodular hyperplasia, right thyroid lobe; no histopathologic
change, isthmus. He was started on a course of anti-TB drugs.

DISCUSSION
Tuberculosis of the thyroid gland whether primary or secondary, is
an extremely rare disease with only isolated reports, and a small number
of case series have been reported in the literature even in countries
endemic for TB.3-4 This may be attributed to the resistance of the thyroid
gland to infections due to a number of factors, namely, a prosperous Figure 2. Gross specimen of the thyroid gland, showing multiple complex
nodules in both thyroid lobes

48 Philippine Journal Of Otolaryngology-Head And Neck Surgery


Philippine Journal Of Otolaryngology-Head And Neck Surgery
Hematoxylin-Eosin Medium Power Objective (100 x)
Figure 3. Histopathologic specimen, hematoxylin-eosin, medium power
objective (100 x), arrow pointing at multinucleated giant cell
Hematoxylin-Eosin Low Power Objective (40 x)
Figure 4. Histopathologic slide, hematoxylin and eosin, low power
objective (40x), showing caseation necrosis.
sex.11 The most frequent clinical presentation is a solitary thyroid
nodule that may present with a cystic component.12 Sometimes the
patients present with thyrotoxicosis, hypothyroidism, thyroid abscess,
thyroid enlargement mimicking cancer, or show signs of subacute
granulomatous thyroiditis (De Quervain’s) or of chronic non-suppurative
thyroiditis.13-16 In the majority of cases, patients are euthyroid just
like in our case.9,10 Imaging techniques are not helpful in establishing
the diagnosis. Ultrasonography mostly shows a heterogeneous,
hypoechogenic mass that may include cystic degeneration9,17 which is
similar to our case. Contrast-enhanced computed tomography (CT) may
reveal a necrotic centre with a peripheral rim enhancement related to the
caseous lesion along with regional lymphadenopathy.17 A CT scan was
not done in our case as it is not routinely requested for thyroid masses
unless mediastinal extension is entertained. Tuberculous thyroiditis can
mimic many pathologies.2 Localized pain is a predominant symptom
and facilitates differential diagnosis in such cases.2 Other pathologies
to consider are infectious thyroiditis and subacute granulomatous
thyroiditis (De Quervain’s and thyroid sarcoidosis).18 In the event that
pain is absent, tuberculous thyroiditis can be mistaken for carcinoma19
with which it may coexist.5,11,20
Tuberculosis of the thyroid gland may be primary or occur in
association with tuberculous infection of other organs.7 In such cases,
the thyroid is affected by the spread of bacilli via hematogenous or
Philippine Journal Of Otolaryngology-Head And Neck Surgery 49
CASE REPORTS
Vol. 32 No. 1 January – June 2017
lymphatic routes or directly from the larynx or cervical lymphadenitis.2
Tuberculosis primarily affecting the thyroid gland is much more rare
and predictably more difficult to diagnose.
The diagnosis is mainly by fine-needle aspiration cytology, a
diagnostic step that helps to avoid unnecessary surgery.2 Tuberculous
lymphadenitis may manifest as a neck mass. Fine needle aspiration
(FNA) specimens may yield cytologic evidence consistent with
tuberculosis including granulomatous inflammation and/or caseation
necrosis. Multiple recent studies have demonstrated greater than
90% accuracy in diagnosis of tuberculous lymphadenitis with FNA.19,21
An improvement in technique to yield more positive acid-fast bacilli
(AFB) and culture results from aspirate is called Forin which uses a
large bore needle for aspiration of abscess, digesting it with sodium
hydroxide and centrifuging it to concentrate microbes at the base of
the tube.19 In most cases definitive diagnosis is made post-operatively
by means of histopathological examination of the surgical specimen as
in our patient.7,22 Since granulomatous lesions are not pathognomonic
of tuberculosis (as they may be seen in sarcoidosis and subacute
thyroiditis), caseating necrosis, if present, confirms the diagnosis of
tuberculosis.10,22,23 As in our case, the left thyroid lobe parenchyma
was infiltrated by multiple aggregates of plump spindled to epitheloid
cells forming granulomas, with interspersed multinucleated giant
cells, central caseation necrosis and surrounding fibrosis with chronic
inflammatory infiltrates. The nodal masses attached to the isthmus
and right thyroid lobe also showed prominent germinal centers
with interspersed epitheloid cells and foamy macrophages. The
demonstration of AFB in the gland by Ziehl Nelsen stain can also validate
the diagnosis.2 However, the mycobacteria are rarely recognised by
the stain.2 Furthermore, the surgical specimen is rarely submitted for
culture unless an infectious process is suspected.2 Other investigative
modalities include chest x-ray, sputum analysis, polymerase chain
reaction and cultures with labelled compounds.1
Treatment includes anti-TB drugs combined with surgical removal
of the affected parts of the thyroid gland or surgical drainage with a
good outcome.2 For early minor cases, drugs alone are sufficient. In
our patient, the affected lobe was also resected and post-operative
multiple TB drug therapy was instituted in accordance with our national
TB control program.2
Thyroid tuberculosis is difficult to diagnose or to differentiate
from other thyroid masses due to non-specific signs and symptoms as
mentioned in this case. If a patient presents with a strong history of
exposure to tuberculosis with cervical lymph adenopathy and fever with
a concomitant anterior neck mass that is cystic, tender, erythematous
and with abscess formation, then thyroid TB should be considered.2
Unfortunately, these were not present in our case.
The routine diagnostic tests performed on our patient did not help
us in making the diagnosis either. If there is a high index of suspicion
based on physical examination and strong history of exposure, it is
 CASE REPORTS
Philippine Journal Of Otolaryngology-Head And Neck Surgery Vol. 32 No. 1 January – June 2017

recommended that Erythrocyte Sedimentation Rate (ESR) and chest

x-ray should be done.1 The most helpful diagnostic test is an ultrasound
guided FNA and microbiological tests.2
Because we had not made the diagnosis of TB preoperatively and
with multiple nodules in both lobes, our patient underwent total
thyroidectomy. He was subsequently prescribed anti-TB drugs following
the histopathologic report. Appropriate treatment still consists of anti-
TB drugs since it is now recognized that complete resolution usually
follows an appropriate antituberculous drug treatment only. The total
duration of chemotherapy was 8 months with favourable outcome.2
Surgical intervention is recommended in cases with large abscess or a
grossly diseased thyroid gland.2

REFERENCES
1. Mpikashe P, Sathekge MM, Mokgoro NP. Tuberculosis of the thyroid gland: a case report. South
Afr Fam Pract. 2004; 46:19-20.
2. Zendah I, Daghfous H, Ben Mrad S, Tritar F. Primary tuberculosis of the thyroid gland. Hormones
(Athens). 2008 Oct-Dec; 7(4): 330-3. PMID: 19121995.
3. Collar FA, Huggins CB, 1926 Tuberculosis of the thyroid gland. Ann Surg 84: 804-820
4. Kukreja HK, Sharma ML. Primary tuberculosis of the thyroid gland. Ind J Surg. 1982; 44:190.
5. Al-Mulhim AA, Zakaria HM, Abdel Hadi MS, Al-Mulhim FA, Al-Tamimi DM, Wosornu L. Thyroid
tuberculosis mimicking carcinoma: report of two cases. Surg Today. 2002;32(12): 1064-1067.
DOI: 10.1007/s005950200214; PMID: 12541023.
6. Dawka S, Jayakumar J, Ghosh A. Primary tuberculosis of the thyroid gland. Kathmandu Univ Med
J. 2007 Jul-Sep; 5(3):405-7. PMID: 18604064.
7. Bulbuloglu E, Ciralik H, Okur E, Ozdemir G, Ezberci F, Cetinkaya A. Tuberculosis of the thyroid
gland: review of the literature. World J Surg. 2006 Feb; 30(2):149-55. DOI: 10.1007/s00268-005-
0139-1; PMID: 16425087.
8. Mpikashe P, Sathekge MM, Mokgoro NP. Tuberculosis of the thyroid gland: a case report. South
Afr Fam Pract. 2004; 46:19-20.
9. Terzidis K, Tourli P, Kiapekou E, Alevizaki M. Thyroid Tuberculosis. Hormones (Athens). 2007 Jan-
Mar; 6(1): 75-9. PMID: 17324921.
10. Abdulsalam F, Abdulaziz S, Mallik AA. Primary tuberculosis of the thyroid gland. Kuwait Med J.
2005; 37: 116-118.
11. Alan R, O’Flynn W, Clarke SE. Tuberculosis of the thyroid bed presenting as recurrent medullary
thyroid carcinoma. Tubercle. 1990 Dec;71(4): 301-302. PMID: 2267683.
12. Khan EM, Haque I, Pandey R, Mishra SK, Sharma AK. Tuberculosis of the thyroid gland:
a clinicopathological profile of four cases and review of the literature. Aust N Z J Surg. 1993
Oct;63(10): 807-810. PMID: 8274125.
13. Das DK, Pant CS, Chachra KL, Gupta AK. Fine needle aspiration cytology diagnosis of tuberculous
thyroiditis. A report of 8 cases. Acta Cytol. 1992 Jul-Aug;36(4): 517-522. PMID: 1636345.
14. Johnson AG, Phillips ME, Thomas RJ. Acute tuberculous abscess of the thyroid gland. Br J Surg.
1973 Aug; 60(8): 668-9. PMID: 4724211.
15. Ghosh A, Saha S, Bhattacharya B, Chattopadhay S. Primary tuberculosis of thyroid gland: a rare
case report. Am J Otolaryngol. 2007 Jul-Aug; 28(4): 267-270. DOI: 10.1016/j.amjoto.2006.09.005;
PMID: 17606045.
16. Barnes P, Weatherstone R. Tuberculosis of the thyroid. Two case reports. Br J Dis Chest. 1979 Apr;
73(2):187-191. PMID: 119548.
17. Kang BC, Lee SW, Shim SS, Choi HY, Baek SY, Cheon YJ. US and CT findings of tuberculosis of the
thyroid gland: three case reports. Clin Imaging. 2000 Sep-Oct;24(5): 283-286. PMID: 11331157.
18. Talwar VK, Gupta H, Kumar A. Isolated tuberculous thyroiditis. JIACM. 2003;4(3): 238-239.
19. Maharjan M, Hirachan S, Kafle PK, Bista M, Shrestha S, Toran KC, et al. Incidence of tuberculosis in
enlarged neck nodes, our experience. Kathmandu Univ Med J (KUMJ). 2009 Jan-Mar; 7(25):54-8.
PMID: 19483454.
20. Magboo ML, Clark OH. Primary tuberculous thyroid abscess mimicking carcinoma diagnosed
by fine needle aspiration biopsy. West J Med. 1990 Dec;153(6): 657-659. PMID: 2127330; PMCID:
PMC1002655.
21. Khan R, Harris SH, Verma AK, Syed A. Cervical lymphadenopathy: scrofula revisited. J Laryngol
Otol. 2009 Jul;123(7):764-7. DOI: 10.1017/S0022215108003745; PMID: 18845038.
22. El Malki HO, Mohsine R, Benkhraba K, Amahzoune M, Benkabbou A, El Absi M, et al.
Thyroid tuberculosis. Diagnosis and treatment. Chemotherapy 2006;52(1): 46-49. DOI:
10.1159/000090244; PMID: 16340200.
23. Kabiri H, Atoini F, Zidane A. Thyroid tuberculosis. Ann Endocrinol (Paris). 2007 Jun;68(2-3): 196-
198. DOI: 10.1016/j.ando.2007.04.007; PMID: 17532284.

50 Philippine Journal Of Otolaryngology-Head And Neck Surgery


Philippine Journal Of Otolaryngology-Head And Neck Surgery
Veronica Marie M. Mendoza, MD
Juan Ramon V. Perez De Tagle, MD
Adrian F. Fernando, MD
Department of Otorhinolaryngology
Head and Neck Surgery
University of Santo Tomas Hospital

Correspondence: Dr. Adrian F. Fernando
Department of Otorhinolaryngology
Head and Neck Surgery

University of Santo Tomas Hospital
 II. Significant decrease in size of the auricular mass was noted from the second cycle until no mass
España Boulevard, Manila 1108
Philippines


Phone: (632) 731 3001 local 2478
 up period. (Figure 3)
Email: ianfernando_md@yahoo.com
The authors declared that this represents original material, that
the manuscript has been read and approved by the authors,
that the requirements for authorship have been met by the
authors, and that the authors believe that the manuscript
represents honest work.
Disclosures: The authors signed a disclosure that there are no
financial or other (including personal) relationships, intellectual
passion, political or religious beliefs, and institutional affiliations
that might lead to a conflict of interest.
Presented at the 2nd International Congress Free Paper
Presentation for Medical Sciences, January 16, 2016. St. Paul
University, Tugegarao City, Philippines.
Institutional Review Board approval and written informed
consent for publication were obtained for this Case Report.
Creative Commons (CC BY-NC-ND 4.0)
Attribution - NonCommercial - NoDerivatives 4.0 International
Philippine Journal Of Otolaryngology-Head And Neck Surgery 55
FEATURED GRAND ROUNDS
Vol. 32 No. 1 January – June 2017
Peripheral T-Cell Lymphoma
Presenting as an Auricle Mass
When evaluating patients with a non-traumatic auricular deformity that presents like a
soft tissue infection unresponsive to antibiotic therapy and progressively resembles a tumor,
immediate biopsy and imaging should be instituted to obtain an accurate diagnosis and avoid
unnecessary procedures. After all, not all head and neck masses are managed with surgery.
CASE REPORT
A 64-year-old diabetic man with a 30-pack/year smoking history presented with progressive
diffuse swelling of the right auricule with exudative yellow non-foul smelling discharge. Initially
diagnosed with auricular cellulitis by an ENT specialist, there was no response to oral and topical
antibiotic treatment as the swelling developed into a large cauliflower-like deformity. Incisional
biopsy only revealed fibrocollagenous tissue with chronic inflammation without evident
granuloma.
With the progressively enlarging right auricular mass unresponsive to medical treatment for
over six months, the man underwent a series of multi-disciplinary consultations in our institution.
Also noted were left tragal enlargement without ulceration or bleeding, palpable level II-III
cervical lymph nodes (measuring 2.5 cm in widest diameter), but no palpable skin lesions, other
signs or associated symptoms. (Figure 1) Otoscopy was normal with normal hearing thresholds on
the right and mild conductive hearing loss on the left on pure tone audiometry. The rest of the
physical examination and blood laboratory tests were unremarkable.
A temporal bone CT scan (to determine mass extent and the best site for repeat incisional
biopsy) showed an intensely enhancing external ear mass extending to the outer cartilaginous
portion of the auditory canal with multiple sub-centimeter enhancing nodules in the right parotid
gland. (Figure 2) An excision biopsy between the junction of the mass and grossly normal-looking
tissue of the right helix revealed Atypical Round Cell Tumor, subsequently diagnosed as T-cell
Lymphoma after strongly staining with CD3 and Ki67 immunohistochemistry studies.
After unremarkable repeat chest x-ray and abdominal CT findings, the patient underwent
six cycles of chemotherapy using the CHOP (Doxorubicin, Vincristine, Cyclophosphamide,
Prednisone) protocol for Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), Stage
was evident after completion of the regimen. No recurrence was noted during a 48-month follow-
Figure 1. External ears on presentation A. Right nodular, non-tender auricular mass almost completely
occupying the entire pinna and anterior cartilaginous portion of the external auditory canal (asterisk*);
and B. Enlarged left tragus (arrow).
Philipp J Otolaryngol Head Neck Surg 2017; 32 (1): 55-56 c Philippine Society of Otolaryngology – Head and Neck Surgery, Inc.
 FEATURED GRAND ROUNDS
Philippine Journal Of Otolaryngology-Head And Neck Surgery
Figure 2. Temporal bone and neck contrast CT imaging A. Axial view showing intensely-enhancing
right auricular mass with ill-defined borders extending to surrounding soft tissues (asterisk*); B.
Coronal view showing enhancing right auricular mass extending to peri-parotid region with multiple
enlarged right intra-parotid and cervical lymph nodes (Arrow).
Figure 3. Response to CHOP treatment A. Right auricle before chemotherapy B. After 2nd cycle
C. After 6th cycle D. Left ear before chemotherapy E. After 6th cycle of chemotherapy.
DISCUSSION
Because the external ear and auditory canal can be affected
by various organisms especially in elderly, diabetic, and
immunocompromised individuals, aggressive medical treatment is
often warranted. A neoplastic etiology should be suspected when
rapidly progressive ear deformities arise in cases of perichondritis
and other non-infectious inflammatory conditions that are non-
responsive even to culture-guided therapy. In the absence of
trauma, such other causes of ear deformity as sarcoidosis, perniosis,
polychondritis and auricular pseudocyst must be carefully
investigated by adequate biopsies and histopathologic studies to
rule out malignant processes.1,2
Lymphomas represent approximately 2.5% of head and neck
malignancies, and the majority present with cervical lymph node
involvement.2 While 40% of head and neck lymphomas occur in such
extranodal sites as the nasopharynx, lacrimal sac, temporal bone, or
salivary glands, they rarely involve the auricle and external auditory
canal.2 More common malignancies that may lead to auricular masses
56 Philippine Journal Of Otolaryngology-Head And Neck Surgery
Vol. 32 No. 1 January – June 2017
and deformities such as squamous cell carcinoma, adenocarcinoma,
adenoid cystic carcinoma, mucoepidermoid carcinoma, basal cell
carcinoma and rhabdomyosarcoma, must be ruled out.3,4 These
conditions have distinct presentations and may arise from the external
ear, middle ear or temporal bone before affecting the external auditory
canal.5
The literature on extra-nodal lymphomas is scarce, with B- cell
origin more commonly reported. On the other hand, peripheral T-cell
lymphomas (PTCL) represent only 10-15% of non-Hodgkin lymphoma,
categorized as nodal, extra nodal or leukemic.6 A subtype of PTCL that
do not correspond to any of the specifically defined T-cell entities in
the World Health Organization (WHO) classification are defined as not
otherwise specified PCTL (PTCL-NOS).7,8 However, based on a search
of PubMed and HERDIN using the search terms “peripheral T-cell
lymphoma,” “auricle,” and “external ear,” to the best of our knowledge,
PTCL-NOS has not been locally reported as primarily affecting the
external ear.6,8
The clinical presentation of primary lymphomas of the EAC is non-
specific and they can be easily misdiagnosed and treated as infectious
or inflammatory conditions of the external ear. As with other conditions,
early and accurate diagnosis based on good clinical correlation with
imaging studies must be achieved to allow early and specific treatment.
For PTCL-NOS, the Ann Arbor staging system still applies although it
was originally designed for Hodgkin lymphoma.7 Surgical management
has been reported for isolated auricular lymphomas but disseminated
disease or involvement of complex structures such as the external ear
warrant chemotherapy as the primary and definitive treatment.2 External
beam radiation has likewise been reported as an option but may not be
applicable in this particular case where structural preservation of the
auricle is considered.2 To date, no therapeutic guidelines have been
established due to the paucity of cases.
This case of PTCL-NOS of the auricle, just like other reported cases of
lymphoma arising from the external auditory canal, appear to respond
well with the standard CHOP regimen. The favorable resolution in our
case suggests that surgical resection of the auricle should be reserved
for non-response to standard treatment for lymphoma.
REFERENCES
1. Kindem S, Traves V, Requena C, Alcalá R, Llombart B, Serra-Guillén C, et al. Bilateral cauliflower
ear as the presenting sign of B-cell chronic lymphocytic leukemia. J Cutan Pathol. 2014 Feb;
41(2): 73–77. DOI: 10.1111/cup.12290; PMID: 24460879.  

2. Bruschini L, De Vito A, Fortunato S, Pelosini M, Cervetti G, Petrini M, et al. A Case of Primary Non-
Hodgkin’s Lymphoma of the External Auditory Canal. Case Rep Otolaryngol. 2013; 2013: 138397.
DOI:10.1155/2013/138397; PMID: 23984144; PMCID: PMC3747615 

3. Merkus P, Copper MP, van Oers MH, Schouwenburg PF. Lymphoma in the ear.  ORL J
Otorhinolaryngol Relat Spec. 2000 Sep-Oct; 62(5): 274–77.  DOI: 27759; PMID: 10965264. 

4. González Delgado A, Argudo Marco F, Sánchez Martínez N, Sprekelsen Gassó C. T cell Non
Hodgkin’s lymphoma of the external auditory canal.  Acta Otorrinolaringol Esp. 2008 Apr;
59(4):200–201. PMID: 18447981.

5. National Cancer Institute [Internet]. Cancer facts. Head and neck cancer: questions and answers.
[cited 2017 Feb 4]. Available from: http://www.cancer.gov/cancertopics/factsheet/Sites-Types/
head-and-neck/. 


6. Shuto J, Ueyama T, Suzuki M, Mogi G. Primary lymphoma of bilateral external auditory
canals. Am J Otolaryngol. 2002 Jan-Feb; 23(1):49-52. PMID: 11791249.
7. Lister TA, Crowther D, Sutcliffe SB, Glatstein E, Canellos GP, Young RC, et al.  Report of a
committee convened to discuss the evaluation and staging of patients with Hodgkin’s disease:
Cotswolds meeting.  J Clin Oncol. 1989 Nov; 7(11): 1630–6. DOI: 10.1200/JCO.1989.7.11.1630;
PMID: 2809679.
8.  Peripheral T-Cell Lymphoma Facts [Internet]. White Plains, NY: Leukemia and lymphoma society.
[Revised 2014 Jul; cited 2017 Feb 4]. Available from: http://www.cancer.gov/cancertopics/
factsheet/Sites-Types/head-and-neck/. 

 FROM THE VIEWBOX
Philippine Journal Of Otolaryngology-Head And Neck Surgery Vol. 32 No. 1 January – June 2017

Ian C. Bickle, MB,BCh,BAO, FRCR

Intracranial Complications
Department of Radiology of Acute Sinusitis on Brain CT
RIPAS Hospital
Bandar Seri Begawan
Brunei

This 35-year-old woman presented to a peripheral hospital Accident and Emergency

department in a moribund state. She was intubated, stabilized and transferred urgently to a
tertiary centre. She had attended the hospital in the prior week with a diagnosis of sinusitis.
An urgent CT brain was requested by the attending A and E officer which was undertaken on
the basis of her low Glasgow coma scale (GCS). The paranasal sinuses were partially visualised
on this investigation.

Correspondence: Dr. Ian C. Bickle

Consultant Radiologist Figure 1 A. Axial CT Brain (non-contrast): thin bilateral subdural collections. Low attenuation in the inferior right temporal lobe and external
Department of Radiology internal capsule suggestive of an acute infarct. B. Axial CT Brain (with contrast): enhancing bilateral subdural collections in keeping with
RIPAS Hospital empyemas.
Bandar Seri Begawan BA1710
Negara Brunei Darussalam
Phone: +673 224 2424
Fax: +673 224 2690 Acute bacterial rhinosinusitis is a common disease presenting to both general practitioners
Email: firbeckkona@gmail.com
and ENT surgeons. It is on the most part short-lived in duration responding to antibiotics and
The author declared that this represents original material
that is not being considered for publication or has not been
symptomatic medications. Rarely it may be associated with severe life threatening complications,
published or accepted for publication elsewhere, in full or in in the form of intra-orbital extension or even less so intracranial complications. These typically
part, in print or electronic media; that the manuscript has been
read and approved by the author, that the requirements for occur in the pediatric and young adult population.1
authorship have been met by the author, and that the author
believes that the manuscript represents honest work.
Cross-sectional imaging plays an essential role in the assessment of this small sub-set of
patients and is largely and almost always in the first instance with CT.2 Computed Tomography
Disclosures: The author signed disclosures that there are no
financial or other (including personal) relationships, intellectual is broadly available even out of standard working hours and facilitates the review of potential
passion, political or religious beliefs, and institutional affiliations
that might lead to a conflict of interest.
intracranial complications and thereby guide neurosurgical management. Given that a proportion
of the paranasal sinuses are always visualised on a CT brain it is an important review area especially
in patients with sepsis.
Creative Commons (CC BY-NC-ND 4.0)
Philipp J Otolaryngol Head Neck Surg 2017; 32 (1): 57-58 c Philippine Society of Otolaryngology – Head and Neck Surgery, Inc.
Attribution - NonCommercial - NoDerivatives 4.0 International

Philippine Journal Of Otolaryngology-Head And Neck Surgery 57

 FROM THE VIEWBOX
Philippine Journal Of Otolaryngology-Head And Neck Surgery Vol. 32 No. 1 January – June 2017

performed with drainage of a large volume of pus from the sphenoid,

ethmoidal and right maxillary sinuses.4
This case demonstrates intracranial complications are not an entity
unique to the paediatric population. When caring for patients with
acute sinusitis always have a high index of suspicion for these potential
complications and have a low threshold for engagement with radiology
colleagues for imaging if concerned.

Figure 2. Axial CT Brain: The ethmoid and sphenoid sinuses are opacified with fluid. No bony
destruction.

There are a number of well recognized intracranial complications

of acute rhinosinusitis which include; meningitis, cerebral abscess,
subdural empyema, cavernous sinus and dural venous thrombosis.3
Additional sequelae from the intracranial infection may result such as
arterial territory cerebral infarction, ventriculitis and hydrocephalus.
Those patients in whom intracranial extension occurs often
demonstrate bony destruction of the sinuses on imaging.  Disease
involving the frontal sinus is typically associated with intracranial
complications, through foci of bony dehiscence or osteomyelitis
involving the floor of the anterior cranial fossa.3
In this case, the patient presented in a moribund state due to severe
intracranial complications following failed treatment in the community.
The initial CT imaging identified subdural collections (Figure 1a and
1b) as well as pan-sinusitis (Figure 2) and the suggestion of an arterial
territory infarct (Figure 1a). The frontal sinus however was not involved REFERENCES
1. Sultész M, Csákányi Z, Majoros T, Farkas Z, Katona G. Acute bacterial rhinosinusitis and its
in this instance. complications in our pediatric otolaryngological department between 1997 and 2006. Int J
Pediatr Otorhinolaryngol. 2009 Nov;73(11):1507-12. DOI: 10.1016/j.ijporl.2009.04.027 PMID:
A complete CT study of the paranasal sinuses (with a dedicated 19500861
paranasal sinuses protocol) is merited including isotropic reconstructions 2. Dankbaar JW, van Bemmel AJM, Pameijer FA. Imaging findings of the orbital and intracranial
complications of acute bacterial rhinosinusitis. Insights Imaging. 2015 Oct; 6(5): 509–518. doi:
to review the bony integrity and aid the planning of ENT surgical 10.1007/s13244-015-0424-y PMCID: PMC4569601
3. Osborn MK, Steinberg JP. Subdural empyema and other suppurative complications of
intervention. An MRI brain if available would eloquently confirm the CT paranasal sinusitis. Lancet Infect Dis. 2007 Jan;7(1):62-7. DOI: : 10.1016/S1473-3099(06)70688-0
findings including confirmation of the acute parietal lobe infarct.4 PMID: 17182345
4. Bickle IC. Intracranial complications of acute sinusitis. Case rID: 45559. Created 30 May 2016
Neurosurgical drainage of the subdural empyemas was undertaken. in Radiopaedia.org ©2005-2017. [Cited 2017 June 13] Available from: https://radiopaedia.org/
Furthermore, functional endoscopic sinus surgery (FESS) was also cases/intracranial-complications-of-acute-sinusitis.

58 Philippine Journal Of Otolaryngology-Head And Neck Surgery

 ORIGINAL ARTICLES
Philippine Journal Of Otolaryngology-Head And Neck Surgery Vol. 32 No. 1 January – June 2017

Paula Luz G. Caballero, MD

Joseph E. Cachuela, MD Bleeding Time Using Moringa Oleifera
(Malunggay) Leaf Extract versus Saline Control
Department of Otorhinolaryngology
Head and Neck Surgery
Southern Philippines Medical Center, Davao City
in a Rabbit Epistaxis Model:
Philippines
A Randomized Controlled Trial
ABSTRACT
Objective: To determine bleeding time using Moringa oleifera leaf extract versus saline control in
an experimental epistaxis model.

Methods:
Design: Randomized controlled trial
Setting: Tertiary Government Training Hospital
Participants: Ten adult male New Zealand White rabbits were acclimatized for 1
week in a standard environment. One-centimeter long, full-thickness mucosal wounds in the
junction of the nasal floor and anterior part of the septum were treated randomly with topical
Moringa oleifera extract or colored isotonic saline control in either right or left nasal cavity, one
site at a time. The duration of bleeding – time bleeding started to time bleeding stopped -- was
recorded in seconds. Data was subjected to a t-test for paired samples.

Correspondence: Dr. Joseph E. Cachuela

Results: The mean bleeding time for wounds treated with Moringa extract was 53 seconds (range
Department of Otorhinolaryngology 38-70 secs), versus 159 seconds (range 100-218 secs) for controls. The bleeding time in the former
Head and Neck Surgery
ENT Clinic, 2nd Floor, JICA Building was significantly shorter than in the latter (p = .000019, t-stat = 8.139), with a mean difference of
Southern Philippines Medical Center
JP Laurel Avenue, Bajada, Davao City 8000
106 seconds between the two groups.
Philippines
Phone: +6382-227-2731 local 4707
Email address: j_cachuela_md@yahoo.com Conclusion: Moringa oleifera leaf extract was associated with significantly shorter bleeding time
The authors declared that this represents original material that
than saline control in this experimental epistaxis model and may be worth investigating further
is not being considered for publication or has not yet been as a hemostatic agent for epistaxis.
published or accepted for publication elsewhere, in full or in
part, in print or electronic media; that the manuscript has been
read and approved by all the authors, that the requirements
for authorship have been met by each author, and that each
Keywords: epistaxis, malunggay, Moringa oleifera extract, topical hemostatic agent
author believes that the manuscript represents honest work.

The authors signed disclosures that there are no financial or
other (including personal) relationships, intellectual passion,
political or religious beliefs, and institutional affiliations that
might lead to conflict of interest.
Presented at the Philippine Society of Otolaryngology – Head
and Neck Surgery Analytical Research Contest (2nd place).
November 17, 2016. Bella Ibarra, Quezon City.
Presented at Southern Philippines Medical Center 9th Annual
Interdepartmental Oral Research Contest (3rd place). December
15, 2016. Southern Philippines Medical Center, Davao City.
Creative Commons (CC BY-NC-ND 4.0)
Attribution - NonCommercial - NoDerivatives 4.0 International
Epistaxis is one of the most common acute conditions seen in the emergency department and
a common problem encountered by primary care physicians and ear, nose and throat surgeons
alike. Recurrent epistaxis can be troublesome and alarming especially in the pediatric and the
elderly groups.1 At least once in their lifetime, 60% of the population will experience epistaxis,
6% of which require medical attention.2 Its high frequency is associated to the nasal septum’s
abundant vascularity and risk for external trauma. Between 90 to 95% of epistaxis originates from
Kiesselbach’s plexus in the antero-inferior nasal septum.3 Traditional treatment includes nasal
packing, cautery, and topical hemostatic agents. However, most of these interventions have
accompanying side effects and complications such as increase in blood pressure for some of the
topical hemostatic agents, infection, septal perforation and even aspiration with prolonged or
Philipp J Otolaryngol Head Neck Surg 2017; 32 (1): 14-16 c Philippine Society of Otolaryngology – Head and Neck Surgery, Inc.

14 Philippine Journal Of Otolaryngology-Head And Neck Surgery


Philippine Journal Of Otolaryngology-Head And Neck Surgery
dislodged nasal packing. Thus, investigators have continued to look for
alternative methods to treat this common problem.3
Moringa oleifera, also known as malunggay, mulangay, horseradish
tree, drumstick tree, or Ben oil tree, is a perennial softwood tree with
low timber quality. It has long been known for its traditional medicinal
as well as its industrial uses, and has been attributed with antibiotic and
anti-inflammatory properties.4 Studies revealed that topical application
of its extract promotes wound healing.5,6 However, its hemostatic effect
on epistaxis has yet to be established. Using the keywords “Moringa,”
“hemostatic” and “epistaxis,” we found no published study regarding
the hemostatic effect of Moringa on epistaxis in a search of PubMed, the
Cochrane Library, Science Direct, Philippine E-Journals, and the journals
Philippine Journal of Health Research and Development, Otolaryngol Head
Neck Surg, and Philipp J Otolaryngol Head Neck Surg.
In order to explore its potential hemostatic effects, the objective of
this study is to determine the bleeding time using Moringa oleifera leaf
extract versus saline control in an experimental epistaxis model.
METHODS
Preparation of Moringa Extract and Control
A modification of extract preparation yielding 13% aqueous extract
was utilized.7 Fresh, green Moringa oleifera leaves procured from the
local market were authenticated by a local biologist. The leaves were
chopped and air-dried under shade for 72 hrs. Powdered leaves were
obtained by crushing the dried leaves using a mortar and pestle. One
hundred grams of powdered leaves was soaked in 500 ml of distilled
water and left standing for 48 hours at 30˚C, then filtered using Whatman
No. 1 filter paper to obtain Moringa extract.
A liter of isotonic saline solution with 20 ml of green food coloring
(McCormick, McCormick Philippines Inc., Novaliches, Quezon City) made
up control solution with similar appearance to the Moringa extract.
The Moringa extract and control solutions were separately put in
opaque specimen bottles with 20 ml solution per bottle. The bottles
were labeled Solution A and Solution B by the principal investigator,
with Solution A (Moringa extract) and Solution B (control) unknown
to the blinded examiner, a licensed veterinarian. The solutions in each
bottle were only used once.
Animal Experiment
Ten adult male New Zealand White rabbits with a mean weight of
1.26 kg (range, 1.1 – 1.5 kg) were purchased from a certified animal
distributor and acclimatized for 1 week in a standard environment.
They were housed in standard cages of 1m2 area each, in a room with
a constant temperature of 22°C ± 4°C and a 12-hour light/dark cycle,
fed twice daily with 200g generic rabbit growing pellets, and unlimited
Philippine Journal Of Otolaryngology-Head And Neck Surger 15
ORIGINAL ARTICLES
Vol. 32 No. 1 January – June 2017
access to tap water. The study was approved by the Institutional Animal
Care and Use Committee (IACUC): <IACUC Protocol Number M003>.
The experiment was conducted in the clinic of one licensed
veterinarian, who performed all the procedures with one assistant.
Both veterinarian and assistant were blinded.
All animals were intramuscularly sedated using 0.02 mg/kg
Acepromazine (Labistress® 5 mg/mL,Labiana Life Sciences, Barcelona,
Spain) and 11 mg/kg Ketamine chloride (Ceva Ketamine 100 mg/mL,
Ceva Santé Animale, Sydney, Australia).
One-centimeter long full-thickness longitudinal mucosal wounds,
not advancing to the cartilage, were made using Blade #11(Kai Medical,
Kai Industries Co. Ltd., Seki City, Japan), at the junction of the nasal floor
and anterior part of the septum of the right and left nasal cavity, one
Figure 1. The area of the rabbit’s nose where the incision was done (▲).
site at a time. (Figure 1) The wounds were randomized to be treated with
either Solution A or B on either side.
Solutions were topically applied with cotton pledgets soaked in
either solution as soon as bleeding started, and pressed gently on the
wounds for 1 second, every 30 seconds (re-soaking the cotton pledget in
solution for every application), until the bleeding stopped. The duration
of bleeding – time bleeding started to time bleeding stopped-- was
recorded in seconds by the assistant.3
Post-operative care consisted of application of topical Clotrimazole
10 mg, gentamicin sulfate 1 mg, betamethasone dipropionate 500 mcg,
per gram cream (Polyderm 3, Lloyd Laboratories Inc., Malolos, Bulacan)
on the wounds, right after the procedure. The rabbits were observed and
monitored after 1 hour and 24 hours after conclusion of the procedure
for any adverse effects or complications such as recurrence of bleeding,
swelling, or mucosal irritation, and donated to a local animal habitat 3
days after the procedure.
 ORIGINAL ARTICLES
Philippine Journal Of Otolaryngology-Head And Neck Surgery
Sample Size Computation
Sample size was computed using an online sample size calculator
(Select Statistical Services Ltd., Exeter, Devon, UK) to compare 2 means
(http://select-statistics.co.uk/sample_size_calculation_two_means).
Assuming a 95% confidence level with a power of 80 to detect a mean
difference of 30 seconds with a variance of 500 seconds, 10 samples
each were needed for the Moringa and control groups.
Statistical Analysis
Data was subjected to the Wilk-Shapiro test for normality (W statistic,
0.842), with computed W statistic of 0.889 (normal distribution). Data
was then analyzed manually using the t-test for paired samples.
RESULTS
Ten adult male New Zealand white rabbits with ages ranging
from 16 – 20 weeks completed the study. None of the rabbits died or
acquired any disease during the time of acclimatization. The weight of
the rabbits during the study period ranged from 1.1 – 1.5 kg.
The mean bleeding time for wounds administered Moringa extract
was 53 seconds (range, 38 – 70 secs) compared to 159 seconds (range,
100 – 218 secs) for controls. The bleeding time in the former (mean, 53.3
secs) was significantly shorter than in the latter (mean, 159.3), with a
mean difference of 106 seconds between the two groups (p = .000019,
t-stat = 8.139). No adverse effects or complications were noted.
DISCUSSION
Mucosal healing undergoes a process that follows the stages of
fibroplasia, angiogenesis, and reepithelialization.8 Topical application
of Moringa oleifera extract has been shown to promote wound
healing.5,6 Application of the extract on wounds increases its tensile
strength through rapid re-epithelialization and collagen formation.5 It
also increases fibroblast proliferation.6
Moringa extract has also been known to act on the blood
coagulation cascade. The presence of proteolytic activity is one of
the important characteristic features of Moringa oleifera. In a study by
Satish et al., both extracts from the leaves and roots of the plant showed
proteolytic activity in a dose-dependent manner with the leaf extract
exhibiting a significantly higher activity. The study suggested that both
extracts exhibited procoagulant activity and reduced recalcification
time in clot formation by activation of factors involved in the blood
coagulation cascade or by precipitation of the co-factors. Both extracts
also exhibited fibrinogenolytic and fibrinolytic activities.9
Whether procoagulant activity and reduced recalcification time in
clot formation or fibrinogenolytic and fibrinolytic properties of Moringa
extract were involved in reducing bleeding time in this study were
16 Philippine Journal Of Otolaryngology-Head And Neck Surgery
Vol. 32 No. 1 January – June 2017
not established, and can at best be inferred. However, the significant
difference in bleeding time between treatment and controls makes
a compelling argument to pursue the potential hemostatic effects of
Moringa for epistaxis.
Further studies are recommended to determine the
histopathologic effects of Moringa extract on nasal mucosa; its toxic
dose and approximate effective dose; the effect of tonicity, pH and
temperature settings of Moringa extract in the coagulation process;
the hemostatic effect of Moringa extract versus such usual topical
agents as oxymetazoline and epinephrine; sterilization techniques in
the preparation of the extract; before actual clinical trials.
Our study has established that Moringa oleifera leaf extract was
associated with significantly shorter bleeding time than saline control in
this experimental epistaxis model, and may thus be worth investigating
further as a hemostatic agent for epistaxis.
ACKNOWLEDGEMENT
The authors would like to thank Mr. Reynaldo G. Abad for authentication of the malunggay
leaves, Dr. Rojim Sorrosa for sharing his inputs in the writing process, and Mr. Jesse Mari F. Santos, Mr.
Arturo E. Caballero, and Mrs. Luz-Minda G. Caballero for helping the authors in processing the animal
ethics approval and data gathering.
REFERENCES
1. Kotecha B, Fowler S, Harkness P, Walmsley J, Brown P, Topham J. Management of epistaxis:
a national survey.Ann R Coll Surg Engl. 1996 Sep;78(5):444-446. PMID: 8881728; PMCID:
PMC2502947.
2. Pope LE, Hobbs CG. Epistaxis: an update on current management. Postgrad Med J. 2005
May;81(955):309-314. DOI: 10.1136/pgmj.2004.025007. PMID: 15879044; PMCID: PMC1743269.
3. Kurtaran H, Ark N, Ugur KS, Sert H, Ozboduroglu AA, Kosar A, et al. Effects of a topical hemostatic
agent on an epistaxis model in rabbits. Curr Ther Res Clin Exp. 2010 Apr;71(2):105-110. DOI:
10.1016/j.curtheres.2010.03.003. PMID: 24683256; PMCID: PMC3967325.
4. Fahey J. Moringa oleifera: a review of the medical evidence for its nutritional, therapeutic, and
prophylactic properties Part 1. Trees for Life Journal. 2005 December; 1:5. [cited 2016 January
15]. Available from: http://www.TFLJournal.org/article.php/20051201124931586.
5. Vijay L, Kumar U. Evaluation of in vivo wound healing activity of Moringa oleiferabark extracts
on different wound models in rats. Pharmacologia. 2012;3(11):637-640. DOI: 10.5567/
pharmacologia.2012.637.640.
6. Muhammad AA, Pauzi NAS, Arulselvan P, Abas F, Fakurazi S. In vitro wound healing potential
and identification of bioactive compounds from Moringa oleiferaLam. BioMed Research
International. 2013 Nov; 2013, Article ID 974580. DOI: 10.1155/2013/974580.
7. Moyo B, Masika PJ, Muchenje V. Antimicrobial activities of Moringa oleiferaLam leaf extracts.
African Journal of Biotechnology. 2012 Feb;11(11): 2797-2802. DOI: 10.5897/AJB10.686.
8. Wabnitz D. Factors affecting mucosal healing, reciliation, and ciliary function after Endoscopic
Sinus Surgery in the sheep [dissertation]. University of Adelaide; 2005. [cited 2016 Aug 8].
Available from: http://hdl.handle.net/2440/37719.
9. Satish A, Sairam S, Ahmed F, Urooj A. Moringa oleifera Lam.: Protease activity against blood
coagulation cascade. Pharmacognosy Res. 2012 Jan;4(1):44-9. DOI: 10.4103/0974-8490.91034.
PMID: 22224061; PMCID: PMC3250039.
 ORIGINAL ARTICLES
Philippine Journal Of Otolaryngology-Head And Neck Surgery Vol. 32 No. 1 January – June 2017

Tracy Camille P. Chan, MD

Ma. Clarissa S. Fortuna, MD Demographic Profile and Risk Factors of Patients
with Benign Vocal Fold Lesions Diagnosed through
Patrick S. Enriquez MD

Department of Otorhinolaryngology
Head and Neck Surgery
Laryngeal Videoendoscopy and Stroboscopy
The Medical City

ABSTRACT
Objective: To determine the prevalence of benign vocal cord lesions among Filipino patients in
a tertiary institution and identify the demographic characteristics and possible risk factors found
among these patients.

Methods:
Design: Retrospective Case Series
Setting: Private Tertiary Hospital
Participants: Records of 2,375 patients who underwent laryngeal video endoscopy
and stroboscopy from 2012-2014 were reviewed.

Results: There were 632 records of patients with benign vocal fold lesions, of which nodules were
most common (211, 33.38%) followed by Reinke’s edema (165, 26.10%), cysts (122, 19.30%) and
polyps (74, 11.70%) with hoarseness as the most common symptom (542, 85.76%). More than
half (336, 53.16%) were aged 21-40 years and almost two-thirds (469, 74.21%) were female. The
most common associated factors were caffeine intake (445, 70.41%) and inadequate water intake
(370, 58.54%), followed by alcohol (253, 40.03%). Smoking was only present in 146 (23.19%).
Correspondence: Dr. Ma. Clarissa S. Fortuna
Department of Otorhinolaryngology
Head and Neck Surgery
Conclusions: Baseline evidence on the prevalence of benign vocal fold lesions in this institution
The Medical City as well as baseline data on the common characteristics and associated factors seen in the sample
Ortigas Avenue, Pasig City 1600
Philippines population may assist us in current practices and guide future studies directed toward treatment
Phone: (632) 635 6789 local 6250
Fax: (632) 687 3349
and prevention.
Email: ent@medicalcity.com.ph

The authors declare that this represents original material, that Keywords: Vocal Cord; Stroboscopy; Vocal Cord Nodules; Benign Vocal Cord; Stroboscopy/Benign;
the manuscript has been read and approved by all the authors, Stroboscopy/Nodules
that the requirements for authorship have been met by each
author, and that each author believes that the manuscript
represents honest work.
Current advances in technology have led to the development of tools for easier visualization
Disclosures: The authors signed disclosures that there are no and diagnosis of the larynx. Particularly useful is laryngeal videoendoscopy and stroboscopy
financial or other (including personal) relationships, intellectual
passion, political or religious beliefs, and institutional affiliations (LVES).1, 2 Over 50% of patients presenting with voice complaints have have benign vocal
that might lead to a conflict of interest.
cord lesions,1, 3-5 among which nodules are most prevalent,2, 5, 7 followed by vocal cord polyps,
Presented at the Philippine Society of Otolaryngology Head Reinke’s edema, cysts and papillomas.8, 9 Hoarseness is the most frequent presenting symptom
and Neck Surgery Descriptive Research Contest (3rd Place),
September 24, 2015. Natrapharm, The Patriot Bldg., Paranaque although other symptoms such as cough, foreign body sensation, heartburn, throat-clearing,
City, Philippines.
pain, breathlessness and vocal breaks are also noted.2,5,7 Benign vocal cord lesions are more often
diagnosed in males than females and are more often found in the 20-60 year old age group.5, 8
Commonalities include talkative personalities and voice-requiring occupations related to voice
Creative Commons (CC BY-NC-ND 4.0)
Philipp J Otolaryngol Head Neck Surg 2017; 32 (1): 27-29 c Philippine Society of Otolaryngology – Head and Neck Surgery, Inc.
Attribution - NonCommercial - NoDerivatives 4.0 International

Philippine Journal Of Otolaryngology-Head And Neck Surgery 27

 ORIGINAL ARTICLES
Philippine Journal Of Otolaryngology-Head And Neck Surgery Vol. 32 No. 1 January – June 2017

abuse and misuse.2, 5-7, 9 Other factors that may play a role are smoking,
RESULTS
alcohol intake, reflux, allergies, chronic cough and infection,5, 7 with
A total of 2,375 patient records were reviewed for inclusion
smoking contributing heavily to the appearance of lesions.8 However,
in this study. Of these, 632 had a diagnosis of benign vocal cord
other data has shown no significant relationship between smoking and
lesions and were included. Excluded were 1,743 records; 265 with
the presence of benign vocal cord lesions.6
laryngopharyngeal reflux (LPR), 688 with other laryngeal pathologies
Moreover, data about the prevalence of benign vocal cord lesions as
(i.e. infectious, cancer), 442 with non-glottic/non-laryngeal pathologies,
well as the patient profiles and postulated risk factors associated with
84 with normal laryngeal findings, 201 without a written diagnosis and
them are available in foreign but not local literature and it is important
63 with insufficient data.
to establish if such data is applicable and comparable to local data.
Of the 632 patients included, the majority (178, 28.16%) belonged
This study seeks to determine the prevalence of benign vocal cord
to the 21-30 year old age bracket closely followed by the 31-40 year-old
lesions among Filipino patients in a tertiary institution and identify the
(158, 25.00%), and 41-50 year-old (131, 20.73%) age groups. There were
demographic characteristics and possible risk factors found among
thrice more females (469, 74.21%) than males (160, 25.32%).
these patients.
The most common occupations were customer service
representative (200, 31.64%) and office employee (64, 10.12%). Other
METHODS
occupations included teachers (49, 7.75%), housewives (29, 4.58%) and
With institutional review board protocol approval, a retrospective
businessmen (27, 4.27%).
review of records of all patients who underwent laryngeal
Of the benign vocal cord lesions, nodules were most common (211,
videoendoscopy and stroboscopy (LVES) at the Voice and Swallowing
33.38%) followed by Reinke’s edema (165, 26.10%), cysts (122, 19.30%),
Laboratory of our tertiary hospital from January 1, 2012 to December
and polyps (74, 11.70%). Least common were laryngeal papilloma (7,
31, 2014, and were subsequently diagnosed to have benign vocal
1.10%), sulcus (26, 4.11%) and granuloma (27, 4.27%). A total of 246
cord lesions (nodules, cysts, polyps, granulomas, Reinke’s edema,
(38.92%) were found to have concomitant LPR.
papillomas) were considered for inclusion. Excluded were records of
The majority presented with hoarseness (542, 85.76%) followed
caucasian patients, lesions that were diagnosed as neither benign nor
less commonly by pain (22, 3.48%), globus sensation (13, 2.06%) and
malignant (i.e. atrophy, varices, web), overtly malignant lesions and
throat discomfort (13, 2.06%). Aside from their primary diagnosis, 353
lesions of infectious etiology.
(55.85%) had a past history of other illnesses (i.e. GERD, rhinitis, asthma),
Primary sources of data included patient questionnaires and
and 257 (40.66%) had received some form of treatment (i.e. antibiotics,
printed-out LVES results. Prior to undergoing LVES, patients were
antihistamines, PPI) prior to the evaluation.
routinely interviewed using the questionnaire. Data obtained from this
Among the risk factors evaluated, the most common were caffeine
questionnaire included the presenting symptom, age, sex, occupation,
intake (445, 70.41%) and inadequate water intake (370, 58.54%)
prior treatment, concomitant medical conditions and risk factors.
followed by alcohol (253, 40.03%). Surprisingly, smoking was only
All LVES had been conducted using a Kay RLS 9100 Rhino-Laryngeal
present in 146 (23.19%).
Stroboscope and Digital Videostroboscopy System (Kay Elemetrics,
NJ, USA). Printouts included pertinent images and the subsequent
DISCUSSION
diagnosis.
Consistent with previous studies,5,8 benign lesions were
Data on voice usage was excluded from the study as this was a
predominantly found in the 20-60 year-old age group. However, unlike
subjective factor and could not be quantified. The Reflux Symptom
these studies5, 8 benign lesions in our study were more predominant in
Index (RSI) was also excluded as this was considered more relevant for
females than in males.
reflux as a separate disease entity.
Also consistent with previous studies,2, 5, 7 vocal cord nodules
Patient anonymity was protected in the collection of data.
were the most common of the benign vocal cord lesions. However,
Confidential patient data was only known to the authors who were also
certain differences were noted in this study that may be attributed
the physicians who conducted LVES examinations.
to differences in culture and possibly to the local surge in call center
Data was compiled and analyzed with descriptive statistics using
workers whose profession requires long hours of voice use. The second
Microsoft Excel for Mac 2011 Version 14.6.8 (Microsoft Corporation,
most common benign lesion in this study was Reinke’s edema followed
Redmond, WA, USA).
by cysts then polyps in contrast to studies elsewhere8, 9 where polyps
are second most common followed by Reinke’s edema and cysts.

28 Philippine Journal Of Otolaryngology-Head And Neck Surgery


Philippine Journal Of Otolaryngology-Head And Neck Surgery
It is well established that benign lesions are most frequently
diagnosed in those with voice abuse related occupations. 2, 5, 7, 9 This
was affirmed in our study where a large number were customer service
representatives whose jobs are very much voice-dependent. Our
finding of hoarseness as the most common presenting symptom is also
consistent with the literature.2,5,7
On the other hand, contrary to previous reports,5, 7, 8 caffeine intake,
rather than smoking, was the most common risk factor in our study.
This study was intended to benefit both clinicians and professionals
in the academe who wish to acquire locally - based descriptive data
about the prevalence and demographic profile of patients with benign
vocal cord disorders.
The study is limited in that despite the availability of data with which
Philippine Journal Of Otolaryngology-Head And Neck Surgery 29
ORIGINAL ARTICLES
Vol. 32 No. 1 January – June 2017
may be inadequate and should not be considered a representative
sample of the population. This may be resolved by extending the period
of the study to more than just 5 years or by increasing the number of
subjects by obtaining data from other institutions/facilities.
In conclusion, laryngeal videoendoscopy and stroboscopy plays a
valuable role in the detection of vocal pathologies and has enabled
us to gather baseline evidence on the prevalence of benign vocal
fold lesions in our institution as well as baseline data on the common
characteristics and associated factors seen in the sample population.
Knowing these factors may assist us in current practices and guide
future studies directed toward the treatment and prevention of these
lesions.
REFERENCES
1. Samlan RA, Gartner-Schmidt J, Kunduk M. Visualization of the Larynx. In Flint PW, Haughey BH,
Lund VJ, Niparko JK, Richardson MA, Robbins KT, et al (editors). Cummings Otolaryngology
Head and Neck Surgery. 5th ed., Vol. 1. Philadelphia, PA: Elsevier- Mosby. 2010. pp.813-824.
2. Yogesh S, Daharwal A, Prasad R, Singh S, Shankari -Raipur V. Shankari -Raipur (Chhatisgarh).
Videostroboscopy study of larynx in primary school teachers. National Journal of Otolaryngology
and Head and Neck Surgery. 2014 Jan; 11(1), 32-33. [Retrieved 2015 Feb 13]. Available from:
https://www.researchgate.net/publication/281889037_Videostroboscopy_study_of_larynx_
in_primary_school_teachers.
3. Bohlender J. Diagnostic and therapeutic pitfalls in benign vocal fold diseases. GMS Curr Top
Otorhinolaryngol Head Neck Surg. 2013 Dec 13; 12: Doc01. [Retrieved 2015 Feb 14]. Available
from http://www.egms.de/static/pdf/journals/cto/2013-12/cto000093.pdf. DOI: 10.3205/
cto000093; PMID: 24403969; PMCID: PMC3884536.
4. Dabirmoghadam P, Azimian S, Mokhtari Z. Stroboscopic findings in patients with benign
laryngeal lesions: A brief report. Tehran Univ Med J. 2012 Nov; 70(8): 508-513. [Retrieved 2015
Feb 13]. Available from http://tumj.tums.ac.ir/browse.php?a_id=88&sid=1&slc_lang=en.
5. Wani AA, Rehman A, Hamid S, Akhter M, Baseena S. Benign mucosal fold lesion as a cause of
hoarseness of voice - a clinical study. Otolaryngology. 2012; 2(3). [Retrieved 2015 Feb 13]. Available
from: https://www.omicsonline.org/benign-mucosal-fold-lesion-as-a-cause-of-hoarseness-of-
voice-a-clinical-study-2161-119X.1000120.pdf. DOI:10.4172/2161-119X.1000120.
6. Byeon H. Exploring potential risk factors for benign vocal fold mucosal disorders using weighted
logistic regression. International Journal of Bio-Science and Bio-Technology. 2014; 6(4), 77-86.
[Retrieved 2015 Feb 13]. Available from: http://www.sersc.org/journals/IJBSBT/vol6_no4/8.pdf.
DOI: dx.doi.org/10.14257/ijbsbt.2014.6.4.08.
7. Smith S, Underbrink M. Benign vocal fold lesions. Grand Rounds Presentation, The University
of Texas Medical Branch in Galveston, Department of Otolaryngology. 2013 Nov 26. [Retrieved
2015 Feb 13]. Available from http://www.utmb.edu/otoref/GRNDS/vocal-cord-benign-lesions-
2013-11/vocal-cord-2013-11.pdf.
8. Gupta N, Gurnani D, Patel N, Patel T, Sharma P, Jindal S, et al. Benign vocal cord lesions. National
Journal of Otorhinolaryngology and Head & Neck Surgery. 2013 Jan; 1(2): 19-20. [Retrieved
2015 Feb 13]. Available from: https://www.researchgate.net/publication/291911634_Benign_
vocal_cord_lesions.
9. Nunes RB, Behlau M, Nunes MB, Paulino JG. Clinical diagnosis and histological analysis of vocal
nodules and polyps. Braz J Otorhinolaryngol. 2013 Aug; 79(4): 434-440. [Retrieved 2015 Feb 14].
Available from http://www.scielo.br/pdf/bjorl/v79n4/en_v79n4a07.pdf. DOI: 10.5935/1808-
8694.2013007; PMID: 23929142.
10. Perez Fernandez CA, Preciado Lopez J. Vocal fold nodules, risk factors in teachers. A case control
study design. Acta Otorrinolaringol Esp. 2003 Apr; 54(4): 253-260. [Retrieved 2015 Feb 14].
Available from http://www.ncbi.nlm.nih.gov/pubmed/12825241. PMID: 12825241.

Philippine Journal Of Otolaryngology-Head And Neck Surgery
Gerard F. Lapiña, MD
Samantha S. Castañeda, MD
Department of Otorhinolaryngology
Head and Neck Surgery
Rizal Medical Center
Correspondence: Dr. Samantha S. Castañeda
Department of Otorhinolaryngology
Head and Neck Surgery
Rizal Medical Center
Barangay Pineda, Shaw Boulevard, Pasig City 1600
Philippines
Phone: (632) 865 8400 local 197
Email: ent.hns_rmc@yahoo.com
The authors declared that this represents original material
that is not being considered for publication or has not been
published or accepted for publication elsewhere, in full or in
part, in print or electronic media; that the manuscript has been
read and approved by all the authors, that the requirements
for authorship have been met by each author, and that each
author believes that the manuscript represents honest work.
Disclosures: The authors signed disclosures that there are no
financial or other (including personal) relationships, intellectual
passion, political or religious beliefs, and institutional affiliations
that might lead to a conflict of interest.
Presented at the Philippine Society of Otolaryngology Head
and Neck Surgery Descriptive Research Contest (1st Place),
October 6, 2016. Natrapharm, The Patriot Bldg. Parañaque City.
Creative Commons (CC BY-NC-ND 4.0)
Attribution - NonCommercial - NoDerivatives 4.0 International
Philippine Journal Of Otolaryngology-Head And Neck Surgery 33
ORIGINAL ARTICLES
Vol. 32 No. 1 January – June 2017
Diagnostic-to-Treatment Interval and Disease
Progression among Head and Neck Cancer
Patients Undergoing Surgery
ABSTRACT
Objective: To determine whether the interval from pathological diagnosis to treatment is
significantly delayed, and the presence or absence of disease progression occurring in those with,
and without treatment delay, among head and neck cancer patients in our institution.
Methods:
Design: Retrospective Chart Review
Setting: Tertiary Government Hospital
Participants: Medical records of 70 patients with newly diagnosed head and neck
cancer who underwent primary surgery from January 2011 to December 2015 were retrieved and
available data were extracted.
Results: A total of 28 patients were included in this study. Majority of the cancers were in the
larynx (42.9%) and oral cavity (42.9%). The mean diagnostic-to-treatment interval (DTI) was 54
days but 5 (17.8%) out of the 28 had a DTI of more than 60 days. Four (80%) with a DTI more
than 60 days had an upstage during surgery while 4 (17.4%) patients with DTI less than or equal
to 60 days also had an upstage. 2 (60%) patients with treatment delay had tumor progression
compared to 5 (21.7%) of those without treatment delay. Only 1 (20%) out of the 5 patients with
treatment delay had increased nodal metastasis in contrast to 8 (34.8%) of those who did not
have treatment delay.
Conclusion: A number of patients undergoing surgery in our institution experienced delay to
initiate treatment of more than 60 days and majority of these patients were noted to have disease
progression. However, even patients with treatment prior to 60 days had increases in tumor stage,
which may suggest that the interval aimed for should be shorter than 60 days.
Keywords: head and neck cancer, treatment delay, diagnostic interval, tumor progression
Neoplasms, including head and neck cancers, are the third leading of cause of mortality in
the Philippines.1 Establishing diagnoses at an earlier stage and early initiation of treatment are
essential to achieve good treatment outcome.2 Diagnostic-to-treatment interval (DTI) is defined
as the interval from which histopathological diagnosis is established until radiotherapy or
chemotherapy is commenced or the actual date of surgery.2,3 Various factors can cause delay or
prolonged DTI in the management of patients with head and neck cancer and should be avoided
if possible.4 A significant delay that confers a detrimental effect on survival is defined as more
Philipp J Otolaryngol Head Neck Surg 2017; 32 (1): 33-36 c Philippine Society of Otolaryngology – Head and Neck Surgery, Inc.
 ORIGINAL ARTICLES
Philippine Journal Of Otolaryngology-Head And Neck Surgery Vol. 32 No. 1 January – June 2017

than 60 days from the pathological diagnosis to commencement of median of 54 days. Out of the 28 patients, 5 (17.9%) had a significant
treatment.5 In our institution, despite priority given to head and neck delay in the initiation of treatment.
cancer patients, there are still patients who worsen from the time they The most common primary sites were the larynx (42.9%) and
are diagnosed to the actual day of the surgery. This study aimed to oral cavity (42.9%). Treatment delay (DTI > 60 days) was present in
determine whether there is treatment delay in head and neck cancer 16.67% of patients with laryngeal malignancy in compared to 25% of
patients operated on in our institution and to determine if there is patients with oral cavity malignancy as shown in Figure 1. A minority of
progression in stage, tumor size and lymph node status occurring in patients (14.29%) were diagnosed with malignancies of the parotid and
these patients. paranasal sinus. No treatment delay was noted in these patients.
The majority (75%) of patients were diagnosed at a late stage
METHODS (stage III and IV) with a smaller portion (25%) diagnosed at an earlier
With Ethical Review Board approval, records of all 70 patients with stage (Stage I and II). Across all the stages, there were patients who
newly diagnosed head and neck cancers that underwent surgery in Rizal experienced treatment delay (13.33 - 33.33%). (Figure 2)
Medical Center from January 2011 to December 2015 were identified,
and retrieved to extract patient and tumor characteristics such as age,
sex, primary site of cancer, date of pathological diagnosis and exact
date of surgery. Corresponding TNM Staging, based on the American
Joint Committee on Cancer Staging in 2010 (7th edition)6 during the
time of diagnosis and eventual surgery were also noted. Excluded were
patients with thyroid neoplasms (due to their relatively better prognosis
compared to other head and neck cancers), those with incomplete
records or who were admitted for surgery of tumor recurrence. Patients
No. of patients

with unresectable tumors and those with metastasis during the time
of diagnosis were also not included in this study. The patients were
divided into two groups based on DTI of ≤ 60 days and > 60 days. Data
were tabulated in Microsoft Excel 2016 (v16.0.6769.2017, Microsoft
Figure 2. Diagnostic-to-Treatment Interval and Stage at Diagnosis
Corp., Redmond, WA, USA) and descriptive statistics were computed. *Stage at diagnosis based on the 2010 AJCC TNM Staging

RESULTS
A total of 31 out of 70 patient records were initially considered for
inclusion, with one more excluded due to inadequate data, and two
more excluded because they underwent surgery for recurrence, leaving
a total of 28 patient records included. The ages of the patients ranged
from 26-72 years (mean, 56.9 years), with 46.4% more than 60 years of
age and 67.9% were male. The DTI ranged from 10 to 363 days with a
No. of patients
Figure 3 shows that 4 out of 5 patients (80%) with treatment delay
had an increased stage at the time of diagnosis either due to increased
tumor size, increased nodal metastases or both. Despite having been
operated on within 60 days from the time of pathological diagnosis,
there were still 4 out of 23 patients (17.4%) that had increased stage at
the time of surgery.
No. of patients

Figure 3. Diagnostic-to-Treatment Interval and TNM Staging

Figure 1. Diagnostic-to-Treatment Interval and Site of Primary Lesion *Stage according to the 2010 AJCC TNM Staging

34 Philippine Journal Of Otolaryngology-Head And Neck Surgery


Philippine Journal Of Otolaryngology-Head And Neck Surgery
Tumor Stage
Increase in tumor stage was noted in 3(60%) of 5 patients with
treatment delay, compared to 5(21.7%) of 23 patients without treatment
delay as shown in Figure 4. Among the patients who were operated on
or before 60 days, there were still patients who experienced marked
tumor growth as documented by an increase in tumor stage. The
shortest interval observed in which there was tumor upstage was 25
days.
No. of patients
Figure 4. Diagnostic-to-Treatment Interval and Tumor Stage
*Tumor Stage according to the 2010 AJCC TNM Staging
Nodal Metastases
Increase in nodal metastasis was observed in 8(34.8%) of 23
patients without treatment delay and only 1(20%) of the 5 patients with
treatment delay. (Figure 5) Increased nodal stage was observed in as
early as 12 days from the time of histopathological diagnosis. There was
one patient with laryngeal squamous cell carcinoma initially diagnosed
as N2c but the final histopathologic diagnosis was N2b.
No. of patients
Figure 5. Diagnostic-to-Treatment Interval and Nodal Stage
*Nodal Stage according to the 2010 AJCC TNM Staging
Philippine Journal Of Otolaryngology-Head And Neck Surgery 35
ORIGINAL ARTICLES
Vol. 32 No. 1 January – June 2017
DISCUSSION
This study aimed to determine if there was treatment delay and the
presence or absence of disease progression in patients undergoing
surgery for head and neck cancer. The authors found out that the
median DTI for head and neck cancers in our institution was 54 days. This
interval is subpar compared to the findings of Lynhe et al. of decreasing
median DTIs of 47 days in 1992, 31 days in 2002 and 25 days in 2010
among different institutions in Denmark, mandated by government
to initiate treatment without delay in head and neck cancer patients.7
Another study with a shorter median DTI of 48 days found out on
subgroup analysis, that the median DTI of patients with late stage head
and neck cancer in their institution was significantly prolonged at 57
days,2 similar to our study.
Even though the median time in our institution did not exceed 60
days, this is still unfavorable, according to the findings of Murphy et al.
“a DTI of at least 46 days seemed to affect survival, and a DTI of more
than 60 days persistently had a detrimental effect on survival.”5 The
Dutch guidelines also proposed that the interval from initial consult to
treatment should not be more than 30 days because tumor doubling
times of 30 days or less in some of these cancers implies progression
of disease.10 However, this is difficult to achieve in our setting where
a lot of factors, professional and patient-related, possibly result in
prolonged DTI. Studies have shown that doubling time of tumors occur
at an average 87-96 days and or as brief as 30 days for fast growing
tumors.10,11 This concept is essential since we could expect to see tumor
progression at a similar rate in our study in which the shortest interval
was 25 days.
We found out that even in patients without treatment delay, 34.8%
had an increase in lymph node metastases which translates to poorer
outcomes since this is included in the independent factors that affect
survival rate negatively.9 The presence of nodal metastases in the neck
has been said to decrease 5-year survival by 50% and increase the risk
for metastasis two-fold.13 Similarly, another study also concluded that
an increasing number nodes positive for malignant cells confers a
worse outcome for these patients.14 Interestingly, one of the patients
had clinically positive nodes bilaterally and only those on the ipsilateral
side turned out positive for malignant cells resulting in a lower nodal
stage. This could be explained by the study of Finn et al. in 2002 which
concluded that not all clinically positive and suspicious nodes would
turn out to have invasion with malignant cells and that 30% of clinically
positive nodes are falsely positive.9,15
Specific causes for delay were not identified due to the limited data
available on the retrieved charts as to why the DTI was prolonged in
some patients. Another limitation is that patients who underwent non-
surgical management were not included in this study. Patients who
were initially candidates for surgery and rendered non-operable due to
disease progression not identified since this study only encompassed
 ORIGINAL ARTICLES
Philippine Journal Of Otolaryngology-Head And Neck Surgery Vol. 32 No. 1 January – June 2017

those who underwent surgery. We recommend that a prospective

study be done which would include all patients diagnosed with head
and neck cancer, both surgically and non-surgically managed patients,
wherein close monitoring and documentation is done from initial
consult up until any form of therapeutic intervention is done. In this
way, specific and significant causes of delay may be identified and
analyzed to recommend preventive measures and expedite health care
for these patients.
In conclusion, a number of patients undergoing surgery in our
institution experience treatment delay. There was also disease
progression, in terms of increase in size of the primary tumor or
increased nodal metastases, noted in majority of these patients.

REFERENCES
1. Department of Health [Internet] Philippines: Statistics; c2016 [updated 2013 April 26; cited 2016
Aug 1]. Leading Causes of Mortality. Available from: http://portal.doh.gov.ph/node/198.html.
2. Patel UE, Brennan TE. Disparities in head and neck cancer: assessing delay in treatment initiation.
Laryngoscope. 2012 Aug;122(8):1756-60. DOI: 10.1002/lary.23357; PMID: 22570084.
3. Stoker SD, Wildeman MA, Fles R, Indrasari SR, Herdini C, Wildeman PL, et al. A prospective study:
current problems in radiotherapy for nasopharyngeal carcinoma in Yogyakarta, Indonesia. PLoS
One. 2014 Jan 23;9(1): e85959. DOI: 10.1371/journal.pone.0085959; PMID: 24465811; PMCID:
PMC3900459.
4. Nash R, Hughes J, Sandison A, Stewart S, Clarke P, Mace A. Factors associated with delays in
head and neck cancer treatment: case–control study. J Laryngol Otol. 2015 Apr;129(4):383-5.
DOI: 10.1017/S0022215115000687; PMID: 25788249.
5. Murphy CT, Galloway TJ, Handorf EA, Egleston BL, Wang LS, Mehra R, et al. Survival impact of
increasing time to treatment initiation for patients with head and neck cancer in the United
States. J Clin Oncol. 2016 Jan 10;34(2):169-78. DOI: 10.1200/JCO.2015.61.5906; PMID: 26628469;
PMCID: PMC4858932.
6. Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A. Seventh Edition of AJCC Cancer
Staging Manual. Springer-Verlag, New York, NY. 2010.
7. Lyhne NM, Christensen A, Alanin MC, Bruun MT, Jung TH, Bruhn MA, et al. Waiting times for
diagnosis and treatment of head and neck cancer in Denmark in 2010 compared to 1992 and
2002. Eur J Cancer. 2013 May;49(7):1627-33. DOI: 10.1016/j.ejca.2012.11.034; PMID: 23274198.
8. Hörmann K, Sadick H. Role of surgery in the management of head and neck cancer: a
contemporary view of the data in the era of organ preservation. J Laryngol Otol. 2013
Feb;127(2):121-7. DOI: 10.1017/S0022215112002988; PMID: 23298649.
9. Tong XJ, Shan ZF, Tang ZG, Guo XC. The impact of clinical prognostic factors on the survival of
patients with oral squamous cell carcinoma. J Oral Maxillofac Surg. 2014 Dec;72(12):2497.e1-10.
DOI: 10.1016/j.joms.2014.07.001; PMID: 25454713.
10. van Harten MC, de Ridder M, Hamming-Vrieze O, Smeele LE, Balm AJ, van den Brekel MW.
The association of treatment delay and prognosis in head and neck squamous cell carcinoma
(HNSCC) patients in a Dutch comprehensive cancer center. Oral Oncol. 2014 Apr;50(4):282-90.
DOI: 10.1016/j.oraloncology.2013.12.018; PMID: 24405882.
11. Waaijer A, Terhaard CH, Dehnad H, Hordijk GJ, van Leeuwen MS, Raaymakesr CP, et al. Waiting
times for radiotherapy: consequences of volume increase for the TCP in oropharyngeal
carcinoma. Radiother Oncol. 2003 Mar;66(3):271-6. PMID: 12742266.
12. van Harten MC, Hoebers FJ, Kross KW, van Werkhoven ED, van den Brekel MW, van Dijk BA.
Determinants of treatment waiting times for head and neck cancer in the Netherlands and their
relation to survival. Oral Oncol. 2015 Mar;51(3):272-8. DOI: 10.1016/j.oraloncology.2014.12.003;
PMID: 25541458.
13. Wan XC, Egloff AM, Johnson J. Histological assessment of cervical lymph node identifies
patients with head and neck squamous cell carcinoma (HNSCC): who would benefit from
chemoradiation after surgery? Laryngoscope. 2012 Dec;122(12):2712–2722. DOI: 10.1002/
lary.23572; PMID: 23060119; PMCID: PMC3522766.
14. Finn S, Toner M, Timon C. The node-negative neck: accuracy of clinical intraoperative lymph
node assessment for metastatic disease in head and neck cancer. Laryngoscope. 2002
Apr;112(4):630-3. DOI: 10.1097/00005537-200204000-00007; PMID: 12150514.
15. Coskun HH, Medina JE, Robbins KT, Silver CE, Strojan P, Teymoortash A, et al. Current philosophy
in the surgical management of neck metastases for head and neck squamous cell carcinoma.
Head Neck. 2015 Jun; 37(6):915-26. DOI: 10.1002/hed.23689; PMID: 24623715; PMCID:
PMC4991629.

36 Philippine Journal Of Otolaryngology-Head And Neck Surgery

 ORIGINAL ARTICLES
Philippine Journal Of Otolaryngology-Head And Neck Surgery Vol. 32 No. 1 January – June 2017

Nikkoh P. Muñoz, MD1

Adrian F. Fernando, MD1 Fibular Dimensions for Mandibular
Reconstruction among Filipinos
Samantha S. Castañeda, MD1,2

Department of Otorhinolaryngology
Head and Neck Surgery1
The Medical City

Ateneo School of Medicine and Public Health2

ABSTRACT
Objective: To determine if the anatomic dimensions (length, cross-sectional width, cortical
thickness) of the Filipino fibula are ideal for mandibular reconstruction.

Methods:
Design: Cross-Sectional Study
Setting: Anatomy dissection laboratory
Participants: 40 fibulas from 20 adult cadavers

Results: Morphometric examination showed the mean length of the harvested fibulas was 33.5
cm. The mean horizontal (a-d) and vertical (b-c) widths of the proximal cross-section (point B)
were 15.1 ± 0.28 mm and 9.9 ± 0.15 mm respectively. The mean horizontal (a-d) and vertical (b-c)
widths of the distal cross-section (point D) were 15.4 ± 0.24 mm and 10.3 ± 0.49 mm, respectively.
The mean cortical thickness of the anterior (a), lateral (b), posterior (c) and medial (d) aspects of
the proximal cross-section (point B) were 5.2 ± 0.1 mm, 3.2 ± 0.04 mm, 3.6 ± 0.01 mm, and 2.9 ±
Correspondence: Dr. Adrian F. Fernando 0.06 mm, respectively. The mean cortical thickness of the anterior (a), lateral (b), posterior (c) and
Department of Otorhinolaryngology
Head and Neck Surgery medial (d) aspects of the distal cross-section (point D) were 5.1 ± 0.21 mm, 3.1 ± 0.11 mm, 3.5 ±
The Medical City
Ortigas Avenue, Pasig City 1600
0.04 mm, and 2.9 ± 0.09 mm, respectively.
Philippines
Phone: (632) 635 6789 local 6250
Fax: (632) 687 3349 Conclusion: Our findings show that the Filipino fibulas studied have dimensions that are ideal for
Email: ent@medicalcity.com.ph
mandibular reconstruction.
The authors declared that this represents original material
that is not being considered for publication or has not been
published or accepted for publication elsewhere in full or in Keywords: Mandibular reconstruction, Fibula, Free Flaps, Fibular bone dimensions, Filipino
part, in print or electronic media; that the manuscript has been
read and approved by the authors, that the requirements for
authorship have been met by the authors, and that the authors Over the past years, the fibular free flap has been considered the workhorse for mandibular
believe that the manuscript represents honest work.
reconstruction, having all the ideal features of adequate length, width, bone quantity and quality,
Disclosures: The authors signed disclosures that there are no
financial or other (including personal) relationships, intellectual
and good success rate.1 In the Philippines, the fibular free flap has been previously described for
passion, political or religious beliefs, and institutional affiliations head and neck reconstruction particularly for segmental mandibular defects and as a condylar
that might lead to a conflict of interest.
autograft since 2005.2 Although great success has been encountered locally in terms of its
survival, evaluation of its dimensions especially for dental restoration remains a challenge.

Creative Commons (CC BY-NC-ND 4.0)

Attribution - NonCommercial - NoDerivatives 4.0 International Philipp J Otolaryngol Head Neck Surg 2017; 32 (1): 23-26 c Philippine Society of Otolaryngology – Head and Neck Surgery, Inc.

Philippine Journal Of Otolaryngology-Head And Neck Surgery 23

 ORIGINAL ARTICLES
Philippine Journal Of Otolaryngology-Head And Neck Surgery Vol. 32 No. 1 January – June 2017

To the best of our knowledge, based on a search of MEDLINE
PubMed, WPRIM and Google Scholar using the keywords “mandibular
reconstruction,” “fibula,” “free flap/s,” and “fibular bone dimensions,”
data on the anatomic dimensions of the Filipino fibula has not yet
been published to show if it meets ideal dimensions for mandibular
reconstruction.
This study aims to determine the suitability of anatomic dimensions
of harvested fibulae for mandibular reconstruction in Filipinos in terms
of length (cm) from fibular head to the lateral malleolus, cross-sectional
width (mm) along pre-determined segments and cross-sectional
cortical bone thickness (mm) along pre-determined segments.
marked with points “a”, “b”, and “c” referred respectively as its anterior
margin, medial crest and lateral margins. (Figure 2) The mid portion
from points “b” and “c” was marked as point “d”. The distance between
points “a” and “d” was used to measure the vertical width of the fibular
cross section while the distance from points “b” and “c” was used to
measure its horizontal width. Measurements of cross-sectional width
were sequentially obtained by two separate observers using a single
3.5” Castroviejo caliper (Braun - Aesculap Inc., PA, USA) and recorded in
millimeters, averaged and tabulated.

METHODS
With Institutional Review Board approval, 40 fibulas of 20 formalin-
preserved cadavers consisting of 12 males and 8 females located in the
Anatomy Dissection Laboratory of the Ateneo School of Medicine and
Public Health were harvested and measured. The number of available
cadavers determined our sample size.

Measurement of Fibular Length

The fibulas were exposed along their length. For each fibula, the
apex of the fibular head and apical margin of the lateral malleolus
were referred to as ‘A’ and ‘E’, respectively. (Figure 1) The segment A-E
was divided into 4 segments. Point ‘C’ was midline and point ‘B’ and
‘D’ were marked 4 cm above and below point ‘C’ corresponding to
the standard osteotomy sites in harvesting the fibula for free tissue
Figure 2. Model showing how cross-sectional width was determined
Measurement of Cross-Sectional Cortical Bone Thickness
At points B and D of each fibular segment, cortical bone thickness
was sequentially measured by two separate observers using the same
caliper at its anterior, lateral, posterior and medial aspects that were
respectively marked as points [a], [b], [c], and [d]. (Figure 3)

Figure 1. Transverse view of fibula showing segments used as reference

transfer. Measurements were sequentially obtained by two separate

observers using a single soft tape measure (TR-13W Tailor’s Tape, The
Perfect Measuring Tape Company, Portland, OR, USA) and recorded in
millimeters. A single recorded discrepancy above 10mm was verified by
re-measurement and consensus before recorded measurements were
averaged and tabulated.

Measurement of Cross-Sectional Width

Osteotomies were performed on each fibula using a single
oscillating saw (Mopec Autopsy Saw, Stryker®, MI, USA) at points ‘B’ and
‘D’ corresponding to the actual osteotomy sites for fibular harvesting.
The cross section of the segmentally osteotomized fibula were Figure 3. Model showing how cross-sectional cortical bone thickness was determined

24 Philippine Journal Of Otolaryngology-Head And Neck Surgery


Philippine Journal Of Otolaryngology-Head And Neck Surgery
Statistical Analysis
Each distance was separately measured by 2 observers and
encoded on MS Excel 2010 (Microsoft Corporation, Redwood WA, USA)
for statistical data analysis using percentages, means and standard
deviation. Discrepancies in measurements obtained by the two
observers were insignificant (sub-centimeter) and simply averaged,
except for the previously mentioned readings of fibular length of >10
mm that were re-measured to obtain a consensus.
RESULTS
Forty fibulas were successfully harvested and measured from 20
cadavers, of which there were 12 males (60 %) and 8 females (40 %)
with a 3:2 male to female ratio.
Fibular length and cross-sectional width at various segments
The mean length of the harvested fibulas was 33.5 cm. The mean
horizontal (a-d) and vertical (b-c) widths of the proximal cross-section
(point B) were 15.1 ± 0.28 mm and 9.9 ± 0.15 mm, respectively. The
mean horizontal (a-d) and vertical (b-c) widths of the distal cross-
section (point D) were 15.4 ± 0.24 mm and 10.3 ± 0.49 mm, respectively.
(Figure 2)
Thickness of Cortical Bone in Various Cross-Sectional Levels
The mean cortical thickness of the anterior (a), lateral (b), posterior
(c) and medial (d) aspects of the proximal cross-section (point B)
were 5.2 ± 0.1 mm, 3.2 ± 0.04 mm, 3.6 ± 0.01 mm, and 2.9 ± 0.06 mm
respectively. The mean cortical thickness of the anterior (a), lateral (b),
posterior (c) and medial (d) aspects of the distal cross-section (point D)
were 5.1 ± 0.21 mm, 3.1 ± 0.11 mm, 3.5 ± 0.04 mm, and 2.9 ± 0.09 mm,
respectively. (Figure 3)
DISCUSSION
The osteocutaneous fibula free flap (OFFF) presents numerous
advantages. The bony architecture is similar to that of the mandible,
which on cross section shows a marble-like bone structure of thick
compact layer giving an excellent anchorage for dental implants unlike
iliac crest or scapula.3 The fibula also shows similarity to mandibular
width and shape, and this also facilitates the insertion of dental
implants. A study by Huryn et al.4 showed that fibula free flaps behave
like an edentulous mandible. Thus, osseointegration can generally
be expected. The grafts can easily be adjusted to the curvature of
the mandible using osteotomy or the intersection technique. Owing
to its extensive vascular network, the diaphysis of the fibula can be
osteotomized into different segments without danger of necrosis.
Philippine Journal Of Otolaryngology-Head And Neck Surgery 25
ORIGINAL ARTICLES
Vol. 32 No. 1 January – June 2017
Germain et al.5 reported that the fibula can provide up to 25 cm of
bone for harvesting and it is necessary to preserve 6 – 7 cm of bone
distally and proximally to maintain the integrity of the knee and ankle
joint. Uchiyama et al.6 showed that it is necessary to preserve at least
6 cm of bone and that the distal fibula is responsible for stabilizing the
ankle mortise during external rotation and inversion.
The fibula is a long thin non weight-bearing bone of the lower
extremity. Frodel et al.7 measured the height and weight of the fibula
and the cortical thickness in transverse cross sections. It is one of the
strongest bones available for transfer due to its tubular shape with
thick cortical bone around the entire circumference.7
Analysis of our data suggests that the Filipino fibulas sampled have
adequate length for mandibular reconstruction. The average length
was noted to be 33.5 cm. Sparing the necessary 6 cm (proximally and
distally) to retain stability of the knee and ankle joint would still leave
21.5 cm of bone for mandibular reconstruction. A study by Apinhasmit
et al.8 showed mean total fibular length and mean length of harvested
fibulae were 34.2 +/- 2.3 cm and 18.2 +/- 2.3 cm, respectively. A
harvested fibula of 16 to 20 cm in length is sufficient to provide bone
for reconstructing mandible defects.8
The fibulas were also noted to have a cross-sectional width of no
less than 8 mm with the greatest diameter at segment a-d (15.4 mm).
This was consistent with the study by Matsuura et al.,9 where segment
a-d was the longest in cross sections at C, D and E. The a-d segment
or the anterior margin of the fibula is often used to reconstruct the
alveolar crest and the lateral surface of the fibula or the b-c segment
is used to reconstruct the labiobuccal aspect. These findings should
be useful for mandibular reconstruction.
In our study, the greatest cortical thickness was noted to be 6.5 mm
with a mean of 5.2 mm at point a. This is again consistent with the study
of Matsuura et al.9 which showed the greatest cortical thickness at apex
a (4.1 mm). This is useful for osseointegrated implants, considering that
osseointegrated implants have a width of 4 mm, the fibula then has
adequate cortical bone to surround the implant for better stability and
thus success of the osseointegration.10
The use of osseointegrated implants restores both function and
aesthetics. According to Anne-Gaelle et al.,11 the success rate for
osteointegration ranges from 86% to 99%. Mandibular reconstruction
by microvascular fibula free flap has dramatically improved the quality
of life of patients treated by surgery.
The OFFF has its limitations. Because of its limited height (rarely
more than 15 mm) compared with the height of the mandible, vertical
distance between the reconstructed segment and the occlusal plane
can be substantial. To address this, Choo-Lee et al.12 showed that vertical
 ORIGINAL ARTICLES
Philippine Journal Of Otolaryngology-Head And Neck Surgery Vol. 32 No. 1 January – June 2017

distraction osteogenesis of free vascularized flaps is a reliable technique

that optimizes implant positioning for ideal prosthetic rehabilitation,
after mandibular reconstruction following tumor surgery.
Despite the sample size limitation imposed by the availability of
cadavers, our study shows that the anatomic dimensions (length,
cross-sectional width, cortical thickness) of the Filipino fibulas studied
are sufficient for mandibular reconstruction. However, the sample of
cadavers dissected may not be representative of the larger Filipino
population, limiting the generalizability of our findings. Subsequent
studies that are more representative may be more generalizable.

REFERENCES
1. Akheel M, Tomar SS, Bhargava A. Vascularized Free Fibula Flap for Reconstruction of Mandibular
Defects. J Surg. Special Issue: Craniofacial Surgery. 2014 Dec; 2(6-1): 1-5. DOI: 10.11648/j.
js.s.2014020601.11.
2. Yao M, Castaneda S, David J, Alonzo D. Condylar Autograft with Fibular Free Flap for Mandibular
Reconstruction. Philipp J Otolaryngol Head Neck Surg. 2005; 20 (1-2): 31-38.
3. Stoll P. Indications and technical considerations of different fibula grafts. In: Greenberg AM,
Prein J (editors). Craniomaxillofacial reconstructive and corrective bone surgery: Principles of
internal fixation using the AO/ASIF technique. NY: Springer-Verlag; 2002. 327-334.
4. Huryn JM, Zlotolow JM, Piro JD, Lenchewski E. Osseointegrated implants in microvascular fibula
free flap reconstructed mandible. J Prosthet Dent. 1993;70:443. PMID: 8254548.
5. Germain MA, Gomez NG, Demers G, Hureau J. Anatomic basis of mandibular reconstruction by
free vascularized fibula graft. Surg Radiol Anat 1993;15:213–214. PMID: 8235966.
6. Uchiyama E, Suzuki D, Kura H, Yamashita T, Murakami G. Distal fibular length needed for ankle
stability. Foot Ankle Int. 2006 Mar; 27(3): 185-189. DOI: 10.1177/107110070602700306; PMID:
16539900.
7. Frodel JL Jr, Funk GF, Capper DT, Fridrich KL, Blumer JR, Haller JR, et al. Osseointegrated implants:
A comparative study of bone thickness in four vascularized bone flaps. Plast Reconstr Surg 1993
Sep;92:(3): 449-455. PMID: 8341743.
8. Apinhasmit W, Sinpitaksakul P, Chompoopong S. Anatomical considerations of the Thai fibula
used as a fibula osteocutaneous free flap in mandibular reconstruction and dental implant
placement. J Med Assoc Thai. 2012 Apr; 95(4): 561-8. PMID: 22612012.
9. Matsuura M, Ohno K, Michi K, Egawa K, Takiguchi R. Clinicoanatomic examination of the fibula:
anatomic basis for dental implant placement. Int J Oral Maxillofac Implants. 1999 Nov-Dec;
14(6): 879–884. PMID: 10612927.
10. Teoh KH, Huryn JM, Patel S, Halpern J, Tunick S, Wong HB, et al. Implant prosthodontic
rehabilitation of fibula free-flap reconstructed mandibles: a Memorial Sloan-Kettering Cancer
Center review of prognostic factors and implant outcomes. Int J Oral Maxillofac Implants. 2005
Sep-Oct; 20(5):738-46. PMID: 16274148.
11. Anne-Gaelle B, Samuel S, Julie B, Renaud L, Pierre B. Dental implant placement after
mandibular reconstruction by microvascular free fibula flap: current knowledge and
remaining questions. Oral Oncol. 2011 Dec; 47(12):1099-104. Epub 2011 Aug 27. DOI: 10.1016/j.
oraloncology.2011.07.016. PMID: 21873106.
12. Cho-Lee GY, Naval-Gías L, Martos-Díaz PL, González-García R, Rodríguez-Campo FJ. Vertical
distraction osteogenesis of a free vascularized fibula flap in a reconstructed hemimandible for
mandibular reconstruction and optimization of the implant prosthetic rehabilitation. Report of
a case. Med Oral Patol Oral Cir Bucal. 2011 Jan 1;16(1):e74-8. PMID: 20711151.

26 Philippine Journal Of Otolaryngology-Head And Neck Surgery

 ORIGINAL ARTICLES
Philippine Journal Of Otolaryngology-Head And Neck Surgery Vol. 32 No. 1 January – June 2017

Mark Jansen D. G. Austria, MD

Rodante A. Roldan, MD Laryngeal Cancer Neck Node Metastases:
Patterns of Spread
Department of Otolaryngology
Head and Neck Surgery
Rizal Medical Center

ABSTRACT
Objective: To determine the patterns of neck node metastases of patients with laryngeal
carcinoma in our institution.

Methods:
Design: Chart Review
Setting: Tertiary Public Hospital
Participants: Records of thirty-eight (38) laryngeal cancer patients who underwent
laryngectomy with neck dissection from January 2010 to January 2017 were considered.

Results: Records of 34 laryngeal cancer patients with ages ranging from 45-72 years old were
included. The most common subsite was the glottis with 19 (55.88%) patients. The distribution
of neck node metastases for all subsites were 0/64 (0%) for level I, 22/64 (34.37%) for level II,
12/64 (18.75%) for level III, 7/64 (10.93%) for level IV, 0/64 (0%) for level V, and 1/64 (1.56%) for
level VI. Distributions of lymph nodes per subsite for supraglottic SCCA were 0 (0%) for level I,
3/22 (13.63%) for level II, 2/12 (16.66%) for level III, 1/7 (14.28%) for level IV, 0 (0%) for level V, and
0/1 (0%) for level VI. For glottic SCCA, they were 0 (0%) for level I, 12/22 (54.54%) for level II, 8/12
(66.66%) for level III, 3/7 (42.85%) for level IV, 0 (0%) for level V, and 1/1 (100%) for level VI; and for
transglottic SCCA, they were 0 (0%) for level I, 7/22 (31.81%) for level II, 5/12 (41.66%) for level III,
3/7 (42.85%) for level IV, 0 (0%) for level V, and 0/1 (0%) for level VI.
Correspondence: Dr. Rodante A. Roldan
Department of Otolaryngology
Head and Neck Surgery Conclusion: Our findings show that neck node levels II, III and IV are most frequently affected in
Rizal Medical Center
Pasig Blvd., Pasig City 1600
laryngeal carcinoma patients in our sample and may guide recommendations for neck dissection
Philippines in our institution.
Phone: (632) 865 8400 local 106
Email: raroldan@rmc.doh.gov.ph / raroldanmd@gmail.com

The authors declared that this represents original material

Keywords: Laryngeal Cancer, Metastases, Neck dissection, Supraglottic, Subglottic, Glottic,
that is not being considered for publication or has not been Transglottic
published or accepted for publication elsewhere, in full or in
part, in print or electronic media; that the manuscript has been
read and approved by all the authors, that the requirements
for authorship have been met by each author, and that each
Lymph nodes may serve as barriers to the spread of tumor cells, as vehicles for progression
author believes that the manuscript represents honest work. of tumor spread within lymphatics, and as vehicles for progression of tumor spread from
Disclosures: The authors signed disclosures that there are no lymphatics to more remote sites.1 There are predictable pathways of lymphatic drainage within
financial or other (including personal) relationships, intellectual
passion, political or religious beliefs, and institutional affiliations
the subsites of the upper aerodigestive tract.2 Neck dissection is a surgical procedure in head
that might lead to a conflict of interest. and neck cancers to either remove or prevent disease progression.
The role of elective treatment of the neck in laryngeal cancer continues to be controversial
and variations in type and extent of surgical dissection have evolved.3 A complete functional neck
Creative Commons (CC BY-NC-ND 4.0)
Attribution - NonCommercial - NoDerivatives 4.0 International Philipp J Otolaryngol Head Neck Surg 2017; 32 (1): 30-32 c Philippine Society of Otolaryngology – Head and Neck Surgery, Inc.

30 Philippine Journal Of Otolaryngology-Head And Neck Surgery


Philippine Journal Of Otolaryngology-Head And Neck Surgery
dissection has been considered unnecessarily extensive for treatment
of the clinically negative neck and therefore selective neck dissection
is now routinely employed for elective and some therapeutic neck
dissections in patients with laryngeal cancer.4
To guide our recommendations for neck dissection, the objective
of this paper was to determine the pattern of neck node metastases of
patients with laryngeal carcinoma in our institution.
METHODS
With Ethical Review Board (ERB) approval, a chart review of all
patients with laryngeal carcinoma who underwent laryngectomy and
neck dissection in the Department of Otolaryngology-Head and Neck
Surgery of Rizal Medical Center from January 2010 to January 2017
was performed. The neck dissections done were either prophylactic or
elective and the type of dissection was selective or modified radical.
Data was retrieved from the hospital records section and recorded
using Microsoft Excel 2010 version 14.0.4760.1000 (32-Bit) (Microsoft
Corp., Redwood, CA, USA). Only the initials of patients were recorded
to maintain confidentiality. Records of 38 patients were initially
considered but because of inadequate data and chart unavailability, 4
records were excluded. Data obtained were gender, age, TNM staging,
type and number of neck dissections performed and relative frequency
of positive nodes in each nodal group for each subsite. Descriptive
statistics were generated using the same MS Excel program.
RESULTS
The records of 34 patients who underwent total laryngectomy with
neck dissection were included in our study (31 males, 3 females) with
ages ranging from 45 to 72 years old. Table 1 shows the TNM staging
of our patients with most cases in Stage 4 (58.82%). There were sixty-
four (64) neck dissections performed, sixty (60) selective and four (4)
modified radical, thirty-two (32) on the right and thirty-two (32) on
the left neck, respectively. The subsites involved were supraglottic in
5 (14.7%), glottic in 19 (55.88%) and transglottic in 10 (29.41%). The
relative frequency of positive nodes in each nodal group for each
subsite is shown in Table 2.
Table 1. TNM Staging
TNM Stage Number of Patients (N) Percentage (%)
I 2 5.88
II 1 2.94
III 11 32.35
IVa 20 58.82
TOTAL 34 100.00
Philippine Journal Of Otolaryngology-Head And Neck Surgery 31
ORIGINAL ARTICLES
Vol. 32 No. 1 January – June 2017
Table 2. Relative frequency of positive nodes in each nodal group for each subsite
Lymph Node Supraglottic Glottic Transglottic
Levels (n/N) % (n/N) % (n/N) %
I 0 0 0
II (3/22) 13.63 (12/22) 54.54 (7/22) 31.81
III (2/12) 16.66 (8/12) 66.66 (5/12) 41.66
IV (1/7) 14.28 (3/7) 42.85 (3/7) 42.85
V 0 0 0
VI 0 (1/1) 100 0
DISCUSSION
Among the 34 laryngeal cancer patients who underwent total
laryngectomy with neck dissection in our study, the most commonly
involved lymph node groups were levels II, III and IV. The lymph node
groups involved per laryngeal subsite in our sample were levels II, III,
IV for supraglottic; levels II, III, IV,VI for glottic; and levels II,III,IV for
transglottic cancer.
Supraglottic SCCA usually metastasizes to levels II, III and IV
because of its rich lymphatic network and midline location that has a
high propensity for bilateral lymph node involvement.5 The lymphatic
channels from the supraglottis pass through the thyrohyoid membrane
and drain into the jugular chain.5,6 The posterior cervical nodes (levelV) are
seldom involved, and submandibular (level IB) and submental
(level IA) nodes are almost never involved.5 The results of our study
are comparable to those of Lindberg et al. where the main spread was
along levels II, III and IV among 2,044 patients including supraglottic
SCCA. Our findings also echo those of Candela et al.7 that revealed
levels II, III and IV had the highest risk of nodal metastases from
squamous cell carcinoma among 247 patients who underwent 267
neck dissections.7,8
On the other hand, the nodes at risk of metastasis from glottic
SCCA are those in levels II, III, IV and VI.6 Bilateral or contralateral
metastases are rare because the true vocal folds are nearly devoid of
lymphatics.5,6 It is interesting to note that patients with glottic SCCA
who were operated on in our institution had multiple lymph node
involvement (II, III, IV) at the time of surgery. This may be explained
by the fact that majority (52.63%) of glottic SCCA in our institution
presented at Stage 4a. On the other hand, our series had only one
patient with level VI involvement. This is in contrast to the study of
Waldfahrer et al.9 that reported an incidence of occult metastases
of 18%. Though the reasons for this need to be investigated, one
possible explanation may involve the diligence of the surgeon and
pathologist in identifying and isolating level VI lymph nodes in the
specimen, separating them from the primary tumor.
 ORIGINAL ARTICLES
Philippine Journal Of Otolaryngology-Head And Neck Surgery
Primary subglottic carcinoma is rare, constituting from 1-3.6% of
the laryngeal cancers reported in the literature.10 Paratracheal node
(level VI) metastases are more frequent in patients with primary
subglottic carcinoma.11 The rarity of primary subglottic carcinoma
and late stage of presentation in our patients may have limited us
from obtaining such cases.
Our study is limited to one type of carcinoma and by a small sample
size. Hence, we recommend future multi-center studies that include
the experience of other institutions. Moreover, though not a formal
32 Philippine Journal Of Otolaryngology-Head And Neck Surgery
Vol. 32 No. 1 January – June 2017
part of the study, we noticed that majority of our patients presented
with cancer in later stages. While searching for and addressing
underlying reasons for this, we should strengthen our head and neck
cancer awareness and education programs for health promotion,
disease prevention, and early detection. Meanwhile, our findings that
neck node levels II, III and IV are most frequently affected in laryngeal
carcinoma patients in our sample may guide recommendations for
neck dissection in our institution.
REFERENCES
1. Aarsvold JN, Alazraki NP. Update on detection of sentinel lymph nodes in patients with
breast cancer. Semin Nucl Med. 2005 Apr; 35(2):116-28. Epub 2005/03/15. DOI: 10.1053/j.
semnuclmed.2004.11.003; PMID: 15765374.
2. Mukherji SK, Armao D, Joshi VM. Cervical nodal metastases in squamous cell carcinoma of the
head and neck: what to expect. Head Neck. 2001 Nov; 23(11): 995-1005. Epub 2002/01/05. PMID:
11754505.
3. Ferlito A, Rinaldo A, Silver CE, Robbins KT, Medina JE, Rodrigo JP, et al. Neck dissection for
laryngeal cancer. J Am Coll Surg. 2008 Oct; 207(4):587-93. Epub 2008/10/18. DOI: 10.1016/j.
jamcollsurg.2008.06.337; PMID: 18926464.
4. Genden EM, Ferlito A, Silver CE, Jacobson AS, Werner JA, Suarez C, et al. Evolution of the
management of laryngeal cancer. Oral Oncol. 2007 May; 43(5):431-9. Epub 2006/11/23. DOI:
10.1016/j.oraloncology.2006.08.007; PMID: 17112771.
5. Cahlon O, Lee N, Le QT, Kaplan MJ, Colevas AD. Cancer of the Larynx. In: Hoppe R, Phillips TL,
Roach III M (editors). Leibel and Phillips Textbook of Radiation Oncology 3rd ed. Vol 2. Philadelphia,
PA; Saunders. 2010; 31, 642-665.
6. Armstrong WB, Vokes DE, Verma SP. Malignant Tumor of the Larynx. In: Flint PW, Haughey BH,
Lund VJ, Niparko JK, Robbins KT, Thomas JR, et al (editors). Cummings Otolaryngology Head and
Neck Surgery, 6th ed. Vol 2. Philadelphia (PA): Mosby, c2010. P1613-1614.
7. Candela FC, Shah J, Jaques DP, Shah JP. Patterns of cervical node metastases from squamous
carcinoma of the larynx. Arch Otolaryngol Head Neck Surg. 1990 Apr; 116(4): 432-5. Epub
1990/04/01. PMID: 2317325.
8. Byers RM, Wolf PF, Ballantyne AJ. Rationale for elective modified neck dissection. Head Neck
Surg. 1988 Jan-Feb; 10(3): 160-7. Epub 1988/01/01. PMID: 3235344.
9. Waldfahrer F, Hauptmann B, Iro H. [Lymph node metastasis of glottic laryngeal carcinoma].
Laryngorhinootologie. 2005 Feb; 84(2): 96-100. Epub 2005/02/16. DOI: 10.1055/s-2004-826075;
PMID: 15712044.
10. Santoro R, Turelli M, Polli G. Primary carcinoma of the subglottic larynx. Eur Arch Otorhinolaryngol.
2000 Dec; 257(10): 548-51. Epub 2001/02/24. PMID: 11195034.
11. Coskun HH, Medina JE, Robbins KT, Silver CE, Strojan P, Teymoortash A, et al. Current philosophy
in the surgical management of neck metastases for head and neck squamous cell carcinoma.
Head Neck. 2015 Jun; 37(6):915-26. Epub 2014/03/14. DOI: 10.1002/hed.23689; PMID: 24623715
PMCID: PMC4991629.
 ORIGINAL ARTICLES
Philippine Journal Of Otolaryngology-Head And Neck Surgery
Roderick B. De Castro, MD
Michelle Angelica B. Cruz-Daylo, MD
Monique Lucia A. Jardin, MD
Department of Otorhinolaryngology
Head and Neck Surgery
Ospital ng Makati
Correspondence: Dr. Michelle Angelica B. Cruz-Daylo
Department of Otorhinolaryngology
Head and Neck Surgery
5th floor, Ospital ng Makati
Sampaguita St. cor Gumamela St., Pembo, Makati City 1218
Philippines
Telefax: (632) 8826316 local 309
Email: angeldaylomd@gmail.com
The authors declared that this represents original material
that is not being considered for publication or has not been
published or accepted for publication elsewhere in full or in
part, in print or electronic media; that the manuscript has been
read and approved by all the authors, that the requirements
for authorship have been met by each author, and that each
author believes that the manuscript represents honest work.
Disclosures: The authors signed disclosures that there are no
financial or other (including personal) relationships, intellectual
passion, political or religious beliefs, and institutional affiliations
that might lead to a conflict of interest.
Presented at the Philippine Society of Otolaryngology Head
and Neck Surgery Analytical Research Contest, November 10,
2015. Bella Ibarra, Quezon City.
Creative Commons (CC BY-NC-ND 4.0)
Attribution - NonCommercial - NoDerivatives 4.0 International
6 Philippine Journal Of Otolaryngology-Head And Neck Surgery
Vol. 32 No. 1 January – June 2017
Low Frequency Ultrasound in Chronic
Rhinosinusitis with Nasal Polyposis
and Recovery after Endoscopic Sinus Surgery:
A Randomized Controlled Trial
ABSTRACT
Objective: The study aimed to determine the role of low frequency ultrasound in patients
with Chronic Rhinosinusitis with Nasal Polyposis (CRS-NP) and recovery after Endoscopic Sinus
Surgery (ESS) using Sino Nasal Outcome Test 22 (SNOT-22) questionnaires, modified Lund MacKay
endoscopic appearance and histopathologic examination.
Methods:
Design: Single Blinded Randomized Controlled Trial
Setting: Tertiary Government Hospital
Participants: 42 adult Filipinos aged 19 to 76 years old diagnosed with Chronic
Rhinosinusitis with grade 2 and 3 Nasal Polyposis and failure of maximal medical management
(3-month course of antibiotics, nasal douche, topical steroids and other modalities) between June
2013 to June 2015 were randomized into two groups of 21 participants each-- the ultrasound-
treated group and control group. Specimens (nasal polyps) from both groups were obtained and
processed with Hematoxylin-Eosin (H&E) and gram staining. Specimens from the ultrasound-
treated group received low frequency ultrasound (1 MHz, 1.0 watt/cm2, 20% pulsed mode for
5 minutes at 370C) post-extraction and prior to staining. In phase II, the ultrasound group also
received the same ultrasound treatment while the control group underwent ultrasound at 0 MHz
frequency, 0 watt/cm2, both twice a week for 3 weeks, beginning one (1) week post operatively.
Both groups accomplished SNOT-22 forms and were evaluated via modified Lund MacKay
endoscopic appearance at 1 week (week 0 of treatment), 2 weeks, 3 weeks, and 1 month post
operatively (week 3 of treatment).
Results: Paired T-test showed a statistically significant difference between control and treatment
groups in epithelial thickness with a p-value of 2.29E-10 (average of 73.34um for controls and
31.1um for the treatment group) at 95% confidence interval. The inflammatory cell count
also differed significantly between control and treatment groups (average 293.85 and 29.65
inflammatory cells per high-power field in 10 random microscopic fields, respectively), p-value
of 1.05E-17 on paired T-test; CI 95%. In phase II of the study, SNOT-22 results showed significant
differences in improvement of symptoms in ultrasound-treated patients after Endoscopic
Sinus Surgery (weekly mean scores of 38.05, 21, 11.3, and 10.45) and in modified Lund Mackay
endoscopic appearance scores (weekly mean scores of 7.88, 4.35, 3.02, 2.08). Two-way analysis
of variance showed significant differences between control and treatment groups for both
Philipp J Otolaryngol Head Neck Surg 2017; 32 (1): 6-13 c Philippine Society of Otolaryngology – Head and Neck Surgery, Inc.

Philippine Journal Of Otolaryngology-Head And Neck Surgery
SNOT-22 (p = 1.07E-80; 9.71E-119; CI 95%) and modified Lund Mackay
endoscopic appearance scores (p = 3.89E-60; 1.85E-95; CI 95%).
Conclusion: Low frequency therapeutic ultrasound demonstrated
possible efficacy as an agent in disrupting epithelial architecture
in patients with CRS-NP as well as in symptom improvement after
endoscopic sinus surgery patients based on histopathologic evaluation,
SNOT-22 and modified Lund MacKay endoscopic appearance scores.
Low frequency ultrasound may be an adjuvant to conventional medical
treatment in CRS-NP.
Keywords: Biofilm, Sinusitis, Nasal Polyps, Chronic disease, Ultrasonic
therapy
Chronic Rhinosinusitis (CRS) is an inflammation of the nasal
cavity and paranasal sinuses that has been present for at least
12 weeks characterized by: (1) nasal congestion, obstruction or
blockage with (2) facial pain or pressure, (3) discolored discharge,
or (4) hyposmia or anosmia.1 Nasal polyposis (NP) is a subgroup
of CRS.1 Chronic Rhinosinusitis with Nasal Polyposis (CRS-NP) is
considered an immunological disease affected by immunological
disorders, environmental factors, Staphylococcus superantigens,
fungal infections and the presence of microbial biofilms which lead
to its chronicity and/or recurrences especially in patients with biofilm
formation.2 Biofilms are highly organized communities of bacteria
which produce a protective extracellular matrix against host defense
and antibiotics.3 Hypotheses explaining reduced susceptibility
of biofilms are poor antimicrobial penetration, deployment of
adaptive stress responses, physiological heterogeneity in the biofilm
population, and the presence of phenotypic variants or persister
cells.3 Traditionally, biofilms are detected using electron microscope
and confocal scanning electron microscope.4 However, some studies
showed correlation of histopathological evaluation using gram stain
and hematoxylin-eosin staining in detecting biofilm in the sinonasal
discharge of patients with CRS.5 The presence of a biofilm in H&E-
stained slides was diagnosed on the following criteria (1) irregularly
shaped group­ings of small basophilic material one third of the size
of the sur­rounding epithelial or inflammatory cells; (2) presence of a
biofilm over the epithelial lining, not in or under the epithe­lial lining;
(3) biofilm tightly adherent to the surface epithelium or pulled away
slightly; or (4) a dense extra­cellular polysaccharide substance (EPS)
material with embedded basophillic substance coating the epithelial
surface.5
The current treatment for CRS focuses on the use of steroids and
antimicrobials.6 With the premise of biofilm presence, alternative
therapeutic strategies are being explored to block inter-bacterial
molecular communication, inhibiting biofilm production and
disrupting bacterial biofilms.7 Proposed interventions include the use
Philippine Journal Of Otolaryngology-Head And Neck Surgery 7
ORIGINAL ARTICLES
Vol. 32 No. 1 January – June 2017
of biocides like manuka honey and vitamin D, chelating agents and
biophysical agents such as low frequency therapeutic ultrasound.8
Ultrasound consists of waves (greater than 20,000 cycles per second)
that transmit energy by alternating compressing and rarefying
material to the crystal (piezoelectric properties) in the transducer
of an ultrasound machine.9 Waves produced at therapeutic level
(1-3MHZ) by pulsed ultrasound acts on a cellular and molecular
level which alters membrane permeability and ionic concentration
gradients thus changing cellular biochemical activity.9 Hseieh et al.
demonstrated that pulsed ultrasound decreased the number of nitric
oxide synthase-producing neurons in rats with induced inflammatory
arthritis therefore decreasing pain in inflammatory conditions.10
In CRS, ultrasound may cause a bioaccoustic effect, breaking down
biofilms directly by killing or reducing the viability of bacteria, making
them accessible to antibiotic intervention11 This non-thermal effect of
ultrasound increases blood flow to the area and decreases edematous
swelling resulting in microcavitation and acoustic streaming which
produces vibration and subsequent transmission of ultrasound
energy to the cell membrane, vascular walls and biofilm.9 Young et al.,
reported that use of 1MHz therapeutic ultrasound caused worsening of
symptoms in 10% of participants with CRS with total mean percentage
improvement of overall symptom score of 16.7% (Wilcoxon test) and
34% improvement in 20-item Sino-Nasal Outcome Test.11
This study aimed to determine the role of low frequency ultrasound
in patients with CRS-NP via histopathological analysis (H&E and Gram
staining) and in recovery after ESS using subjective assessment of
the Quality of Life using SNOT-22 questionnaire as well as objective
assessment of the nasal mucosal recovery and endoscopic appearance
via Modified Lund MacKay endoscopic appearance.
METHODS
With ethics committee approval, this single blinded randomized
controlled trial was conducted at a tertiary public training hospital from
June 1, 2013 to June 30, 2015. Written informed consent was obtained
from all participants.
Subjects/ sampling
A sample size of 20 was computed based on the institutional
outpatient department annual CRS census using the formula n= t2 x
p(1-p)/m2 (base sample size calculation) with a type 1 error of 0.05 and
type 2 error of 95% and a prevalence of 1.35% of total OPD consults.
Considered for inclusion were adult patients aged 19 and above who
satisfied the operational definition of Chronic Rhinosinusitis with
Grade 2 or 3 Nasal Polyposis and were recommended to undergo
functional endoscopic sinus surgery based on Philippine Society of
Otolaryngology - Head and Neck Surgery (PSO-HNS) Clinical Practice
Guidelines;1 who had undergone maximal medical management (more
than 3 month course of antibiotics, nasal douche, topical steroids and
 ORIGINAL ARTICLES
Philippine Journal Of Otolaryngology-Head And Neck Surgery
other modalities) with no appreciable improvement; and had evidence
of sinus mucosal disease and nasal polyps demonstrated on sinus CT
imaging and nasal endoscopy. Those who had chronic diseases or
co-morbidities (diabetes, hypertension), were immunocompromised,
pregnant, had sinonasal malignancy, known ciliary disorder, skin
diseases of the face (acne), other facial skin lesions or allergies, and
contraindications for ultrasound (thrombophlebitis, pacemaker,
fracture with titanium implants) were excluded from the study.
Randomization/ Blinding
Participants were randomly divided into 2 groups, ultrasound-
treated and control, using a simple randomization technique. A total
of 21 patients were allocated to each group. Assignment was made
by a research assistant (ORL resident) other than the researchers by
providing written codes designating control or intervention. These
papers were placed in a folded sheet of foil inside the envelope. There
was no detectable difference in size or weight between intervention
and control envelopes. Envelopes used were colored brown and were
opened sequentially only after writing subjects tracking information on
the envelope.
Procedure and data analysis
Histories were obtained and otorhinolaryngological examinations
performed by two ORL residents. All participants had routine laboratory
parameters (chest x-ray, complete blood count, urinalysis, prothrombin
and partial thromboplastin time, fasting blood sugar, blood typing)
checked pre-operatively. All underwent early pre-operative anesthesia
evaluation. Patients more than 34 years old also underwent medical risk
assessment.
The study was divided in 2 phases. The first phase determined the
role of low frequency ultrasound on nasal polyps via histopathological
analysis (Hematoxylin - Eosin and Gram stain). The second phase
determined the effect of ultrasound treatment on recovery among
participants after ESS using SNOT-22 questionnaire and monitoring
mucosal recovery using modified Lund MacKay endoscopic
appearance.
Phase 1
All procedures were performed under inhalational general
endotracheal anesthesia using sevoflorane. Six different surgeons
by rotation performed ESS using the Messerklinger technique with
cutting and grasping forceps without a microdebrider. Different
anesthesiologists administered the same anesthesia protocol for each
patient.
Nasal polyps that were analyzed from both arms measured at least
2 cm x 2 cm or larger and were extracted carefully by Blakesly forceps
at the root or 5mm from the root of the polyp to avoid iatrogenic injury
to the mucosal surface of the specimens. After extraction, specimens
8 Philippine Journal Of Otolaryngology-Head And Neck Surgery
Vol. 32 No. 1 January – June 2017
were immediately placed in a laboratory beaker containing 0.9%
sodium chloride solution. Specimens from the control group were
sent directly to the laboratory for tissue processing and staining while
specimens from the ultrasound group went directly to the physical
therapy department for treatment. All specimens from the treatment
group received ultrasound therapy from the same machine (Metron
Accusonic Plus Ultrasound Therapy unit Model AP 170, Balkowitsch
Enteprises Inc; Chicago IL) using 3.5cm diameter probe within 30
minutes of sampling. Pulsed ultrasound (20%) treatment with 1
MHz frequency and 1 watt/cm2 sound pressure was employed for 5
minutes at 370C in 100 ml total volume of 0.9% (w/v) sodium chloride
solution. A distance of approximately 2cm was maintained between
the ultrasound probe and the specimen. A digital thermometer
was applied to register any temperature changes during treatment.
Specimens were also sent to the laboratory after treatment. All
specimens were fixed in 10% (w/v) formaldehyde one hour after
sampling. Specimens were processed for conventional staining with
Hematoxylin and Eosin and Gram staining according to institutional
standard operating procedures.
The criteria for the histopathological detection of microbial biofilms
were the presence of characteristic morphology: (1) irregularly shaped
group­ings of small basophilic material one third of the size of the sur­
rounding epithelial or inflammatory cells; (2) presence of a biofilm over
the epithelial lining, not in or under the epithe­lial lining; (3) biofilm
tightly adherent to the surface epithelium or pulled away slightly; or
(4) a dense extra­cellular polysaccharide substance (EPS) material with
embedded basophillic substance coating the epithelial surface.5 Due
to technical difficulties and in absence of electron microscope for
standard comparison, only the epithelial thickness (structural) and
number of inflammatory cells per 10 HPF (epithelial and subepithelial
cellular infiltration) were studied to correlate the effect of ultrasound on
the architectural integrity of nasal polyps between the two groups.
The histopathological characteristics of biofilms and epithelial
and subepithelial layers in control group specimens were compared
to ultrasound-treated nasal polyps. The number of inflammatory cells
per high power field in 10 random microscopic fields were counted
and recorded. Histological examinations were performed by blinded
pathologists; two residents in training supervised by a board-certified
consultant.
Data analysis for phase 1
Collated results were tabulated. Data were entered on Microsoft
Excel spreadsheets (Microsoft Office 2013, Microsoft Corporation, WA,
USA) and analyzed per criterion. Statistical analysis utilized Student T
test to compare control and treatment groups with 95% confidence
interval and level of significance set at p<0.05 and 2-way ANOVA to
analyze effects of time and treatment.

Philippine Journal Of Otolaryngology-Head And Neck Surgery
Phase II the study because of a final histopathology result of inverted papilloma
Patients’ symptoms were graded initially according to the 22-item
Outcome Test (SNOT-22).
We used the modified Lund-MacKay score of endoscopic
appearance to assess the following endoscopic parameters: polypoid
appearance, edema, presence of granulation, presence of discharge,
adhesion, and crusting. Each parameter was graded 0 (absent), 1 (mild),
2 (moderate) or 3 (severe), according to endoscopic appearance16 each
side could have a minimum score of 0 and a maximum score of 18. Nasal
endoscopy was performed by two ORL residents with the guidance of a
board-certified ORL Consultant using 0 degree and 30 degree Hopkins
endoscopes (Karl Storz GmbH &Co., Germany). Evaluators were blinded
regarding group assignment of the participants.
The ultrasound-treated group received the same ultrasound
treatment used in phase 1 for a total of 6 treatments, 2 sessions
per week, 3 and 4 days apart, for 3 weeks, beginning 1 week post
operatively. In sitting position, water-based ultrasound gel (Biocare
Medical System Inc, Makati Philippines) was applied over the skin
overlying the maxillary sinuses and frontal sinus, and the area of the
nasal dorsum in a circular pattern and a 1-MHz pulsed low-intensity
ultrasound probe (Metron Accusonic Plus Ultrasound Therapy unit
Model AP 170, Balkowitsch Enteprises Inc; Chicago IL) was applied
systematically, moving in circular patterns over the areas mentioned
above within a period of 5 minutes. The control group also underwent
ultrasound treatment with the following parameters (0 Hz, 0 W/cm-2,
20% pulsed mode, for 5 minutes). They were all asked to accomplish
Sino-Nasal Outcome Test (SNOT-22) questionnaires once a week for 4
weeks during pre treatment (week 0 of treatment/1 week post op), and
weeks 1, 2 and 3 of treatment (weeks 2, 3 and 4 post-op). All participants
also started using sodium chloride nasal spray (2 sprays per nostril
thrice daily) and topical steroids (Fluticasone propionate 50mcg nasal
spray, UNILAB, Philippines) 2 sprays per nostril once a day 1week post
operatively. All participants were compliant with the medications and
follow up sessions.
Data analysis for phase II
Collated results were tabulated and data was entered on Microsoft
Excel (Microsoft Office 2013, Microsoft Corporation, Washington)
spreadsheets. Data was described in terms of means and percentage.
Statistical Analysis used Student T test to compare control and
ultrasound treated groups with level of significance set at p<0.05
(confidence interval of 95%) and a 2-way ANOVA to analyze effects of
time and treatment.
RESULTS
A total of 42 patients consisting of 19 males and 23 females (mean
age = 42.8 years; range 19-72 years) were recruited and consented.
Forty-one (41) participants with CRS-NP completed this study. One
subject from the treatment group was withdrawn during phase 1 of
Philippine Journal Of Otolaryngology-Head And Neck Surgery 9
ORIGINAL ARTICLES
Vol. 32 No. 1 January – June 2017
(withdrawal rate of 2.38%). There were no dropouts. Thirty-one (76%)
had grade II Nasal Polyps and 10 (24%) had grade III nasal polyps. Eight
patients (20%) had previous Endoscopic Sinus Surgery with one of
them having had 2 prior surgeries. All patients were treated with topical
fluticasone propionate 50 mcg nasal spray 2 sprays both nostrils bid
prior to surgery. Mean average use of intranasal topical steroids was 6.2
months with range from 4 to 10 months.
Phase 1
All histopathology results from this study showed inflammatory
polyps with infiltration of eosinophils, neutrophils and granulocytes
except for one specimen in the treatment group that showed inverted
papilloma. In the control group, 18 specimens (86%) showed average
epithelial thickness (surface epithelium + biofilm thickness) of 73.34um
(range 33 um to 115.2um). (Figure 1) Of these 18 specimens, two (9.5%)
showed areas with stratified squamous epithelium metaplasia while
three (14%) out of total number of specimens in control showed normal
architecture. The treatment group specimens showed an average
epithelial thickness (surface epithelium + biofilm thickness) of 31.18um
with range from 19.3um to 45.2um. (Figure 2) The paired T-test revealed
a statistically significant difference between control and treatment
groups (p = 2.29E-10; CI 95%). (Figure 3)
Of an average of 10 high power objective magnification microscopic
fields, the control group showed 293.86 inflammatory cells (range
174 to 480), mostly neutrophils, granulocytes and eosinophils. The
ultrasound treated group had 29.65 inflammatory cells (7 to 48) per
10 HPO magnification fields. The paired T-test showed a statistically
significant difference between control and treatment groups (p =
1.05E-17; CI 95%). (Figure 4)
Phase 2
SNOT-22 mean score control group results for weeks 0 (1week
post op), 1, 2, and 3 were 38.29 (SD 1.62); 37.48 (SD 1.36); 28.1 (SD
1.73) and 16.57 (SD 1.78) respectively. Paired T-test scores showed no
statistically significant difference between week 0 and week 1 scores
in the control group. However, there was a statistically significant
difference in symptom regression for weeks 2 and 3 in the control
group. (Table 1)
SNOT-22 mean scores for the ultrasound treated group were 38.05
(SD 1.96), 21 (SD 1.49), 11.3 (SD 1.59), and 10.45 (1.19) for week 0 to
week 3, respectively. There was greatest decrease in mean scores
between week 0 and week 1 (from 38.05 to 21). The paired T-test
revealed a statistically significant difference in means of the treated
group per week especially at week 1 and week 2 of treatment. (Table 1)
Comparing SNOT-22 results between two groups showed the
greatest difference occurred after week 1 and week 2 of treatment.
The Student T-test revealed a statistically significant difference
 ORIGINAL ARTICLES
Philippine Journal Of Otolaryngology-Head And Neck Surgery Vol. 32 No. 1 January – June 2017

Hematoxylin-Eosin Low Power View (100x) Hematoxylin-Eosin Low Power View (100x)

A A

Hematoxylin-Eosin High Power View (400x) Hematoxylin-Eosin High Power View (400x)

B B

Hematoxylin-Eosin High Power View (400x) Hematoxylin-Eosin High Power View (400x)

C C
Figure 1. Photomicrographs, histopathological (H&E) examination of Figure 2. Photomicrographs, histopathological (H&E) examinations of
nasal polyps from control group showing columnar epithelium (with nasal polyps from treatment group showing columnar epithelium (with
measurement) overlaid by biofilm layer (black arrow). A. Low power view measurement) without/disrupted biofilm layer (black arrow). A. Low power
(100x). B & C. High power view (400x) showing biofilm and submucosal view (100x). B. High power view (400x) C. High power
lymphoplastic infiltrates (yellow arrow)

10 Philippine Journal Of Otolaryngology-Head And Neck Surgery


Philippine Journal Of Otolaryngology-Head And Neck Surgery
Figure 3. Comparison of epithelial thickness of nasal polyps (surface epithelium + biofilm matrix)
Figure 4. Comparison of average number of inflammatory cells per high power field in 10 random
sites
Figure 5. Comparison of SNOT-22 mean scores between control and ultrasound treated groups
Figure 6. Comparison of modified Lund MacKay endoscopic appearance scores between control and
ultrasound treated groups
Philippine Journal Of Otolaryngology-Head And Neck Surgery 11
ORIGINAL ARTICLES
Vol. 32 No. 1 January – June 2017
(p = 2.052E-32; 9.26E-30; CI 95%) between the two groups. This
suggests that improvement from ESS in the ultrasound treated
group was much better and faster compared to the control group.
(Figure 5) This result was further strengthened by two-way analysis
of variance that showed significant differences between the two
groups with respect to treatment and time (p = 1.07E-80; 9.71E-
119). (Table 2)
Modified Lund-MacKay Endoscopic Assessment mean scores for the
control group in weeks 0 to week 3 were 8 (SD 0.61), 7.78 (SD 0.54),
5.02 (SD 0.37), and 4.36 (SD 0.32), respectively. For the ultrasound
treated group, mean results were 7.86 (SD 0.58), 4.35 (SD 0.46), 3.02
(SD 0.30), and 2.08 (SD 0.29), respectively. Analyzing results from the
control group with respect to time, student T-test showed statistically
significant changes only at week 2 (p = 6.04E-22; CI 95%) and week 3
(p = 6.04E-22; CI 95%), while results from the ultrasound treated group
showed statistically significant differences starting from week 1 to
week 3 scores (p = 1.14E-22, 4.57E-13, 2.73E-12). (Table 3) Comparing
both groups, student T-test showed a statistically significant difference
in week 1 to week 3 with the greatest difference between week 1 and
week 2 of treatment (p = 1.62E-23). (Figure 6) Two-way ANOVA showed
also significant difference between the two groups with respect to
treatment and time (p = 3.89E-60; 1.85E-95). (Table 4)
DISCUSSION
Generally, therapeutic ultrasound is defined as frequency between
0.7-3.3 MHz with maximum energy absorption at a depth of 2 to 5
cm of soft tissue.8 In addition, attenuation of ultrasound through
skin is approximately 2.7cm.9 This study used 1 MHz which is within
therapeutic range and 2 cm distance of the transducer from the
polyp to mimic the approximate distance from the skin to the nasal
cavity and sinuses. All these are in conformity with the therapeutic
parameters proposed by Cameron.8
As ultrasound needs a medium through which sound waves will
freely pass to reach the tissue, we used NaCl as a coupling medium in
phase 1 and ultrasound gel in phase 2. They are ideal coupling media
that fill all available spaces and are viscous enough to allow energy
transmission with minimal absorption, attenuation, or disturbance.9
Phase 1 of the study centered on biofilm detection. The gold
standard for biofilm detection is still electron microscopy but several
studies demonstrated good correlation of Hematoxylin and Eosin
staining in detection of biofilm in CRS.5 Watelet et al. stated that
basement membrane thickening, a sign of chronic inflammation
and airway remodeling and seromucinous gland abundance were
displayed mostly in nasal polyps.12 Though the enumerated criteria
for histopathological correlation of biofilm detection were not all met,
results from this study may suggest a possible role of low-frequency
ultrasound on the epithelial thickness and number of inflammatory
cells between control and treatment groups. The difference in epithelial
thickness may be attributed to conversion of the absorbed ultrasound
 ORIGINAL ARTICLES
Philippine Journal Of Otolaryngology-Head And Neck Surgery Vol. 32 No. 1 January – June 2017

Table 1. Comparison of SNOT-22 total mean scores between control and ultrasound treated groups

Week 0 Week 1 Week 2 Week3

control ultrasound control ultrasound control ultrasound control ultrasound

Total 804 761 787 420 590 226 348 209
Mean 38.26 38.05 37.47 21 28.06 11.3 16.57 10.45
Standard deviation 1.62 1.96 1.36 1.41 1.73 1.59 1.78 1.19
p-value 0.09 7 .24E-29 4.76E-22 4.80E-22 2.62E-23 0.06

Table 2. Analysis of Variance (2-way ANOVA) of weekly (4 weeks) SNOT-22 Scores between Table 4. Analysis of Variance (2-way ANOVA) of Weekly (4 weeks) Lund MacKay endoscopic
control and ultrasound treated groups appearance scores between control and ultrasound treated groups

Source of SS df MS F P-value F crit Source of SS df MS F P-value F crit

Variation Variation

Sample 3890.756 1 3890.756 1502.719 1.07E-80 3.903366 Sample 153.0766 1 153.0766 736.0265 3.89E-60 3.903366
Columns 14087.87 3 4695.956 1813.709 9.7E-119 2.664107 Columns 542.8797 3 180.9599 870.0958 1.85E-95 2.664107
Interaction 1998.069 3 666.0229 257.2366 2.49E-59 2.664107 Interaction 56.86719 3 18.95573 91.1434 8.51E-34 2.664107
Within 393.55 152 2.589145 Within 31.6125 152 0.207977

Total 20370.24 159 Total 784.4359 159

Table 3. Comparison of modified Lund MacKay endoscopic appearance scores between control and ultrasound treated groups

Week 0 Week 1 Week 2 Week3

control ultrasound control ultrasound control ultrasound control ultrasound

Total 168 157.5 163.5 87 105.5 60.5 91.5 41.5
Mean 8 7.875 7.78 4.35 5.02 3.025 4.36 2.075
Standard deviation 0.61 0.58 0.54 0.46 0.37 0.30 0.32 0.29
p-value 0.24 1.14E-22 6.04E-22 1.14E-22 2.25E-07 2.73E-12

energy to mechanical energy that led to destruction of the outermost
layer of epithelium. This can be observed from the photomicrograph
examination (Figure 1) of nasal polyps from control group showing
columnar epithelium overlaid by an outer layer made of dense extra­
cellular polysaccharide substance (EPS) material compared to the
sample from the treatment group showing no EPS layer on top of the
columnar epithelium. (Figure 2) The mechanical disturbance caused
by alternating rarefraction and compression of ultrasound may have
affected diffusion rates and membrane permeability of sodium and
calcium ions resulting in changes in the cell membrane potential and
altered protein synthesis leading to biofilm instability and subsequent
damage.9 This effect of ultrasound may also account for the decreased
inflammatory cell count in the stromal and submucosal layer in the
ultrasound treated group (Figure 2) compared with the control group
showing predominance of lymphoplastic infiltrates in the submucosal
layer. (Figure 1) Others explained this phenomenon secondary to
increasing hydrophobic molecular transport through cell membrane,
bacterial cell wall damage and loss of calcium in biofilm matrix causing
instability and subsequent damages.13 This is consistent with results in
an experimental study by Karosi et al.14 in which the ultrasound treated
group showed disruption of biofilm layer with significant decrease in
inflammatory cell count in the epithelial and stromal layer. Ensing et
al.15 demonstrated reduction of planktonic and biofilm viability of
E.coli, P. aeruginosa, S. aereus and coagulase negative staphylococci after
gentamycin treatment following prolonged ultrasound treatment.
Phase II results of the study showed faster recovery of patients in the

12 Philippine Journal Of Otolaryngology-Head And Neck Surgery


Philippine Journal Of Otolaryngology-Head And Neck Surgery
treatment group after ESS as shown on SNOT-22 mean weekly reports,
supported by objective assessment via modified Lund MacKay mean
results. Though not established in this study, these results may also
be related to the mechanical effect of pulsed ultrasound in reducing
inflammation, loosening stagnant secretions and possibly facilitating
sinus drainage.16 Naghdi et al. studied 30 CRS adults who underwent
10 sessions of continuous therapeutic ultrasound, with percentage
improvements of 74% and 72% at the end of the treatment and
one month after treatment.17 Ansari et al. used low intensity pulsed
ultrasound in a case series of 57 CRS patients that showed significant
changes of most major and minor symptoms of CRS after ultrasound
therapy.18
With respect to wound healing, faster recovery of patients
under the ultrasound group with marked decreased of granulation,
edema, crusting compared to the control group as early as week 1 of
treatment suggest a possible role of ultrasound as an inflammatory
optimizer. A study by Harvey et al. demonstrated that low dose pulsed
ultrasound increases protein synthesis and enhanced fibroplasia and
collagen synthesis in human fibroblasts.19 Rocha et al. reported that
1MHz low intensity ultrasound at 1W/cm2 for 4 minutes over maxillary
sinus and nasal septum not only reduced nasal block and congestion
by 64% but also resulted in regression in major symptoms of CRS.20
One unexpected finding in this study was squamous metaplasia
in two specimens in the control group. A study by Baird et al.21 of
20 patients with nasal polyps found that 50% showed squamous
metaplasia. They attributed this finding to chronicity of the disease. This
was corroborated by the study of Shulbha et al.22 which showed 16% of
91 patients with nasal polyposis had squamous metaplasia, suggesting
it is more common than previously thought.
One weakness of this study is that Hematoxylin and Eosin findings
of biofilm presence were not confirmed by standard methods. Also,
a double blinding would have been more appropriate in minimizing
evaluator bias. The clinical portion of this study was limited by its small
sample size and short duration of follow up. Future clinical trials may
investigate intranasal application of ultrasound as part of medical
management of CRS with grade 1 polyps to further establish the
effect of low intensity therapeutic ultrasound on nasal polyps cellular
architecture and on inflammation and recovery after ESS. In time,
it may prove to be a valuable adjuvant treatment to conventional
medical therapy for Chronic Rhinosinusitis with Nasal Polyposis and be
recommended to improve recovery after Endoscopic Sinus Surgery.
There was no adverse effect to the use of therapeutic low
frequency ultrasound reported in this study. Comparing the
recovery between the two groups, the ultrasound group showed
early and marked improvement in CRS symptoms and improved
endoscopic appearance after Endoscopic Sinus Surgery. The anti-
inflammatory and antimicrobial effects of low frequency ultrasound
are well documented in vitro, but its in vivo effects need further
Philippine Journal Of Otolaryngology-Head And Neck Surgery 13
ORIGINAL ARTICLES
Vol. 32 No. 1 January – June 2017
investigation. Our results suggest the possible use of low frequency
therapeutic ultrasound in disrupting epithelial barriers or extra­
cellular polysaccharide substance (EPS of biofilm) in patients with
CRS with Nasal Polyposis as well as in recovery after Endoscopic Sinus
Surgery based on SNOT-22 and modified Lund MacKay endoscopic
appearance scores.
REFERENCES
1. Antonio T, Hernandez J, Lim M, Mangahas L, Quiambao R, Tan GP, et al. Diagnosis and
Management of Chronic Rhinosinusitis in Adults. In Jose EM, Caro RM, Acuin JM (editors).
PSO-HNS Clinical Practice Guidelines on Otitis Media, Rhinitis, Sinusitis, Tonsilitis, Obstructive
Adenoidal Hypertrophy. Quezon City; PSO-HNS, Inc. 1997. Pp. 11-20.
2. Bachert C, Pawankar R, Zhang L, Bunnag C, Fokkens W, Hamilos D, et al. ICON: chronic
rhinosinusitis. World Allergy Organ J. 2014 Oct 27; 7(1):25. [cited 2014 Nov]. Available from:
http://www.waojournal.org/content/7/1/25. DOI: 10.1186/1939-4551-7-25; PMID: 25379119
PMCID: PMC4213581.
3. Chambless JD, Hunt SM, Stewart PS. A Three-dimensional Computer Model of Four Hypothetical
Mechanisms Protecting Biofilms from Antimicrobials. Appl Environ Microbiol. 2006 Mar; 72
(3):2005-2013. DOI: 10.1128/AEM.72.3.2005-2013.2006; PMCID: PMC1393201.
4. Fellers TJ, Davidson MW. Introduction to Confocal Microscopy. Olympus Fluoview Resource
Center. National High Magnetic Field Laboratory. [Internet] Florida; c2004-2009. [Retrieved
2007 Jul 25]. Available from: http://fluoview.magnet.fsu.edu/theory/confocalintro.html.
5. Hong SD, Dhong HJ, Chung SK, Kim HY, Park J, Ha SY. Hematoxylin and eosin staining for
detecting biofilms: practical and cost-effective methods for predicting worse outcomes after
endoscopic sinus surgery. Clin Exp Otorhinolaryngol. 2014 Sep; 7(3): 193-197. DOI: 10.3342/
ceo.2014.7.3.193; PMID: 25177435 PMCID: PMC4135155.
6. Naghdi S, Ansari N, Farhadi M. A clinical trial on the treatment of chronic rhinosinusitis with
continuous ultrasound. J Phys Ther Sci. 2008; 20(4):233–238.
7. Al-Haddad M, Al-Jumaily A, Brooks J, Bartley J. Biophysical Effects on Chronic Rhinosinusitis
Bacterial Biofilms. In: Mahboub BH (editor). Respiratory Disease and Infection - A New Insight.
2013. Atlanta Georgia: Intech. p.79-97. DOI: 10.5772/53860.
8. Cameron MH. Physical Agents in Rehabilitation (from research to practice). 4th ed. St Louis:
Saunders; 2013.
9. Watson T. Ultrasound in contemporary physiotherapy practice. Ultrasonics. 2008 Aug; 48(4):
321-329. DOI: 10.1016/j.ultras.2008.02.004; PMID: 18466945.
10. Hsieh YL. Reduction in induced pain by ultrasound may be caused by altered expression of
spinal neuronal nitric oxide synthase producing neurons. Arch Phys Med Rehabil. 2005 Jul;
86(7):1311-1317. PMID: 16003656.
11. Young D, Morton R, Bartley J. Therapeutic ultrasound as treatment for chronic rhinosinusitis:
preliminary observations. J Laryngol Otol. 2010 May; 124(5):495–9. DOI: 10.1017/
S0022215109992519; PMID: 20053307.
12. Watelet JB, Bachert C, Claeys C, Van Cauwenberge P. Matrix metalloproteinases MMP-7, MMP-9
and their tissue inhibitor TIMP-1: expression in chronic sinusitis vs nasal polyposis. Allergy. 2004
Jan; 59(1): 54-60. PMID: 14674934.
13. Mortimer AJ, Dyson M. The effect of therapeutic ultrasound on calcium uptake in fibroblast.
Ultrasound Med Biol. 1988; 14(6):449-506. PMID: 3227573.
14. Karosi T, Sziklai I, Csomor P. Low frequency ultrasound for biofilm disruption in chronic
rhinosinusitis with nasal polyposis: in vitro pilot study. Laryngoscope. 2013 Jan; 123(1): 17-23.
DOI: 10.1002/lary.23633; PMID: 22893599.
15. Ensing GT, Neut D, van Horn JR, van der Mei HC, Busscher HJ. The combination of ultrasound
with antibiotics released from bone cement decreases the viability of planktonic and biofilm
bacteria: an in vitro study with clinical strains. J Antimicrob Chemother. 2006 Dec; 58(6): 1287–
90. DOI: 10.1093/jac/dkl402; PMID: 17041238.
16. Ansari NN, Fathali M, Naghdi S, Hasson S, Jalaie S, Rastak MS. A randomized, double-
blind clinical trial comparing the effects of continuous and pulsed ultrasound in
patients with chronic rhinosinusitis. Physiother Theory Pract. 2012 Feb; 28(2):85–94. DOI:
10.3109/09593985.2011.571751; PMID: 21823980.
17. Naghdi S, Ansari N, Farhadi M. A Clinical Trial on the Treatment of Chronic Rhinosinusitis with
Continuous Ultrasound. J Phys Ther Sci. 2008; 20:233–238.
18. Ansari NN, Naghdi S, Farhadi M, Jalaie S. A preliminary study into the effect of low-intensity
pulsed ultrasound on chronic maxillary and frontal sinusitis. Physiother Theory Pract. 2007 Jul-
Aug; 23(4):211–8. DOI: 10.1080/09593980701209360; PMID: 17687734.
19. Harvey W, Dyson M, Pond JB, Grahame R. The stimulation of protein synthesis in human
fibroblasts by therapeutic ultrasound. Rheumatol Rehabil. 1975 Nov; 14(4): 237. PMID: 1198016
20. Rocha WA, Rodrigues KM, Pereira RR, Nogueira BV, Goncalves WL. Acute effects of therapeutic.
1-mhz ultrasound on nasal unblocking of subjects with chronic rhinosinusitis. Braz J Otolaryngol.
2011 Jan-Feb; 77(1): 7-12. PMID: 21340182.
21. Baird AR, Hilmi O, White PS, Robertson AJ. Epithelial atypia and squamous metaplasia in nasal
polyps. J Laryngol Otol. 1998 Aug; 112(8): 755-7. PMID: 9850317.
22. Shulbha VS, Dayananda BS. Clinicopathological study of nasal polyps with special references
to the mast cells in inflammatory polyps. Basic Appl Pathol. 2012 Sep; 5(3): 59-62. DOI: 10.1111/
j.1755-9294.2012. 01136.
 ORIGINAL ARTICLES
Philippine Journal Of Otolaryngology-Head And Neck Surgery Vol. 32 No. 1 January – June 2017

Rajarshi Sannigrahi, MBBS1

Debangshu Ghosh, MBBS, MS (ENT)1 Traumatic Perforation of the Tympanic Membrane:
Etiologies and Risk Factors
Jayanta Saha, MBBS, MS (ENT)2
Sumit Kumar Basu, MBBS, MS(ENT)1

1
Department of Ear, Nose, Throat
for Healing and Intervention
R.G. Kar Medical College
Kolkata, West Bengal, India

2
Department of Ear, Nose, Throat
Burdwan Medical College
Burdwan, West Bengal, India
ABSTRACT
Objective: To study various etiologies of traumatic tympanic membrane perforation; evaluate
the factors involved in healing of traumatic tympanic membrane perforation; and identify
patients with perforations unlikely to benefit from conservative management.

Methods:
Design: Prospective observational study
Setting: Tertiary Government Medical College and Hospital
Participants: 64 consecutive cases of traumatic tympanic membrane perforation
seen over one year were followed for 3 months. Perforations were assessed in terms of size,
etiology, condition of edge and other associated factors or combinations of factors with regards
to spontaneous healing using descriptive statistics and chi-square tests.

Results: Of the 64 cases, 51 perforations healed while 13 did not. There were significant
associations between tympanic membrane condition after 3 months and explosive mode
of injury (χ2 = 23.30; p=.00001) as well as with size of perforation ((χ2 = 25.75; p=.00001). The
Correspondence: Dr. Debangshu Ghosh risk of persistence of a tympanic membrane perforation was 34.57 times more among patients
Kalyan Nagar (Near K.G. School)
P.O.-Kalyan Nagar, Via-Panshila with a perforation size >50% compared to those with perforation size ≤50% [OR-34.57 (6.28,
Dist.-24 Parganas (North)
Kolkata-700112, West Bengal, India 190.14); p= .00001]. Combined, explosive etiology and perforation size >50% were significantly
Phone: +91 903 833 6301 / +91 943 303 8925 associated with non-healing ((χ2 = 37.60; p = .00001). There were no significant associations with
Email: ghoshdr.d777@ymail.com
the condition of the edge of the perforation and upper respiratory tract infection.
The authors declared that this represents original material that
is not being considered for publication or has not yet been
published or accepted for publication elsewhere, in full or in Conclusions: An explosive etiology and tympanic membrane perforation size >50% may be
part, in print or electronic media; that the manuscript has been
read and approved by all the authors, that the requirements significant risk factors predicting non-healing of the perforation. Risk stratification of patients
for authorship have been met by each author, and that each
author believes that the manuscript represents honest work. having one or both of these risk factors with early intervention for those with both, and close
monitoring for those with any one of these may lessen unnecessary morbidity. Bigger multicenter
The authors signed disclosures that there are no financial or
other (including personal) relationships, intellectual passion, future studies are necessary to confirm these initial findings.
political or religious beliefs, and institutional affiliations that
might lead to conflict of interest.
Keywords: tympanic membrane perforation, tympanic membrane, risk factors, wound healing, early
intervention
Creative Commons (CC BY-NC-ND 4.0)
Traumatic perforation of the tympanic membrane is a commonly-encountered problem
Philipp J Otolaryngol Head Neck Surg 2017; 32 (1): 17-22 c Philippine Society of Otolaryngology – Head and Neck Surgery, Inc.
Attribution - NonCommercial - NoDerivatives 4.0 International

Philippine Journal Of Otolaryngology-Head And Neck Surgery 17

 ORIGINAL ARTICLES
Philippine Journal Of Otolaryngology-Head And Neck Surgery Vol. 32 No. 1 January – June 2017

in our day-to-day Ear, Nose and Throat (ENT) practice. Traumatic

perforation can result from blunt or penetrating injuries. Blasts, slaps,
rapid airplane descent or deep-water diving can create a column of
compressed air within the external auditory canal that can implode the
tympanic membrane. Penetrating injuries are mostly self-inflicted but
may also be due to procedures like removal of wax or foreign bodies.
In most studies, spontaneous healing of the tympanic membrane
happens in about 80% of cases within 3 months of injury.1 Thus,
masterly inactivity is the standard mode of treatment for the first 3 A B
months. But in doing so, patients are unnecessarily exposed to disabling Figure 1. Representative photographs. A. At presentation, showing a <50% dry, antero-inferior
central perforation and B. Unhealed after 3 months follow up.
symptoms (decreased hearing, discharge from ears) and the need to
modify lifestyles for those 3 months. If we can identify the causes of
failure of spontaneous tympanic membrane healing after traumatic
perforation, we may be able to recommend early intervention and
reduce morbidity.
This paper aims to study various etiologies of traumatic tympanic
membrane perforation; evaluate the factors involved in healing of
traumatic tympanic membrane perforation; and identify the patients
who are unlikely to benefit from conservative management so that
early surgical intervention may be recommended.

METHODS
With institutional review board approval, this prospective
observational study was conducted in the department of ENT of
our tertiary medical teaching institution in Kolkata from January to
December 2015. The inclusion criterion was a traumatic perforation of
the tympanic membrane irrespective of time of presentation. Patients Figure 2. Percentage of patients with perforation size (as percentage ≤50% or >50% of total TM
surface area) versus healing of tympanic membrane.
with history of previous ear discharge or impaired hearing, ear surgery
or chronic otitis media in the same ear and patients who were lost to
follow up were excluded. A total of 64 patients were enrolled in the
study.
After obtaining a history in terms of perforation etiology and duration
from occurrence to patient presentation, all patients underwent ENT
and general examinations. These included otoscopy, serial tuning fork
tests (256, 512 and 1024 Hz) followed by pure tone audiometry (PTA)
and impedance audiometry and examination under microscope (EUM)
in the operating theatre. The size, site and margin of the perforation
were documented by taking photographs. (Figure 1) All the patients
were advised to keep their ear dry and follow up regularly every two
weeks. All the patients were followed up serially up to three months.
The perforation sizes were compared with the tympanic membrane
using ImageJ v.1.47 (open source software, public domain). Statistical
analysis included descriptive statistics and chi-square test using Epi
Info™ 3.5.3 (Centers for Diseases Control and Prevention, CDC, Atlanta,
Figure 3. Percentages of patients and etiologies of perforation(explosive or non-explosive) versus
GA, USA). condition of tympanic membrane(healed or perforated) after three months.

18 Philippine Journal Of Otolaryngology-Head And Neck Surgery

 ORIGINAL ARTICLES
Philippine Journal Of Otolaryngology-Head And Neck Surgery Vol. 32 No. 1 January – June 2017

membrane was 34.57 times more among patients with a perforation

Figure 4. Bar graph showing distribution of persistently perforated and healed perforations based on
combined factors (size of perforation ≤50% or >50% and explosive and non-explosive etiology).
size >50% compared to patients with perforation size ≤50% [OR-34.57
(6.28, 190.14); p = .00001]. (Figure 3) Most of the traumatic injuries
were due to either explosive or non-explosive causes and none
were iatrogenic or penetrating. In addition, majority (61.5%) of the
persistent perforations after 3 months were from explosive followed
by non-explosive (38.5%) injuries. (Figure 4) The most common
explosive injuries were from bomb blasts, and the most common
non-explosive injuries were from a slap over the ear arising out of
domestic violence. Chi-square test showed a significant association
between mode of injury and tympanic membrane condition after
three months (χ2 = 23.30; p = .00001). (Table 3)
There was no significant association between appearance of the
perforation edges and healing of tympanic membrane perforation
after 3 months (χ2 = 1.48; p = .47). The healed and perforated cases
were more or less equally distributed for all types of perforation edges.
(Table 4)
There was no significant association between upper respiratory
tract infections (URTI) and tympanic membrane healing after 3 months
(χ2 = 1.83; p = .17). While 7.4% of cases with clinical evidence of URTI
did not heal within 3 months, 29.7% of cases with no clinical evidence
of URTI also did not heal within 3 months. (Table 5)
Combinations of factors were also analyzed and explosive
etiology and perforation size >50% were significantly associated with
non-healing (χ2 = 37.60; p = .00001). (Table 6) Most of the persistent
perforations after 3 months (53.8%) were those with perforations of
>50% and explosive in etiology while 36.4% had perforations of >50%

Figure 5. Sample measurement of area of perforation using Image J software, where surface area of Table 1. Age Distribution
perforation, 6609/area of TM, 270503= <50%.
Age Group
(in years) Number (N) Percentage (%)
RESULTS
Sixty four (64) participants, 18 (28%) males and 46 (72%) females
<15 6 9.4%
with a male : female ratio of 1:2.5 completed the study. Their mean age
15-44 53 82.8%
was 27.85±12.05 years while the range was 7 – 67 years and median age
>44 5 7.8%
of 25 years. Most (82.8%) were between 15-44 years of age, significantly
Total 64 100.0%
higher than that of other age groups (Z = 9.27, p = .0001). (Table 1)
Most of the perforations (51, 79.7%) healed within three months.
Table 2. Distribution of condition of tympanic membrane after 3 months
Among the 13 unhealed perforations, 6 developed ear discharge while
the other 7 were dry. (Table 2) According to size, 95.7% of the perforations Tympanic membrane condition after 3 months Number Percentage (%)
≤50% healed within 3 months while 84.6% of the perforations >50% Healed 51 79.7%
remained unhealed at the end of 3 months. (Table 3) Chi-square test Persistent perforation with discharge 6 9.4%
showed that there was a significant association between size of Dry perforation 7 10.9%
perforation and condition of the tympanic membrane after 3 months
Total 64 100.0%
(χ2 = 25.75; p = .00001). The risk of persistence of a perforated tympanic

Philippine Journal Of Otolaryngology-Head And Neck Surgery 19

 ORIGINAL ARTICLES
Philippine Journal Of Otolaryngology-Head And Neck Surgery Vol. 32 No. 1 January – June 2017

Table 3. Table showing healing of traumatic perforation of TM as a product of size and mode Table 4. Table showing healing of traumatic perforation of TM as a product of appearance of
of injury its edge
Condition of TM Statistically Condition of TM Statistically
Factors after 3 months Total x2 - p-value significant Factors after 3 months Total x2 - p-value significant
value (S) or not value (S) or not
Healed Perforated (NS) Healed Perforated (NS)
Size of Edges of
Perforation 25.75 .00001 S Perforation 1.48 .47 NS
≤50% 44 2 46 Ragged 21 3 24
Row% 95.7 4.3 1 00.0 Row% 87.5 12.5 100.0
Col % 86.3 15.4 71.9 Col % 41.2 23.1 37.5
>50% 7 11 18 Everted 14 5 19
Row% 38.9 61.1 100.0 Row% 73.7 26.3 100.0
Col % 13.7 84.6 28.1 Col % 27.5 38.5 29.7
TOTAL 51 13 64 Inverted 16 5 21
Row% 79.7 20.3 100.0 Row% 76.2 23.8 100.0
Col % 100.0 100.0 100.0 Col % 31.4 38.5 32.8
Mode of Total 51 13 64
injury 23.30 .00001 S Row% 79.7 20.3 100.0
Explosive 3 8 11 Col % 100.0 100.0 100.0
Row% 27.3 72.7 100.0
Col % 5.9 61.5 17.2 Table 5. Table showing healing of traumatic perforation of TM due to effect of upper
Non- respiratory tract infection
explosive 37 5 42 Condition of TM Statistically
Row% 88.1 11.9 100.0 Factors after 3 months Total x2 - p-value significant
Col % 72.5 38.5 65.6 value (S) or not
Healed Perforated (NS)
Iatrogenic 6 0 6
Clinical
Row% 100.0 0.0 100.0 evidence 1.83 .17 NS
Col % 11.8 0.0 9.4 of URTI
Penetrating 5 0 5 Yes 25 2 27
Row% 100.0 0.0 100.0 Row% 92.6 7.4 1 00.0
Col % 9.8 0.0 7.8 Col % 49.0 15.4 42.2
Total 51 13 64 No 26 11 37
Row% 79.7 20.3 100.0 Row% 70.3 29.7 100.0
Col % 100.0 100.0 100.0 Col % 51.0 84.6 57.8
TOTAL 51 13 64
and non-explosive etiology. Only 7.7% of persistent perforations after
Row% 79.7 20.3 100.0
3 months had perforations ≤ 50% AND explosive etiology and size of
Col % 100.0 100.0 100.0
perforation ≤ 50% and non-explosive etiology combined. (Figure 5)

DISCUSSION and psychosocial impact at individual as well as national levels most of

Trauma with its manifold manifestations is on an exponential rise in which is difficult to quantify. Trauma to the ear can range from simple
India given the diversity of political, cultural and social interests of its to complex cases like blunt trauma, laceration, or avulsion of part or
millions. This could be in form of assault, road traffic injury, domestic all of the pinna; uncomplicated tympanic membrane perforation;
violence, industrial and sports injuries. This has significant economic dislocation of the ossicles; and longitudinal and transverse fractures of

20 Philippine Journal Of Otolaryngology-Head And Neck Surgery

 ORIGINAL ARTICLES
Philippine Journal Of Otolaryngology-Head And Neck Surgery Vol. 32 No. 1 January – June 2017

Table 6. Composite table showing healing of TM as a product of size of perforation, mode Almost all standard textbooks and previous large scale studies consider
of injuries and combinations of these factors with their correlation coefficient and statistical a ‘wait and watch’ policy of management for traumatic tympanic
significance
membrane perforation.4 However, there is still a subset of patients,
Condition of TM Statistically albeit small, who will not spontaneously heal and tend to suffer
Factors after 3 months Total x2 - p-value significant
increased morbidity for three months. Our study attempts to identify
value (S) or not
Healed Perforated (NS) this subset of patients who may benefit from early intervention based
Presence on certain risk factors, etiology and characteristics of the perforation.
of combi- Our focus was to propose criteria based on a set of parameters for
nation of 37.60 .00001 S identification of these patients.
factors
In our study the high ratio of females (72%) may likely be due
Size of
to increased domestic violence, corroborating the findings of
perforation 0 7 7
>50% other Indian studies.5 After 3 months of masterly inactivity, almost
+Explosive 80% (51) of the perforations healed spontaneously. Among the
Row% 0.0 100.0 1 00.0 13 unhealed cases, 6 developed discharge, a marker of increased
Col % 0.0 53.8 10.9 morbidity. Other studies show similar rates of spontaneous healing.1
Size of In this study, non-healing perforations had a direct and statistically
perforation significant correlation with >50% perforation, suggesting that there
>50% + 7 4 11 a 34.7 times greater chance of persistent perforation after 3 months
Non
Explosive when the perforation size is greater than 50% of the total tympanic
Row% 63.6 36.4 1 00.0 membrane surface area. That larger perforations have less chances to
Col % 13.7 30.8 17.2 heal spontaneously has also been shown by other studies.6
Size of We used ImageJ software on photographs obtained during
perforation examination under microscope to calculate perforation size as a
≤50% 3 1 4 percentage of the size of whole tympanic membrane. (Figure 6)
+ Explosive The reliability of ImageJ software has been validated in a previous
Row% 75.0 25.0 1 00.0 quantitative analysis of tympanic membrane perforations compared
Col % 5.9 7.7 6.3 to blinded data on perforation area obtained independently from
Size of assessments by two trained otologists.7
perforation
In this study the mode of injury was classified as explosive,
≤50% + 41 1 42
Non iatrogenic, non-explosive (blunt trauma) and penetrating in
Explosive accordance with a standard textbook.4 Of the 11 cases due to explosive
Row % 97.6 2.4 100.0 injuries, 8 remained unhealed after three months of observation,
Col % 80.4 7.7 65.6 and this was statistically significant. Previous studies show up to
Total 51 13 64 62% non-healing after traumatic perforation from explosive injuries
Row% 79.7 20.3 100.0 like bomb blasts.8 There was no statistically significant association
Col % 100.0 100.0 100.0 between the condition of perforated margins or URTI and healing of
the tympanic membrane in this study. There have been contradictory
*S-Significant, **NS-Non-significant
results regarding these findings in prior studies. Whereas inverted or
the petrous temporal bone with associated loss of inner ear and facial everted edges compared with no curled edges did not significantly
nerve function.2,3 affect  healing rate9 and edge approximation of inverted edges had
The current study focused on tympanic membrane perforation little benefit in improving the  healing outcome,10 the results of
as a consequence of trauma. While the management of the otologic another study showed a definite correlation of non-healing with
complications of trauma are well validated, tympanic membrane curled edges.11 The relationship with URTI was positively correlated in
perforation has been considered to be mostly a self-healing condition. the study by Griffin et al.6 and accelerated healing has been shown

Philippine Journal Of Otolaryngology-Head And Neck Surgery 21

 ORIGINAL ARTICLES
Philippine Journal Of Otolaryngology-Head And Neck Surgery
following treatment with antibiotics and nasal decongestants,12 but
URTI was found to have no correlation in the study of Lou et al.13
Our study categorized the non-healed cases into four groups
based on combinations of statistically significant risk factors. All
of the seven cases with >50% perforation and explosive causes of
perforation remained unhealed after three months. In the 11 cases
where perforation was >50% but the cause was not explosive, 4 cases
remained unhealed. With perforation <50% and explosive cause, 1 out
of 4 case remained unhealed. Lastly, with perforation <50% and non-
explosive cause, only 1 out of 42 remained unhealed. These results
show a statistical significant association of non-healing when a >50%
perforation size and explosive cause are combined. This may provide
a preliminary basis for stratification of patients into a high-risk group
22 Philippine Journal Of Otolaryngology-Head And Neck Surgery
Vol. 32 No. 1 January – June 2017
having a combination of these factors who might benefit from early
intervention while groups having any one of these risk factors alone
may benefit from close and stringent monitoring. To the best of our
knowledge, there have been no prior studies in English proposing a
similar risk-stratification for patients.
In conclusion, an explosive etiology and tympanic membrane
perforation size >50% may be significant risk factors predicting non-
healing of the perforation. Risk stratification of patients having one or
both of these risk factors with early intervention for those with both
and close monitoring for those with any one of these may lessen
unnecessary morbidity. Bigger multicenter future studies are necessary
to confirm these initial findings.
Acknowledgement
The authors would like to thank the Principal, R.G. Kar Medical College, Kolkata, India for allowing
us to conduct the study.
REFERENCES
1. Kristensen S. Spontaneous healing of traumatic tympanic membrane perforations in man: A
century of experience. J Laryngol Otol. 1992 Dec; 106(12): 1037-50. PMID: 1487657.
2. Ologe FE. Traumatic perforation of tympanic membrane in Ilorin, Nigeria. Nig J Surg. 2002; 8 (1):
9-12.
3. Toner JG, Kerr AG. Ear Trauma. In: Booth JB, Kerr AG, Groves J (editors). Scott-Brown’s
Otolaryngology. London: Butterworth Heinemann; 1997.p. 3/711-3/7/13.
4. Sismanis AA. Tympanoplasty: Tympanic Membrane Repair. In: Gulya AJ, Minor LB, Poe DS
(editors). Glasscock–Shambaugh Surgery of the Ear 6th edition. New York: PMPH-USA; 2010. p
468.
5. Sarojamma, Raj S, Satish HS. A Clinical Study of Traumatic Perforation of Tympanic Membrane.
IOSR-JDMS. 2014 Apr; 13(4): 24-28.
6. Griffin WL Jr. A retrospective study of traumatic tympanic membrane perforations in a clinical
practice. Laryngoscope. 1979 Feb; 89 (2 part 1): 261-282. DOI: 10.1288/00005537-197902000-
00009; PMID: 423665.
7. Ibekwe TS, Adeosun AA, Nwaorgu OG. Quantitative analysis of tympanic membrane
perforation: a simple and reliable method. J Laryngol Otol. 2009 Jan; 123(1): e2.  DOI:10.1017/
S0022215108003800; PMID: 18940030.
8. Miller IS, Mcgahey D, Law K. The otologic consequences of Omagh bomb disaster. Otolaryngol
Head Neck Surg. 2002 Feb; 126(2): 127-8. DOI: 10.1067/mhn.2002.122186; PMID: 11870341.
9. Lou ZC, Tang YM, Yang J. A prospective study evaluating spontaneous healing of aetiology, size
and type‐different groups of traumatic tympanic membrane perforation. Clin Otolaryngol. 2011
Oct; 36(5): 450-460.
10. Lou ZC, Wang YB. Healing outcomes of large (> 50%) traumatic membrane perforations with
inverted edges following no intervention, edge approximation and fibroblast growth factor
application; a sequential allocation, three‐armed trial. Clin Otolaryngol. 2013 Aug; 38(4): 289-
296. DOI: 10.1111/coa.12135; PMID: 23731690 PMCID: PMC4234003.
11. Shetty H, Gangadhar KS. Study of conservative treatment in traumatic perforation of tympanic
membrane and its clinical outcome. IOSR-JDMS. 2015 Aug; 14(8):21-23.
12. Ng L, Monagle K, Monagle P, Newall F, Ignjatovic V. Topical use of antithrombotics: review
of literature. Thromb Res. 2015 Apr; 135(4): 575-581. DOI: 10.1016/j.thromres.2015.01.006;
PMID:25704903.
13. Lou ZC, Lou ZH, Zhang QP. Traumatic tympanic membrane perforations: a study of etiology
and factors affecting outcome. Am J Otolaryngol. 2012 Sep-Oct; 33(5): 549-55. DOI: 10.1016/j.
amjoto.2012.01.010; PMID: 22365389.

Philippine Journal Of Otolaryngology-Head And Neck Surgery
Rozelle O. De Leon, MD
Jay Pee M. Amable, MD
Department of Otorhinolaryngology
Head and Neck Surgery
UERM-Memorial Medical Center, Inc.
Correspondence: Dr. Jay Pee M. Amable
Department of Otorhinolaryngology
Head & Neck Surgery
Rm. 463, Hospital Service Bldg., UERMMMC, Inc.
64 Aurora Blvd., Quezon City 1113
Philippines
Phone: (632) 715 0861 local 257
Fax: (632) 7161789
E-mail: orlhns_uerm@yahoo.com
The authors declared that this represents original material
that is not being considered for publication or has not been
published or accepted for publication elsewhere, in full or in
part, in print or electronic media; that the manuscript has been
read and approved by the authors, that the requirements for
authorship have been met by the authors, and that the authors
believe that the manuscript represent honest work.
Disclosures: The authors signed a disclosure that there are no
financial or other (including personal) relationships, intellectual
passion, political views or beliefs, and institutional affiliations
that might lead to conflict of interest.
Creative Commons (CC BY-NC-ND 4.0)
Attribution - NonCommercial - NoDerivatives 4.0 International
Philippine Journal Of Otolaryngology-Head And Neck Surgery 51
SURGICAL INNOVATIONS AND INSTRUMENTATION
Vol. 32 No. 1 January – June 2017
Optical Myringotomy Knife
ABSTRACT
Objective: To describe an improvised optical myringotomy knife essential in creation of an
incision in a myringotomy simulator.
Methods:
Design: Instrumental Innovation
Setting: Tertiary Private Hospital
Subject: None
Results: The optical myringotomy knife was able to create incisions on mock membranes
made up of polyethylene film (Cling Wrap) in a myringotomy simulator. The incisions measured
approximately 2mm with sharp edges indicating that the myringotomy knife was able to
penetrate the mock membrane with ease. It provided good control in performing myringotomy
incisions under endoscopic visualization of the tympanic membrane.
Conclusion: Our initial experience with this optical myringotomy knife for tympanostomy tube
insertion suggests that it may greatly improve the performance of myringotomy especially
among less experienced surgeons. Further studies may establish its accuracy and replicability in
vitro, after which formal in vivo trials can be attempted.
 Keywords: tympanostomy, middle ear ventilation, endoscopy, instrumentation
Otitis Media with Effusion (OME) is the presence of fluid in the middle ear with no signs of
infection or tympanic membrane perforation.1 OME is a very common disease affecting people
of all ages worldwide though more commonly encountered in children. Myringotomy with or
without tympanostomy tube insertion has become the standard of care for patients with OME
lasting more than three months with associated significant hearing loss and unresponsive to
conservative management.2
Through the years, approaches to myringotomy have evolved, recently involving microscopic,
endoscopic and even laser-assisted procedures.3 With the advent of endoscopes, endoscopic
myringotomy under topical anesthesia has been proven to be safe and practical.4 Endoscopic
myringotomy provides better visualization of the tympanic membrane and some of the middle
ear structures. We describe a simple optical myringotomy knife with accuracy and precision in
placement of myringotomy incisions.
Philipp J Otolaryngol Head Neck Surg 2017; 32 (1): 51-54 c Philippine Society of Otolaryngology – Head and Neck Surgery, Inc.
 SURGICAL INNOVATIONS AND INSTRUMENTATION
Philippine Journal Of Otolaryngology-Head And Neck Surgery
METHODS
A. Endosheath Fabrication
A 3/10cc insulin syringe was used to create the endosheath for a
0 degree 2.7mm x 110mm rigid endoscope. (Figure 1) The attached
needle and flange were removed using a cutter creating a 55mm
hollow tube with inner diameter of 3mm and outer diameter of 6mm
with smooth edges. (Figure 2) Two insulin syringes were utilized in the
construction to form a 110mm endosheath. (Figure 3)
Figure 1. 3/10cc Insulin syringe
Figure 2. Trimmed insulin syringe
Figure 3. Two insulin syringes connected with attached needle at one end
B. Improvised Myringotomy Knife
A gauge 19 needle was flattened to create a 2mm improvised knife
using pliers without violating the sharp edge of the needle. (Figure 4)
The pinpoint sharpness of the needle was maintained to facilitate
Figure 4. Gauge 19 needle
52 Philippine Journal Of Otolaryngology-Head And Neck Surgery
Vol. 32 No. 1 January – June 2017
puncturing of the tympanic membrane. The needle was then attached
to the distal end of the insulin syringe using 100% Ethyl Cyanoacrylate
exposing 5mm of the tip. This ensured that only 5mm of the needle
would penetrate the tympanic membrane and the middle ear cavity.
(Figure 5)
Figure 5. Attachment of needle to insulin syringe
C. Technique
The optical myringotomy knife was fitted into the endoscope with
just enough length to visualize the tip of the needle from the scope. The
needle tip was designed to create a stab incision of 2mm in length with
sharp edges. (Figure 6)
Figure 6. Optical myringotomy knife with endoscope
In a myringotomy simulator measuring 2.5 cm long x 0.7 cm wide to
more or less replicate the average length and diameter of the Filipino
adult ear canal, polyethylene film (Cling Wrap) was used to create the
mock membrane. (Figure 7) The optical myringotomy knife with the
Figure 7. Myringotomy simulator (anterior, lateral and posterior view)
 SURGICAL INNOVATIONS AND INSTRUMENTATION
Philippine Journal Of Otolaryngology-Head And Neck Surgery
endoscope was advanced into the model ear canal using a one-hand
technique. (Figure 8) The endoscope had an advantage of allowing
visualization of the entire tympanic membrane, allowing the surgeon
to determine where to perform the stab incision and to direct the
needle tip to that particular quadrant. Once the quadrant of choice was
identified and visualized, the device could be advanced using the index
and middle fingers without moving the endoscope. As the needle tip
punctured the mock membrane, an incision was created. (Figure 9) The
endoscope also allowed immediate evaluation of incision placement.
Several myringotomy trials using the optical myringotomy knife were
conducted to verify the technique.
Figure 8. Endoscopic view of tympanic membrane with optical myringotomy
knife at the 5 o’clock position (arrowhead)
Figure 9. Endoscopic view of tympanic membrane with incision at the antero-
inferior quadrant (arrowhead)
Philippine Journal Of Otolaryngology-Head And Neck Surgery 53
Vol. 32 No. 1 January – June 2017
DISCUSSION
Myringotomy with or without tympanostomy tube insertion
is one of the most common procedures in Otolaryngology. It is a
relatively rapid procedure which can be performed under local or
general anesthesia. Generally, myringotomy entails at least two
maneuvers to achieve the end result. First, myringotomy is performed
using a myringotome to create a stab incision which is usually at the
antero-inferior (sometimes postero-inferior) quadrant. Afterwards,
insertion of tympanostomy tubes can be done using applicators
or alligator forceps. Commercial devices like the Hummingbird™
TTS (Tympanostomy Tube System) claim to lessen maneuvers and
facilitate myringotomy and tympanostomy tube insertion in one
pass.5 In our setting, a novel low-cost tympanostomy tube with
applicator was conceptualized which also perforated the tympanic
membrane and inserted the tympanostomy tube at the same time.8
With the aid of endoscopy, one is able to perform myringotomy with
better visualization and a closer view of the tympanic membrane.4
The EndoSheath® Technology is a sterile, disposable protective
barrier between the scope and the patient which works like a condom.
This technology also incorporates a channel for suction, irrigation
and tool passage.6 This was the inspiration for the development of
this device. The insulin syringe served as the “EndoSheath” which
snugly fits the endoscope. Optical forceps have been also part of
ENT instrumentation ideal for foreign body removal and biopsy
procedures.9 The telescope joined with the forceps provides a close-
up view and allow control and visualization in biopsy or foreign
body removal. This resulted in the idea for the improvised optical
myringotomy knife wherein a Gauge 19 needle was attached to the
distal end of the syringe. The endoscope and optical myringotomy
knife provided a close-up view of the tympanic membrane and
allowed precise control and accurate placement of the myringotomy
incision. The endoscope provides better resolution and depth
perception in performing myringotomy. It has been reported that
the most frequent human errors during myringotomy are failure to
perform a unidirectional myringotomy incision and multiple attempts
to complete the myringotomy.10 This can be eliminated with the use
of an optical myringotomy knife that provides excellent visualization
of the tympanic membrane and allows creation of a 2mm single stab
incision sufficient for inserting tympanostomy tubes.
The dimensions of the adult external auditory canal and tympanic
membrane were taken into account in conceptualizing the design of
this optical myringotomy knife. During the procedure, instruments
would have to be maneuvered in the external auditory canal and
visualize the tympanic membrane. The average length of an adult
ear canal is approximately 25mm with an average diameter of 7
 SURGICAL INNOVATIONS AND INSTRUMENTATION
Philippine Journal Of Otolaryngology-Head And Neck Surgery
to 10mm.4,7 With this in mind, we utilized a rigid endoscope with
a diameter of 2.7mm to fit inside an insulin syringe with an inner
diameter of 3mm and outer diameter of 6mm. This would have
enough room for manipulation inside the ear canal although its
shape and cross sectional dimensions change along its length.4,7 The
tympanic membrane dimensions along its two major perpendicular
axes are 9 to 10 mm and 8 to 9 mm with an average thickness of
approximately 70 μm but can vary from approximately 30 to 120 μm7
The exposed needle tip used to puncture the tympanic membrane is
approximately 5mm which would safely penetrate the usual middle
ear cavity without injuring middle ear structures.
This exploratory study has several limitations. Due to the lack
of appropriate equipment for fabrication, the ideal size and shape
of the myringotomy knife was not achieved since we utilized a
54 Philippine Journal Of Otolaryngology-Head And Neck Surgery
Vol. 32 No. 1 January – June 2017
flattened gauge 19 needle as the knife. A customized medical grade
stainless steel myringotomy knife can be fabricated to ensure sharp
instrumentation, but it would definitely cost more than our fabricated
instrument. Difficulties in the one-hand technique were also
identified such as a good hand-eye coordination, ease of advancing
the endoshealth and handling the endoscope at the same time and
the finesse in puncturing the tympanic membrane. The lack of formal
trials by multiple operators is another limitation of our study.
Our initial experience with this optical myringotomy knife for
tympanostomy tube insertion suggests that it may greatly improve
the performance of myringotomy especially among less experienced
surgeons. Further studies may establish its accuracy and replicability
in vitro, after which formal in vivo trials can be attempted.
REFERENCES
1. Chiong CM, Yang NW, Almazan-Aguilar NA, Cabungcal AC, Diaz JGP, Perez AB, et al. Otitis Media
with Effusion in Children. In: Magiba-Caro R, Acuin JM, Jose EM, Chiong CM, Villafuerte CV,
Pontejos AQY, et al (editors). PSO-HNS Clinical Practice Guidelines. 2006:23-30.
2. Rosenfeld RM, Culpepper L, Doyle KJ, Grundfast KM, Hoberman A, Kenna MA, et al.
Clinical practice guidelines: Otitis media with effusion. Otolaryngol Head Neck Surg. 2004
May:130(5Suppl):595-118. DOI: 10.1016/j.otohns.2004.02.002; PMID: 15138413.
3. Tan KK, Liang W, Pham LP, Huang S, Gan CW, Lim HY. Design of a Surgical Device for Office-Based
Myringotomy and Grommet Insertion for Patients with Otitis Media with Effusion. J Med Devices
2014 Jul 21: 8(3). DOI: 10.1115/1.4027247.
4. Fernando AF, Calavera KZ. Endoscopic Myringotomy and Ventilation Tube Placement: A
Valuable Otolaryngologic Procedure under Topical Anesthesia. Philipp J Otolaryngol Head Neck
Surg 2012: 27(1):41-43.
5. Hummingbird TTS (Tympanostomy Tube System). [cited 2014 Sep 26]. Available from http://
www.preceptismedical.com/product/.
6. EndoSheath Technology. [cited 2014 Sep 26]. Available from http://www.visionsciences.com/
HealthcareProfessionals/ProductsCatalog/EndoSheath-Technology.
7. Maroonroge S, Emanuel DC, Letowski TR. Chapter 8: Basic Anatomy of the Hearing System.
[cited 2014 Sep 26]. Available http://www.usaarl.army.mil/publications/HMD_Book09/files/
Section%2015%20-%20Chapter%208%20Ear%20Anatomy.pdf.
8. Aguila KP. Self-Retaining Harpoon Tympanostomy Tube with Applicator. Philipp J Otolaryngol
Head Neck Surg. 2007: 22(1-2):27-30.
9. Optical Forceps. [cited 2014 Sep 26]. Available from: : http://www.teleflex.com/en/usa/pdf/
Optical%20Forceps%20sell%20sheet.pdf.
10. Montague ML, Lee MS, Hussain SS. Human error identification: an analysis of myringotomy and
ventilation tube insertion. Arch. Otolaryngol Head Neck Surg. 2004 Oct 1; 130 (10): 1153-7. DOI:
10.1001/archotol.130.10.1153; PMID: 15492160.
 UNDER THE MICROSCOPE
Philippine Journal Of Otolaryngology-Head And Neck Surgery Vol. 32 No. 1 January – June 2017

Jose M. Carnate, Jr., MD1

Vincent G. Te, MD2 Middle Ear Paraganglioma
Michelle Anne M. Encinas-Latoy, MD1

1
Department of Pathology,
College of Medicine A 51-year-old woman underwent mastoidectomy with labyrinthectomy on the right for
University of the Philippines Manila
a polypoid external auditory canal mass accompanied by tinnitus and ear discharge. She was
2
Department of Laboratories, reported to have undergone mastoidectomy on the same site seven years prior to the present
University of the Philippines Manila consult. The material from this prior surgery was not made available to us.
Philippine General Hospital
The submitted specimen from this surgery consisted of several dark brown irregular tissue
fragments with an aggregate diameter of 4.2 centimeters. Histologic sections show tumor cells
arranged in “ball-like” clusters that are surrounded by a network of sinusoidal channels. The cells
are round to oval with round, uniform nuclei that have finely granular chromatin and moderate
amounts of eosinophilic to amphophilic cytoplasm. (Figure 1) Mitoses, nuclear pleomorphism
and hyperchromasia are not observed. Immunohistochemical studies show diffuse cytoplasmic
positivity for synaptophysin and chromogranin. (Figure 2) The S100 stain highlights a peripheral
layer of cells taking up the stain around the cell clusters. (Figure 3) Based on these features, we
diagnosed the case as a paraganglioma likely a recurrence.
Paragangliomas are neuroendocrine neoplasms that arise from paraganglia found in various
anatomic locations.1 In the middle ear, they arise from paraganglia found in the adventitia of the
jugular bulb – hence, the old synonym “glomus jugulare” and “glomus tympanicum.” Other sites
where they can develop include paraganglia of the carotid artery bifurcation (“chemodectoma”),
the larynx and the vagal trunk (“glomus vagale”). The World Health Organization has simplified
the nomenclature of these tumors by calling all of them simply “paraganglioma” and specifying
the site involved.1 In our case, it is likely a middle ear paraganglioma borne out by the history,
clinical picture, and the morphology. Head and neck paragangliomas occur in adults from the 5th
– 6th decade, more commonly in females, and present mostly with mass-related symptoms.2,3

(Hematoxylin – Eosin , 100X)

Correspondence: Dr. Jose M. Carnate, Jr.

Department of Pathology
College of Medicine, University of the Philippines Manila
547 Pedro Gil St. Ermita, Manila 1000
Philippines
Phone (632) 526-4450
Telefax (632) 400-3638
Email: jmcjpath@gmail.com

The authors declared that this represents original material

that is not being considered for publication or has not been
published or accepted for publication elsewhere, in full or in
part, in print or electronic media; that the manuscript has been
read and approved by the authors, that the requirements for
authorship have been met by the authors, and that the authors
believe that the manuscript represents honest work.

Disclosures: The authors signed disclosures that there are no

financial or other (including personal) relationships, intellectual
passion, political or religious beliefs, and institutional affiliations
that might lead to a conflict of interest.
Figure 1. Tumor cells arranged in “ball-like” clusters surrounded by vascular channels (Hematoxylin-eosin, 100X
magnification). High power (inset) shows round to oval cells with round uniform nuclei and finely granular chromatin
(Hematoxylin-eosin, 400X magnification).

Creative Commons (CC BY-NC-ND 4.0)

Philipp J Otolaryngol Head Neck Surg 2017; 32 (1): 59-60 c Philippine Society of Otolaryngology – Head and Neck Surgery, Inc.
Attribution - NonCommercial - NoDerivatives 4.0 International

Philippine Journal Of Otolaryngology-Head And Neck Surgery 59

 UNDER THE MICROSCOPE
Philippine Journal Of Otolaryngology-Head And Neck Surgery
(Horseradish Peroxidase, 100X)
Figure 2. Diffuse cytoplasmic positivity on synaptophysin and chromogranin immunohistochemistry (Horseradish
peroxidase method, 100X magnification).
(Horseradish Peroxidase, 400X)
Figure 3. Peripheral positivity highlighting a layer of sustentacular cells around the cell clusters on S100
immunohistochemistry, (Horseradish peroxidase method, 400X magnification).
REFERENCES
1. Kimura N, Capella C, Gill A, Lam AKY, Tischler AS, Williams MD. Paraganglion tumours. In: El-
Naggar AK, Chan JKC, Grandis JR, Takata T, Slootweg PJ. World Health Organization Classification
of Head and Neck Tumors. Lyon: IARC Press. 2017. P. 276-284.
2. Stelow EB, Mills SE. Biopsy interpretation of the upper aerodigestive tract and ear. 2nd ed.
Philadelphia: Lippincott Williams and Wilkins. 2013. P. 163-165.
60 Philippine Journal Of Otolaryngology-Head And Neck Surgery
Vol. 32 No. 1 January – June 2017
The morphology of paragangliomas in all head and
neck locations is similar. Hematoxylin-eosin sections show
cells arranged in organoid groups (“cell-ball”, “Zellballen”)
surrounded by a vascular network. There are two cell
types encountered: the chief cells which comprise the
bulk of the cell nests and have abundant eosinophilic
cytoplasm and the sustentacular cells which are spindly
and located at the periphery of the nests. Neuroendocrine
immunohistochemical stains (e.g. synaptophysin,
chromogranin, CD56) highlight the chief cells while S100
and glial fibrillary acidic protein (GFAP) highlight the
sustentacular cells. Cytokeratin is typically non-reactive
and distinguishes this tumor from neuroendocrine tumors
(i.e. carcinoid, neuroendocrine carcinoma) and middle ear
adenoma.1,3 There are no consistent histologic features
that can discriminate between benign and malignant
cases, nor are there criteria that can predict aggressive
behavior and metastasis.1,2,3
Head and neck paragangliomas are slow-growing
tumors and surgery is the most common treatment
option. Radiotherapy is an option, especially for vagal
paragangliomas where severe vagal nerve deficits occur
in surgically treated cases.1 Recurrence after surgery is
reported to be less than 10% for carotid and up to 17%
in laryngeal cases.1 Metastasis on the other hand occur
in 4 – 6 % of carotid, 2% of middle ear and laryngeal, and
16% of vagal tumors.3 The World Health Organization
nomenclature states that “all paragangliomas have some
potential for metastasis (albeit variable).”1 Thus, long-term
follow-up may be prudent for all cases.
3. Williams MD. Paragangliomas of the head and neck: an overview from diagnosis to genetics.
Head Neck Pathol. 2017 March 20. [Epub ahead of print] doi: 10.1007/s12105-017-0803-4.
PMID: 28321772.
 A case report on catamenial epilepsy*
By Lara Jessica G. Murao, MD; Vaneza Valentina Penolio, MD, FPOGS
and Emille Teresa Apepe, MD, FPOGS
Department of Obstetrics and Gynecology, Quirino Memorial Medical Center

ABSTRACT

A case of a 17-year-old nulligravid with onset of seizure episodes since menarcheis reported. She was diagnosed with Seizure
Disorder treated with Phenobarbital and was seizure free for 2 years. Two years prior to consult, seizure recurrences were noted
to coincide with menstruation, hence, was diagnosed with Catamenial Epilepsy. Patient was shifted to Lamotrigine but seizure
exacerbations were still observed, prompting referral to the Reproductive Medicine service for adjunctive hormonal therapy. Depot
medroxyprogesterone acetate was added to the antiepileptic drug which provided seizure control. Adjunctive hormonal therapy
proved to be helpful in the management of intractable seizures in this patient.
The report aims to give a better understanding of the neuroactive properties of estrogen and progesterone and its role in the
development of Catamenial Epilepsy. Gender-related and psychosocial issues in the treatment of Epilepsy in the child-bearing years
up to the menopause are also discussed.

Keywords: Catamenial epilepsy, seizure, antiepileptic drug, hormonal therapy

INTRODUCTION others argue that Catamenial Epilepsy can be diagnosed

E
pilepsy is a disorder characterized by unpredictable
seizure episodes and has long been associated with
other medical conditions. Regularity of seizures that
coincides with menstruation is a reason to explore the role
of estrogen and progesterone in seizure development.
Catamenial Epilepsy is derived from the Greek word
katamenios, meaning monthly, first described by Charles
Locock in 1857 as “hysterical epilepsy”1. It was described
as regular seizure episodes confined to women connected
with the menstruation. Verrotti et al. defined Catamenial
Epilepsy as having at least 75% of the attacks during a
10-day period of the menstrual cycle beginning 4 days
before menstruation and 6 days after its onset2. Navis and
Harden specified that the term Catamenial Epilepsy does
not refer to a specific Epilepsy syndrome, but rather to
catamenial seizure exacerbations3. Catamenial Epilepsy is
more common in women with focal Epilepsy than those
with generalized Epilepsy, though any type of Epilepsy can
have a catamenial exacerbation2. In women with Epilepsy
during the reproductive years, a correlation has been
observed between the cyclic monthly levels of estrogen
and progesterone and seizure frequency4.
Catamenial seizure exacerbations can affect 10% to
70% of reproductive age of women2. The wide range of
incidence is due to the absence of a fixed definition of
the disease entity. Diagnostic criteria are still vague since
*Finalist, 2017 Philippine Obstetrical and Gynecological Society (POGS)
Interesting Case Paper Contest, April 6, 2017, Citystate Asturias Hotel,
Puerto Princesa City, Palawan
with occurrence of seizures around menstruation, while
some consider such diagnosis with an increase in seizures
in relation to the menstrual cycle. The percentage of
increase in seizure episodes is also not well defined.
Duncan et al. documented successive seizure episodes for
3 consecutive months in 40 women. Only 5 women out of
40 fulfilled the criteria of Catamenial Epilepsy of having
at least 75% of seizures each month in the 10-day time
frame5. There is no local report on Catamenial Epilepsy to
date.
This paper aims to present a case of Catamenial
Epilepsy and discuss its pathophysiology, diagnosis,
management, and issues in Reproductive Medicine.
CASE REPORT
A 17-year-old nulligravid, single, Roman Catholic,
from Quezon City, consulted due to recurrent generalized
seizures. Onset of seizure wasatage 12, upon patient’s
menarche. The attacks were noted on day -5 to +8 of
menstruation, with 1-4 episodes of jerking movements
of both upper extremities, circumoral cyanosis and
drooling of saliva lasting for 1 minutes. There was no loss
of consciousness or anyprodromal signs and symptoms.
Consult with the Pediatric-Neurology service of a
government hospital was done 4 years prior to consult
(PTC). Workup such as cranial magnetic resonance imaging
(MRI) and electroencephalogram (EEG) were normal.
(Figures 1 and 2). A diagnosis of Seizure disorder etiology
to be determined was given.
Pharmacotherapy in the form of Phenobarbital 90
mg/tab twice a day was given providinga 2-year seizure
Volume 41, Number 3, PJOG May-June 2017 33

Figure 1. Cranial magnetic resonance imaging report of index
patient done last October 12, 2012
free interval. However, she was noted to be impatient,
irritable, and exhibited excessive attention-seeking
behavior. Aggressive behavior in school was reported
where she would inflict physical injury to classmates
for no reason. A psychiatric consult was done and was
prescribed with Olanzapine 5 mg/tab 1 tab once a day
and Na Valproate + Valproic Acid 500 mg/tab once a day.
Psychiatric assessment was Behavioral Changes due to
another Medical Condition (Seizure Disorder). School
psychiatrist advised discontinuation of Phenobarbital
and suggested to take a break from school. Olanzapine
was shifted to Clozapine 100mg/tab ½ tab at bedtime.
Pediatric neurologist was informed of the behavioral
changes and said that it was an expected side effect of
patient’s medications. She was forced to stop school
for two years due to unpredictable behavior and poor
concentration. She also suffered from low self-esteem
and social withdrawal due to discrimination during seizure
attacks in public.
34 Volume 41, Number 3, PJOG May-June 2017
Figure 2. Electroencephalogram of the index patient last October
5, 2012
Two years PTC, seizures recurred and observed to
be coinciding with menstruation. She consulted at the
Pediatric-Neurology service of this institutionand was
given the diagnosis of Catamenial Epilepsy. Phenobarbital
was tapered and was shifted to Lamotrigine. Despite
dose adjustments of Lamotrigine, persistence of
seizure attacks prompted referral to the Reproductive
Medicine service for adjunctive hormonal therapy. Depot
medroxyprogesterone acetate (DMPA) was started in
conjunction with Lamotrigine and patient has been seizure
free up to present.
Past medical and family history were non-
contributory. Menarche was at age 12, each period lasting
for 5-6 days in a 28-day cycle consuming 3 pads per day with
reported seizures and hypogastric pain on days -5 to +8.
She has no sexual intercourse. Currently, she is a 9th grade
student at a Special Education (SPED) school and claims to
be well adjusted in school with no mood fluctuations nor
depressive episodes. Current medications are Lamotrigine
50mg/tab twice a day, Clozapine 100mg/tablet ½ tablet at
bedtime, Sodium Valproate + Valproic acid 500 mg/tablet
twice a day, and DMPA 150 mg intramuscularly every 3
months.
On physical examination, she is classified as Tanner
stage IV for breast and pubic hair. Rectal examination increasing neuronal excitability while progesterone is an
showed good sphincteric tone, cervix was firm, long, with anticonvulsant by enhancing GABA-mediated inhibition7.
a normal-sized corpus and no adnexal mass palpated. The three main pathophysiological determinants of
Neurologic examination revealed normal cortical Catamenial Epilepsy involve the neuroactive properties of
function. No cranial nerve lesions with intact sense of reproductive steroids, the variation of neuroactive steroid
smell, pupils are 2-3 millimeter, equally reactive to light, levels across the menstrual cycle, and the susceptibility of
primary gaze midline, full extraocular movements, intact the epileptic substrate to neuroactive steroid effects8.
and symmetrical sensation on bilateral cranial nerves Herzog et al. presented statistical evidence which
V1-V3. No facial asymmetry, able to do facial muscle is in current use showing at least 3 distinct patterns of
movements, intact gross hearing, intact gag reflex, uvula at seizure exacerbation in relation to the menstrual cycle:
the midline, equal palatal elevation, good shoulder shrug, (1) perimenstrual (2) periovulatory in normal cycles and
good sternocleidomastoid tone and strength, and able to (3) luteal in patients within adequate luteal phase cycles
protrude tongue without any deviation. Motor examination (Figure 3).9
shows 5/5 muscle strength on all extremities with no Catamenial type 1 (C1 pattern) is the most common
atrophy. No sensory deficit noted. Patient is normoreflexic type, wherein seizures occur perimenstrually from Days
with no noted pathologic reflex. She has a supple neck, -3 to 3 due to the withdrawal of the anticonvulsant
no nystagmusnor tremors, dysdiadochokinesia, able to do effects of progesterone accompanied by decrease in
finger to nose test, without gait disturbances. allopregnanolone, a potent positive allosteric modulator
Diagnosis given was G0, Catamenial Epilepsy. of GABAA receptor. In Catamenial type 2 (C2 pattern),
seizures occur between Day 10 to -13 due to the pro-
CASE DISCUSSION convulsant effect of the estradiol surge. In Catamenial
type 3 (C3 pattern) seizures occur during the entire
Seizures may be attributed to vascular disorders, luteal phase in an anovulatory cycle, from Day 10 of one
infections, trauma, autoimmune, metabolic or toxic cycle to Day 3 of the following cycle. There is inadequate
causes, neoplastic, structural or congenital disorders6. progesterone secretion in the luteal phase of anovulatory
The regularity of the patient’s seizure attacks coinciding cycles as compared to ovulatory cycles, hence one is more
with the menstrual period makes Catamenial Epilepsy susceptible to seizure attacks.9 The decline in EPratio
a likely diagnosis. It is diagnosed clinically and is the
primary consideration in this patient. Vascular, structural
disorder and neoplasm as the cause of seizure in this
patient were ruled out due to normal imaging studies.
Metabolic disorders such as hypoglycemia, hypocalcemia,
hypomagnesemia, and hypo/hypernatremia were ruled
out with negative findings on blood chemistries. No history
of trauma and infections elicited. Autoimmune disorders
usually present with other clinical symptoms, not seen in
the index patient.
Patient’s onset of seizure and its exacerbations occur
around the time of menstruation. Such seizure pattern
clearly attributes the attacks to the cyclic variation and
neuroactive properties of endogenous steroid hormone,
hence was diagnosed with Catamenial Epilepsy. More than
75% of the attacks during a 10-day period of the menstrual
cycle was observed in the index patient which qualifies
her for the diagnosis of Catamenial Epilepsy as defined
by Verotti et al.2 Estrogen and progesterone are steroid
hormones which have a role in neuronal development
and plasticity due to their capacity to regulate synthesis,
release, and transport of neurotransmitters7. The estrogen
progesterone ratio (EP ratio) has a positive correlation to
one’s susceptibility to seizure occurrence throughout a
normal menstrual cycle. High EP ratio leads to clustering Figure 3. Types of Catamenial seizure. (A) C1 and C2 pattern of
catamenial seizure (B) C3 pattern of catamenial seizure. (Herzog
of seizures, since estrogen is a pro-convulsant by
et al., 1997)
Volume 41, Number 3, PJOG May-June 2017 35
during the midluteal phase makes it the period where
seizure is least likely to occur.
The three patterns of Catamenial Epilepsy can be
distinguished by (1) charting menses and seizures and
(2) obtaining a mid-luteal phase serum progesterone to
differentiate normal from an inadequate luteal phase cycle
(<5 ng/ml).10 Seizures in the index patient were observed
to occur from day -5 to +8 of the menstrual cycle and does
not strictly fall under any of the abovementioned patterns
(Figure 4). She still qualifies as a case of Catamenial
Epilepsy since more than 75% seizures occurred during
the 10-day period of the menstrual cycle beginning 4 days
before menstruation and 6 days after its onset.
Antiepileptic drugs (AEDs) are the mainstay
treatment of Catamenial Epilepsy.11 Seizures are caused
by paroxysmal discharges from neurons arising due to
excessive excitation or loss of inhibition which needed
to be controlled to prevent neuronal damage that can
have an adverse effect on cognition, development,
and reproductive function. Phenobarbital, an allosteric
modulator of GABAA receptor, was the initial drug given
to the patient. However, there are no direct studies
of effectiveness of this drug in Catamenial Epilepsy.
Phenobarbital is limited by its enzyme-inducing activity,
interaction with sex steroid hormone and undesirable side
effects such as behavioral changes which was exhibited by
the patient. She was shifted to Lamotrigine, a phenyltriazine
antiepileptic which inhibits release of excitatory glutamate
and voltage-sensitive sodium channel stabilizing neuronal
membrane. Gilad et al. prospectively studied women with
Catamenial Epilepsy who were treated with Lamotrigine
for 3 months and concluded that Lamotrigine is efficacious
Figure 4. Seizure diary of the index patient for 2016
36 Volume 41, Number 3, PJOG May-June 2017
in 66% of women, with disappearance of seizures or 50%
reduction in the number of seizures.12 Lamotrigine also
increases progesterone levels however its mechanism of
action is unknown.11 A tri-directional interaction between
Epilepsy, AEDs and sex steroid hormones exist. AEDs and
Epilepsy itself can adversely disturb the hypothalamic-
pituitary ovarian axis and affect sexual and reproductive
functioning causing disorders such as hyperandrogenism,
menstrual disorders, ovarian failure, polycystic ovary
syndrome, hyperinsulinemia, and weight gain. On the other
hand, the decrease in both estrogen and progesterone
pre-menstrually activates enzymes that metabolize AEDs
in the liver causing breakthrough seizure.11
Despite dose adjustments the patient continued to
experience seizure attacks, therefore adjunctive hormonal
therapy was started in the form of DMPA. It suppresses
ovulation by inhibiting secretion of gonadotropins from
the pituitary gland and is currently being studied in the
treatment of Catamenial Epilepsy. Mattson et al. used
DMPA as an adjunct treatment to antiepileptic medication
and reported a 39% decrease in seizures per month13.
Levonorgestrel intrauterine device appears to be effective
as an alternative with the advantage of having no drug
interactions.14 Progesterone has a more definite role
in preventing seizure than estrogen. It exerts a direct
membrane-mediated inhibitory effect by potentiating
GABAA-mediated chloride conductance.11 Progesterone
also acts by decreasing estrogen receptor numbers
antagonizing estrogen effects. Chronic progesterone
decreases the number of hippocampal CA1 dendritic
spines and excitatory synapses faster than the simple
withdrawal of estrogen.11 However, progestin-only pills
(POP) have been found to be ineffective when used in
combination with enzyme-inducing AEDs due to increased
hepatic clearance thus decreasing bioavailability of POP.
Subdermal progestin implants are also not recommended
due to high failure rates.14 The index patient became
seizure-free when DMPA treatment was started, however,
long term administration is not advised because of
associated bone mineral density loss, amenorrhea
and delayed return of ovulation. A study by Clark et al.
comparing bone mineral density of women aged 18-35 on
DMPA reported that DMPA-related bone mineral density
loss is significant and occurs mostly in patients given
DMPA for 2 years.15
Treatment should take into consideration the
catamenial pattern type, age, regularity of menstruation,
response to initial medication and financial resources.
Navis and Harden proposed an algorithm for women
with suspected Catamenial Epilepsy (Figure 5) wherein
oral natural progesterone is given during luteal phase in
C1 types.3 Nonhormonal drugs such as acetazolamide,a
carbonic anhydrase inhibitor, clobazem or other

Figure 5. Algorithm for treatment if female patients with
suspected catamenial epilepsy (Navis A, Harden C, 2016)
benzodiazepines are suggested medications in C2 and
C3 types. Those with irregular menses are prescribed
Medroxyprogesterone acetate or oral contraceptives with
withdrawal weeks every 3-12 months.3
Epilepsy is more complicated in females than in
males since estrogen and progesterone affect seizure
thresholds due to the close interaction between regions
of the brain that generate seizures and regions that
control hormonal activity. Patient awareness is imperative
on how the disease and its treatment can affect sexual
development, menstrual cycles, contraception, sexual
dysfunction, such as infertility, impaired libido, and
reproduction.16 The index patient presented with seizure
upon menarche making her anxious during menstruation.
Social withdrawal and isolation are commonly reported
among people with Epilepsy as was seen in this case.
She verbalized her concern over discrimination received
every time a seizure occurs in a public. Part of the social
withdrawal and isolation can be due to parents’ over-
protectiveness wherein children’s activities are closely
monitored and restricted, rendering the child more
socially inept, more dependent and attached. Patients
also adopt a more passive role in family interactions and
are less involved in family decision-making.16 The index
patient has regular consultations with a psychiatrist who
provides behavioral therapy and makes the patient better
understand the effect of the disease process.
Decreased fertility has been reported in women with
Epilepsy which can be related to anovulatory cycles and/
or hyperandrogenism upon initiation of anti-epileptic
drugs.16 Seizure attacks can damage the preoptic area
of the hypothalamus where gonadotropin-releasing
hormone (GnRH) is produced. Hattemer et al. discussed
how temporal lobe Epilepsy lateralization is associated
with reproductive dysfunction.17 It was noted that left
temporal lobe discharges were associated with polycystic
ovary syndrome, and right-sided discharges with
hypothalamic hypogonadism.17
Should the patient desire to become pregnant,
preconception counseling should be offered. Teratogenic
risks of AEDs must be balanced alongside risks of poor
seizure control. The lowest effective dose should be used
and monotherapy is advised. Malformation rates with
Lamotrigine exposure ranges from 0-4.4%, Phenobarbital
2.9 to 10.4%, and Valproic Acid 5.7-16.8%.14 It is expected
that patients with perimenstrual catamenial epilepsy have
reduced seizure frequency throughout the pregnancy due
to the absence of cyclical hormone variations and the
increase in circulating progesterone levels.18
Women with Epilepsy may be at risk for early onset
of menopause.16 Those with catamenial seizure should
be monitored until their perimenopausal years since
as high as 40% of women report worsening of seizures,
while 27% improve, and a third had no observed change.8
This is due to an initial steady increase in estrogen levels
during the peri-menopausal transition. In other women,
estrogen levels can remain stable, or become erratic with
surges until estrogen levels diminish in the menopause.
Hormone replacement therapy is significantly associated
with an increase in seizure frequency during menopause,
which is more likely in women with a history of Catamenial
Epilepsy.16 Osteoporosis and increased risk for fractures
during menopause should be discussed with patients
on long term DMPA since it is implicated in promoting
accelerated vitamin D metabolism and bone loss.
Adequate calcium supplementation and yearly bone scans
are advised.
Long term plan for the patient includes maintaining
her on AED and hormonal therapy with monthly visits to
Neurology and Reproductive Medicine until control of
seizure is achieved. Medications are tapered until a 10-
year seizure free period is attained. Thereafter, AEDs may
be discontinued. Regular psychiatric consult is advised.
SUMMARY
A case of a female adolescent who upon menarche
experienced seizure attacks with exacerbations on day
-5 to +8 of menstruation is reported. A diagnosis of
Catamenial Epilepsy was given after ruling out other
causes. Antiepileptic drugs and adjunctive hormonal
therapy was necessary to control catamenial seizure
Volume 41, Number 3, PJOG May-June 2017 37
exacerbations. Gender- related and psychosocial issues in
the treatment of Epilepsy in the child-bearing years up to
the menopause are discussed.
RECOMMENDATIONS
1. Formulation of a standard definition of Catamenial
Epilepsy will aid in its diagnosis and management.
2. Research on neuroactive properties of reproductive
steroids will improve management of intractable
catamenial seizure exacerbation to enable health care
professionals provide correct treatmentand support
services.
3. Females with a first seizure attack coinciding with
REFERENCES
1. Locock C. Analysis of fifty-two cases of epilepsy observed
by the author. Med Times Gaz. 1857; 14:524-6.
2. Verrotti A, D’Egidio C, Agostinelli S, et al. Diagnosis
and management of catamenial seizures: a review.
International Journal of Women’s Health. 2012; 4:535-541.
3. Navis A, Harden C. A Treatment Approach to Catamenial
Epilepsy. Curr Treat Options Neurol. 2016; 18:30.
4. Crawford P. Best Practice Guidelines for the Management
of Women with Epilepsy. Epilepsia. 2005; 46(9):117-124.
5. Duncan S, Read CL, Brodie MJ. How common is catamenial
epilepsy? Epilepsia. 1993; 34:827-831.
6. Gowers WR. Epilepsy and other chronic convulsive
diseases. Their causes, symptoms, and treatment. London:
J&A Churchill; 1881.
7. Speroff L, Fritz M: Clinical Gynecologic Endocrinology
and Infertility, 8th ed. USA: Lippincott Williams & Wilkins,
2011.
8. Herzog AG. Catamenial epilepsy: Update on prevalance,
pathophysiology and treatment from the findings of the
NIH Progesterone Treatment trial. Seizure. 2015; 28:18-25.
9. Herzog AG, Klein P, Ransil BJ. Three patterns of catamenial
epilepsy. Epilepsia. 1997; 38:1082-8.
10. Verrotti A, Luis V, Coppola G et al. Catamenial epilepsy:
hormonal aspect. Gynecological Endocrinology. 2010;
26(11):783-790.
38 Volume 41, Number 3, PJOG May-June 2017
menarche and subsequent menstrual periods should
be referred to the Reproductive Medicine service.
4. Being a life-long disease, astrong neurologist-
gynecologist-patient relationship is important to
ensure open communication andclose monitoring up
to the menopausal years.
5. Women with epilepsy of childbearing age and desirous
of pregnancy should be counseled regarding fertility
issues.
6. Campaigns to increase public awareness and
understanding of Catamenial Epilepsy, and all types
of Epilepsy is imperative to facilitate acceptance of
patients for them to live productive lives.
11. Reddy D. Pharmacotherapy of catamenial epilepsy. Indian
J Pharmacol. 2005. 37(5):288-293.
12. Gilad R, Sadeh M, Rapoport A, Dabby R, Lampl Y.
Lamotrigine and catamenial epilepsy. Seizure. 2008;
17:531-534.
13. Mattson R, Cramer J, Caldwell B, Siconolfi B. Treatment of
seizures with medroxyprogesterone acetate: preliminary
report. Neurology. 1984; 34:1255-8.
14. Schwenkhagen AM Stodieck SR. Which contraception for
women with epilepsy? Seizure. 2008; 17:141-4.
15. Clark M, Sowers M, Levy B, et al. Bone mineral density
loss and recovery during 48 months in first-time users of
depot medroxyprogesterone acetate. Fertil Steril. 2006;
86(5):1466-74.
16. Pennell PB. Pregnancy, Epilepsy, and Women’s Issues.
Continuum (Minneap Minn). 2013; 19(3):697-714.
17. Hattemer K, Knake S, Reis J et al. Cyclical excitability of
the motor cortex in patients with catamenial epilepsy: A
transcranial magnetic resonance imaging. Seizure. 2006;
15:653-657.
18. Cagnetti C, Lattanzi S, Foschi N, Provinciali L, Silvestrini M.
Seizure Course During Pregnancy in Catamenial Epilepsy.
Neurology. 2014; 83:339-344.
 Arteriovenous malformation: A review of four cases*
By Anna Eloisa M. Dominguez, MD and Nephtali M. Gorgonio, MD, FPOGS
Department of Obstetrics and Gynecology, Cardinal Santos Medical Center
INTRODUCTION
U
terine arteriovenous malformation (AVM) is a
rare disorder characterized by multiple abnormal
communications between arteries and veins.
Although its true incidence is unknown, it has been
thought to be more common than reported, with more
cases of traumatic AVMs being increasingly diagnosed4.
Due to its rarity, a high index of suspicion and
timely and accurate diagnosis is especially imperative, as
instrumentation often used for other sources of uterine
bleeding may lead to massive hemorrhage.
This report presents 4 cases of arteriovenous
malformation seen and diagnosed at our institution in
2006, 2012, 2015 and most recently, January 2016.
This report aims to compare the 4 cases, the arrival
at a diagnosis and subsequent management, thereby
presenting a more comprehensive clinical examination
of this rare condition. Because of its nature and highly
variable presentation, it is often overlooked when
searching for a differential diagnosis. This study aims to
present Uterine AVM as a possible consideration in all
women of reproductive age presenting with unexplained,
intermittent, profuse vaginal bleeding.
CASE REPORT
CASE 1
J.F. is a 23-year-old G1P0 (0010), admitted on January
2016 due to heavy menstrual bleeding.
Four months prior to admission, pregnancy test done
was positive. TVS done showed no cardiac activity. Patient
also noted vaginal bleeding consuming 1-2 regular pads.
Repeat ultrasound done after 1 week, still showed no
cardiac activity. Vaginal bleeding spontaneously resolved
and patient advised to await signs of spontaneous passage
of products of conception.
Three months prior to admission, with note of
recurrence of vaginal bleeding, accompanied by passage
of meaty tissues and tolerable crampy, hypogastric pain.
Transvaginal ultrasound done by AMD showed retained
*Finalist, 2017 Philippine Obstetrical and Gynecological Society (POGS)
Interesting Case Paper Contest, April 6, 2017, Citystate Asturias Hotel,
Puerto Princesa City, Palawan
products of conception. She was then scheduled for, and
underwent completion curettage, with no complications
noted. With temporary resolution of vaginal bleeding
until 12 days post curettage, when there was recurrence
of intermittent vaginal spotting staining 2-3 pantyliners.
Patient followed up with AMD, where TVS with Doppler
done showed a heterogenous structure within the
fundal myometrium measuring 1.85 x 1.61 x 1.11cm
with serpiginous vascular flow on color mapping. B-hcg
requested was elevated at 75.74 mg/dL. Impression
was to consider arteriovenous malformation. No further
management done and advised to observe bleeding.
Interval history shows spontaneous resolution
of bleeding until 1 week prior to consult (61 days
post curettage), when there was recurrence of heavy
menstrual bleeding, staining 1 pantyliner to consuming 6
regular pads, fully soaked, with blood clots, and soaking
bedsheets. Patient followed up with AMD where pelvic
CT angiography requested showed uterine arterioveous
malformation with arterial supply from the bilateral
uterine arteries. Repeat Doppler ultrasound showed an
irregular heterogenous structure with multiple cystic areas
occupying the upper anterior myometrium and extending
to the mid portion measuring 2.33 x 2.15 x 1.53cm. Color
Doppler showed the mass to be hypervascular with massive
turbulent flow (Figure 1). She was started on Tranexamic
acid and subsequently admitted for embolization of
bilateral uterine arteries.
Figure 1. (CASE 1) Mosaic/serpiginous pattern characteristic of
AVM on Doppler ultrasound
Volume 41, Number 3, PJOG May-June 2017 39

Figure 2. (CASE 1) endometrial mass representing nidus of
vessels, as visualized on 3D ultrasound
Embolization of bilateral uterine arteries was done
using Polyvinyl Alcohol Particles, with intra-operative
findings of AV Malformation in the right upper uterine
segment with blood arising from the right uterine artery
and an intra-nidal aneurysm. Although left internal
angiogram showed no definite supply to the arteriovenous
malformation, embolization was also done to prevent
recurrence from collaterization. Post embolization of Right
and Left Internal Iliac arteries showed no definite supply
to the arteriovenous malformation (Figure 3). Patient
tolerated the procedure well and was discharged stable
on the 8th hospital day.
Repeat transvaginal ultrasound was done post
embolization showed a homogenous structure at the
endometrial cavity, probably remnants of occluded
vessels, with no flow visualized on color mapping.
Case 2
K.M. is a 38-year-old G2P2 (1102) s/p Diagnostic D&C
x 2 (1st – decidual tissues, 2nd – endometrial polyp) who
came in due to heavy postpartum vaginal bleeding.
Her first pregnancy was uncomplicated and delivered
40 Volume 41, Number 3, PJOG May-June 2017
Figure 3. (CASE 1) AVM originating from the Right Internal Iliac
Artery (pre embolization); No AVM appreciated arising from the
Left internal Iliac artery; compared to post embolization imaging
via primary ceasarean section for non reassuring fetal
status. Past Medical and Gynecologic history were
uncomplicated and non-contributory.
Two months prior to admission, on approximately day
13 postpartum, patient noted increase in vaginal bleeding
consuming 5 maternity pads fully soaked, with blood clots.
She was then admitted at our institution where Transvaginal
ultrasound showed an enlarged anteverted uterus with
thickened endometrium at 2.76cm; dilated endocervical
canal with blood clots (volume of 8.44mL); fluid collection
within the anterior lower uterine segment or cesarean
section scar with intact serosal surface; consider blood
clots vs retained placental tissue/membranes within the
fundal cavity and normal ovaries.
Impression was retained placental secundines for
which she then underwent dilatation and curettage.
The histopathologic finding was predominantly blood
clots with fibrinous tissues, showing acute on chronic
inflammation and decidual tissues. Blood transfusion of 4
units of blood given and discharged stable; with no active
bleeding noted.
One month prior to admission, on approximately
day 32 postpartum, patient had recurrence of heavy
menstrual bleeding described as consuming 1 pantyliner
per day, fully soaked, with blood clots. She then consulted
at the ER of another institution where CBC done showed
a hemoglobin of 6.8mg/dL. She was admitted, transfused
with 3 units pRBC, and again underwent dilatation and
curettage, revealing an endometrial polyp, proliferative
endometrium and fragments of benign ectocervical tissue.
Fourteen days prior to admission, on approximately
day 43 postpartum, repeat ultrasound done by an OB
sonologist, showed an intact anterior lower uterine
segment measuring 0.79cm. An anechogenic ovoid
structure was noted within the uterus at the right corneal
area measuring 1.57 x 1.01 x 0.98 cm. The intrauterine
mass noted may be a placental tissue or a clotted blood.
 Twelve days prior to admission, on day 45 postpartum,
patient had recurrence of heavy menstrual bleeding, as
described, now associated with hypotension, with BP
at 80/60 and PR 126. Transvaginal ultrasound done on
admission showed: normal sized midpositioned uterus
measuring 5.08 x 5.43 x 4.91 cm with no focal mass seen.
Endometrial thickness at 1cm with note of fluid motion
within. IMPRESSION: Normal sized midpositioned uterus
with intact and hyperechoic endometrium.
CBC done showed a hemoglobin of 6.9mg/dL.
Admitted and transfused with 3 units Fresh Whole Blood
and 1 unit pRBC. Repeat CBC post transfusion revealed a
hemoglobin of 10.6mg/dL.
Patient was sent home with Progesterone only
contraceptive pill and Ferrous Sulfate. Bleeding resolved
Figure 4. (CASE 2) Color Mosaic pattern seen on Doppler
and patient was asymptomatic until few hours prior to
sonography: hypervascularity juxtaposed with orange and blue
admission, patient noted recurrence of vaginal bleeding mosaic pattern with high velocity waveforms
fully soaking 1 regular pad and 1 adult diaper, with blood
clots. Patient was admitted at our institution,started
on Tranexamic Acid 500mg IV and Micropill 1 cap TID
for hemostasis and advised to continue ferrous sulfate
BID. Transfused with 1 unit pRBC for correction of
anemia. During admission, a transvaginal ultrasound was
repeated (on day 57 postpartum) and revealed normal
sized retroverted uterus measuring 5.29 x 5 x 5.54 cm.
No focal mass seen. Cervix measures 2.72 x 3.42 x 4.03
cm. The endocervical canal is heterogenous and slightly
dilated to 0.32 cm. Color flow shows increased stromal
vascularity with complex serpentine vessel pattern and
distinct venous and arterial waveforms. Endometrium
measures 0.46cm. Intact subendometrial halo. Within the
anterior lower uterine segment are irregular hypoechoic
areas surrounded by hyperechoic border measuring 1.94 x
0.90cm. Color Doppler shows hypervascularity juxtaposed
with orange and blue mosaic pattern with high velocity
waveforms (Figure 4). Superior and lateral to the uterine
corpus is a thin walled (0.18cm) cystic structure measuring
7.67 x 4.20 x 6.40cm (previously 6.91 x 6.55 x 3.73cm) with
low level echogenicity. Borders are vague on TVS however
supplemental TAS shows cyst to be well defined with
echogenic borders. No flow on color mapping but adjacent
to right uterine vessels.
Figure 5. (CASE 2) gross appearance on TAHBSO
Impression: normal sized retroverted uterus with thin
and intact endometrium; normal ovaries; hypervascular
cervix; lower uterine segment heterogeneity with color measures 1.6 cm, both with cystic spaces filled with blood.
flow pattern suggestive of AVM; right pelvic cyst, consider Right ovary converted to a multiloculated cystic structure
encysted fluid vs hematoma or hematosalpinx. measuring 5 x 5 x 2.5 cm, with chocolate like fluid on
She then underwent total abdominal hysterectomy inadvertent rupture. Left fallopian tube and Left ovary
with right salpingoophorectomy, with intraoperative were grossly normal in appearance.
findings of (Figure 5): a slightly enlarged uterus measuring Histopathology done showed chronic cervicitis with
6.5 x 5.5 x 2.3 cm. Endometrial thickness of 0.4 cm, smooth, squamous metaplasia. Adenomyosis and Endometrial
with note of a 1.5 x 1.5 cm fleshy mass in the fundal area. Polyp. Intramural thick and thin walled vascular channels
Anterior wall measures 1.5 cm while the posterior wall present compatible with arteriovenous malformation.

Volume 41, Number 3, PJOG May-June 2017 41

Proliferative endometrium. Ovary, Right, Endometrial
Cyst. Fallopian tube, right, No diagnostic abnormality
recognized.
The rest of the hospital stay was unremarkable and
she was discharged stable, with no complaints.
Case 3
J.A., a 24-year-old, G1P0 (0010), was admitted in July
2012 due to vaginal bleeding.
Three months prior to admission, patient underwent
completion curettage for a miscarriage, which showed
decidual tissues and endometritis on histopath.
Two weeks prior to admission, the patient noted
vaginal bleeding consuming 4 to 5 pads per day with
blood clots. Patient consulted with an obstetrician where
a transvaginal ultrasound revealed an irregular, ill-defined
complex mass with rich color flow occupying the lower
one third of the uterus to the fundal area measuring
4.5 x 3.4 x 2.7 cm. Sonographic impression was “Cannot
totally rule out an invasive mole versus an arteriovenous
malformation”. β-hCG done was normal at 1.46 mIU/
mL. CBC revealed Hemoglobin of 8.4 mg/dL and she was
transfused with 2 units of packed RBC. Repeat β-hCG done
after 2 days was still normal limits at 1.46 g/dL. She was
discharged stable with no vaginal bleeding, given ferrous
fumarate and tranexamic acid, and advised transfer to a
tertiary institution for further work-up.
One week prior to admission, patient had recurrence
of vaginal bleeding now consuming 1 maternity pad, fully
soaked with blood clots, for which she sought consult
with AMD. On examination, patient had pale palpebral
conjunctivae and nail beds, abdomen was soft and
nontender, no palpable masses noted. Internal examination
revealed a closed cervix and a slightly enlarged uterus.
Patient underwent correction of anemia with transfusion
of 2 units of packed RBC.
Repeat transvaginal ultrasound done revealed a
myometrial multicystic hypervascular mass, to consider
an arteriovenous malformation. CT angiography was
performed which showed a conglomeration of tortuous
vascular structures predominantly involving the anterior
myometrium, supplied by a branch of the anterior division
of the right internal iliac artery (Figure 5).
Patient subsequently underwent embolization of
the right uterine artery using gel foam, with complete
occlusion of the uterine artery on post injection and
confirmatory angiography and discharged improved on
the 2nd post-operative day.
One month after embolization, repeat ultrasound
showed was a significant change in the appearance of
the arteriovenous malformation on gray scale imaging,
showing markedly reduced blood flow pattern on color
doppler.
42 Volume 41, Number 3, PJOG May-June 2017
Two months after embolization, repeat ultrasound
was again done, which showed a homogenous anterior
myometrium, with no demonstrable arteriovenous
malformation on gray scale imaging and flow only within
the periphery of the myometrium on color doppler
application. She was maintained on combined oral
contraceptive pills with no recurrence of vaginal bleeding
post operatively.
Case 4
A.C. is a 28-year-old G2P1 (1011), admitted in July
2006, who came in due to vaginal bleeding. First term
pregnancy in 2004 was delivered via caesarean section for
cephalopelvic disproportion.
3 months prior to admission, she underwent
completion curettage for a miscarriage with an
unremarkable hospital stay.
2 months prior to admission, patient noted vaginal
bleeding consuming to 4 pads per day, occurring every 14
days and lasting for 5 days, accompanied by intermittent,
non-radiating, crampy, hypogastric pain. Interval history
showed persistence and worsening of the bleeding,
however no consult was done.
One day prior to admission, the patient noted vaginal
bleeding, with passage of blood clots, sought gynecologic
consult and was admitted. Speculum examination showed
minimal bleeding per os and moderate pooling of blood at
the posterior fornix. On internal examination, the cervix
was firm, short and closed, corpus not enlarged, with
negative adnexae. The rest of the physical exam was normal
and unremarkable. She was then advised subsequent
admission. Assessment was Abnormal Uterine Bleeding,
Rule Out Endometrial Pathology; Rule Out Gestational
Trophoblastic Disease.
On admission, CBC showed hemoglobin of 11.2
mg/dL, and hematocrit of 0.34; Prothrombin and
Partial Thromboplastin times were within normal limits.
Qualitative serum β-hCG was negative.
Doppler ultrasound done demonstrated a complex
vascular mass at the fundal portion with extension to
the uterine cavity measuring 1.22 x 0.88 cm showing
extensive color aliasing or inversing and apparent flow
reversal. Endometrial stripe was 0.44 cm, hyperechoic,
and the subendometrial halo appears intact except at the
fundal portion where the complex vessels were noted.
Doppler studies showed the endometrial mass to have a
Resistance Index of 0.46 and a Pulsatility Index of 0.61.
Impression was a Vascular Intrauterine Mass, to consider
Arteriovenous Malformation, rule out Endometrial
Pathology.
Initially patient was scheduled for pelvic laparotomy
with conservative surgery. However, preoperatively, she
had an episode of profuse vaginal bleeding with passage of
blood clots, after which she was noted to be hypotensive,
with a blood pressure of palpatory 60, and tachycardic at
130 bpm. She was stabilized with intravenous fluids and
colloids, transfused with 1 unit of fresh whole blood and
underwent emergency exploration.
The specimen consisted of a creamy, sessile mass
with irregular surface measuring approximately 3 cm
showing multiple cystic spaces, blood vessels and purplish
black cystic structure (Figure 6). Histopathology of the
specimen revealed: Arteriovenous Malformation of the
Endometrium; Simple Endometrial Hyperplasia without
Atypia (Figure 7).
Figure 6. (CASE 4) A creamy, sessile mass with irregular surface
measuring approximately 3 cm showing multiple cystic spaces,
blood vessels and purplish black cystic structures was obtained
Figure 7. (CASE 4) Histopathology of the specimen showing lack
of distinction between the arteries and veins, thickened intimal
layer and absence of capillaries.
Figure 8. (CASE 4) CT angiogram showed conglomeration of
tortuous vascular structures predominantly involving the
anterior myometrium, supplied by branch of the anterior
division of the right internal iliac artery
And 3D reconstruction of the hypervascular mass showing
conglomeration of tortuous vascular structures predominantly
involving the anterior myometrium
She was given Depo-medroxyprogesterone acetate
150mg intramuscularly once a month for 3 doses with no
recurrence of the abnormal uterine bleeding.
A year after the operation, a repeat transvaginal
ultrasound was done which showed a slightly retroverted
uterus, without any intramural or endometrial masses
noted. Color doppler studies of uterine arcuate arteries
were within normal limits (Resistance index: 0.65;
Pulsatility index: 1.16 cm).
DISCUSSION
Uterine arteriovenous malformations are incredibly
uncommon, with most literature available limited to
case reports or case series; the first of which was written
locally by Dr. JE Sy and published in 2003. The 27-year-
old presented was a G4P3 (2112) who was diagnosed
with AVM and subsequently underwent total abdominal
hysterectomy2.
The second published case was only reported in 2012
by Cacha and Moran, in which the 31-year-old patient, a
G1P1 (1001), was diagnosed through CT angiography
and underwent pelvic angiogram with transcatheter
embolization of the left uterine artery3.
AVMs are a “proliferation of arterial and venous
channels with fistula formation and an admixture of small
capillary like channels”6, which may be classified as either
congenital or acquired.
Congenital AVMs are due to the abnormal
development of primitive vascular structures. Failure of
vascular differentiation results to the multiple aberrant
connections of arteries and veins4. Large flexiform
structures formed in the mesenchyme differentiate
into mature vessels, with the embryonic components
regressing, or partially developing with the embryonic
Volume 41, Number 3, PJOG May-June 2017 43
vascular communications remaining. These AVMs are
therefore considered focal areas of inadequate vascular
development.
In contrast, acquired uterine AVMs are usually
traumatic, following damage to uterine tissue. Known
risk factors include previous curettage, cesarean
section, gestational trophoblastic diseases, exposure
to diethylstilbestrol, endometriosis, fibroids and
endometrial or cervical cancers1,4. It is suggested
that acquired AVMs are merely an “unmasking” of a
congenital type.
The lesions grow by recruiting collateral vascular
channels. Due to the hormonal stimulation during
menstrual cycles, disproportional growth may occur in
women in their 20’s, explaining the increased incidence
of subclinical AVMs in this population. Pregnancy
also appears to play a key role in the pathogenesis of
AVMs, due to the connection of arterial and venous
vessels within the myometrium during involution of the
chorioplacental villi following cessation of pregnancy5.
All 4 cases presented with a history of a previous
cesarean section or curettage. Given this background,
and the absence of earlier confirmatory imaging or prior
profuse bleeding, we may presume an acquired type of
AVM for the latter 3 cases. Case 1, although also with
a history of curettage, may be a congenital type given
its supply arising from a large central artery, that was
merely uncovered postoperatively.
The classical presentation of uterine AVM is often
one of severe uterine bleeding with no obvious cause.
The pattern of bleeding is usually intermittent and
torrential (suggestive of arterial hemorrhage), and
sometimes significant enough to require multiple blood
transfusions1. Repeated spontaneous miscarriages may
also occur owing to vascular alterations at the site of
embryonic implantation8.
The blood flow within AVMs is slow and under
low pressure because of the many capillaries present.
However histologically, in many cases, distinction
between the arteries and veins become indistinct due
to the increased venous intraluminal pressureand
secondary intimal thickening1. Congenital AVMs tend to
have multiple feeding arteries, draining veins, and an
intervening nidus, whereas acquired AVMs, which form
between intramural arterial branches and the myometrial
venous plexus, tend to possess single or bilateral feeding
arteries, are not supplied by extrauterine arteries, and
do not have a nidus7.
There are several diagnostic modalities available,
including angiography, magnetic resonance imaging, and
color Doppler ultrasound. For suspected AVM, Doppler
ultrasonography and MRI are the modalities of choice,
as they not only define a uterine AVM accurately, but
44 Volume 41, Number 3, PJOG May-June 2017
may also non-invasively assess the degree of pelvic
involvement. Ultrasonographic gray scale findings of
uterine AVMs are usually subtle and nonspecific, showing
slight myometrial heterogeneity and small anechoic
spaces in the myometrium4. Diagnosis of a uterine AVM
cannot be made on gray scale sonography alone; a
supplementary Doppler study would have to be done, on
which characteristic findings would be a tangle of vessels
with multidirectional, low-resistance, high-velocity flow
producing a “color mosaic” pattern4. Doppler studies
were implemented to correctly diagnose 2 of our cases
presented, with the arteriovenous shunting and color
mosaic pattern identified. Three-dimensional Doppler
sonography also establishes additional evaluation by
showing a clearer view of the orientation of its tortuous
vessels. It is also used to monitor AVMs for response to
treatment or recurrence after embolizaiton9. Even with
the use of gray scale and color doppler, there may still be
some overlap with other pregnancy related diagnoses,
and it is important to take serum β-hCG levels into
account. β-hCG would expectedly be grossly elevated in
gestational trophoblastic diseases and weakly elevated
in retained products of conception.
Angiography, however, still remains the gold standard
for diagnosis. It would be based on the appearance of
uterine arteries feeding a tortuous hypertrophic arterial
mass, with large accessory feeding vessels, and early
drainage via enlarged veins4. It is not used commonly for
diagnostic purposes alone, but only when therapeutic
embolization is considered.
Treatment of symptomatic uterine AVM is based
on the location, the extent, and the desire for future
fertility, and clinical status of the patient. Traditionally,
hysterectomy and removal of the AVM has been the way
of treatment of such disorders. However, an effective
alternative is embolization of the uterine artery, which is
less invasive and has the benefit of fertility preservation.
Patients presenting with a single episode of bleeding
and who are hemodynamically stable may be treated
more conservatively, but If anemic or hemodynamically
unstable, should be referred for angiography and
embolization. Recurrent bleeding also necessitates
embolization but does not correlate with the size of
an AVM on imaging, but rather on the patient’s clinical
status4.
Many patients will remain asymptomatic, suggesting
that traumatic AVMs do spontaneously regress4. In
cases of recurrence, surgical treatment should be
considered. Selective ligation of the vessels supplying
the malformation is an effective treatment option
when conservative methods have failed and uterine
preservation is of primary concern. In cases of post-
menopausal women or those not desirous of pregnancy,
hysterectomy remains the treatment of choice. It is also
indicated as an emergency treatment in case of life-
threatening or refractory hemorrhage, as seen in the first
case presented.
In the cases presented, although desire for future
fertility was taken into account, a hysterectomy was
performed on case 2 due to the financial burden of
performing a more complicated procedure. However,
all other cases presented opted to preserve fertility and
underwent Bilateral hypogastric artery ligation followed
by excision of the endometrial mass and right uterine
artery embolization with gel foam respectively.
Following embolization, occurrences of pregnancy
are rare, although not impossible. Spontaneous abortion
and growth retardation have been attributed to poor
vascularization of the treated areas interfering with
placental development and maternal-fetal perfusion.
Hyperselective embolization to obstruct the affected
vessels while preserving the other arterial vessels
appears to improve the obstetric outlook10.
SUMMARY
In summary, we presented 4 cases of uterine
arteriovenous malformation, all presenting with heavy,
refractory bleeding. These cases were diagnosed using gray
scale and color Doppler studies, as well as CT angiography.
Treatment differed based on specific clinical findings,
patient status, and desire for fertility preservation.
And although more advanced interventions have been
discovered, surgical management like a hysterectomy may
still be performed when other options are unavailable
or not feasible. Diagnostic modalities and treatments
employed should be individualized to every patient’s
needs.
In a patient presenting with unexplained, intermittent
vaginal bleeding, especially with a history of previous
operations, or curettages, it is worth considering uterine
arteriovenous malformation as a probable cause. The
lack of any hard set rules or algorithms, as well as the
scarcity of information regarding and dealing with this
condition, emphasizes the importance of documentation
and dissemination of literature. A high index of suspicion
is necessary to properly work up and identify or exclude
this diagnosis.
REFERENCES
1. Renu A, Batra A, Saxena P, Gupta P, Minoch B. Arteriovenous
malformation of the uterus. The New Zealand Medical J.
2004; (117):1-5.
2. Sy JE. Arteriovenous Malformation of the Uterus. Phil J of
Obstet Gynecol. 2003:70-75.
3. Cacha HC, Moran JB. The role of embolization in the
management of postpartum hemorrhage and uterine
vascular malformations. Phil J Obstet Gynecol. 2012; 36
(4):189-96.
4. O’Brien P, Neyastani A, Buckley A, Chang S, Leghien G.
Uterine Arteriovenous Malformations: From Diagnosis to
Treatment. J Ultrasound Med. 2006; 25:1387-1392.
5. Kelly SM, Belli AM, Campbell S. arteriovenous malformation
of the uterus associated with secondary postpartum
hemorrhage. Ultrasound Obstet Gynecol. 2003; 21:602-5.
6. Fleming H, O ̈ sto ̈ r A, Pickel H, Fortune D. Arteriovenous
mal- formations of the uterus. Obstet Gynecol. 1989; 73:
209-213.
7. Hoffman MK, Meilstrup JW, Shackelford P, Kaminski PF.
Arteriovenous malformations of the uterus: an uncommon
cause of vaginal bleeding. Obstet Gynecol Surv. 1997;
52:736-740.
8. Polat P, Suma S, Kantarcy M, Alper F, Levent A. Color Doppler
US in the evaluation of uterine vascular abnormalities.
Radiographics. 2002; 22:47-53.
9. Levis J, Gus Gl. Uterine arteriovenous malformations.
In Clinical Emergency Medicine Casebook. Cambridge
University Press, 2009.
10. Delotte J, Chevallier P, Benoit B, Castillon JM, Bongain
A. Pregnancy after embolization therapy for uterine
arteriovenous malformation. American Society for
Reproductive Medicine, Fertility and Sterility Vol. 85, No.
1, January 2006.
Volume 41, Number 3, PJOG May-June 2017 45
 Comparison of the efficacy of metronidazole and
metronidazole plus probiotics capsule in the treatment of
bacterial vaginosis among non-pregnant patients seen at
the outpatient department of a tertiary hospital:
A single blind randomized controlled trial*
By Mary Rose Muñoz-Cruz, MD; Jennifer T. Co, MD, FPOGS and Lylah D. Reyes, MD, FPOGS
Department of Obstetrics and Gnecology, Far Eastern University - NRMF Hospital

ABSTRACT

Background: Bacterial vaginosis (BV) is the most prevalent cause of symptomatic vaginitis. In the Philippines, prevalence of BV is
at 28.16%. The mainstay for the treatment of BV is Metronidazole. Although antibiotic therapy has been shown to eliminate BV
associated organisms, there is extremely high recurrence rate.

Objective: To compare the efficacy of metronidazole and metronidazole plus lactobacilli tablet in the treatment of bacterial vaginosis
among non-pregnant patients seen at the outpatient department of a tertiary medical center.

Methodology: The population included non-pregnant women ages 15 to 44 years old, with bacterial vaginosis diagnosed by Amsel’s
criteria and Nugent’s scoring. The participants were randomly assigned to their treatment group, one is Metronidazole only and
the other received Metronidazole plus Lactobacillus tablet. All participants followed up on day 8, 15, 22 and 56 from initiation of
treatment resolution or persistence of symptoms and collection of vaginal specimen for gram stain and inquire on adverse effects.

Results: On day 8 of treatment, there were significantly more participant in the metronidazole plus probiotic arm with an estimated
lactobacilli count of more than 30/hpf as compared to metronidazole alone. On day 15 post treatment, there was no statistically
significant difference with the estimated Gardnerella vaginalis count, lactobacilli count, presence or absence of malodorous vaginal
discharge between the metronidazole plus probiotic and the metronidazole alone arm. With metronidazole plus probiotic group, the
proportion of women with less than 30 per hpf Gardnerella vaginalis count and absent foul smelling vaginal discharge were accounted
among 100% of the participants from day 8 to 56 post treatment. The early reduction in the causative agent and symptoms can be
attributed to an increase in the estimated lactobacilli count sustained until 56 days post treatment metronidazole plus probiotic.
However, from day 15 to 22 and 56 post-treatment, the proportion of participants who had a nugent’s score of less than 4 were greater
for both the metronidazole plus probiotic (100%) and metronidazole alone (95%) arm, when compared to day 8 post-treatment. This
finding for the metronidazole plus probiotic group is due to sustained reduction in the Gardnerella vaginalis count and increase in
lactobacilli counts. Potentially, the metronidazole plus probiotic treatment was found to be more favorable in sustaining the normal
flora and probiotic can be used as an adjunct may enhance the efficacy of metronidazole in the treatment of BV.

Conclusion: Metronidazole plus probiotic and metronidazole only treatment are comparable in treating bacterial vaginosis. In terms
of restoring and maintaining the normal flora, metronidazole plus probiotic appears to be more significantly efficacious. Probiotic
in the form of lactobacilli is a promising adjunct to enhance the efficacy of metronidazole in the treatment of bacterial vaginosis.

Keywords: bacterial vaginosis, BV, probiotic, lactobacilli, amsel’s criteria, nugent score, metronidazole

INTRODUCTION among women with symptoms of abnormal vaginal

B
acterial vaginosis is the most prevalent cause
of symptomatic vaginitis, with a prevalence of
approximately 15% to 50%. In the Philippines,
*Finalist, 2017 Philippine Obstetrical and Gynecological Society (POGS)
Research Paper Contest, April 6, 2017, Citystate Asturias Hotel, Puerto
Princesa City, Palawan
discharge or lower abdominal pain. Prevalence of BV is
28.16%. In women with BV, the most frequent symptom
is an unpleasant vaginal odor, which is described as
“musty” or “fishy”. The vaginal discharge associated with
BV is thin and gray-white. It is frothy in approximately
10% of women. Rarely will BV be associated with pruritus
or vulvar irritation. It also reflects a shift in vaginal flora
from lactobacilli-dominant to mixed flora, including

Volume 41, Number 3, PJOG May-June 2017 1

genital microplasmas, G. vaginalis, and anaerobes, such
as peptostreptococci, and Prevotella and Mobiluncus
species.
Bacterial vaginosis is clinically diagnosed. The
classic findings on wet smear are clumps of bacteria
and “clue cells,” which are vaginal epithelial cells with
clusters of bacteria adherent to their external surfaces
Leukocytes are not nearly as frequent as epithelial cells
underneath the microscope. The four Amsel criteria for
the diagnosis of BV are the presence of the following: (1)
homogeneous vaginal discharge; (2) vaginal discharge
pH equal to or greater than 4.5; (3) an amine-like
odor when vaginal discharge is mixed with potassium
hydroxide; and (4) clue cells greater than 20% of the
vaginal epithelial cells. Three of the four criteria are
sufficient to make a presumptive diagnosis. Ironically,
50% of women who have three of the four of the clinical
criteria for BV are asymptomatic. If readily available,
a Gram stain of vaginal secretion is an excellent
diagnostic method. The Nugent Score is a Gram stain
scoring system for vaginal smear to diagnose bacterial
vaginosis. Gram’s stain morphology score (1–10) based
on lactobacilli and other morphotypes; a score of 1–3
indicates normal flora, and score of 7–10 bacterial
vaginosis. Nugent score, showed a sensitivity of 97%
and specificity of 98%.
The mainstay for the treatment of BV is
Metronidazole. Although antibiotic therapy has been
shown to eliminate BV associated organisms, there is
high recurrence rate. Another problem that may occur
in the management of BV is resistance to antimicrobial
treatment. With the occurrence of resistance, complete
cure may not be achieved. This may then increase the
risk of developing the complications associated with
BV. These complications include: an increased risk for
susceptibility to HIV infection if exposed to the HIV
virus; development of an infection following surgical
procedures such as a hysterectomy as well the risk
for some complications in pregnancy, such as preterm
delivery and abortion.
Hence, this study would like to further investigate on
the role of an adjuvant treatment that will help eradicate
the organisms as well as promote restoration of the
vaginal flora and prevent recurrence of BV. In a study
done by Omdroff in 1998, the prophylactic use of selected
Lactobacillus was found to be potentially effective in
restoring the normal microbial flora in the vagina. Our
study would like to address this inquiry: Are metronidazole
plus probiotics and metronidazole alone be comparable
in efficacy in the treatment of bacterial vaginosis among
non-pregnant patients seen at the outpatient department
of a tertiary hospital?
2 Volume 41, Number 3, PJOG May-June 2017
OBJECTIVES
A. General Objective:
To compare the efficacy of metronidazole and
metronidazole plus lactobacilli capsule in the Treatment of
Bacterial Vaginosis among Non-Pregnant Patients Seen at
the Outpatient Department of a Tertiary Medical Center.
B. Specific Objectives:
To compare the following between Metronidazole
and Metronidazole plus Lactobacilli capsule in the
Treatment of Bacterial Vaginosis:
1. Estimated Gardenerella vaginalis count
2. Restoration of the vaginal flora
3. Presence or absence of foul smelling vaginal
discharge
4. Recurrence of symptoms
5. Nugent’s Score
Definition of Operational Terms
I. Bacterial vaginosis is diagnosed with the presence of foul-
smelling yellowish-gray vaginal discharge plus a Nugents
score reading of at least 4 or above with clue cells.
II. Independent Variable – this variable refers to the
treatment that was used in the study, encoded and
entered as:
0- Metronidazole only
1- Metronidazole with Lactobacilli capsule
III. Dependent Variables – these include the following:
a. Estimated Gardnerella vaginalis count – this
was obtained from the report of the gram-
stained vaginal discharge issued by the medical
technologist; this was interpreted, encoded, and
entered as follows:
1- few: < 10/hpf
2- moderate: 10-29 per hpf
3- plenty: ≥ 30 per hpf
b. Restoration of vaginal flora – this variable refers
to the presence of lactobacilli count and was
encoded and entered as:
0- Negative: ≤ 30 per hpf lactobacilli
1- Postive: > 30 per hpf lactobacilli
c. Vaginal discharge and foul odor – these variables
was reported as present or absent during
assessment and was encoded and entered as:
0- Absent
1- Present
d. Recurrence of symptoms – refers to the
reappearance of foul odored vaginal discharge
noted on days 8, 15, 22, and 56 post-treatment;
this was encoded and entered as:
 0- Absent
1- Present
e. Nugents’s Score – the score given by the medical
technologist after the assessment of gram stain,
this was encoded and entered as:
1- Normal: score of 1 to 3
2- Intermediate: score of 4 to 6
3- Bacterial vaginosis: score of 7 to 10 or
score of 4 to 6 with clue cells
METHODOLOGY
A. Research Design: Single Blind Randomized Controlled
Trial
B. Setting and Population
The population includes non pregnant women seen
at the Out Patient Department of a Tertiary Medical
Center ages 18 to 44 years old with bacterial vaginosis
diagnosed by Amsel’s criteria and Nugent’s scoring. Those
participants excluded are those who are diagnosed with
other vaginal infections (such as vaginal candidiasis, non
specific cervicovaginitis, trichomoniasis and other sexually
transmitted infections) abnormal uterine bleeding, active
bleeding, pregnant and lactating women, urinary tract
infection, diabetes mellitus, on-going antibiotic therapy
within 2 weeks, as well as those with hypersensitivity
reaction to the drug (metronidazole). Those participants
who were withdrawn from the study are those who had
unprotected sexual intercourse during the course of
treatment, participants who did not have any follow up
after the baseline check up and, personally, for any reason,
those participants who decided to withdraw during the
study proper.
C. Methodology Proper
All women with vaginal discharge were screened for
Bacterial vaginosis using the Amsel’s criteria. This criteria
includes presence of a homogenous vaginal discharge
with fishy or odor amine odor on application of KOH (whiff
test), pH greater than 4.5 detected by litmus paper test
and presence of densely colonized vaginal ‘clue cells’. If 3
out of 4 of the Amsel’s Criteria will be fulfilled, a vaginal
discharge specimen was collected for Gram stain. The
gram stain specimen was submitted to the laboratory for
Nugent’s Scoring. If Nugent’s score will be at 4 to 6 with
presence of clue cells or 7 or more, a diagnosis of bacterial
vaginosis will be made. Women diagnosed with bacterial
vaginosis, eligible to participate in the study were asked to
sign an informed consent.
The participants included in the trial were randomly
assigned to their respective treatment arms using
computer-generated random numbers. There were 2
treatment arms in this study. The participants assigned
in Group A were given Metronidazole, 500 mg per
tablet, was taken by the participants 2x a day on full
stomach for 7 days. For those in Group B they were given
Metronidazole plus Lactobacillus capsule 200 million unit
of lactobacillus, 1 capsule once a day at bedtime was also
taken for 7 days.
One resident was assigned to assess the presence
or absence of discharge and its odor prior to treatment.
The gram stain specimen was submitted to the clinical
laboratory and is read by 1 medical technologist for
Nugent’s Scoring. Both the resident assessor and the
medical technologist were blinded to the treatment
received by the participants. Proper disposal of the
specimen was observed. The liquid in the staining tray was
disposed in sealed bottles as hazardous waste. The slides
used were soaked in a 10% bleach solution, and then were
disposed in sharps containers.
The participants in Group A and B were instructed to
follow-up on day 8, 15, 22 and 56 to determine if there was
resolution or persistence of symptoms such as increased
volume of vaginal discharge with foul odor. Collection of
vaginal specimen for gram stain was also done. Inquiry on
adverse effects was also done during follow up.
The participants were advised to avoid douching
and intake of alcoholic beverages as well as abstain from
sexual intercourse during the whole duration of the study.
If sexual intercourse cannot be avoided, the participants
were instructed to use condom all throughout the duration
of the study. The participants were instructed regarding
the adverse effect of the medications. For metronidazole
the side effects include disulfiram-like reaction (abdominal
distress, nausea, vomiting, flushing, or headache)
when taken concurrently with ethanol; loss of appetite;
constipation; diarrhea; dizziness; headache; metallic taste;
nausea and vomiting. The adverse effect of Lactobacilli it is
usually mild gastrointestinal side effects and bloating. If the
subjects cannot tolerate the side effects of Metronidazole
or Lactobacilli, discontinuation of the treatment may be
required. Clindamycin was the alternative treatment.
Fortunately, the participants tolerated the treatment and
were able to complete the dose required.
A standard data collection tool was used during data
gathering.
D. Sample Size
The sample size calculation was based on the formula
on comparison of proportions from 2 independent
samples. The test of equality of proportions will be carried
out at 0.05 level of significance. A sample size of 103 from
each treatment arm was computed with 80% chance of
rejecting the null hypothesis of equal proportions if the
alternative holds.
Volume 41, Number 3, PJOG May-June 2017 3
DATA MANAGEMENT AND ANALYSIS was 21 to 44 years old with a mean age of 31.6 years. The
partcipants had a gravidity and parity of 0 to 6 with a mean
The data were entered and encoded using Microsoft of 2.
excel and was analyzed using Strata version 9.1. Univariate Upon inclusion in the study all participants had foul
analysis such as mean, median, mode and range were used smelling vaginal discharge. Likewise they were all noted to
to describe the age, gravidity and parity of the participants have latobacilli count of less than 30 per high power field
included in the study. Frequency distribution was used to (hpf) and also they had an estimated Gardnerella vaginalis
determine the proportion of participants with estimated count of greater than 30 per hpf. There was no statistically
G. vaginalis count category, recurrent bacterial vaginosis, significant difference with the baseline characteristics
restoration of normal flora, Nugent’s score category, as well of the participants between the 2 treatment arms. The
as presence or absence of foul smelling vaginal discharge. details can be seen in Table 1
The Chi-square or Fischer exact test were used On day 8 of treatment, a statistically significant
to compare the efficacy of metronidazole alone and difference was noted in the estimated lactobacilli count
metronidazole plus lactobacilli capsule on the reduction between metronidazole alone and metronidazole plus
of estimated Gardnerella vaginalis count, restoration of probiotic arm. There were significantly more participants
normal flora, reduction of recurrence of bacterial vaginosis, in the metronidazole plus probiotic arm with an estimated
as well as relief of foul smelling vaginal discharge. lactobacilli count of more than 30/hpf as compared to
metronidazole alone. The rest of the parameters did not
RESULTS show any statistically significant difference between the
treatment arms. (Table 2)
There were 40 participants included in the trial 20 On day 15 post treatment, there was no statistically
per treatment arm. The age range of our participants significant difference with the estimated Gardnerella
vaginalis count, lactobacilli count, presence or absence of
Table 1. Comparison of the mean demographic and proportion malodorous vaginal discharge between the metronidazole
according to clinical characteristics of participants between the plus probiotic and the metronidazole alone arm. However
metronidazole plus probiotic and metronidazole alone there were more participants with Nugents score of less
than 4 in the metronidazole plus probiotic arm compared
Metronidazole
Metronidazole
+probiotic p-value*
Parameters N=20
N=20 Table 2. Comparison of the proportion of participants according
n (%)
n (%) to clinical characteristics between the metronidazole plus
probiotic and metronidazole alone on day 8 of treatment
Age (mean in 37 34.5 0.78
years) Metronidazole
Metronidazole
+probiotic p-value*
Gravidity 1.5 4 0.40 Parameters N=20
N=20
(mean) n (%)
n (%)
Parity (mean) 1.5 3.5 0.29 Estimated 20(100) 20(100) 0.75
G. Vaginalis
Estimated 13(65) 12(60) 0.344
count
G. Vaginalis
< 30/hpf
count ≤ 30/hpf
Estimated 18(90) 12(60) 0.028*
lactobacilli
Estimated 20(100) 20(100) 1.00
count
lactobacilli
> 30/hpf
count <30/hpf
Absent vaginal 16(80) 12(60) 0.168
Vaginal 20(100) 20(100) 1.00
discharge and
discharge and
foul smelling
foul smelling
odor
odor
Nugent’s score 11(55) 7(35) 0.505*
Nugent’s score 20(100) 20(100) 0.959
<4
5 to 10 with
clue cells
• statistically significant p-value < 0.05
4 Volume 41, Number 3, PJOG May-June 2017
Table 3. Comparison of the proportion of participants according Table 4. Comparison of the proportion of participants according
to clinical characteristics between the metronidazole plus to clinical characteristics between the metronidazole plus
probiotic and metronidazole alone on day 15 of treatment probiotic and metronidazole alone on day 22 of treatment

Metronidazole Metronidazole
Metronidazole Metronidazole
+probiotic p-value* +probiotic p-value*
Parameters N=20 Parameters N=20
N=20 N=20
n (%) n (%)
n (%) n (%)

Estimated 9(45) 7(30) 0.519 Estimated 17(85) 18(90) 0.819

G. Vaginalis G. Vaginalis
count count
< 30/hpf < 30/hpf

Estimated 20(100) 20(100) 1.00 Estimated 16(80) 14(70) 0.465

lactobacilli lactobacilli
count count
> 30/hpf > 30/hpf

Absent vaginal 20 (100) 20(100) 1.00 Absent vaginal 16(80) 14(70) 0.465
discharge and discharge and
foul smelling foul smelling

Nugent’s score 18(90) 2(10) < 0.001* Nugent’s score 10(50) 12(60) 0.525
<4 <4

* statistically significant p-value < 0.05 * statistically significant p-value < 0.05

to the metronidazole alone arm. This difference was Table 5. Comparison of the proportion of participants according
statistically significant. The details of the result are to clinical characteristics between the metronidazole plus
tabulated in Table 3. probiotic and metronidazole alone on day 22 of treatment
On day 22 of treatment, there was no statistically
significant difference with all the parameters between Metronidazole
Metronidazole
+probiotic p-value*
metronidazole and metronidazole plus probiotic arm. Parameters N=20
N=20
Although, there is slightly greater proportion of participants n (%)
n (%)
with G.vaginalis count of less than 30/hpf and estimated
lactobacilli count of more than 30/hf in the metronidazole Estimated 19(95) 16(80) 0.284
plus probiotic arm. While the proportion of participants in G. Vaginalis
the metronidazole arm having a Nugents score of less than count
4 was slightly higher. (Table 4) < 30/hpf
On day 56 of treatment, there was a statistically Estimated 18(90) 14(70) 0.114
significant difference between metronidazole and lactobacilli
metronidazole plus probiotic arm with the Nugents count
score. Seventeen out of the twenty participants in the > 30/hpf
metronidazole plus probiotic arm had nugents score of less
than 4. This was only observed in half of the participants Absent vaginal 18(90) 14(70) 0.114
in the metronidazole arm. Likewise the presence of foul discharge and
foul smelling
smelling discharge vaginal discharge less commonly
among participants who belong to the metronidazole Nugent’s score 17(85) 10(50) 0.018*
plus probiotic arm but the difference was not statistically <4
significant. The rest of the parameters did not also show
statistically significant diferrence between the 2 treatment * statistically significant p-value < 0.05
arm. (Table 5)
Comparison of gram stain result and symptoms probiotic and metronidazole alone arms. On day 8 post-
before (at baseline) and after day 8, 15, 22 and 56 treatment with metronidazole plus probiotic, there was
treatment was done for both the metronidazole plus a statistically significant difference in the proportion of
Volume 41, Number 3, PJOG May-June 2017 5
participants noted on all parameters when compared
with the parameters observed before such treatment.
The results showed that on day 8 after treatment all the
participants in the metronidazole plus probiotic had less
than 30/hpf Gardnerella vaginalis count. There were more
participants in the metronidazole plus probiotic arm with
greater than 30/hpf lactobacilli count. There were fewer
participants in the same arm with a negative gram stain
smear for BV based on nugents score when compared with
those in the metronidzole arm. (Table 6)
When the results of day 15 post-treatment was
compared with the pre-treatment data, there was a
statistically significant difference in the proportion
of participants noted on all parameters for both the
metronidazole plus probiotics and metronidazole. Both
treatment arms showed a significant reduction in the
Gardnerella vaginalis count, increase in lactobacilli count,
and decrease in the nugents score in almost all participants.
A significantly greater reduction in the proportion of
participants with foul-smelling vaginal discharge was also
noted in both treatment arms. (Table 7).
Comparison of the proportions on all parameters
was also done before and after day 22 of treatment for
both the metronidazole plus probiotics and metronidazole
arms. Similar to the other post treatment results, there
was a statistically significant difference in the proportion
of participants noted on all parameters for both the
metronidazole plus probiotic and metronidazole arm
although the lactobacilli count a markedly greater
proportion of participants in the metronidazole plus
probiotic group (80%) had greater 30 count than those in
the metronidazole arm alone (30%).
Analysis on the comparison of the proportions of
participants on all parameters done pretreatment and
post treatment for both the metronidazole plus probiotics
and metronidazole alone arms also showed statistically
significant difference. The results showed that on day
56 after treatment, majority of the participants in the
metronidazole plus probiotic arm had less than 30 per hpf
of G.vaginalis count, greater than 30 per hpf lactobacilli
count, absent foul smelling vaginal discharge and negative
gram stain smear for BV based on nugents score while
there were slightly fewer participants in the metronidazole
arm had such results. (Table 9)
In this trial there were no adverse effects reported
by the participants in both treatment arms. There were
also no drop-outs noted in both the metronidazole plus
probiotic and metronidazole alone groups.
DISCUSSION
Bacterial vaginosis (BV) reflects a shift in vaginal flora
from lactobacilli-dominant to mixed flora. It is the most
prevalent vaginal infection in reproductive aged women

Table 6. Comparison of the proportion of participants according to clinical characteristics before and after day 8 of treatment with
metronidazole plus probiotic and metronidazole alone

Metronidazole +
Day 8 of Metronidazole Day 8 of
probiotic p-value*
treatment p-value* N=20 treatment
Parameters Category N=20
n (%) Before treatment n (%)
Before treatment
n (%)
n (%)

Estimated ≤ 30/ hpf 5(25) 20(100) < 0.001 8(40) 20(100) < 0.001
G. Vaginalis
count
< 30/hpf

Estimated > 30/ hpf 0(0) 18(90) < 0.001 0(0) 12(60) < 0.001
lactobacilli
count
> 30/hpf

Vaginal Present 20(100) 4(20) < 0.001 20(100) 8(40) < 0.001
discharge and
foul smelling

Nugent’s score <4 0(0) 7(35) < 0.001 0(0) 11(55) < 0.001
<4

* statistically significant p-value < 0.05

6 Volume 41, Number 3, PJOG May-June 2017
Table 7. Comparison of the proportion of participants according to clinical characteristics before and after day 15 of treatment with
metronidazole plus probiotics and metronidazole alone

Metronidazole +
Day 15 of Metronidazole Day 15 of
probiotic
treatment N=20 treatment p-value*
Parameters Category N=20 p-value*
n (%) Before treatment n (%)
Before treatment
n (%)
n (%)

Estimated ≤ 30/ hpf 5(25) 9(45) 0.17 8(40) 20(100) < 0.51
G. Vaginalis
count
< 30/hpf

Estimated > 30/ hpf 0(0) 20(100) < 0.001 0(0) 20(100) < 0.001
lactobacilli
count
> 30/hpf

Vaginal Present 20(100) 0(0) < 0.001 20(100) 0 < 0.001

discharge and
foul smelling

Nugent’s score <4 0(0) 18(90) < 0.001 0(0) 18(90) < 0.001
<4

* statistically significant p-value < 0.05

Table 8. Comparison of the proportion of participants according to clinical characteristics before and after day 22 of treatment with
metronidazole plus probiotic and metronidazole alone

Metronidazole +
Day 22 of Metronidazole Day 22 of
probiotic
treatment N=20 treatment p-value*
Parameters Category N=20 p-value*
n (%) Before treatment n (%)
Before treatment
n (%)
n (%)

Estimated ≤ 30/ hpf 5(25) 19(95) < 0.001 0(0) 20(100) < 0.001
G. Vaginalis
count
< 30/hpf

Estimated > 30/ hpf 0(0) 16(80) < 0.001 20(100) 6(30) < 0.001
lactobacilli
count
> 30/hpf

Vaginal Present 20(100) 4(20) < 0.001 20(100) 6(30) < 0.001
discharge and
foul smelling

Nugent’s score <4 0(0) 10(50) < 0.001 0(0) 12(60) < 0.001
<4

* statistically significant p-value < 0.05

Volume 41, Number 3, PJOG May-June 2017 7

Table 9. Comparison of the proportion of participants according to clinical characteristics before and after day 56 of treatment with
metronidazole plus probiotic and metronidazole alone

Metronidazole +
Day 56 of Metronidazole Day 56 of
probiotic
treatment p-value* N=20 treatment p-value*
Parameters Category N=20
n (%) Before treatment n (%)
Before treatment
n (%)
n (%)

Estimated ≤ 30/ hpf 0(0) 19(95) < 0.001 8(90) 16(80) 0.001
G. Vaginalis
count
< 30/hpf

Estimated > 30/ hpf 0(0) 18(90) < 0.001 0(0) 14(70) < 0.001
lactobacilli
count
> 30/hpf

Vaginal Present 20(100) 2(10) < 0.001 20(100) 6(30) < 0.001
discharge and
foul smelling

Nugent’s score <4 0(0) 17(85) < 0.001 0(0) 10(50) < 0.001
<4

* statistically significant p-value < 0.05

reported in 8% to 29% of cases. It is the most common
etiology of vaginal symptoms prompting medical care.
Of 3,739 women enrolled in a nationally representative
sample of the U.S. civilian non-institutionalized population
from 2001 to 2004, almost one in three (29.2%; 95%
C.I. 27.2 – 31.3) had bacterial vaginosis as diagnosed by
Gram stain of vaginal fluid. Bacterial vaginosis has been
consistently associated with adverse outcomes related
to the upper genital tract, and with increased risk of HIV
acquisition.
According to Gardner and Dukes, there is a strong
correlation between BV and the presence of Gardnerella
vaginalis. The resident Lactobacillus species in cases of
BV are replaced by an overgrowth of vaginal anaerobes
or gram-negative bacteria including Gardnerella vaginalis,
Atopobium vaginae, bacterial vaginosis-associated
bacteria, Megasphaera species, Mycoplasma hominis,
Mobiluncus species, Ureaplasma urealyticum, Prevotella,
and Peptostreptococcus species. Moreover, BV-associated
bacteria have been shown to form a prolific polymicrobial
biofilm. The main component of which was found to be
G. vaginalis and A. vaginae, that adheres to the vaginal
epithelium.
As stated in the review of related literature, effects
of untreated symptomatic bacterial vaginosis is not
life threatening, but in pregnancy it is associated with
adverse pregnancy outcomes, leading to high perinatal
mortality. This infection can also cause brain injuries in
8 Volume 41, Number 3, PJOG May-June 2017
fetuses as well as permanent neurological brain damage.
If left untreated or if treatment is inadequate due to poor
compliance, recurrence may be common. This can be an
added burden to those having such an infection. This will
then entail greater cost of treatment due to frequent visits
to the clinic for evaluation and repeated therapy with the
standard antibiotic. Repeated exposure to the antibiotic
may lead to emergence of resistant strains.
For Jean Pirre Menard et al the cure rate for bacterial
vaginosis 7 days post treatment was at 45% compared to
14 days post treatment, which is 63%. Cure rate in our
study was calculated at 67.5%. In our study the findings
of less than 30 per hpf estimated Gardnerella vaginalis
count with absent foul smelling vaginal discharge was
noted only in all participants on day 8 post treatment in
the metronidazole arm. With metronidazole plus probiotic
group, the proportion of women with less than 30 per hpf
Gardnerella vaginalis count and absent foul smelling vaginal
discharge were accounted among 100% of the participants
from day 8 to 56 post treatment. The early reduction in
the causative agent and symptoms can be attributed to an
increase in the estimated lactobacilli count sustained until
56 days post treatment metronidazole plus probiotic. With
increased lactobacilli levels overgrowth and colonization
with Gardnerella vaginalis count and other BV associated
organisms will be reduced.
Furthermore, on day 8 of treatment in our trial,
metronidazole plus probiotic arm had a significant decrease
in the estimated gardnerella vaginalis count. It was also
observed in the same arm that participants who were
observed to have significant restoration of the lactoballi,
as compared to those in the metronidazole group.
In the latter arm, restoration of the lactobacilli was
noted to be significant proportion of participants only on
day 15 and 22 post-treatment. The faster restoration of
lactobacilli in the metronidazole plus probiotic group may be
attributed to the anti microbial property of metronidazole
enhanced by the presence of lactobacillus specie that have
host protective characteristics, including hydrogen peroxide,
lactic acid and biosurfactant production, antimicrobial
activity and co-aggregation with pathogens
The proportion of the participants in the
metronidazole plus probiotic (16/20 = 80%) and
metronidazole alone (14/20 = 70%) having such score
was found to be comparable from day 8 to 22 post-
treatment. However, when the before and after treatment
analysis was done, there were more participants in the
metronidazole plus probiotic arm who had such score
as compared to those in the metronidazole arm. This
effect may be explained by achieving lactobacilli count in
shorter period of time in the metronidazole plus probiotic.
Hence, the lactobacilli count will be greater coupled with
the faster reduction in the Gardnerella vaginalis count.
This then led to attainment of a lower score. However,
from day 15 to 22 and 56 post-treatment, the proportion
of participants who had a nugent’s score of less than 4
were greater for both the metronidazole plus probiotic
(100%) and metronidazole alone (95%) arm, when
compared to day 8 post-treatment. This finding for the
metronidazole plus probiotic group is due to sustained
reduction in the Gardnerella vaginalis count and increase
in lactobacilli counts. Potentially, the metronidazole plus
probiotic treatment was found to be more favorable in
sustaining the normal flora and probiotic can be used as
an adjunct may enhance the efficacy of metronidazole in
the treatment of BV.
In bacterial vaginosis, the prominent complaint is
foul-smelling vaginal discharge. Hence, the evaluation of
the efficacy of the agent in the management of bacterial
vaginosis should not only be confined to lowering
bacterial load and restoring lactobacilli but alleviating such
bothersome symptoms as well. In the study conducted by
Cardone et al, 40 out of 45 participants reported complete
resolution of symptoms while only 3 reported a reduction
in symptomatology. In our trial, starting on day 8 post
treatment with metronidazole and metronidazole plus
probiotic, there was resolution of the vaginal discharge
and foul odor sustained up to day 56 post-treatment.
The explanation for the result can be attributed to the
antimicrobial property of metronidazole, which is cytotoxic
to the DNA molecule of the organisms causing BV, thereby
early eradication of the organisms leads to alleviation
of the symptoms. Lactobacillus species maintain the
vaginal ecosystem in a healthy condition by production of
antimicrobial substances and this might be the reason for
the sustained effect up to day 56 post treatment.
Another important factor in the management of
any disease entity or infectious process is compliance.
The adverse effect of metronidazole can be a limitation
in terms of compliance. These adverse effects include
diarrhea, dizziness or lightheadedness, headache, loss of
appetite, nausea or vomiting, stomach pain or cramps.
However, none of our patients reported such side effects.
Even the mild gastric irritation with lactobacilli was also
not noted by the patient in this trial. But still such problems
in treatment should be taken into consideration. Hence,
reassurance and proper education regarding the drug
must be emphasized to the patient.
Our study results are promising as far as management
of BV is concerned. However, we cannot make a definitive
conclusion because of our limited sample size. Hence,
it is sufficient to say that our preliminary findings for
metronidazole plus probiotic are potentially more
favorable than metronidazole alone in managing BV
among patients. We cannot generalize the results since it
was only done at our outpatient department among non-
pregnant patients. Hence, our population may not be truly
representative of the diverse characteristics of patients
with such infection usually encountered in the clinics.
CONCLUSION
Our trial showed that the metronidazole plus probiotic
and metronidazole only treatment are comparable in
treating bacterial vagnosis. However, in terms of restoring
and maintaining the normal flora, metronidazole plus
probiotic appears to be more significantly efficacious.
Thereby, maintaining a suppressive effect in the
proliferation of Gardnerella vaginalis. Probiotic in the form
of lactobacilli is a promising adjunct to enhance the efficacy
of metronidazole in the treatment of bacterial vaginosis.
RECOMMENDATIONS
To be able to make a definitive conclusion further
study should be done with a wider population. The
follow up period should be extended up to 90 days post
treatment to further evaluate the effect on long term
prevention of the recurrence of bacterial vaginosis. This
is important since recurrence is a vital issue in providing
adequate cure for those women who had previous
infection with bacterial vaginosis. Thereby, further aids in
preventing the recurrence of the bothersome symptoms
of the infection.
Volume 41, Number 3, PJOG May-June 2017 9
REFERENCES
1. Boris, Soledad, et al, Adherance of Human Vaginal Lactobacilli
to Vaginal Epithelial Cells and Interactions with Uropathogens,
1997.
2. Bradshaw, et al, Efficacy of Oral Metronidazole with Vaginal
Clindamycin or Vaginal Probiotic for Bacterial Vaginosis,
November 2011.
3. Carr et. al. Evaluation and management of vaginitis. Journal of
Global Information Management. 1998; 13:339-341.
4. De-Vera, et al, Comparison of the Efficacy of Hydrogen Peroxide
with Metronidazole and Metronidazole alone in the treatment
of bacterial vaginosis among women ages 18 to 42 years old at
the Out Patient Department in a Tertiary Medical Center from
November to December 2013: A Preliminary Report an Open
Labelled Randomized Control Trial, 2013.
5. Dover, et al, Natural Antimicrobials and their Role in Vaginal
Health: A Short Review, National Institute of Health, 2008.
6. Fredericks DN et al, Molecular Identification of Bacteria
Associated with Bacterial Vaginosis, England Medicine, 2005.
7. Katz et al, Comprehensive Gynecology 5th edition, Mosby
Philadelphia, 2007 pp 590-591.
8. Koumans et al, The Prevalence of Bacterial Vaginosis in the
United States, 1993.
9. Larsson, et al. Extended antimicrobial treatment of bacterial
vaginosis combined with human lactobacilli to find the best
treatment and minimize the risk of relapse, BMC, Infectious
Disease, 2011.
10. Leitich H, Bodner-Adler B, Brunbauer M, Kaider A, Egarter C,
Husslein P. Bacterial vaginosis as a risk factor for preterm delivery:
A meta-analysis. Am J Obstet Gynecol. 2003; 189(1):139-147.
[PubMed: 12861153]
10 Volume 41, Number 3, PJOG May-June 2017
11. Ling Z. et al. The restoration of vaginal microbiota after treatment
for bacterial vaginosis with metronidazole or probiotics. Microb
Ecol. 2013 Apr; 65(3):773-80.
12. Lugo-Miro VI, Green M, Mazur L. Comparison of different
metronidazole therapeutic regimens for bacterial vaginosis.
JAMA. 1992; 268:92-95.
13. Jean-Pierre Menard. Antibacterial treatment of bacterial
vaginosis: current and emerging therapies. International Journal
of Women’s Health. 2011; 3:295-305.
14. Mochtar, et al, Oral Lactobacillus and Metronidazole in the
Management of Bacterial.
15. Vaginosis in Pregnant Woman: A Double Blind Randomized
Controlled Trial, 2007.
16. Nugent RP, Krohn MA, Hillier SL. Reliability of diagnosing bacterial
vaginosis is improved by a standardized method of gram stain
interpretation. J Clin Microbiol. 1991.
17. Richard Beigi et al, Factors Associated with Absence of H2O2-
Producing Lactobacillus among Women with Bacterial Vaginosis,
The Journal of Infectious Diseases, Volume 191.
18. Sweet RL. Gynecologic conditions and bacterial vaginosis:
implications for the non-pregnant patient. Infect Dis Obstet
Gynecol. 2000; 8(3-4):184-190. [PubMed: 10968604]
19. J Wilson, Managing recurrent bacterial vaginosis, Sex Transmitted
Infection 2004; 80:8-11 Vol:10.1136/sti.2002.002733.
20. NCBI, Probiotics in the prevention of BV recurrence, 2014.
21. Cardone et al, Utilization of hydrogen Peroxide in the treatment
of Recurrent Bacterial Vaginosis. Minerva Gynecol. 2003; 55:
483-92.
 “Hairy potty”
Ovarian dermoid cyst with fistula to bladder*
By Sheryl M. Deterala, MD; and Alma Bella G. Rivera, MD, FPOGS
Department of Obstetrics and Gynecology, Bicol Regional Training and Teaching Hospital

ABSTRACT

Dermoid cysts are usually asymptomatic until complications occur. Spontaneous rupture of a dermoid into an adjacent organ
is a rare complication and no such case has been reported in the Philippines.
A 24-year-old primipara consulted for pilimiction. Three years earlier, she had recurrent urinary tract infection and was
diagnosed to have a dermoid cyst. Left untreated, the cyst grew in size and urinary symptoms worsened. Ultrasound, CT scan and
subsequent laparotomy revealed that the dermoid cyst has penetrated the bladder wall resulting to fistula formation between
the dermoid and the urinary bladder. Hair and sebum were seen inside the bladder. A left salpingo-oophorectomy and partial
cystectomy of the urinary bladder were done.
The first locally documented case of an ovarian dermoid cyst with fistula to the bladder is presented. A review of literature is
made, the predisposing factors, possible cause, diagnosis and management are discussed.

Keywords: dermoid cyst, primipara, pilimiction, fistula, salpingo-oophorectomy, cystectomy

INTRODUCTION Menarche was at age 14. Subsequent menses

M
ature cystic teratomas or dermoid cysts are
the most common benign germ cell tumor of
the ovary. They may occur at any time during
the woman’s reproductive years but are commonly
seen in young females. Ovarian dermoids are usually
asymptomatic and often discovered incidentally.
Symptoms are observed in the presence of complications
like torsion, infection, hemorrhage, or rupture.1 Torsion
is the most frequent complication while fistula formation
between the benign cystic teratoma and surrounding
organs such as the urinary bladder, colon, or rectum is
one of the least common. When such a communication
occurs, the bladder is the most common site.2 There have
been a few reported cases of fistula formation between
a dermoid cyst and an adjacent organ in foreign journals.
However, in a review of the locally published literature,
this is the first documented case of this rare complication.
CASE REPORTS
J.B., a 24-year-old G1P1 (1001), from Legazpi City, was
admitted for the first time to our institution last October 6,
2015 with a chief complaint of inability to void.
Her past medical, family and personal history are
non-contributory.
*Finalist, 2016 Philippine Obstetrical and Gynecological Society (POGS)
Interesting Case Paper Contest, August 18, 2016, 3rd Floor POGS
Building, Quezon City
were at regular monthly intervals, lasting 4-7 days, with
3 moderately soaked napkins per day. No history of
dysmenorrhea. Her last normal menstruation was on the
3rd week of September 2015.
She is a Gravida 1 Para 1 (1001). She had an
uncomplicated full term spontaneous vaginal delivery last
June 6, 2012. Prenatal check-ups were at a health center,
no pelvic ultrasound was done.
The history of present illness started 3 years prior to
admission when the patient palpated a soft, tender, fist-
sized hypogastric mass associated with on and off fever
and urinary frequency. These symptoms were noted about
six months after her vaginal delivery. She consulted a
private doctor and was treated for urinary tract infection.
A transvaginal ultrasound showed a dermoid cyst. She
was referred to our institution, was advised laparotomy
however the patient was lost to follow up.
One year prior to admission, she again experienced
urinary frequency and occasional dysuria. She self-
medicated with Cefuroxime which relieved her symptoms.
No consult was done.
Eight months prior to admission, the mass was noted
to have increased in size to approximately 8 cms. Urinary
frequency persisted and dysuria became more frequent.
She also noticed oil droplets or sebum in her urine, later
accompanied by occasional passage of hair or pilimiction.
Still, no consult was done.
4 months prior to admission, there was persistence
and worsening of her urinary symptoms. She had to pull
tufts of hair from her urethra just to be able to void. She

22 Volume 41, Number 3, PJOG May-June 2017

sought consult in our institution, was prescribed Cefuroxime
for her UTI and scheduled for pre-operative evaluation.
However, the patient was again lost to follow up.
One month prior to admission, she returned to
our institution and was presented at the OB-GYN pre-
operative conference. Strands of hair were seen coming
out of her urethra (Figure 1). An 8 x 8 cm cystic to doughy
mass was palpated anterior to the normal-sized corpus.
A repeat transvaginal ultrasound confirmed the presence
of a left ovarian dermoid cyst but with a much bigger size
of 11.3 x 10.5 x 9.9 cms. The uterus and the right ovary
were normal. Hyperechoic linear structures were also
Figure 1. Strands of hair coming out of patient’s urethra.
seen within the bladder (Figure 2). A fistula to the urinary
bladder was entertained so an outpatient referral to the
Urology Service was made.
One day prior to admission, she experienced severe
hypogastric pain and was unable to void. She was brought
to the emergency room and was subsequently admitted
by the Department of Surgery with a diagnosis of bladder
mass, to consider dermoid cyst.
On admission under the service of Surgery, the patient
was conscious, coherent, and not in cardiorespiratory
distress with the following vital signs: BP: 120/70 mmHg,
CR: 81/minute, RR: 22/minute, Temp: 36.5°C. An indwelling
foley catheter was inserted. CBC revealed mild anemia
with Hgb of 95 and Hct of 0.29. Urinary tract infection
was confirmed with >50 pus cells seen on urinalysis. BUN
and creatinine were normal. Whole abdominal CT scan Figure 2. Transvaginal ultrasound of the patient showing
with contrast was requested and cystoscopy with biopsy dermoid cyst and hyperechoic linear structures within the
urinary bladder.
was planned. Co-Amoxiclav 600 mg IV q12 hours and
Paracetamol 300 mg IV q6 hours were started.
On the 3rd hospital day, whole abdominal CT scan
with contrast was done which revealed dermoid cyst with
contained rupture and suspicious communication with the
urinary bladder at the vesical dome (Figure 3). Cystoscopy
was deferred and she was referred to the Department of
OB-GYN.
On the 5th hospital day, patient was transferred to the
OB-GYN ward. She was conscious, coherent, ambulatory,
and with normal vital signs. Pertinent physical examination
findings centered on the abdomen and the pelvis, there
was an 8 x 8 cm doughy mass at the hypogastric area.
The mass was slightly tender and with limited mobility.
Pelvic examination revealed normal external genitalia and
parous vagina. The cervix was firm, closed and smooth, Figure 3. Patient’s CT scan with contrast showing communication
the corpus not enlarged. A slightly tender, cystic to between the dermoid cyst and the urinary bladder.
doughy mass measuring 8 x 8 cm was palpated superior
and anterior to the uterus. The admitting diagnosis was under spinal anesthesia. On laparotomy, the left ovary
Gravida 1 Para 1 (1001), Ovarian New Growth, left, most was converted into a cystic to doughy mass measuring
likely a Dermoid Cyst with probable fistula to the bladder. 8 x 7 x 4 cm with a smooth, opaque white capsule. The
The patient was prepared for an elective pelvic laparotomy mass was partially twisted on its pedicle and was densely
to be done together with the surgery residents. adherent to the urinary bladder (Figure 4). Attempts at
On the 8th hospital day, the patient underwent surgery adhesiolysis revealed a fistulous connection between

Volume 41, Number 3, PJOG May-June 2017 23


Figure 4. Partially twisted dermoid cyst densely adherent to the
urinary bladder. Hair and sebum are seen inside the bladder.
the cyst and the urinary bladder (Figure 5). Tangled mass
of hair and sebaceous fluid were seen inside the urinary
bladder (Figure 4). The corpus, the right ovary and both
fallopian tubes were grossly normal. There was no ascites
nor spillage of the contents of the dermoid cyst into the
peritoneal cavity. A left salpingo-oophorectomy and
partial cystectomy of the urinary bladder were done. Cut
section of the mass showed a unilocular cyst containing
pockets of sebum and hair. There were no solid areas,
no necrosis nor hemorrhages. Her post-operative course
was uneventful.
On the 12th hospital day, her 4th post-op day, patient
Figure 5. Fistulous connection between dermoid cyst and
urinary bladder.
was discharged with the indwelling foley catheter retained
for 6 more days. Home medications were Cefuroxime 500
mg BID to complete 7 days, FeSO4 1 tab OD for 1 month
and Celecoxib 200 mg BID for pain.
The patient came for follow up on her 10th post-op
day. Her urinary symptoms were resolved and the surgical
wound was dry and well coaptated. The foley catheter
was removed and she was able to void spontaneously.
24 Volume 41, Number 3, PJOG May-June 2017
Final histopathologic result of the specimens
submitted revealed a mature cystic teratoma, ovary, left,
adherent to the bladder, both with severe acute and
chronic inflammation (Figure 6). No diagnostic abnormality
recognized, fallopian tube, left.
Figure 6. Histopath picture of the specimen submitted showing
ovarian and urinary bladder tissues.
FINAL DIAGNOSIS:
Gravida 1 Para 1 (1001)
Dermoid Cyst, Left Ovary, with Fistula to the Urinary
Bladder
Operative Procedure done:
Exploratory Laparotomy
Left Salpingo-oophorectomy with Partial Cystectomy,
Urinary Bladder under SAB
DISCUSSION
Mature cystic teratomas are benign cystic structures
that contain mature cell elements from all three germ cell
layers. The term dermoid cyst is often used interchangeably
with the term mature cystic teratoma. Dermoid is a
descriptive term that emphasizes the preponderance of
ectodermal tissue. Dermoid cysts contain mostly dermal
and epidermal elements like hair, skin, sebaceous glands
and sometimes even nails and teeth.1
Benign teratomas are slow-growing tumors that may
occur from infancy to the postmenopausal years with
more than 50% seen in women between the ages of 25
and 50 years. Dermoids are the most common ovarian
neoplasm in prepubertal females and are also common in
teenagers.1
The patient was 24-years-old on admission but was
diagnosed to have a dermoid cyst three years earlier, at
age 21. Since dermoid cysts are slow-growing tumors, she
may have had the cyst for years, possibly even during her
prepubertal or teenage years.
 About 50 - 60% of dermoids are asymptomatic and
are usually discovered incidentally during a routine pelvic
examination, during pelvic imaging, or at laparotomy.
Symptoms of pain and pelvic pressure are often reported in
the presence of complications. Torsion is the most frequent
complication (16%) and is commonly seen in young women.
Rupture (1-4%) is more common in pregnancy. Infection,
hemorrhage, malignant degeneration, and invasion
into an adjacent viscera are all unusual complications of
dermoids, occurring in less than 1% of patients.1,2 Fistula
formation between a benign cystic ovarian teratoma and
an adjacent organ is a rare occurrence with the urinary
bladder as the most commonly involved.2
There have been a few documented cases of dermoid
cyst with fistula to adjacent organs in foreign journals but
none locally.
T. Nagamaniet.al. reported a case of a 32-year-old
parous woman with straining at micturition, narrow
stream, passing hair or pilimiction and turbid urine
occasionally. On cystoscopy, hair ball was visualized.
CECT demonstrated an ovarian dermoid cyst invading
the urinary bladder. TAHBSO and partial cystectomy were
done. The diagnosis of fistulous tract between ovarian
dermoid with bladder was confirmed.3 Kaniz Zehra Naqvi
et.al. also reported a case of a 25-year-old nulliparous
female who presented with lower abdominal pain and
pilimiction. Examinations revealed a right sided dermoid
which had penetrated the wall of bladder and expelled its
contents in the bladder.4 Rantomalala et al. discussed a
case of a right ovarian dermoid cyst which fistulated to the
bladder who presented with recurrent urinary infection.5
Tandon et al. presented a case of a 30-year-old woman
with pyuria and dysuria, where ultrasound examination
clearly demonstrated an ovarian dermoid cyst invading
the urinary bladder. Pathologic evaluation confirmed the
diagnosis.2 Mohammad Mehdi Hosseini et. al. reported a
case of a 63-year-old woman with prolonged dysuria and
hematuria who had bilateral ovarian dermoid cysts with
urinary bladder involvement.6
Fistula to other organs such as the colon and rectum
were also reported. Landmann et. al. has reported a
benign ovarian teratoma that fistulated to the rectum
which presented with rectal bleeding and a polypoid
mass in the rectum.7 Khanna et. al. reported the case
of an 18-year-old woman who had a left teratoma that
ruptured into the sigmoid colon and a 39-year-old woman
with lower abdominal pain and hematochezia which, upon
evaluation, had a mass in the anterior rectal wall from a
benign cystic teratoma in her left ovary.8
Patients with spontaneous rupture of a dermoid
cyst into the bladder may present with complaints such as
pilimiction, pyuria, hematuria or passage of other material
from a dermoid cyst and at times repeated episodes of
urinary retention due to blockage of urethral meatus by hair.2
The patient presented with passage of hair in urine
which is a pathognomonic sign, recurrent UTI and difficulty
in voiding due to blockage of the urethral meatus with
clumps of hair.
Various etiologies have been postulated for fistula
formation in dermoid cyst. Shiels et. al. reported a case
of entero-ovarian dermoid cyst fistula and suspected that
a small leak from the cyst caused dense adhesions with
the bowel resulting in fistula formation.9 Peterson et al.
found that torsion, trauma, infection, chronic pressure
in labor and malignant transformation can cause leakage
and fistulation.10 Chronic leakage thus appears to be a
common denominator in non-malignant fistulation with
adjacent viscera.2
In this case, torsion of the dermoid cyst and the
patient’s pregnancy and labor may have predisposed her
to the fistula formation. Very significant and relevant in the
patient’s history is the fact that all her urinary symptoms
started six months following her vaginal delivery. The
patient may have had the dermoid cyst for a long time
but it remained asymptomatic until after her pregnancy
and delivery. Chronic pressure on the dermoid cyst during
her pregnancy and labor could have led to focal ischemic
necrosis of the cyst wall which resulted to slow leakage,
causing dense adhesions with the bladder, and eventually
fistula formation.
A diagnosis of a dermoid cyst is considered when on
pelvic examination, a semisolid mass is palpated anterior
to the broad ligament. Ultrasound has a more than 95%
positive predictive value and a less than 5% false positive
rate in detecting dermoid cysts. Most dermoids have a
characteristic ultrasound picture: a dense echogenic area
within a larger cystic area, a cyst filled with bands of mixed
echoes, and an echoic dense cyst.1
Fistula formation between a dermoid cyst and the
urinary bladder is suspected because of the patient’s
symptoms and the findings on abdominal and pelvic
examination. Diagnosis may be confirmed by ultrasound
and CT scan as what happened in this case.
The patient had recurrent urinary tract infection,
pilimiction and ended up unable to void. On pelvic
examination, a cystic to doughy mass was palpated
anterior to the uterus. Transvaginal ultrasound showed
the “typical picture” of a dermoid cyst. Also seen were
hyperechoic linear structures within the urinary bladder
which suggested a fistula formation between the dermoid
cyst and the urinary bladder. The whole abdominal CT
scan confirmed this pre-operative diagnosis.
As to the management of benign cystic teratomas,
cystectomy is the procedure of choice in premenopausal
women where normal ovarian tissue is still appreciated.
Unilateral oophorectomy or salpingo-oophorectomy is
Volume 41, Number 3, PJOG May-June 2017 25
indicated in patients in whom ovarian tissue cannot be
preserved, and when there is involvement of the fallopian
tube particularly in large-sized masses.11
In this case, a left salpingo-oophorectomy was done
because intraoperatively, no remaining normal ovarian
tissue was seen. As in previously reported cases, partial
cystectomy of the bladder had to be done.
SUMMARY AND CONCLUSION
In summary, an unusual case of a dermoid cyst with
fistula to the urinary bladder in a 24-year-old primipara
was presented. Rupture or perforation of the contents of
REFERENCES
1. Vern L. Katz. Benign Gynecologic Lesions, Comprehensive
Gynecology, 2012 (6th edition).
2. A. Tandon, K. Gulleria, S. Gupta, S. Goel, S. K. Bhargava and N.
B.Vaid, Mature ovarian dermoid cyst invading the urinary bladder,
Article first published online: 9 DEC 2009.
3. T. Nagamani, Vani Isukapali, Nimmana Swathi Priya, Manoj Kumar.
Ovarian Cystovesical Fistula causing Pilimiction: An Unusual
Complication of Ovarian Cyst. Department of Urology, King George
Hospital, Visakhapatnam, Andhra Pradesh, India, 2015.
4. Kaniz Zehra Naqvi, Aziz Abdullah, Maria Jabeen, Farah Iqba, and
Muzzamil Edhi. Ovarian Dermoid Causing Pilimiction, Journal of
the College of Physicians and Surgeons Pakistan. 2015; Vol. 25 (1):
71-72 71.
5. Rantomalala HY, Raveloson JR, Rakotoarisoa B, Rabesata JO,
Tovone XG. Bladder fistula of an ovarian dermoid cyst. Ann Urol
(Paris). 2003; 37(3):102-4.
6. Mohammad Mehdi Hosseini, ShahrokhJahanbini, Sara Pakbaz,
Shahryar Zeighami. Bilateral Ovarian Dermoid Cyst with Bladder
Involvement and Hematuria: A Case Report and Literature Review,
Middle East Journal of Cancer; October 2014; 5(4): 225-228
Nephrology-Urology Research Center, Shiraz University of Medical
Sciences, Shiraz, Iran.
26 Volume 41, Number 3, PJOG May-June 2017
the dermoid cyst into an adjacent organ like the urinary
bladder may be extremely rare but should be promptly
attended to as it could lead to grave consequences. A
complete history, a thorough physical examination, a high
index of suspicion and the use of appropriate diagnostic
modalities like ultrasound and CT scan help in making
an early and correct diagnosis of such a case. A rational
approach in the management by a multidisciplinary team
that includes obstetrician-gynecologists and surgeons
would best benefit the patient. Most important too
would be the cooperation and compliance of the patient
and her family.
7. Landmann DD, Lewis RW. Benign cystic ovarian teratoma with
colorectal involvement.Report of a case and review of the
literature. Dis Colon Rectum. 1988; 31(10):808-13.
8. Khanna S, Srivastava V, Saroj S, Mishra SP, Gupta SK. An unusual
presentation of ovarian teratoma: a case report. Case Rep Emerg
Med. 2012; 2012: 845198.
9. Shiels WE, Dueno F, Hernandez E. Ovarian dermoid cyst
complicated by an entero-ovarian fistula. Radiology. 1986; 160:
443-444. 5.
10. Peterson WF, Prevost EC, Edmunds FT, Hundley JM Jr, Morris FK.
Benign cystic teratomas of the ovary: a clinico-statistical study of
1007 cases with a review of the literature. Am J Obstet Gynecol.
1955; 70:368-382.
11. Clinical practice guidelines on myoma and adnexal masses,
Philippine Obstetrical and Gynecological Society (Foundation),
Inc., November 2010.
 Human chorionic gonadotropin surveillance in
hydatidiform mole: A need for reevaluation*
By Marie Christine Valerie R. Mendoza, MD; Melissa Lourdes B. De Quiros, MD
and Agnes L. Soriano-Estrella, MD, MHPEd, FPOGS, FPSSTD
Department of Obstetrics and Gynecology, Philippine General Hospital, University of the Philippines-Manila

ABSTRACT

Introduction: Serial beta human chorionic gonadotropin (βhCG) monitoring after molar evacuation is advised for early detection
of persistent trophoblastic disease. The aim of this study was to determine the percentage of patients who developed post-molar
gestational trophoblastic neoplasia during a 6-month follow up period after normalization of βhCG titers to that during a 12-month
follow up period in order to ascertain the appropriate period of βhCG surveillance for patients who underwent treatment for molar
pregnancy.

Methods: Data was analyzed from the Section of Trophoblastic Diseases at the Philippine General Hospital - Department of
Obstetrics and Gynecology to estimate the incidence of persistent trophoblastic disease among 258 women with molar pregnancy
from 2000-2011.

Results: Among the 258 registered hydatidiform mole patients, 205 patients (79.5%) attained normal βhCG titers titer levels after
evacuation of molar products. There was no occurrence of postmolar gestational trophoblastic neoplasia among patients who
achieved normalization of βhCG titers after treatment. βhCG levels did not attain normalization following evacuation in 53 patients
(20.5%). Out of the 53 patients, 50 patients (94.3%) were detected to have gestational trophoblastic neoplasia within the first six
months post-treatment. Only 3 patients (5.7%) were determined to have disease progression after six months during the one-year
follow-up period.

Conclusion: The follow-up period after a molar pregnancy may be reduced for patients whose serum βhCG levels spontaneously
decline to normal levels after evacuation. The results of this study showed that the median time to obtaining normal βhCG levels is
88 days for those who received chemoprophylaxis and 85 days for those with lower initial βhCG values (less than 100, 000 mIU/ml).

Keywords: human chorionic gonadotropin, hydatidiform mole, surveillance

INTRODUCTION patients with persistence of disease after molar pregnancy,

H
ydatidiform moles are abnormal conceptions
with excessive placental proliferation, and little
or no fetal development. Its incidence varies
worldwide. In North America, the incidence is 0.6 to 1.1
per 1000 pregnancies. This value is three times higher
in Asia.2 In the Philippines, the prevalence rate is 2.4 per
1000 pregnancies. At the Philippine General Hospital, the
prevalence increases to 14 per 1000 pregnancies.3
The risk of persistent trophoblastic disease (PTD) or
gestational trophoblastic neoplasia (GTN) after a complete
mole is 15-25 percent while the risk is lower for partial
mole which is 0.5 to 4 percent.4 Due to these numbers,
patients are advised to have serial beta human chorionic
gonadotropin (βhCG) monitoring after molar evacuation
for early detection of PTD. To guide us in recognizing
* Oral presentation, XVIII World Congress, International Society for the
Study of Trophoblastic Diseases, Bali, Indonesia, Sept. 15-18, 2015
the International Federation of Gynecology and Obstetrics
has established the following guidelines for the diagnosis
of persistent tumor after molar pregnancy: high levels
of βhCG more than 4 weeks post-evacuation (serum
level of 20, 000 mIU/ml, urine level of 30, 000 mIU/ml),
a rise in βhCG of 10% or greater (2 consecutive weekly
determination), plateauing βhCG values (<10% rise or
decline) at any time after evacuation (minimum of 3
consecutive weekly determinations), clinical or histologic
evidence of metastasis at any site, persistently elevated
βhCG titer at 14 weeks post-evacuation, and elevation of
a previously normal βhCG titer after evacuation provided
the diagnosis of pregnancy is excluded.5
Differences in recommendations for βhCG
surveillance following molar evacuations have prompted
investigators to determine the appropriate frequency
and duration of monitoring. The American College of
Obstetricians and Gynecologists recommends serum βhCG
levels to be determined every 1 to 2 weeks in all patients
while the levels are elevated and then at monthly intervals
Volume 41, Number 3, PJOG May-June 2017 11
for an additional 6 months once the levels become
undetectable (<5 mIU per milliliter).6 In the study by
Kerkmeijer and colleagues, weekly βhCG measurements
are recommended for all patients until normal levels are
achieved. For patients who achieved normal βhCG levels
within 2 months after evacuation, it was deemed safe to
discontinue monitoring.7
In the study by Sebire, et al., the policy of extended
(2 years) follow up was evaluated. Three women developed
postmolar gestational trophoblastic disease at 402, 677
and 1267 days after evacuation following spontaneous
normalization of βhCG levels. Only one woman was
detected by routine extended follow up. The protocol in
United Kingdom was then revised to recommend a follow
up of 6 months after spontaneous return of βhCG levels to
normal for all women.10 In another study by Pisal, et al.,
a less intensive follow up was recommended for patients
with normal βhCG titers, however, a definite period was
not stated.11
Currently, there are varying recommendations
for the monitoring of βhCG following evacuation of a
molar pregnancy. Worldwide, follow-up of βhCG levels
for gestational trophoblastic disease is increasingly
individualized. The follow-up period can be as short as 56
days and can even extend to 2 years. Follow-up continues
indefinitely because it is unclear when it is safe to cease
monitoring.4 In our country, the Philippine Society for
the Study of Trophoblastic Diseases, Inc. recommends
measurement of the βhCG titer one week after molar
evacuation then every two weeks until the level becomes
normal for three determinations. Normal βhCG is defined
as less than 5 mIU/mL. The monitoring is then decreased
to every month for six months followed by every 2 months
for 6 months. This equates to a period of one year after
three normal βhCG titers.3
This study was therefore undertaken to determine
the appropriate period of βhCG surveillance for patients
who underwent treatment for molar pregnancy. Given
the current follow up of one year in the Philippines, the
question arises whether this period may be reduced to six
months. Once the period is decreased to six months, this
will provide several advantages for the patients in terms
of cost reduction and decreased anxiety associated with
anticipating the development of malignancy. This will also
solidify the practice that patients with molar pregnancy
are allowed to be pregnant six months after treatment.
OBJECTIVES
General Objective
To compare the percentage of patients who developed
post-molar gestational trophoblastic neoplasia during the
6-month follow up period following normalization of βhCG
12 Volume 41, Number 3, PJOG May-June 2017
titers to that during the 12-month follow up period
Specific Objectives:
1. To determine the incidence of postmolar GTN during
the period of January 2000 to December 2010
2. To determine the difference in the incidence of
gestational trophoblastic neoplasia after a complete
and partial hydatidiform mole
3. To determine the interval from evacuation of molar
products to development of gestational trophoblastic
neoplasia
4. To determine the interval from evacuation of molar
products to achieving three normal βhCG titers
METHODOLOGY
Study Design
This is a retrospective cohort study of all patients
with hydatidiform mole who were managed at the Section
of Trophoblastic Diseases at the Department of Obstetrics
and Gynecology of the Philippine General Hospital from
January 2000 to December 2010. The protocol for this
investigation was approved by the University of the
Philippines Manila Research Ethics Board (UPMREB) PGH
Review Panel. No informed consent was necessary because
there was no actual interaction with the participants of the
study. Nevertheless, personal information and research
data that were collected from the patient records were
kept confidential, and their names did not appear in the
analysis or in the reporting of the study.
Subject Selection
This study included all patients who were diagnosed
and managed as cases of hydatidiform mole at the Philippine
General Hospital from January 2000 to December 2010.
The patients should have histopathological confirmation
of hydatidiform mole, completed the prescribed 1-year
follow up period, and had complete patient data that
included all serum βhCG titers during the 1-year follow
up period. Excluded in this study were patients who had
accompanying gynecologic malignancy.
Study Procedure
The study aimed to compare the percentage
of patients who developed post-molar gestational
trophoblastic neoplasia during a 6-month follow up period
to that during a 12-month follow up period.
Data for all patients with hydatidiform mole who were
admitted and managed at the Section of Trophoblastic
Diseases at the Department of Obstetrics and Gynecology
of the Philippine General Hospital between the dates of
January 1, 2000 to December 31, 2010 was gathered
from the case registries of the Section of Trophoblastic
Diseases. A detailed review of each patient’s hospital
record was conducted. For each patient included in the
study, the following data was extracted and recorded in
a patient data form:age, gravidity and parity, βhCG titers
taken upon admission and during the follow-up period,
procedure for molar evacuation, type of hydatidiform
mole, chemoprophylaxis, outcome (development of GTN,
achievement of normal βhCG titer), and number of days
to progression to GTN or attainment of normal βhCG titer.
Diagnosis of postmolar gestational trophoblastic
disease was based on the following parameters:
1. High level of hCG more than 4 weeks post-evacuation
(serum level of 20,000mIU/ml)
2. Progressively increasing or plateauing hCG values
at any time after evacuation (minimum of 3 weekly
determinations)
3. Clinical or histologic evidence of metastasis at any
site
4. Persistently elevated hCG titer at 14 weeks post-
evacuation
5. Elevation of a previously normal hCG titer after
evacuation provided the diagnosis of pregnancy is
excluded.
The data extracted by the investigator from the
charts and all the information were manually entered
into a spreadsheet and processed using Microsoft Excel
computer software.
RESULTS
During the period of January 1, 2000 to December
31, 2010, there were 258 patients diagnosed with
hydatidiform mole and were subsequently managed by the
Section of Trophoblastic Diseases at the Philippine General
Hospital. Table 1 presents the baseline demographic
factors of patients. The age of patients diagnosed with
hydatidiform mole ranged from 16 years to 52 years with
a mean of 30.81 years. The gravidity ranged from 1-7
with a mean of 3.22, and the parity ranged from 0-6 with
a mean of 1.96. There were 196 patients (75.97%) who
underwent the more conservative form of evacuation of
hydatidiform mole which is suction curettage while 62
patients (24.03%) underwent total hysterectomy with
mole-in-situ. On histopathology, 215 patients (83.3%) had
findings consistent with complete mole while 43 patients
(16.6%) had partial mole. After evacuation, a majority
of patients (202 patients out of 258 or 78.29%) received
chemoprophylaxis in the form of Methotrexate.
Normalization group
There were 205 patients (79.45%) who were able to
achieve normal βhCG titer levels after treatment. More
than half of the patients were younger than 35 years, and
only 66 patients (25.58%) were greater than 35 years of age.
In terms of baseline βhCG titer levels, 84 patients (40.98%)
had values greater than or equal to 100, 000 mIU/ml. There
were 168 patients (81.95%) who had histopathologically

Statistical Analysis Table 1. Distribution of Characteristics among Sample Population

Data processing and analysis were carried out using
the CDC Epi Info 7. Summary data were reported as means
with standard deviations for continuous variables, survival- All Subjects (n=258)
computed median weeks to events and hazard ratios with
95% confidence intervals, and proportions (percentages)
for categorical data, which were compared with Demographic N %
contingency table (χ2) or Fisher’s exact test (p). Statistical
Age >35 years old 76 29.46
tests of hypotheses were two-sided, at a=p≤0.05.
First pregnancy 78 30.23
Kaplan-Meier survival analyses determined median
weeks to start of a first recurrence with 95% confidence Gravida >4 94 36.43
intervals (CIs), with unadjusted univariate Mantel-Cox log- Baseline 110 42.64
rank tests to compare survival times between groups. Cox β-HCG≥100,000
multivariate proportional hazards modeling estimated the Complete molar 215 83.33
hazard ratio and 95% CI for median time to persistence pregnancy
between the groups, with adjustment for predictors of
persistence suggested by preliminary univariate analyses. Partial molar pregnancy 43 16.67
Logistic regression modeling was also used to evaluate risk Treatment
factors for significant and independent association with Suction curettage 196 75.97
persistence. Also, the number of patients who developed
GTN over a 6 month period and over a 12 month period Surgical management 62 24.03
following molar evacuation were determined. Chemoprophylaxis 202 78.29

Volume 41, Number 3, PJOG May-June 2017 13

confirmed results of complete hydatidiform mole while 37
patients (18.05%) had partial hydatidiform mole. Majority
of patients underwent suction curettage (n=147; 71.71%)
while 58 patients (28.29%) underwent total hysterectomy
with mole-in-situ. After evacuation, 171 patients (83.41%)
received methotrexate chemoprophylaxis (Table 2).
The median time to normal βhCG levels from the
time of evacuation of molar products was 85 days (95% CI:
74-96 days) among those who have an initial βhCG of less
than 100,000 mIU/mL (n=148), and 107 days (95% CI: 89-
125 days) among those who have an initial βhCG greater
than or equal to 100,000 mIU/mL (n=110; χ2≥3.06, df=1,p-
value>0.05), a 1.26-fold difference (Figure 1).
The median time to achieving normal βhCG levels
from the time of evacuation of molar products was 126
days (95% CI: 99-153 days) among those who did not
receive chemoprophylaxis (n=56) and 88 days (95% CI:
80-96 days) among those who received chemoprophylaxis Figure 1. Kaplan-Meier Survival Functions for Gestational
(n=202; χ2≥10.59, df=1,p-value<0.01). There was a 1.43- Trophoblastic Disease Patients controlling for Initial hCG Levels
fold difference (Figure 2).
There was no occurrence of postmolar gestational
trophoblastic neoplasia among the patients who achieved
normalization of βhCG titers after treatment.

Persistent trophoblastic disease

Among the population, 53 patients (20.5%) developed
gestational trophoblastic neoplasia. For these patients
whose disease progressed, the age ranged from 16-51
years. About 10 patients (18.87%) were greater than 35

Table 2. Distribution of Characteristics comparing the

normalization group and persistent trophoblastic disease group

Normalization Progression
pa
(n=205) (n=53)

Demographic N % N %
Figure 2. Kaplan-Meier Survival Functions for Gestational
Age >35 years old 66 32.20 10 18.87 .08 Trophoblastic Disease Patients controlling for Treatment
First pregnancy 60 29.27 18 33.96 .62
Gravida >4 81 39.51 13 24.53 .06
years old and 13 (24.53%) of them had a gravidity greater
Baseline 84 40.98 26 49.06 .37 than 4.
β-HCG≥100,000 The initial βhCG titer levels varied from as low as 10.6
Complete molar 168 81.95 47 88.68 .33 mIU/ml up to a value of greater than one million. Forty
pregnancy nine of them (92.4%) underwent suction curettage while
Partial molar pregnancy 37 18.05 6 11.32 .33 total hysterectomy was performed on four patients (7.5%).
Only thirty one patients (58.5%) received methotrexate
Treatment chemoprophylaxis. For the results of the histopathology,
Suction curettage 147 71.71 49 92.45 .01** 47 patients (88.7%) had complete hydatidiform mole
Surgical management 58 28.29 4 7.55 .01** while 6 patients (11.3%) had partial hydatidiform mole.
Most of the patients with persistent GTN had a higher rate
Chemoprophylaxis 171 83.41 31 58.49 .01** of suction curettage (92%, p=0.001), and a lower rate of

14 Volume 41, Number 3, PJOG May-June 2017

chemoprophylaxis (58%, p<0.001). determine the appropriate period of βhCG surveillance for
During the one-year follow-up period, 50 patients patients who underwent treatment for molar pregnancy.
(94.3%) were detected to have gestational trophoblastic Information including demographics, baseline βhCG
neoplasia within the first six months post-treatment levels, treatment, and subsequent βhCG levels during the
while only 3 patients (5.7%) were determined to have the follow-up period of patients diagnosed with hydatidiform
disease progression after six months. As early as 36 days mole during the period of January 1, 2000 to December
after treatment, gestational trophoblastic neoplasia was 31, 2010 at the institution were obtained for data analysis.
already identified in seven patients among the population Based on the results, among the 258 patients
of this study. The period of detection of disease progression managed for molar pregnancy, 53 patients (20.5%)
ranged from 36 to 246 days. For the 50 patients identified progressed to post-molar gestational trophoblastic
during the first six months after treatment, the period neoplasia. This is comparable to the study by Wolfberg, et
of development of gestational trophoblastic neoplasia al, wherein 15% of the population developed gestational
ranged from 36 to 159 days with a mean of 65 days. For the trophoblastic neoplasia.11 It was also noted in that study
three patients who developed gestational trophoblastic that the median time required for serum hCG levels
neoplasia beyond the 6 months from molar evacuation, to become undetectable among the 238 women with
the period of detection ranged from 195-246 days. remission was 46 days. In the study by Kerkmeijer on
Majority of the patients who progressed to postmolar recurrent gestational trophoblastic disease, 355 patients
gestational trophoblastic neoplasia were diagnosed due to with hydatidiform mole registered at the Dutch Central
rising βhCG levels (n=44, 83%) while 9 patients (16.9%)had Registry of hydatidiform mole were serially monitored
plateauing βhCG values. using βhCG assays. There were ninety patients (25%)
whose βhCG levels did not decline to normal (defined as
DISCUSSION < 2.0 ng/ml in the study). Relapse rates were 8.1% and
6.3% for the low-risk and high-risk groups.8 Based on the
The purpose of this study was to compare the group’s analysis, the risk for relapse in hydatidiform mole
percentage of patients who developed post-molar patients with spontaneous normalization of βhCG levels is
gestational trophoblastic neoplasia during the 6-month extremely low at 1 in 265 patients after two normal βhCG
follow up period following normalization of βhCG titers levels were achieved.8
to that during the 12-month follow up period in order to Most patients with post-molar gestational
trophoblastic neoplasia are diagnosed early due to rising
Table 3. Distribution of Characteristics comparing the patients levels of βhCG. Out of the 53 patients with persistent
with progression during the 6 month follow-up period and 12 disease, fifty (n=50, 94.3%) patients were detected during
month follow-up period the first six months after evacuation of molar products.
This is comparable to a retrospective study done at the
Progression Progression United Kingdom wherein data on women who were
during 6 during 12
registered for βhCG monitoring following evacuation of
month month
follow-up follow-up molar products were reviewed. Of those patients who
period period developed postmolar gestational trophoblastic neoplasia,
(n=50) (n=3) 98% of patients presented within the first six months after
evacuation.9 Hence, their protocol for monitoring of βhCG
Demographic N % N % titers after treatment was based on when the hCG reached
Age >35 years old 10 20 0 0 normal levels. When the hCG concentration became
First pregnancy 17 34 1 33.3 normal within 56 days, urine surveillance continued for
Gravida >4 13 26 0 0 a total of 6 months from the evacuation date. However,
when the hCG levels became normal after 56 days from
Baseline 25 50 2 66.7
the evacuation date, additional 6 months surveillance
β-HCG≥100,000
from the time the levels became normal was required.
Complete molar 45 90 2 66.7 In the study by Kerkmeijer, 414 patients with
pregnancy complete hydatidiform mole were studied to determine
Partial molar pregnancy 5 10 1 33.3 the number of patients who spontaneously achieved
normal βhCG levels but eventually developed gestational
Treatment
trophoblastic neoplasia. The study recommended weekly
Suction curettage 46 92 3 100 βhCG measurements for all patients until normal levels are
Chemoprophylaxis 29 58 2 66.7 achieved. It was stated in the study that among patients

Volume 41, Number 3, PJOG May-June 2017 15

who attained normal βhCG levels within 2 months after
evacuation of molar products, monitoring may be safely
discontinued once normal levels are achieved. However,
for patients who do not achieve normal βhCG level by 2
months post-evacuation, monthly βhCG titer determination
should be done for one year after normalization.8
Worldwide, the recommendations regarding the
protocol for monitoring patients after a molar pregnancy
are not standard. However, most studies have shown that
in a large percentage of patients, the βhCG levels reach
normal levels within the first six months after evacuation
of molar products and the risk of progression or relapse to
gestational trophoblastic neoplasia is extremely low.
The results of this study showed that the median
time to obtaining normal βhCG levels is 88 days for those
who received chemoprophylaxis and 85 days for those
with lower initial βhCG level (less than 100, 000 mIU/ml).
Furthermore, only three patients were detected to have
abnormal βhCG titers after the 6 month follow-up period.
A reduction in the surveillance period after normalization
of βhCG levels leads to reduction in financial cost, decrease
in fertility consequences especially in elderly women
attempting to become pregnant after a hydatidiform mole,
and spares the patients unnecessary anxiety during the
follow-up period.
REFERENCES
1. Cunningham FG, Leveno KJ, Bloom SL, Spong C, Dashe J, Hoffman
B, Casey B. Gestational Trophoblastic Disease: Williams Obstetrics,
23rd edition. USA: McGraw Hill Companies, 2010: 11.
2. Sermer DA, MacFee MS. Gestational trophoblastic disease:
epidemiology. Seminars in Oncology. 1995; 22:109-113.
3. Clinical Practice Guidelines for the Diagnosis and Management
of Gestational Trophoblastic Diseases, Philippine Society for the
Study of Trophoblastic Diseases, Inc., November 2011.
4. Sebire N J, M J Seckl. Gestational trophoblastic disease: current
management of hydatidiform mole. BMJ. 2008; 337:1193.
5. Ngan, H. Y. The FIGO staging for gestational trophoblastic neoplasia
2000, FIGO Committee Report. Int. J. Gynecol. Obstet. 2002; 77:
285-287.
6. Soper JT, Mutch DG, Schink JC. Diagnosis and treatment of
gestational trophoblastic disease: ACOG Practice Bulletin No. 53.
Gynecol Oncol. 2004; 93:575-85.
7. Kerkmeijer L, Wielsma S, Bekkers R, Pyman J, Tan J, Quinn M.
Guidelines following hydatidiform mole: a reappraisal. Aust N Z J
Obstet Gynaecol. 2006; 46:112-118.
16 Volume 41, Number 3, PJOG May-June 2017
CONCLUSION
Majority of cases of postmolar gestational
trophoblastic neoplasia presents within the first six months
after treatment. In this study, there was no occurrence
of postmolar gestational trophoblastic neoplasia in
the patients who attained normalization of βhCG titers
after treatment. Patients who received methotrexate
chemoprophylaxis and had lower initial βhCG values (less
than 100,000 mIU/ml) had shorter periods of obtaining
normal βhCG results from the time of treatment,with
period of 88 days and 85 days respectively. Furthermore,
ninety-four percent of the patients who had persistent
gestational trophoblastic neoplasia were diagnosed within
the first six months during follow-up while only three
patients were detected after six months.
A period of six months seems to be adequate in
monitoring βhCG levels in patients following molar
pregnancy. A shorter follow-up period has several
advantages such as cost reduction especially in our
setting wherein patients often have difficulty completing
the proper monitoring due to financial limitations, and
diminishing the patient’s anxiety associated with her
disease.
8. Kerkmeijer LGW, Wielsma S, Massuger LFAG, Sweep FCGJ, Thomas
CMG. Recurrent gestational trophoblastic disease after hCG
normalization following hydatidiform mole in The Netherlands.
Gynecol Oncol. 2007; 106:142-6.
9. Sebire NJ, Foskett M, Short D, Savage P, Stewart W, Thomson M,
et al. Shortened duration of human chorionic gonadotrophin
surveillance following complete or partial hydatidiform mole:
evidence for revised protocol of a UK regional trophoblasticdisease
unit. BJOG. 2007; 114:760-762.
10. Pisal N, Tidy J, Hancock B. Gestational trophoblastic disease: is
intensive follow up essential in all women? BJOG. 2004; 111:1449-
51.
11. Wolfberg AJ, Feltmate C, Goldstein DP, Berkowitz RS, Lieberman
E.Low risk of relapse after achieving undetectable HCG levels in
women with complete molar pregnancy. Obstet Gynecol. 2004
Sep; 104:551-4.
 Recurrent hydatidiform mole with NLRP7 mutation:
The first confirmed case in the Philippines*
By Martin Antonio B. Medina, MD and Agnes L. Soriano-Estrella, MD, MHPEd, FPOGS, FPSSTD
Department of Obstetrics and Gynecology, Philippine General Hospital, University of the Philippines-Manila

ABSTRACT

High gravidity hydatidiform mole (HM) without normal pregnancy is very rare. The challeng of managing such cases will dwell
on the concern of having normal conception versus having another molar gestation and its neoplastic sequelae.
Presented in this paper is a case of a 32-year-old, gravida 5 para 0 (0040) who was admitted for the management of her fifth
molar pregnancy. She underwent suction curettage and administration of methotrexate chemoprophylaxis. Genetic testing was
done, which revealed a homozygous mutation in NLRP7, the gene implicated in recurrent molar gestations. This paper discusses the
proper approach to determine the cause of recurrent molar pregnancies, as well as the management and prognosis of such cases.

Keywords: familial hydatidiform mole, recurrenthydatidiformmole, NLRP7 mutation.

INTRODUCTION The patient’s past medical, family medical, personal-

H
ydatidiform mole (HM), the most common
gestational trophoblastic disease (GTD), is a non-
viable genetically abnormal conception with excess
expression of paternal genes and abnormal proliferation
of the placental trophoblast.1 There are two types of HM,
complete and partial which can be differentiated based on
morphologic, cytogenetic, and clinicopathologic features.
HMs can also be categorized based on the number of molar
pregnancies a patient has had. One molar pregnancy is
termed as sporadic hydatidiform mole while two or more
molar pregnancies is termed recurrent hydatidiform mole
(RHM).
High gravidity recurrent molar pregnancy is
extremely rare, the highest number of molar gestation
in a single patient is 18 and was reported in 1912.1 This
paper discusses the case of a 32-year-old multigravid who
presented with her fifth molar pregnancy. Proper approach
to determine the cause of her repeated molar gestations,
as well as the management and prognosis of such case will
be discussed in this paper.
social, and menstrual histories were unremarkable. There
were no cases of hydatidiform moles noted in her family
from the first up to the third generation (Figure 1).
This is her fifth pregnancy. All her previous
pregnancies were hydatidiform moles for which she
underwent suction curettage. The age of gestation based
on her last menstrual period is 13 weeks.
The patient’s history started three weeks prior to
admission, when, after experiencing missed menses,
pregnancy test was performed which showed a negative
result. No consultation was done.
Six days prior to admission, patient had vaginal
spotting. She consulted at a local hospital where a
transvaginal ultrasound was done, which revealed
molar pregnancy. Patient was then advised to consult
a trophoblastic disease specialist for further work-up
and management, hence subsequent admission at our
institution.
At the admitting section, the patient was awake,

THE CASE

This is the case of a 32-year-old, gravida 5 para 0

(0040) from Majayjay, Laguna who was referred by a
private obstetrician-gynecologist for the management of
her RHM.

*Finalist, 2017 Philippine Obstetrical and Gynecological Society (POGS)

Interesting Case Paper Contest, April 6, 2017, Citystate Asturias Hotel,
Puerto Princesa City, Palawan Figure 1. Index patient’s family pedigree.
Volume 41, Number 3, PJOG May-June 2017 27
coherent, ambulatory, and not in cardio-respiratory
distress. She had normal vital signs with blood pressure of
100/60 mmHg, heart rate of 84 bpm, respiratory rate of 20
cpm and temperature of 36.8°C. The abdomen is globular
and non-tender.
The pelvic examination revealed a normal external
genitalia and nulliparous vagina. The cervix was 3 x 2 cm
smooth, soft and closed. The corpus was doughy and
symmetrically enlarged to about 16 to 18-week size.
No adnexal masses nor tenderness noted. Rectovaginal
examination was unremarkable
The pregnancy test was positive. The baseline
laboratory examinations included: complete blood count
(CBC), blood typing, serum urea nitrogen, creatinine,
electrolytes, aspartate aminotransferase (AST), alanine Figure 2. Transvaginal ultrasound of the patient revealing a
amino transaminase (ALT), diluted serum ß human heterogenous mass with multiple sonuluscent cystic spaces
chorionic gonadotropin (ß-HCG), thyroid function test, measuring 10.7 x 10.8 x 6.9 cm (volume of 418cc) occupying the
chest radiograph, and transvaginal ultrasound (Table 1). endometrial cavity.
Results showed an elevated diluted serum ß-HCG of
551, 100.00 mIU/mL. She also had an elevated AST and mL. The patient was advised serial ß-HCG determination
ALT which were 16 times and 14 times elevated than and contraception during the period of monitoring. The
the normal, respectively. Urinalysis revealed bacteriuria. histopathologic result of the suction curettage specimen
Her serum thyroid stimulating hormone (TSH) was low revealed complete hydatidiform mole and the sharp
with high normal free thyroxine (FT4). The transvaginal curettage specimen showed decidual tissues (Figure 3B).
ultrasound (TVS) revealed that the uterus was anteverted In order to detect a possible genetic cause for the
with globular contour and homogenous echopattern RHM, blood samples from the patient, her husband,
measuring 16.8 x 11.6 x 9 cm. The cervix measured 3.1 mother, grandmother and sister were sent to a genetics
x 2.6 x 3.32 cm with homogenous stroma and distinct laboratory in Canada. Results revealed that the patient
endocervical canal. The endometrial cavity was dilated has an NLRP7 mutation by genomic DNA amplification of
by a heterogeneous mass measuring 10.7 x 10.8 x 6.9 cm the 11 exons and sequencing in the two directions. This
(volume of 418cc), with multiple sonoluscent cystic spaces analysis revealed the presence of a previously reported
within. The myometrium was thinnest at the posterior mutation, c.2571_2572dupC, predicted to lead to a
fundal area measuring 1.1 cm. No myometrial invasion protein truncation, p.Iso858Hisfs*11, in a homozygous
was noted. The subendometrial halo was intact. The right state. Moreover, her sister was also found to have
ovary was not visualized. The left ovary measured 3.1 x 3.9 homozygous mutation of NLRP7 gene and her mother
x 0.9cm. There were no adnexal masses seen. There was was a carrier of the mutation in a heterozygous state
no free fluid in the cul-de-sac. The sonologic impression (Figure 4).
was endometrial mass, consider gestational trophoblastic The results were thoroughly explained to the patient
disease, probably hydatidiform mole; normal left ovary and her family. Her risk for another RHM and possible
(Figure 2). neoplastic sequelae were emphasized. Latest ß-HCG titer
The initial working impression was recurrent
hydatidiform mole, asymptomatic bacteriuria. The
patient was then admitted for suction curettage and
chemoprophylaxis. On suction curettage, about 400cc
of vesicular materials with no fetal tissues nor normal
appearing-placental tissue were evacuated (Figure 3A).
The specimen was sent for histopathologic studies.
Chemoprophylaxis in the form of Methotrexate 0.3mg/kg
body weight was given once daily for five days. Antibiotic Figure 3. Gross and microscopic pictures of the specimen.
coverage for asymptomatic bacteriuria was also given in (3A) The suction curettage specimen showing multiple vesicular
the form of Cefuroxime 500mg/tablet every 12 hours for materials admixed with blood clots. (3B) Low power magnification
seven days. Repeat diluted serum ß-HCG obtained a week of the specimen showing hydropic villi (yellow arrow) with
after molar evacuation revealed a value of 2,109.10 mIU/ peripheral proliferation of trophoblast (white arrows).

28 Volume 41, Number 3, PJOG May-June 2017

of the patient is 1.20mIU/mL and she remains compliant
with her follow-up consultations and ß-HCG monitoring.
Figure 4. NLRP7 genetic test result
DISCUSSION
Hydatidiform mole is the most common form of
gestational trophoblastic disease occurring in about 1
in 500–1000 pregnancies. The incidence varies widely,
depending on the geographic location. Estimates from
studies conducted in North America, Australia, and Europe
have shown the incidence of hydatidiform mole to range
from 0.57–1.1 per 1000 pregnancies, whereas studies in
Southeast Asia and Japan have suggested an incidence of
2.0 per 1000 pregnancies.1
Studies have shown that after a molar pregnancy,
the risk of another molar pregnancy rises to 1-2%.2 After
two molar gestations, the risk for a third mole is 15-
20%.1 Review of literatures also showed that the highest
frequency of molar pregnancy in a single patient is 18
as reported by Essen-Moeller in 1912.1 More recently,
patients with seven and six consecutive molar pregnancies
were reported in the years 2001 and 2011 respectively.3,4
In our institution, based on review of records, the
earliest documented case of RHM was in 1983 with the
patient having two molar pregnancies complicated with
choriocarcinoma. Although similar cases have been
sporadically documented in the succeeding years, the
first case study published regarding high gravidity molar
pregnancy was reported by Cristi et al. in 2006.5 To date,
the highest frequency of molar pregnancy recorded in our
institution is of our index patient who had five consecutive
molar gestations without a normal pregnancy.
Central to the diagnosis and management of HM
is thorough history taking, comprehensive physical
examination and appropriate laboratory tests. RHMs
have no distinguishing clinical characteristics from the
non-recurrent sporadic moles except for the history of
repeated molar pregnancies. The goal of management
of such cases is to determine the cause of recurrence,
ascertain the patient’s chance for a normal pregnancy and
prevent neoplastic sequelae.
Genotype of HMs are usually androgenic, however,
the degree of paternal contribution may vary. In minority
of cases, some HMs have been reported to have
maternal chromosomes hence are biparental. Diploid
biparental genotype are associated with RHMs and
often run in families. Familial biparental hydatidiform
mole (FBHM) is the only known pure maternal-effect
recessive inherited disorder in humans. Affected women,
although developmentally normal themselves, suffer
repeated pregnancy loss because of the development
of the conceptus into a CHM in which extraembryonic
trophoblastic tissue develops but the embryo itself suffers
early demise. This developmental phenotype results from
a genome-wide failure to correctly specify or maintain a
maternal epigenotype at imprinted loci.1 Moreover, these
patients appear to have an autosomal recessive condition,
causing them to have recurrent molar gestations with very
little chance of a successful normal pregnancy.
Most cases of FBHM result from mutations of
NLRP7. Wang et al. analyzed the NLRP7 gene in affected
individuals from 20 families with a confirmed diagnosis of
FBHM and identified 16 different mutations in 17 of the
families.6 This was subsequently confirmed by Fallahian
et al. in their genetic analysis of tissues from the CHM
patients, which was previously studied by Wang. Patients
were found to be homozygous for a 14-bp duplication in
the NLRP7 gene. In their study, they concluded that these
findings were consistent with a role for NLRP7 in setting
and/or maintaining the maternal imprint.7
Currently, the two genes that have been identified
as the causative agents for the development of RHM are
NLRP7 and KHDC3L. NLRP7 is a nucleotide oligomerization
domain (NOD)-like receptor, pyrin containing 7, maps to
19q13.4.1 The family of genes where NLRP7 belongs are
commonly expressed in the germline and early embryos,
suggesting their involvement in early developmental
process.1 In the study done by Slim and Wallace (2013),
they concluded that oocytes from patients with the gene
mutation are defective at several levels and are unable
to sustain early embryonic development. As a result,
the retention of these non-viable pregnancies with no
Volume 41, Number 3, PJOG May-June 2017 29
embryos to later gestational stages leads to the hydropic genetic testing plays a vital role in patient management.
degeneration of the chorionic villi.8 Moreover, the gene Phuong Nguyen and Slim proposed an algorithm that
has also been postulated to have a role in inflammation can be used in patients diagnosed with RHM (Figure 5).
and apoptosis mainly by down regulation of intracellular In their work, they have emphasized that the goal
IL-1β. IL-1β is responsible for cytokine secretion, hence, its of patients seeking DNA testing is to ascertain their
downregulation fail to mount an appropriate inflammatory chances of carrying normal pregnancies and their risk
response to reject the hydropic non-viable gestation as for mole recurrence and malignant degeneration. They
normal women would. Interestingly, a recent study has proposed that patients with at least two HMs should be
identified that NLRP7 knockdown accelerates trophoblast offered DNA testing first for NLRP7.1 Although genetic
differentiation and increase the level of ß-HCG.1 Although testing for patients with history of RHM is the current
several studies are still being conducted to strengthen the recommendation, the cost of running the tests and its
role of NLRP7 mutation, all of these observations lead to availability are its main limiting factors. Fortunately,
the fundamental aspects of recurrent moles. a free genetic test was performed in the index case.
The second recessive gene responsible for RHMs is Result revealed that the patient as well as her sister have
KHDC3L (KH domain containing 3-like), which was identified homozygous mutation in NLRP7 gene. Since 2006, there
in 2011 by Parry et al.1,9 KHDC3L maps to chromosome 6 and are 69 cases with RHM phenotypes documented having
this accounts for 10–14% of patients with RHMs.1 KHDC3L mutations in NLRP7 worldwide (http://fmf.igh.cnrs.fr/
transcripts have been identified in several human tissues, ISSAID/infevers/). In the Philippines, this is the first case
including all oocyte stages, preimplantation embryos, documented with the genetic mutation.
and hematopoietic cells. KHDC3L codes for a small Patients positive to the DNA test must undergo
protein of 217 amino acids belonging to the KHDC1 (KH genetic counseling, a process of communicating
homology domain containing 1) protein family, members information about genetic risks which allows the patient
of which contain an atypical KH domain that does not to have an informed decision. In the index case, focus
bind RNA which is an important step in protein synthesis. was placed on her susceptibility to having another molar
In humans, expression of KHDC3L is highest in oocytes pregnancy, her capability of having normal pregnancy, risk
at the germinal vesicle stage and then decreases during for GTN, and the possible solutions to these risks. With
preimplantation development and becomes undetectable proper and thorough explanation, the patient and her
at the blastocyst stage similar to the expression prolife of husband agreed to avoid pregnancy by using contraceptive
NLRP7.9 Furthermore, KHDC3L co-localizes with NLRP7 to
the microtubule organizing center and the Golgi apparatus
in lymphoblastoid cell lines which suggests that the two
genes may have similar or overlapping functions in oocyte
and early embryonic development.1
In the index case, the long term management post a
major clinical dilemma. The patient’s age, obstetric history
and her desire of a normal pregnancy are the foremost
considerations in our management.
After surgical evacuation of a molar pregnancy
ß-HCG titers eventually fall, however, in 20% of cases
it will persistently elevate.8 An elevated ß-HCG on the
background of a mass in the uterus or somewhere else
is highly suspicious of a GTN. Most of GTNs are seen
after a HM in 60% of cases.1,8 Acosta-Sison et al. in 1959
concluded in their study that there is an increasing
degree of invasiveness with subsequent GTD episodes.9
Moreover, there is also a tendency towards worsening
histology hence an increased incidence of invasive mole
and choriocarcinoma in the subsequent trophoblastic
episodes.1 Considering these findings, the index patient
was given Methotrexate chemoprophylaxis and advised
strict ß-HCG monitoring.
Considering that the cause of molar recurrence is Figure 5. Screening recommendation for genetic testing and
mostly genetic in nature and the remaining is idiopathic, counselling of patients with RHM.1

30 Volume 41, Number 3, PJOG May-June 2017

pills as a means of family planning. The patient verbalized
her understanding and determination for follow-up. The
couple’s strong family ties serve as their main support
group. The patient’s sister was also informed that she has
a strong risk factor for a RHM.
Only 7% of 43 reported cases of RHM with two
defective alleles in NLRP7 had normal spontaneous
pregnancy.1 No other cases of live births have been
reported in patients with RHMs harboring NLRP7 or
KHDC3L mutations. A patient with two defective alleles
in NLRP7 had one livebirth following ovum donation is
an exception. Ovum donation may improve patients’
reproductive outcomes based on the assumption that the
donor of the “normal” ovum has no NLRP7 or KHDC3L
mutation. Thus far, few patients with mutations in NLRP7
have tried ovum donation, and three had normal live
births, which provides some hope for patients despite the
elevated cost of such procedure, its limited accessibility
and ethical issues.1 Reubinoff and colleagues reported
a promising approach for the prevention of repeated
CHM using intracytoplasmic sperm injection (ICSI) and
preimplantation genetic diagnosis (PGD) with fluorescence
in-situ hybridization (FISH), unfortunately, pregnancy was
not achieved using this proposed method.11 Patients with
the genetic mutation who decide not to be pregnant
are given with long term contraceptives or offered with
permanent contraception. In the Philippines, where ovum
donation is not legal, adoption may be offered.
CONCLUSION
Genetic mutation in NLRP7 has been documented
as a cause of recurrent molar gestation in the index
case. It is therefore prudent that a general obstetrician-
gynecologist with the assistance of a trophoblastic
disease specialist emphasize the importance of genetic
testingin patients with RHM. A holistic approach is key in
managing such cases which includes early medical and
surgical intervention, effective family planning method,
and religious follow-up.

Table 1. Baseline laboratory tests and results.

Hematology/Complete Blood Count Blood Chemistry

Hemoglobin 120 Blood Urea Nitrogen 6.7

Hematocrit 0.36 Creatinine 79
White Blood Cells 9.17 Blood Urea Nitrogen 6.7
Neutrophil 0.74 Creatinine 79
Platelet 306 Sodium 135
Platelet 306 Potassium 3.1
Chloride 95
Coagulation
Calcium 2.37
Prothrombin Time (PT) 12.6 Albumin 37
Partial Thromboplastin Time (PTT) 30.6 Aspartate aminotransferase (AST) 584
PT % 111 Alanine amino transaminase (ALT) 752
PT INR 0.94 Lactate dehydrogenease (LDH) 1064

Urinalysis Immunology

White Blood Cells 4 Free T4 48.57

Bacteria 1179 Thyroid Stimulating Hormone 0.0064
Epithelial Cells 66

Volume 41, Number 3, PJOG May-June 2017 31

REFERENCES
1. Nguyen N, Slim R. Genetics and Epigenetics of Recurrent
Hydatidiform Moles: Basic Science and Genetic
Counselling. Curr Obstet Gynecol Rep. 2014; 3(1):55-64.
2. Barroilhet L, Garrett L, Bernstein M, Esselen K, Goldstein D,
Berkowitz R. Update on subsequent pregnancy outcomes
in patients with molar pregnancy and persistent gestational
trophoblastic neoplasia. Gynecologic Oncology. 2012;
125:S83-S84.
3. Al-Ghamdi A. Recurrent hydatidiform mole: A case report
of six consecutive molar pregnancies complicated by
choriocarcinoma, and review of the literature. J Fam
Community Med. 2011; 18(3):159.
4. Ozalp S, Yalcin O, Tanir H, Etiz E. Recurrent Molar Pregnancy:
Report of a Case with Seven Consecutive Hydatidiform
Moles. Gynecologic and Obstetric Investigation. 2001;
52(3):215-216.
5. Cristi M, Jacinto E, Manalastas R. Recurrent hydatidiform
mole: A case report. Philipp J Obstet Gynecol. 2006;
30(4):204-210.
32 Volume 41, Number 3, PJOG May-June 2017
6. Wang C, Dixon P, Decordova S, Hodges M, Sebire N, Ozalp
S et al. Identification of 13 novel NLRP7 mutations in 20
families with recurrent hydatidiform mole; missense
mutations cluster in the leucine-rich region. Journal of
Medical Genetics. 2009; 46(8):569-575.
7. Fallahian M, Sebire N, Savage P, Seckl M, Fisher R. Mutations
in NLRP 7 and KHDC 3 L Confer a Complete Hydatidiform
Mole Phenotype on Digynic Triploid Conceptions. Human
Mutation. 2012; 34(2):301-308.
8. Slim R, Wallace E. NLRP7 and the Genetics of Hydatidiform
Moles: Recent Advances and New Challenges. Front
Immunol. 2013; 4.
9. Acosta-Sison H. The chance of malignancy in a repeated
hydatidiform mole. Am J Obstet Gynecol. 1959; 78:876-7.
10. Reubinoff B, Lewin A, Verner M, Safran A, Schenker J,
Abeliovich D. Intracytoplasmic sperm injection combined
with preimplantation genetic diagnosis for the prevention
of recurrent gestational trophoblastic disease. Human
Reproduction. 1997; 12(4):805-808.
 The association of histopathologic features and
postmolar gestational trophoblastic neoplasia among
patients with complete hydatidifrom mole*
By Kathleen Gizelle J. Samonte, MD and Agnes L. Soriano-Estrella, MD, MHPEd, FPOGS, FPSSTD
Department of Obstetrics and Gynecology, Philippine General Hospital, University of the Philippines-Manila

ABSTRACT

Objective: The study aims to correlate the histopathologic characteristics of patients diagnosed with complete hydatidiform moles
with the risk of developing postmolar gestational trophoblastic neoplasia.

Methodology: A retrospective review of 71 histopathologically-confirmed cases of complete hydatidiform moles was made. Group
1 consisted of 65 patients who achieved normal titers and remained to have normal β-hCG titers after at least 1 year of follow
up. Group 2 included 6 patients who developed postmolar gestational trophoblastic neoplasia. Histopathologic slide review was
done to assess the following: trophoblastic proliferation, nuclear atypia, hemorrhage, necrosis along with measurement of the
shortest diameter of the largesthydropic villus. The association of the histopathologic features and the development of postmolar
gestational trophoblastic neoplasia was done using chi square. Analysis of the association of histopathologic features included in
the study predictive of the development of postmolar gestational trophoblastic neoplasia was done.

Results: Analysis of several histopathologic parameters which may precisely identify which patients with complete hydatidiform
moles were more likely to develop postmolar gestational trophoblastic neoplasia failed to produce statistically significant results.
However, among the all the features studied, the presence of extensive necrosis favored the occurrence of postmolar sequela.

Conclusion: Trophoblastic proliferation, nuclear atypia, hemorrhage and villus size of complete hydatidiform moles do not
predict progression to postmolar disease. In spite of this, all patients with complete hydatidiform moles should be considered for
prophylactic chemotherapy or should be monitored closely.

Keywords: Complete hydatidiform mole, Postmolar gestational trophoblastic disease, Histopathologic features, Villus size

INTRODUCTION It is now known that around eighteen to 28%

H
ydatidiform mole refers to an abnormal pregnancy
characterized by varying degrees of trophoblastic
proliferation and vesicular swelling of the placental
villi associated with an absent or an abnormal fetus/
embryo.1 Two types of hydatidiform mole have been
described based on both morphologic and cytogenetic
criteria: the classical complete hydatidiform mole (CHM)
and the partial hydatidiform mole (PHM). The former is
characterized by rapidly progressing hydatidiform change
affecting the whole placenta, with widespread and gross
trophoblastic hyperplasia in the absence of an embryo and
its covering amnion. In contrast, partial moles demonstrate
a slow hydatidiform change that affects only some of the
villi in the placenta.2
*Finalists, 2012 SGOP Research Contest and 2013 PSO Research
Contest
of patients with complete mole develop gestational
trophoblastic neoplasia or GTN. In contrast, only 2.5-
4% of patients with partial molar pregnancy are at risk
of GTN.3 Clinical parameters that have been implicated
to increase the risk of developing GTN after evacuation
of a complete mole include those that show evidence of
marked trophoblastic growth, such as a pre-evacuation
βhCG level > 100,000 mIU/ mL, excessive uterine
growth (>20- week size), and theca lutein cysts >6 cm
in diameter.1,3 Similarly, patients with an age >40 years,
a repeat molar pregnancy, an aneuploid mole, and
medical complications of molar pregnancy, such as pre-
eclampsia and hyperthyroidism are also at increased risk
for postmolar GTN.1 Although these clinical factors can
be used to identify women at an increased risk for the
development of postmolar GTN, they lack the ability
to predict the course of disease for individual patients.
As a result, the search for a diagnostic test that can
precisely determine which patients will develop GTN
has continued. Parameters that have been investigated
Volume 41, Number 3, PJOG May-June 2017 17
include immunostains, cytogenetic studies and
histopathologic features of the molar pregnancy.
A study by Ayhan and colleagues in 1996 was carried
out on 82 patients in order to define the most powerful
predictors of persistent trophoblastic disease. Among
the pathologic parameters, the degree of trophoblastic
proliferation, marked nuclear atypia, and presence of
necrosis and hemorrhage were significant forecasters of
persistent disease. These findings support the idea by
Hertig et al. that histopathologic evaluation of a specimen
may yield additional information regarding progression
to persistent neoplasia.4 A study undertaken by Kaneki
et al. in 2010 assessed whether the shortest diameter
of the largest villus measured using a stereomicroscope
was predictive of postmolar GTN. This study was the first
to demonstrate that the size of the hydropic villi may be
used as a predictor of postmolar GTD in patients with
androgenetic moles.2
This study was undertaken to determine the
association of histopathologic features of hydatidiform
moles and development of postmolar GTN. Specifically,
the histopathologic parameters that were investigated
included the degree of trophoblastic proliferation, nuclear
atypia, presence of hemorrhage and necrosis and the
smallest diameter of the largest hydropic villus from
complete hydatidiform moles.
Results of this study will have implications on
determining which patients must be considered for
prophylactic chemotherapy or at least careful β-hCG
follow-up with early initiation of therapy when indicated.
MATERIALS AND METHODS
Study Design, Population and Setting
This was a retrospective cohort study involving all
patients admitted at the Department of Obstetrics and
Gynecology at a tertiary government hospital from January
2008 to December 2011 with histopathologically confirmed
complete hydatidiform mole from specimens obtained
during molar evacuation. All patients with sufficient
data were included in the study. Patients with a previous
history of gestational trophoblastic neoplasia, those who
were lost to follow-up (less than 1 year surveillance or
serial hCG monitoring less than 3 months), patients with
incomplete data and those with lost histopathologic slides
were excluded from the study.
Procedure
The investigators evaluated the medical records of
all patients diagnosed with complete hydatidiform mole
at a tertiary government hospital from January 2008 to
December 2011 for possible inclusion in the study. The
following clinical data of the patients were obtained by
18 Volume 41, Number 3, PJOG May-June 2017
retrospective chart review: age at diagnosis, gravidity/
parity, size of the uterus and the pre-evacuation β-hCG
titer. All patients were categorized into two groups. Group
1 consisted of patients who achieved normal titers and
remained to have normal beta hCG titers after at least
1 year of follow-up while Group 2 consisted of patients
who developed post-molar Gestational Trophoblastic
Neoplasia based on the following criteria: (1) High level of
hCG more than 4 weeks post-evacuation (serum level of
20,000mIU/m). (2) Progressively increasing or plateauing
hCG values at any time after evacuation (minimum of 3
weekly determinations). (3) Clinical or histologic evidence
of metastasis at any site. (4) Persistently elevated hCG titer
at 14 weeks post-evacuation. (5) Elevation of a previously
normal hCG titer after evacuation provided the diagnosis
of pregnancy is excluded.
Histopathologic slides of patients included were
retrieved from the files of the Department of Pathology.
The following histopathologic features were evaluated
by a single, blinded pathologist: hydropic villus diameter,
trophoblastic proliferation, nuclear atypia, hemorrhage
and necrosis measurement of the smallest diameter of
the largest hydropic villus in each slide using a microscope
caliper was likewise carried out. Findings were then
correlated with the occurrence of postmolar gestational
trophoblastic disease.
Data Analysis
Data obtained was encoded using Microsoft Excel
2007 and analyzed using SPSS version 18 and Open
Source Epidemiologic Statistics (OpenEpi) version 2.3.1.
Continuous data were expressed as means and standard
deviations. Categorical data were expressed as frequencies
for populations with and without development of
postmolar gestational trophoblastic disease.
The measure of the development of postmolar GTN
was expressed as incidence rate, which was the proportion
of subjects who develop the disease under study within
a specified time period. The numerator of the rate was
the number of diseased subjects and the denominator
was the number of person-years of observation. The
incidence rates for exposed and non-exposed subjects
were calculated separately.
The chi-square was used to determine the correlation
between the different histopathologic features and the
development of postmolar gestational trophoblastic
disease. All levels of significance were set at 0.05.
The Receiver Operator Characteristic (ROC) curve
was used and the area under the curve was calculated
to identify the best discriminator value for villus size.
Using this cut off value, the association with postmolar
gestational trophoblastic neoplasia was determined after
analysis.
RESULTS

Of the 71 patients with complete hydatidiform mole,

sixty five cases (91.5%) had β-hCG levels that spontaneously
returned to normal after molar evacuation. On the other
hand, six patients (8.5%) developed postmolar gestational
trophoblastic neoplasia.
The patients ranged in age from 16 to 46 with gravidity
ranging from G1 to G11. There was no apparent association
between age or gravidity/parity and the subsequent
disease course. Initial β-hCG titers were found to be more
than 100,000 mIU/ml in 69.4% of the cases, while 29.2%
had initial β-hCG levels below 100,000 mIU/ml.
Sufficient histologic material was accessible for review
in 71 cases. Table 1 shows the results of the histopathologic
features of both groups. The degree of trophoblastic Figure 1. Multifocal trophoblastic proliferation
proliferation was graded as being mild, moderate or severe
(Figures 1 and 2). The incidence of postmolar gestational
trophoblastic neoplasia was found to be as follows: 1.4%
with mild, 2.8% with moderate and 4.2% with severe
trophoblastic proliferation. (p value = 0 .61)

Table 1. Result of histopathologic readings for both groups

Histopathologic p-value*
Postmolar GTN
Feature

Yes No
n=6 n=65

Trophoblastic
proliferation Figure 2. Circumferential trophoblastic proliferation
Mild 1 (1.4) 4 (5.6) .34
Moderate 2 (2.8) 28 (39.4) .06
Severe 3 (4.2) 33 (46.5) .97 The degree of atypia was evaluated in the same
manner as trophoblastic proliferation. (Figure 3) The
Atypia
1 (1.4)
results showed that there was no significant correlation
Mild and 19 (26.8) .51
Moderate .51
between the occurence of postmolar gestational
Severe 5 (7.0) 46 (64.8) trophoblastic neoplasia and the degree of nuclear atypia.
(p value = 0.79)
Hemorrhage The presence or absence of hemorrhage and
Present 5 (7.0) 42 (59.2) 0.35 necrosis were also assessed (Figure 4). Hemorrhage was
Absent 1 (1.4) 23 (32.4) seen in 59.2% of patients without PGTN and in only 7%
Necrosis of patients with postmolar gestational trophoblastic
Present 6 (8.5) 30 (42.3) .01 neoplasia. Thus, hemorrhage was not significantly
Absent 0 35 (49.3) correlated with the development of postmolar GTN.
(p value = 0.35) On the contrary, the presence of necrosis
Villous size in 8.5% of patients with postmolar GTN and its absence
(9.28 + 4.26)
in 49.3% of patients without postmolar GTN proved
Less than or 3 (4.2) 46 (64.8) .29
equal to 10
that necrosis is significantly associated with an increase
Greater 3 (4.2) 19 (26.8) in the incidence of postmolar gestational trophoblastic
than 10 neoplasia. (P value = 0.01)

Volume 41, Number 3, PJOG May-June 2017 19

Figure 3. Nuclear atypia
Among patients belonging to Group 1, the shortest
diameter of the largest hydropic villus ranged from 3 to 22
millimeters (mean of 9.09 mm). In contrast, the shortest
diameter of the largest hydropic villus in patients belonging
to Group 2 (with postmolar gestational trophoblastic
neoplasia) ranged from 7.5 to 16.5 millimeters (mean
of 12.5 mm). Using the Receiver Operator Characteristic
(ROC) curve, the cut off value was set at 10 millimeters.
In this analysis, 64.8% of patients with villus size less
than 10 millimeters as well as 26.8% of patients with villus
size greater than 10 millimeters did not develop postmolar
GTN. Regardless of the villus size, only 8.4% of the subjects
developed postmolar GTN. In summary, villus size was not
significantly correlated with the subsequent progression of
complete hydatidiform mole to gestational trophoblastic
neoplasia. (p value = 0.29)
DISCUSSION
Although the bulk of patients with a hydatidiform mole
do not require further treatment after molar evacuation,
an estimated 20% will develop into postmolar gestational
trophoblastic neoplasia. In the current study, the incidence
of postmolargestational trophoblastic neoplasia was
8.5%. Women diagnosed with a complete hydatidiform
molar pregnancy are typically counseled that their risk of
developing persistent gestational trophoblastic neoplasia
(GTN) requiring further management with chemotherapy
is 18–28%.1 To diagnose persistent GTN promptly, patients
are followed up with serial human chorionic gonadotropin
(hCG) levels after molar evacuation. A plateau or rise in
hCG levels indicates persistent disease and the need for
chemotherapeutic management. Complete remission is
typically declared if the hCG level spontaneously declines
to undetectable levels and remains there during a 6-month
20 Volume 41, Number 3, PJOG May-June 2017
Figure 4. Hemorrhage and necrosis
follow-up period.6 Investigators have tried to identify
factors that would predict either persistent disease or
remission to inform women and their physicians about
their risk of developing persistent disease or reduce the
interval between the diagnosis of molar pregnancy and the
diagnosis of persistent disease. A means to predict a high
risk of persistence might allow empiric chemotherapeutic
management in the noncompliant patient at high risk for
developing persistent disease; a method of predicting
remission could reassure a woman at low risk for persistent
disease.
The significant errors which would result from reliance
upon histologic grading alone and the present availability
of accurate methods for following hCG levels after molar
evacuation have caused the histopathologic study of
molar pregnancies to take on less priority. In general,
histopathologic grading of hydatidiform moles appears to
have merit for predicting postevacuation behavior, but as
a single criterion is too limited.5
Several investigators have identified histopathologic
features of hydatidiform moles that are associated with
a higher incidence of postmolar gestational trophoblastic
disease. Hertig et al. found a good correlation
between the degree of trophoblastic hyperplasia and
subsequent development of postmolar trophoblastic
disease, while Deliqdisch et al. reported that nuclear
atypia was associated with an unfavorable response to
chemotherapy.5
In this study, we analyzed several histopathologic
parameters which may precisely identify which patients with
complete hydatidiform moles were more likely to develop
postmolar gestational trophoblastic tumors. However,
trophoblastic proliferation, nuclear atypia, presence of
hemorrhage and hydropic villus size were features found
not to be correlated with progressive disease. Conversely,
the destructive activity of the trophoblast as illustrated by
extensive necrosis was the only parameter associated with
an increase in the incidence of postmolar trophoblastic
sequela.
Kaneki et al. first reported that the size of the
hydropic villi may be used as a predictor of postmolar
gestational trophoblastic neoplasia. They found out that
the frequency of postmolar GTN was higher in patients
with hydropic villi larger than 2 millimeters in their
shortest diameter. These data suggest that measurement
of the shortest diameter of the largest hydropic villus may
be used to estimate the risk of postmolar GTN.2 However,
the present study did not find a significant correlation
between villus size and the subsequent development of
postmolar GTN.
Efforts to promptly identify patients with complete
hydatidiform mole who are likely to progress to malignant
disease without going through an extensive process have
been made to be able to institute empirical chemotherapy.
The results of this analysis were contradictory to the
findings of several previous studies where trophoblastic
proliferation, nuclear atypia, extensive hemorrhage and
hydropic villus diameter were features associated with
REFERENCES
1. Lurain JR. Gestational trophoblastic disease I: epidemiology,
pathology, clinical presentation and diagnosis of gestational
trophoblastic disease, and management of hydatidiform mole.
Am J Obstet Gynecol. 2010; 2003:531-9.
2. Kaneki, et al. Incidence of postmolar gestational trophoblastic
disease in androgenetic moles and the morphological features
associated with low risk postmolar gestational trophoblastic
disease, Cancer Science, Vol 101, No. 7. July 2010. Pp 1717-1721.
3. Garner EIO, Goldstein DP, Feltmate CM, Berkowitz RS. Gestational
trophoblastic disease. Clin Obstet Gynecol. 2007; 50:112-122.
the progression to postmolar trophoblastic tumors. The
disparity in outcomes can be attributed to the small number
of cases included in the study, a subjective assessment
of some of the histopathologic parameters particularly
trophoblastic proliferation and atypia and the preparation
of the histopathologic slides that were analyzed may have
affected the outcome. The retrospective nature of the
study may also have a significant impact on the results.
SUMMARY AND CONCLUSION
The risk of postmolar gestational trophoblastic
disease after a complete hydatidiform mole is reported as
5.7% to 36%. Several histopathologic parameters – nuclear
atypia, trophoblastic proliferation, hemorrhage and
necrosis are significant predictors of persistent disease. In
addition, hydropic villus size may be used as a predictor
of postmolar GTN. Although this study did not statistically
prove that histopathologic parameters and villus size of
complete hydatidiform mole predicts postmolarsequela,
all patients with complete hydatidiform mole should be
considered for prophylactic chemotherapy or should be
monitored closely.
4. Ayhan, et al. Predictors of persistent disease in women with
complete hydatidiform mole, The Journal of Reproductive
Medicine, Vol 41, No. 8. August 1996. Pp 591-594.
5. Murad et al. Hydatidiform mole: clinicopathologic associations
with the development of postevacuation trophoblastic disease,
Int. J. Gynecol. Obstet., Vol 32. 1990. Pp 359-367.
6. Pastorfide et al. Gestational trophoblastic disease with Philippine
experience, 2000. Pp 50.
Volume 41, Number 3, PJOG May-June 2017 21
 A randomized controlled trial: Comparison of malunggay
(moringa oleifera) and ferrous sulfate in preventing anemia
in pregnant patients in the out patient department of a
tertiary hospital (January 2013 – July 2016)*
By Angeli Rose O. Caraos, MD and Antonio C. Cortez, MD, FPOGS
Department of Obstetrics and Gynecology, San Juan de Dios Educational Foundation, Inc. (Foundation)
General Objective:
To compare Malunggay (Moringa oleifera) with
ferrous sulfate in preventing anemia among pregnant
patients in the Out Patient Department of a Tertiary
Hospital
Specific objectives:
• To determine the effect of Malunggay (Moringa oleifera)
supplements in the hemoglobin and hematocrit levels
during pregnancy.
• To determine if Malunggay (Moringa oleifera) capsules
can be better tolerated by pregnant patients in the Out
Patient Department of a Tertiary Hospital
CHAPTER I
A. Introduction
Moringa oleifera, locally known as Malunggay, is the
best known of the 13 species of the genus Moringacae.1
This plant was highly valued in the ancient times as
Romans, Greeks and Egyptians extracted edible oil from
the seeds and utilized it for perfume and skin lotion. In
the 19th century, the West Indies were known to export
Moringa oil to Europe for perfumes as well as lubricants
for machinery. In India on the otherhand, Moringa pods
were eaten while the leaves were consumed in West
Africa and parts of Asia.2 As time evolved, each part of the
plant has proven to be useful particularly for traditional
or alternative medicine. It has been known to be used for
anemia, asthma, intestinal worms, semen deficiency, and
lactation among others.4
*Finalist, Philippine Obstetrical and Gynecological Society (Foundation),
Inc. (POGS) Research Paper Contest, October 25, 2017, 3rd Floor POGS
Building, Quezon City
B. Background of the Study
Anemia is the most common hematologic problem
during pregnancy as physiologic anemia can occur as a
result of a dilutional process secondary to an increase in
plasma volume.3 The estimated average iron loss during
pregnancy is said to be more than 2 liters of blood due
to transfer of iron to fetus, blood loss during delivery, and
iron loss in breast milk amounting to about 900 to 1000
mg.5 Women then require a greater amount of iron during
pregnancy. Other causes of anemia may be deficiency in
other micronutrients aside from iron.
Mineral and vitamin supplements have been
prescribed routinely to pregnant women as a normal
part of prenatal care and have often been prescribed
as preparation that include 25-65 mg of elemental iron
along with other minerals (e.g. calcium, zinc, magnesium,
copper) and vitamins.3 In pregnancy, the recommended
daily dietary allowance of ferrous iron is 27 mg.5
Iron supplements are known to cause unpleasant
gastrointestinal symptoms3 such as nausea, vomiting,
constipation, diarrhea, dark colored stools, and/or
abdominal distress. As such, alternative supplements
may be considered. Malunggay, which is an abundant
vegetable in the Philippines and has been called the
“miracle vegetable”, has been promoted by the World
health Organization (WHO) as a low-cost health enhancer
particularly in developing countries. It is one of the richest
sources of vitamins and is said to contain 17 times more
calcium than milk, 25 times more iron than spinach, and 15
times the potassium in banana, along with other vitamins
and minerals.1 Various parts of the plant have been used
in alternative medicine for different conditions. It has then
been marketed to the public in tea, powder, and capsule
forms apart from the raw vegetables available.
C. Statement of the Problem
Can Malunggay (Moringa oleifera) be used as an
alternative for ferrous sulfate in preventing anemia among
pregnant patients in the Out Patient Department of a
tertiary hospital?
Volume 41, Number 6, PJOG November-December 2017 25
D. Hypothesis
Malunggay (Moringa oleifera) can be used as an
alternative for ferrous sulfate in preventing anemia among
pregnant patients in the Out Patient Department of a
tertiary hospital.
E. Significance of the Study
This study aims to provide an alternative to ferrous
sulfate in preventing anemia among pregnant patients in
the Out Patient Department of a tertiary hospital. Also, to
be able to provide an alternative to those who are unable to
tolerate the gastrointestinal side effects of ferrous sulfate
in preventing anemia of the patients involved. Moreover,
it may serve to be a basis for further studies regarding iron
supplements and Moringa oleifera capsules.
F. Scope and Delimitation of the Study
Subjects will be limited to pregnant patients who
are on their 12th week age of gestation until term at
the Out Patient Department of a tertiary hospital. The
study will exclude pregnant patients with pre-existing
gastrointestinal disorders, or hematologic disorders.
Patients taking multivitamins containing iron will also be
excluded.
G. Definition of Terms
a. Iron sufficiency- Hgb =110g/L; Ferritin = 12 ugL
b. Iron deficiency without anemia- Hgb 110 g/L;
Ferritin <12 ugL
c. Iron deficiency anemia- Hgb <110 g/l; Ferritin <12
ugL
d. Term pregnancy- Pregnancy that has been carried
to 37 weeks age of gestation, which has been
computed based on the patient’s early ultrasound.
CHAPTER II: REVIEW OF RELATED LITERATURE AND STUDIES
The main method by which anemia is prevented
during pregnancy is through iron supplementation. In
a study by Makrides M. Et.al, a randomized controlled
trial was done to determine the efficacy and tolerability
of low dose iron supplement during pregnancy as
compared to high dose iron supplement. They cited
that other trials which supplemented women with high
dose iron supplement (100 mg Fe/d which is 3 times the
estimated requirement of pregnancy) confirmed that
such a dose would cause gastrointestinal side effects
such as upper abdominal discomfort, nausea and
constipation among others. Because of these effects,
some countries such as Australia, New Zealand, the
United Kingdom and Canada do not practice routine
iron supplementation unless anemia is detected in a
26 Volume 41, Number 6, November-December 2017
patient. On the other hand, countries such as France and
the United States recommend routine supplementation
with low dose iron (30-69 mg Fe/d). The researchers
then concluded that low dose iron supplement (20 mg
Fe/d) from 20 weeks age of gestation until delivery
is effective in preventing maternal anemia or iron
deficiency without side effects.7
Moringa oleifera on the other hand, has been
determined to relieve gastrointestinal disorders. Oduro
Ibok, Ellis W.O. and Owusu Deborah reported that the
crude fiber content of Moringa leaves help in digestion
and may be considered as one of the richest sources
of dietary fiber, which may be used in the treatment
of diseases such obesity, diabetes and gastrointestinal
disorders.8
M. E. Cogswell et al conducted a randomized
controlled trial comparing ferrous sulfate and placebo as
iron supplements during pregnancy. There was prevalence
of anemia (hemoglobin concentration <110 g/L) at the 28
week visit for both control and experimental groups. They
attributed this to a possible preferential transfer of the iron
supplement to the placenta and and fetus contributing to
higher birth weight rather than to higher maternal stores.
The mechanisms however, for the said transfer is unknown
according to the authors.9
Several studies regarding iron supplementation
usually use maternal hemoglobin, hematocrit and
ferritin levels in determining maternal iron status. K.
F. Tam and T. T. Lao however, cited that traditionally,
bone marrow biopsy is the only reliable method of
determining true iron status. Since it is impractical to
perform the said procedure on all pregnant women
suspected of iron deficiency, the use of maternal serum
ferritin concentration has been recommended with the
maternal hemoglobin concentration in the early third
trimester considered as the best surrogate for serum
ferritin concentration with hemoglobin level of <11.0 g/l
used as the cut off.10
Research studies evaluating the safety, efficacy
and the benefits from Moringa oleifera have listed
several promising medicinal and nutritional uses
such as neurotransmission, coagulation, anti-viral
and antioxidant effects, use as an anti-fungal agent,
hypoglycaemic activity, radioprotective effect, regulation
of thyroid hormone and hypocholesterol activity among
others. The leaf, seed and fruit powder of the plant have
been proven as naturally rich sources of vitamins and
minerals. 100 grams of the edible portion of Moringa
oleifera pods, fresh/raw leaves and dried leaf powder, as
well as various parts of the plant have been proven to
contain the following - 2.6mg of vitamin B1 (thiamine),
20.5mg of vitamin B2 (riboflavin), 8.2mg of vitamin
B3 (nicotinic acid), and 220mg of vitamin C (ascorbic
acid), 16.3mg of vitamin A, 113mg of vitamin E (alpha-
tocopherol acetate); 423mg of the lipotropic element,
Choline; 19.2 grams of fiber; and several key minerals:
2003mg of Calcium, 368mg of Magnesium, 204mg of
Phosphorus, 1324mg of Potassium, 3.1mg of Copper,
28.2mg of Iron, and 870mg of Selenium, 27.1 grams of
protein (nearly 1/3 of the edible portion) including 19 of
the 20 prominent protein amino acids.11
In the Philippines, Malunggay (Moringa oleifera)
supplementation has been established to improve
lactation among pregnant women with the recommended
dose of 2 capsules three times a day. However, the use
of malunggay has not been investigated to prevent iron
deficiency anemia among pregnant women hence this
research.12
As is the case for fresh leaves of Malunggay,
the reported nutrient content of dried leaves varies
considerably. The amount of iron in 100g of fresh leaves
is 10.8 +/- 6.04 mg as compared to dried leaves which is
32.5 +/- 10.78 mg.13
In a study by Inskandar, et.al, Moringa oleifera leaf
especially extracts, has been proven to have significant
effect to increase haemoglobin levels in pregnant women
and could prevent ferritin serum dismount to 50%.14
Another study by In a study by Nadimin, et.al., wherein
the compared Moringa leaf extract capsules with folic iron
supplementation. It has shown that Moringa leaves can
improve hemoglobin levels. Theses has equal capability
with iron supplements with folic acid in preventing anemia
in pregnant women. They have concluded that it can
also be used as alternative for prevention of anemia in
pregnant women.15
CHAPTER III: METHODOLOGY
A. Research Design to be Used
Randomized controlled trial will be used in this study.
B. Description of respondents
A total of 60 subjects were selected who are on
their 12th week age of gestation from the Out Patient
Department of a tertiary hospital, all of whom were given
written informed to consent to participate in this study.
They were grouped into 2 groups by fish-bowl method of
randomization. The control group, comprised of patients
who were prescribed Ferrous sulfate capsule OD and
the experimental group, comprised of patients were
prescribed Moringa oleifera (Malunggay) 1 capsule TID.
Patients with anemia and other hematologic disorders,
as well as patients with hyperemesis gravidarum and
other gastrointestinal disorders were excluded in this
study.
C. Instruments/Materials to be Used
Generic Ferrous sulfate capsules were prescribed
to the control group while Moringa oleifera (Malunggay)
capsules were prescribed to the experimental group.
Self-administered questionnaire was filled out by each
participant indicating adverse effects that each individual
may or may not experience upon when they took the
prescribed supplement. The said questionnaire would
serve as a record of their compliance to taking their
respective supplement.
D. Data Gathering Procedures
Patients were required to take their respective
supplements until term. Their routine baseline complete
blood count (CBC), costing 300 pesos at the laboratory
of the tertiary hospital was paid for individually by
each patient, were requested prior to their intake of
supplements. During each prenatal check-up, patients
filled out a questionnaire relaying any signs and
symptoms that may be associated with intake of their
supplements. Patient compliance or adherence to
the supplementation regimen were expressed as the
number of capsules consumed as a percentage of the
number of days from enrollment into the study until
delivery. Random monitoring of patient compliance
was done through contacting subjects via phone call.
Hemoglobin and hematocrit were monitored monthly
(costing 155 pesos per month done at the laboratory,
to be sponsored by a pharmaceutical company from
enrolment into the study until 1 month prior to term.
A repeat CBC (c/o each patient) was requested at term
(upon admission) to determine and compare the iron
status between the control and experimental groups.
Subjects that were chosen will be observed within a 7
month period. A copy of the patient’s prenatal record
and hemoglobin and hematocrit monitoring was
obtained.
E. Statistical treatment of Data/Analysis of Data
For this study, descriptive analysis using mean,
standard deviation, minimum and maximum hemoglobin
levels per groups were used. To further analyze the
statistical significance of the gathered descriptive results,
2- way ANOVA was used.
Frequencies and percentages based on the total
subjects per group (30) will be used to compare the signs
and symptoms experienced by both groups upon taking
their respective iron supplements.
Volume 41, Number 6, PJOG November-December 2017 27
CHAPTER IV: RESULTS AND DISCUSSION

Table 1. Ferrous Sulfate Group

Subject Age/ OB Started Iron Baseline Hgb/Hct Hgb/Hct (mg/dl) Hgb/Hct Hgb/Hct
Score supplement Hgb/Hct (mg/dl) at at 24 weeks AOG (mg/dl)at 36 (mg/dl) at
(AOG) (mg/dl) 18 weeks weeks AOG term
AOG
1 M.A. G2P1 12 weeks Hgb 11.8 Hgb 11.5 Hgb 10.9 Hgb 12.5 Admitted
(1001) Hct 34.7 Hct 34 Hct 32.1 Hct 37 at 38 4/7
24 Intervention: Resumed weeks
increased FeSo4 FeSo4 to OD Hgb 13.5
to BID Hct 40.19

2 J.D. G1P0 12 weeks Hgb 14.6 Hgb 13 Hgb 12.5 Admitted at

28 Hct 43 Hct 38.4 Hct 37.17 36 weeks
Hgb 13.9
Hct 41.13
3 J.L 29 G3P2 12 weeks Hgb 12.5 Dropped out because of GDM
(2002) Hct 37
4 F.P. 33 G3P2 12 weeks Hgb 11.9 Hgb 11.9 Hgb 11.5 Hgb 11.6 Hgb 12.5
(0202) Hct 35 Hct 35 Hct 34 Hct 34 Hct 36.88
5 J.I G1P0 12 weeks Hgb 13.9 Hgb 12.6 Hgb 12.5 Lost to follow up
32 Hct 41.13 Hct 37.07 Hct 36.7
6 R.O G2P1 12 weeks Hgb 11.5 Hgb 11.5 Lost to follow up
(1001) Hct 33 Hct 34
35
7 R.P. G2P1 12 weeks Hgb 11.5 Lost to follow up
(1001) Hct 33
29
8 M.N. G1P0 12 weeks Hgb 15.1 Lost to follow up
19 Hct 44
9 C.D. G2P0 12 weeks Hgb 13 Hgb 12.2 Hgb 12.4 Hgb 12.5 Hgb 12.5
(0010) Hct 38.4 Hct 36.1 Hct 36.7 Hct 37 Hct 37.1
26
10 G.C. G3P2 11 2/7 Hgb 12.1 Hgb 12 Hgb 12 Hgb 12.2 3Hgb 12.3
(2002) weeks Hct 35.4 Hct 34.9 Hct 35.5 Hct 36 Hct 36
31
11 A.C. G1P0 11 3/7 Hgb 15.3 Hgb 14 Hgb 12.5 Hgb 13.5 Hgb 13.5
31 weeks Hct 44.7 Hct 41 Hct 37.17 Hct 40 Hct 40.1
12 G.B G2P1 12 1/7 Hgb 13 Hgb 12.2 Hgb 12.4 Hgb 12.5 1Hgb 12.5
(1001) weeks Hct 38.4 Hct 36.1 Hct 36.7 Hct 37 Hct 37.1
21
13 L.A. G3P1 12 weeks Hgb 11.7 Hgb 12.4 Hgb 12.4 Hgb 12.4 Hgb 12.2
(1011) Hct 34 Hct 37.1 Hct 37 Hct 36.9 Hct 36.1
25
14 C.D. G3P2 12 weeks Hgb 13.8 Hgb 13.3 Hgb 12.3 Hgb 12.5 Hgb 12.5
(2002) Hct 41.4 Hct 39 Hct 37 Hct 37 Hct 36.7
22

28 Volume 41, Number 6, November-December 2017

15 E.D. G1P0 12 weeks Hgb 12.6 Hgb 13.3 Hgb 12.6 Hgb 12.7 Hgb 13.3
23 Hct 36. Hct 39.2 Hct 37 Hct 37 Hct 38
16 E.B. G2P1 12 weeks Hgb Hgb 11.6 Hgb 11.9 Hgb 11.6 Hgb 12
(1001) 12.56 Hct 34.1 Hct 35 Hct 34 Hct 35.9
28 Hct 35.7
17 C.B. G1P0 12 weeks Hgb 11.5 Hgb 11.5 Hgb 12.5 Hgb 11.9 Hgb 11.8
28 Hct 34 Hct 34.5 Hct 37.8 Hct 35.6 Hct 35.4
18 V.S. G2P1 12 weeks Hgb 11.7 Hgb 11.6 Hgb 11.9 Hgb 12.3 Hgb 12.2
(1001) Hct 34 Hct 34.1 Hct 35.7 Hct 36.9 Hct 36.6
33
19 A.B. G2P1 12 weeks Hgb 11.5 Hgb 10.8 Hgb 11.8 Hgb 12.1 Hgb 12.9
(1001) Hct 34 Hct 32.4 Hct 35 Hct 36.3 Hct 39
30 FeSo4 BID FeSo4 OD
20 G.N. G3P2 12 weeks Hgb 12.1 Hgb 12.5 Hgb 13 Hgb 12.8 Hgb 14
(2002) Hct 35.4 Hct 38 Hct 39 Hgb 38.4 Hc t42
31
21 E.D. G1P0 12 weeks Hgb 12.6 Hgb 12.7 Hgb 12.5 Hgb 13.3 Hgb 13.3
26 Hct 36. Hct 37 Hct 37.1 Hct 39.2 Hct 38

22 E.B. G2P1 12 weeks Hgb Hgb 12.5 Hgb 12.1 Hgb 12 Hgb 12.2
(1001) 12.32 Hct 37 Hct 35.4 Hct 35.5 Hct 36.3
21 Hct 36.1

23 A.B. G1P0 12 weeks Hgb 11.5 Hgb 13.3 Hgb 13.6 Hgb 13.1 Hgb 13.3
23 Hct 34 Hct 39 Hct 35 Hct 36 Hct 39.1
24 F.S. G2P1 12 weeks Hgb 11.6 Hgb 12.5 Hgb 12.1 Hgb 12.2 Hgb 12.5
(1001) Hct 34.1 Hct 37.16 Hct 35.72 Hct 36 Hct 37.21
24
25 A.B. G2P1 12 weeks Hgb 11.5 Hgb 12.9 Hgb 12.52 Hgb 12.6 Hgb 12.3
(1001) Hct 34 Hct 37.86 Hct 37.4 Hct 37.07 Hct 36.7
29
26 N.A. G3P2 12 weeks Hgb 12.1 Hgb 12.5 Hgb 12.5 Hgb 13.9 Hgb 14.2
(2002) Hct 35.4 Hct 36.7 Hct 37.1 Hct 41.13 Hct 42.7
30
27 J.B. G1P0 11 3/7 Hgb 11.7 Hgb 12.7 Hgb 12.4 Hgb 12.5 Hgb 12.9
34 weeks Hct 34 Hct 37.17 Hct 36 Hct 37.21 Hct 37.86

28 E.D. G1P0 12 weeks Hgb Hgb 12.5 Hgb 12.1 Hgb 12 Hgb 12.2
33 11.72 Hct 37 Hct 35.4 Hct 35.5 Hct 36.3
Hct 34.3
29 M.B. G2P1 12 weeks Hgb 11.4 Hgb 12.5 Hgb 12.5 Hgb 12.3 Hgb 12.2
(1001) Hct 34.6 Hct 37.1 Hct 37 Hct 37.5 Hct 37.2
20
30 J.L. G1P0 12 weeks Hgb 12.1 Hgb 12.3 Hgb 12.2 Hgb 12.4 Hgb 12.4
20 Hct 36.3 Hct 36.1 Hct 35.5 Hct 37 Hct 37.2
31 C.D. G2P1 12 weeks Hgb 13.2 Hgb 13.9 Hgb 13.3 Hgb 13.3 Hgb 13.3
(1001) Hct 39.6 Hct 41 Hct 39 Hct 40.17 Hct 40
27

Volume 41, Number 6, PJOG November-December 2017 29

 32 A.C. G2P1 12 weeks Hgb Hgb 12.3 Hgb 12.2 Hgb 12 Hgb 12
(1001) 12.56 Hct 36 Hct 36 Hct 35.5 Hct 35.3
29 Hct
37.68
33 I.L. G3P2 12 weeks Hgb 11.5 Hgb 11.6 Hgb 12.2 Hgb 12.1 Hgb 12
(2002) Hct 34.2 Hct 34 Hct 36 Hct 36.1 Hct 35.5
28
34 N.P. G1P0 11 6/7 Hgb 11.6 Hgb 12.9 Hgb 12.52 Hgb 12.6 Hgb 12.3
23 weeks Hct 34.1 Hct 37.86 Hct 37.4 Hct 7.07 Hct 36.7
35 J.M. G1P0 12 5/7 Hgb 12.7 Hgb 12.5 Hgb 12.1 Hgb 12 Hgb 12.2
26 weeks Hgb 38 Hct 37 Hct 35.4 Hct 35.5 Hct 36.3

Table 2. Malunggay Group

Subject Age/ OB Started Iron Baseline Hgb/Hct Hgb/Hct Hgb/Hct Hgb/Hct
Score supplement Hgb/Hct (mg/dl) at (mg/dl) at (mg/dl)at (mg/dl) at
(AOG) (mg/dl) 18 weeks 24 weeks 36 weeks term
AOG AOG AOG
1 E.A. 28 G2P1 12 weeks Hgb 13.3 Hgb 13.3 Hgb 13.6 Hgb 12.2 Admitted
(1001) Hct 41.1 Hct 39 Hct 40.03 Hct 36 at 40
weeks
Hgb 13.3
Hct 40.17
2 J.G. G2P1 12 weeks Lost to follow up*
(1001)
23
3 L.B. G4P2 12 weeks Hgb 12.9 Not done Lost to follow up*
(2012) Hct 37.86
31
4 M.A. 30 G2P1 14 5/7 weeks Hgb 13.7 Hgb 12.5 Lost to follow up*
(1001) Hct 39 Hct 36.7
5 M.D.C. 28 G2P1 13 2/7 weeks Lost to follow up*
(1001)
6 C.R. 27 G1P0 12 4/7 weeks Hgb 15.3 Lost to follow up*
Hct 45
7 E.D.C 33 12 weeks Hgb 11.3 Lost to follow up*
G2P1 Hct 34
(1001)
8 R.S. 23 12 3/7 weeks Hgb 15.3 Hgb 12.2 Hgb 13.9 Hgb 13.3 Hgb 13.3
G1P0 Hct 45 Hct 36 Hct 41 Hct 39 Hct 40.17

9 A.V. 33 12 weeks Hgb 13.3 Hgb 12.1 Hgb 12.5 Hgb 12.3 Hgb 12.3
G2P1 Hct 41 Hct 35.72 Hct 37 Hct 36.31 Hct 36.1
(1001)
10 C.D 28 12 weeks Hgb 13 Hgb 12.5 Hgb 12.5 Hgb 12.4 Hgb 12.2
G1P0 Hct 38.4 Hct 37.17 Hct 37 Hct 36.7 Hct 36.1

11 L.L G1P0 12 weeks Hgb 12.1 Hgb 12.3 Hgb 12.2 Hgb 12 Hgb 12
28 Hct 35.4 Hct 36 Hct 36 Hct 35.5 Hct 35.3

30 Volume 41, Number 6, November-December 2017

12 B.F. G2P1 13 weeks Hgb 13.2 Hgb 13.3 Hgb 13.6 Hgb 13.1 Hgb 13.3
(1001) Hct 38 Hct 39 Hct 35 Hct 36 Hct 39.1
32
13 L.A. G2P0 12 weeks Hgb 12.5 Hgb 12.1 Hgb 12.1 Hgb 12.5 Hgb 12.5
(0010) Hct 37 Hct 35.72 Hct 35.4 Hct 37.21 Hct 37.16
31
14 R.B. G1P0 12 weeks Hgb 13.6 Hgb 12.9 Hgb 12.3 Hgb 12.5 Hgb 12.5
31 Hct 35.1 Hct 37.86 Hct 36.7 Hct 37.1 Hct 37

15 C.C. G2P1 12 weeks Hgb 12.2 Hgb 12.5 Hgb 12.6 Hgb 13.9 Hgb 13.9
(1001) Hct 35.99 Hct 36.7 Hct 37 Hct 41.13 Hct 41.1
28
16 M.B. G3P2 12 weeks Hgb 13.4 Hgb 12.7 Hgb 12.4 Hgb 12.5 Hgb 12.5
(2002) Hct 34 Hct 37.17 Hct 36 Hct 37.21 Hct 37
24
17 M.F. G1P0 12 weeks Hgb 12.9 Hgb 12.1 Hgb 12.5 Hgb 12.3 Hgb 12.4
21 Hct 37.7 Hct 35.72 Hct 37.1 Hct 36.31 Hct 36.2
18 C.B. G1P0 12 weeks Hgb 12 Hgb 12.2 Hgb 12.4 Hgb 12.5 Hgb 12.5
30 Hct 36.2 Hct 36.1 Hct 36.7 Hct 37 Hct 37.1

19 A.D. G2P1 13 2/7 weeks Hgb 13.3 Hgb 12 Hgb 12 Hgb 12.2 3Hgb 12.3
(1001) Hct 41.1 Hct 34.9 Hct 35.5 Hct 36 Hct 36
27
20 F.C. G1P0 12 4/7 weeks Hgb 12.9 Hgb 12.5 Hgb 12.5 Hgb 13.5 Hgb 13.5
24 Hct 37.86 Hct 37 Hct 37.17 Hct 40 Hct 40.1

21 I.P. G1P0 11 6/7 Hgb 13.7 Hgb 12.2 Hgb 12.4 Hgb 12.5 1Hgb 12.5
34 weeks Hct 39 Hct 36.1 Hct 36.7 Hct 37 Hct 37.1
22 G.F. G2P1 13 weeks Hgb 13.2 Hgb 13.3 Hgb 13.6 Hgb 13.1 Hgb 13.3
(1001) Hct 38 Hct 39 Hct 35 Hct 36 Hct 39.1
29
23 A.A. G2P0 12 weeks Hgb 12.5 Hgb 12.1 Hgb 12.1 Hgb 12.5 Hgb 12.5
(0010) Hct 37 Hct 35.72 Hct 35.4 Hct 37.21 Hct 37.16
31
24 T.B. G1P0 12 weeks Hgb 13.6 Hgb 12.9 Hgb 12.3 Hgb 12.5 Hgb 12.5
22 Hct 35.1 Hct 37.86 Hct 36.7 Hct 37.1 Hct 37

25 C.C. G2P1 12 weeks Hgb 12.2 Hgb 12.5 Hgb 12.6 Hgb 13.9 Hgb 13.9
(1001) Hct 5.99 Hct 36.7 Hct 37.07 Hct 41.13 Hct 41.1
26
26 L.B. G3P2 12 weeks Hgb 13.4 Hgb 12.7 Hgb 12.4 Hgb 12.5 Hgb 12.5
(2002) Hct 34 Hct 37.17 Hct 36 Hct 37.21 Hct 37
28
27 S.F. G1P0 12 weeks Hgb 12.9 Hgb 12.1 Hgb 12.5 Hgb 12.3 Hgb 12.4
19 Hct 37.7 Hct 35.72 Hct 37.1 Hct 36.31 Hct 36.2

Volume 41, Number 6, PJOG November-December 2017 31

 28 S.B. G1P0 12 weeks Hgb 12 Hgb 12.2 Hgb 12.1 Hgb 11.6 Hgb 12.7
28 Hct 36.2 Hct 35.99 Hct 35.72 Hct 34.8 Hct 37.17

29 P.D. G2P1 13 2/7 weeks Hgb 14 Hgb 13.1 Hgb 12.5 Hgb 12.5 Hgb 12.5
(1001) Hct 42.1 Hct 39.3 Hct 37.21 Hct 37 Hct 37.1
20
30 JLC. G1P0 12 4/7 weeks Hgb 12.7 Hgb 12.1 Hgb 12.7 Hgb 12 Hgb 12.2
30 Hct 37.17 Hct 35.72 Hct 37.17 Hct 36.2 Hct 35.99
31 P.F G1P0 12 weeks Hgb 12.1 Hgb 12.3 Hgb 12.2 Hgb 12.5 Hgb 12.5
31 Hct 35.72 Hct 36.31 Hct 36 Hct 36.9 Hct 37.2
32 A.J. G3P2 12 weeks Hgb 13.4 Hgb 12.5 Hgb 12.5 Hgb 13.9 Hgb 14.2
(2002) Hct 34 Hct 36.7 Hct 37.1 Hct 41.13 Hct 42.7
31
33 M.A. G1P0 12 weeks Hgb 12.7 Hgb 12.9 Hgb 12.5 Hgb 12.3 Hgb 12.5
29 Hct 38 Hct 37 Hct 36.9 Hct 36.2 Hct 37
34 C.C G1P0 12 weeks Hgb 12.1 Hgb12.3 Hgb 12.2 Hgb 12.4 Hgb 12.4
31 Hct 36.3 Hct 36.1 Hct 35.5 Hct 37 Hct 37.2
35 C.S. G2P1 13 2/7 weeks Hgb 11.6 Hgb 12.5 Hgb 12.1 Hgb 12.2 Hgb 12.5
(1001) Hct 34.1 Hct 37.16 Hct 35.72 Hct 36 Hct 37.21
34
36 T.A G1P0 12 4/7 weeks Hgb 12.4 Hgb 12.2 Hgb 12.3 Hgb 12.5 Hgb 13
26 Hct 36.2 Hct 35.99 Hct 36.7 Hct 37.16 Hct 37
37 A.L G1P0 12 5/7 weeks Hgb 11.6 Hgb 11.6 Hgb 12.2 Hgb 12.1 Hgb 12
29 Hct 34.8 Hct 34 Hct 36 Hct 36.1 Hct 35.5

Table 3. Drop out from Ferrous Sulfate Group

Age OB Started Iron Baseline Hgb/Hct Hgb/Hct Hgb/Hct Hgb/Hct
Score supplement Hgb/Hct (mg/dl) at (mg/dl) at (mg/dl)at 36 (mg/dl) at
(AOG) (mg/dl) 18 weeks 24 weeks weeks AOG term
AOG AOG
Admitted
M.G.S. 32 G1P0 14 1/7
at 34 weeks
weeks
AOG for
Gestational
diabetes
mellitus
and severe
preeclampsia,
HELLP
syndrome

C.G. 34 G2P1 12 weeks Hgb 12.2 Patient was no longer accepted as an OPD patient of
(1001) Hct 35.99 SJDH the Social Service due to financial status

Table 4. Excluded from Study

Subject Age/ OB Score Baseline Hgb Intervention
(mg/dl)
M.G. 32 G1P0 10.9 FeSo4 BID for 1 month then repeat CBC
32 Volume 41, Number 6, November-December 2017
Figure 1.1. Hemoglobin levels of pregnant women who used Figure 1.2. Hematocrit levels of pregnant women who used
Malunggay (Moringa oleifera) and ferrous sulfate in prevention Malunggay (Moringa oleifera) and ferrous sulfate in prevention
of anemia in pregnant patients in the out patient department of of anemia in pregnant patients in the out patient department of
a tertiary hospital a tertiary hospital

It shows that the mean hemoglobin levels of pregnant
women who had Malunggay (Moringa oleifera) and
Ferrous Sulfate are 12.92 and 12.31, respectively. Periodic
hemoglobin level determination during the 18th week, 24th
week, 36th week, and at term showed similar pattern even
in the serial determination of hematocrit. Among pregnant
women who had Malunggay (Moringa oleifera) as iron
supplement, there was noted a decrease of 0.30% from
baseline during the 18th week and a steadily increasing trend
since then. Meanwhile, among pregnant women who took
Ferrous Sulfate, an increase of 0.89% from the baseline was
noted on the 18th week. After the 0.83% decrease during the
24th week, the hemoglobin levels continuously increased.
Generally, the hemoglobin levels of pregnant women
who had Ferrous sulfate were lower than the hemoglobin
levels of pregnant women who took Malunggay (Moringa
oleifera), however, with the previously set assumptions and
randomization, these differences were negligible.
It shows that the mean hematocrit levels of pregnant
women who had Malunggay (Moringa oleifera) and
Ferrous Sulfate are 37.35 and 36.35, respectively. Periodic
hematocrit level determination during the 18th week,
24th week, 36th week, and at term showed similar pattern
even in the serial determination of hemoglobin. Among
pregnant women who had Malunggay (Moringa oleifera)
as iron supplement, there was noted a decrease of 0.63%
from baseline, which is more than the 0.30% decrease of
hemoglobin during the 18th week and a steadily increasing
trend since then. Meanwhile, among pregnant women
who took Ferrous Sulfate, an increase of 1.05% from the
baseline, which is also greater than the 0.89% increase in
hematocrit was noted on the 18th week. After the 0.87%
decrease during the 24th week, the hematocrit levels
continuously increased. Generally, the hematocrit levels
of pregnant women who had Ferrous sulfate were lower
than the hematocrit levels of pregnant women who took

Table 5.1 The difference on Hemoglobin levels of pregnant women who used Ferrous Sulfate and Manlunggay (Moringa oleifera)
as supplements

df SS MS
F P

BETWEEN GROUPS 9.87

0.807 F(4,29)
Age of Gestation q-1=4 3.23 0.807 F1 = = 0.14 2.87
5.88

17.56 F(1,29)
Supplement p-1=1 17.56 17.56 F2 = = 2.99 4.35
5.88

2.73 F(4,29)
Interaction (p-1)(q-1)=4 10.91 2.73 F1x2 = = 0.46 2.87
5.88

WITHIN GROUPS N-pq=20 117.53 5.88

TOTAL N-1=29

Volume 41, Number 6, PJOG November-December 2017 33

 Malunggay (Moringa oleifera), however, with the previously set assumptions and randomization, these differences
were negligible. The trend of hematocrit levels are in comparable with the trend of hemoglobin levels among the
subjects across the weeks of gestation.

Figuire 5.1 shows that the p-value of 0.46 is less than Malunggay (Moringa oleifera) does not have statistical
the p-value at significance level of 0.05 F(4,29)=2.87. In difference on the mean hemoglobin level of pregnant
these results, the null hypothesis that states that the women who used Ferrous Sulfate as iron supplement
mean hemoglobin level of pregnant women who used during pregnancy is accepted.

Table 5.2 The difference on Hematocrit levels of pregnant women who used Ferrous Sulfate and Manlunggay (Moringa oleifera) as
supplements

df SS MS
F P

BETWEEN GROUPS 57.15

10.34 F(4,29)
Age of Gestation q-1=4 41.36 10.34 F1 = = 0.19 2.87
53.56

2.03 F(1,29)
Supplement p-1=1 2.03 2.03 F2 = = 0.04 4.35
53.6

3.44 F(4,29)
Interaction (p-1)(q-1)=4 13.77 3.44 F1x2 = = 0.06 2.87
53.56

WITHIN GROUPS N-pq=20 1071.23 53.56

TOTAL N-1=29

Figure 5.2 shows that the p-value of 0.06 is less than (Moringa oleifera) does not have statistical difference on
the p-value at significance level of 0.05 F(4,29)=2.87. In the mean hemoglobin level of pregnant women who used
these results, the null hypothesis that states that the mean Ferrous Sulfate as iron supplement during pregnancy is
hematocrit level of pregnant women who used Malunggay accepted.

The increase in hemoglobin and hematocrit

levels may be attributed to Moringa oleifera because
of its variety of nutrients and contains a wide range of
micronutrients, especially iron. It also contains a number
of important nutrients which helps in absorption of iron
in the body such as vitamin C is approximately 200 mg13.
The vitamin C content in Malunggay leaf may accelarate
iron absorption in the body. According to Witt, vitamin C
amounted to 172 ± 37.7 mg in 100g of dried leaves.
Ascorbic acid is important to improve iron
absorption. This can negate the effects of some inhibitors
such as phytates14. Vitamin C plays a role in helping to
reduce the iron mainly in the form of non-hem iron Figure 2.1. In this graph, we will see that the most common
dissolved form, from ferry into ferrous15. side effect when taking ferrous sulfate is having dark-colored
stool, followed by vomiting. None among the subjects who took
In a study by Nadimin, et.al., Moringa leaves can
ferrous sulfate as iron supplement developed diarrhea. Nausea
improve hemoglobin levels and have equal ability with and abdominal discomfort were also noted among participants
iron supplements with folic acid in preventing anemia who took Ferrous sulfate.
in pregnant women and may be used as supplement for
prevention of anemia in pregnant women.15 This paper
coincides with the results found in their study.
34 Volume 41, Number 6, November-December 2017

Figure 2.2 This graph shows that the most common side effect of
taking Malunggay (Moringa oleifera) capsule is nausea. Among
the participants, lesser GI effects were observed in those who
took Malunggay (Moringa oleifera) capsule as compared who
took Ferrous sulfate.
CONCLUSION
Based on the graphs and figures that were
shown, overall, there is no significant difference in
the haematological parameters (haemoglobin and
REFERENCES
1. Dolcas Biotech LLC. Moringa oleifera. info@dolcas-biotech.com.
2006-2008.
2. Jed W. Fahey, Sc.D., et. Al. Moringa oleifera: A Review of the
Medical Evidence for Its Nutritional, Therapeutic, and Prophylactic
Properties. Part 1. Trees for Life Journal | www.TFLJournal.org
3. John W. Feightner. Routine Iron Supplementation during Pregnancy
4. Philippine Medicinal Plants: Malunggay. http://wwwstuartxchange.
com/Malunggay.html
5. POGS (Foundation), Inc. Clinical Practice Guidelines on Iron
Deficiency Anemia. November 2009.
6. Cunningham et al. Williams Obstetrics: 23rd edition.
7. Makrides M, Crowther CA, Gibson RA, Gibson RS, Skeaff CM.
Efficacy and tolerability of low-dose iron supplements during
pregnancy: a randomized controlled trial 1-3. Am J Clin Nutr. 2003;
78:145-53.
8. Ibok Oduro, W.O. Ellis and Deborah Owusu. Nutritional potential
of two leafy vegetables: Moringa oleifera and Ipomoea batatas
leaves. January 2008.
9. Mary E Cogswell, Ibrahim Parvanta, Liza Ickes, Ray Yip, and Gary M
Brittenham Iron supplementation during pregnancy, anemia, and
birth weight:a randomized controlled trial.
hematocrit) between subjects who received ferrous
sulfate and Malunggay capsules. It may be used as an
alternative to Ferrous sulfate in pregnant women to
prevent anemia.
RECOMMENDATIONS
For future researchers, we would recommend the
following:
• To determine the quantity of different micronutrients
in one preparation
• Use of other parts of Moringa oleifera in comparison
with ferrous sulfate or Moringa oleifera leaves
• Use of different preparation instead of dried leaves
• Use in different populations instead of low risk patients
• Long term effects of using Moringa oleifera
• To determine the exact mechanism of how Moringa
oleifera can increase haematological parameters
• To determine the interaction of other nutrients in
Moringa oleifera in haematological parameters
10. Kar Fai Tam, MRCOG; Terence T Lao, FRCOG. Iron Supplementation
in Pregncy. Journal of Paediatrics, Obstetrics and Gynaecology.
Sept/Oct 2002.
11. Johnson, B.C. Clinical Perspectives on the Health Effects of Moringa
oleifera: A Promising Adjunct for Balanced Nutrition and Better
Health.KOS Health Publications – August 2005.
12. Medrano, G.B. and Perez, M.L. The efficacy of Malunggay (Moringa
Oleifera) given to near term pregnant women in inducing early
postpartum breast milk production – a double blind randomized
clinical trial. 2002.
13. Witt KA, The Nutrient Content of Moringa Oleifera leaves. Messiah
College of Department of Nutrition and Diatetics.
14. Iskandar, I.et.al, Effect of Moringa Oleifera Leaf Extracts
Supplementation in preventing Maternal Anemia and Low-
Birth-Weight. International Journal of Scientific and Research
Publications, Volume 5, Issue 2, February 2015.
15. Agussalim B, Nadimin VH, and Suryadi A. The Extract of Moringa
Leaf Has an Equivalent Effect to Iron Folic Acid in Increasing
Hemoglobin Levels of Pregnant Women: A randomized Control
Study in the Coastal Area of Makassar. International Journal of
Sciences: Basic and Applied Research. Volume 22, No. 1, pp 287-
294.
Volume 41, Number 6, PJOG November-December 2017 35
 A study on the knowledge and management practices of
hypertension in pregnancy among midwives in the different
public health centers of Cebu City*
By Maria Carlyn Rodriguez-De Vera, MD and Geraldine Isabella B. Uyheng, MD, FPOGS
Department of Obstetrics and Gynecology, Chong Hua Hospital

ABSTRACT

Background: The Millennium Development Goal (MDG) for 2015 has a target MMR of 52/100,000 live births but this goal has
been difficult to achieve. In the Philippines, 11 mothers die everyday from pregnancy related complications, a bulk contributed
by Hypertension. Public health midwives sometimes attend to these obstetrical emergencies often in the absence of a physician.
This led to the BEmONC program, which addresses the rising morbidities from far-flung areas where resources are scarce, and
helps train midwives in essential obstetrical emergency care. The midwives are our allies in providing the best standard of care
every mother and child rightfully deserves. Only thru periodic evaluation can we help strengthen the BEmONC program, making
it crucial to evaluate the midwives’ knowledge and management practices in hypertension to help identify the setbacks that have
impeded our progress in achieving the MDG.

General Objective: To assess the knowledge and management practices of midwives in the management of hypertension in
pregnancy in accordance to the BEMONC protocol.

Study Design: Descriptive Study

Study Setting: The 69 public health centers of Cebu City

Study population: Public health midwives

Methodology: This is a descriptive study where a survey questionnaire was used and convenience sampling was done. Chi
square and Fischer exact tests were employed to compare proportions. Descriptive statistics was used to summarize the data in
proportion.

Result: More than 70% of the midwives were knowledgeable regarding expected competencies, where BEmONC-trained midwives
were 5-14x more likely to identify appropriate function. However, only a dismal 22-36% will actually administer Magnesium
Sulfate, which shows that knowledge is not translated into practice. Also, more than 70% were knowledgeable on the risk
factors and danger signs of hypertension. However, only less than 40% knowledge rate was demonstrated in the diagnosis and
classification of hypertension in pregnancy. It also showed that midwives agreed to give antihypertensive medications- where
Methyldopa was most commonly given. Among those who agreed to give Methyldopa, majority were BEmONC-trained. A number
also agreed to give hydralazine and diazepam in the setting of severe preeclampsia and eclampsia, where more non-BemONC
midwives agreed. Alarmingly, only less than 50% will refer to a physician in the management of gestational hypertension and
mild preeclampsia, and only 50-60% agreed to facilitate hospital transport in the setting of severe preeclampsia and eclampsia.

Conclusion: The BEmONC manual must be updated to keep up with current guidelines and ensure the conversion of knowledge
into practice. The BEmONC coverage of training must also be expanded so that all practicing midwives know the protocol.
However, the DOH must further strengthen their role in the active surveillance of public health midwives and review the retention
of their skills and regular practice of knowledge. Midwives must also be certified proficient, not merely trained. The midwives
must also be consulted to explore their problems in the implementation of current guidelines so we can better understand their
situation as to why knowledge is not put into practice. By identifying deficiencies, we can improve and address setbacks that
have impeded our progress towards achieving the Millennium Development Goal.

Keywords: BEmONC, CPG, DOH, hypertension in pregnancy, knowledge, practices, public health midwives

*Finalist, Philippine Obstetrical and Gynecological Society (Foundation),

Inc. (POGS) Research Paper Contest, October 25, 2017, 3rd Floor POGS
Building, Quezon City
Volume 41, Number 6, PJOG November-December 2017 1
INTRODUCTION
M
idwives are the frontline health providers in the
provision of maternal care especially in far-flung
barangays where doctors are scarce. Midwives
in public health centers attend to prenatal care and
delivery, at times, unexpected obstetrical emergencies,
often in the absence of a readily available physician.
According to the health statistics of the Cebu City Health
Office for the year 2014, midwives delivered 42.87% of
the total live births in the city. For 2015, this number grew
to 45.86%.1 This shows the impact and role that midwives
play in the society, especially towards the marginalized.
In the Philippines, maternal mortality rate is still
notably high, where 11 mothers die everyday from
pregnancy related complications, of which hypertension
and hemorrhage together account for more than half
of the maternal deaths.2,3 The Millennium Development
Goal (MDG) for 2015 has a target maternal mortality ratio
of 52/100,000 live births, and while Philippine maternal
mortality rate is slowly improving, from 209/100,000
live births in 1993 to 120/100,000 live births in 2013,
the government’s effort to reach the MDG has not been
met.3,4
The Cebu City Epidemiology Surveillance and
Statistics Unit reported 19 maternal deaths in Cebu City
for the year 2014 and alarmingly, 7 of these deaths were
due to preeclampsia. In 2015, 11 out of 19 mothers
died from complications of eclampsia. This depicts the
impact that hypertension has in contributing to maternal
morbidity and morality.
In any developing country, public health midwives
play an essential role in the care of pregnant patients.
Hence, conducting a study on their knowledge and
management practices is crucial to help evaluate whether
correct standards are being followed. This is to ensure
whether midwives remain within the bounds of their
expected competencies.
Lohre and Liljevik in Urban, Tanzania did a similar
study on knowledge and management practices of
hypertension in pregnancy among health care workers.
According to the study, the level of knowledge and
management of hypertension was low, at 65% and
21%, respectively.5 To date, there has been no other
published study done in the Philippines that evaluates the
knowledge and actual management practices of midwives
with regards to hypertension in pregnancy.
Knowledge is evaluated because it is vital to
practice. Understanding and remaining within expected
competencies will help ensure patient safety. The
Midwifery Act of 1992 (R.A. 7392) states that that all
emergency drugs need to be prescribed by a doctor.
However, this has been modified thru Administrative
2 Volume 41, Number 6, November-December 2017
Order 2010-0014 and Republic Act No. 10354 Section
25 which states that midwives are allowed to administer
lifesaving drugs such as magnesium sulfate, in accordance
with the guidelines set by the DOH, under emergency
conditions, when no physician is available, provided that
they are appropriately trained and certified.
Knowledge on risk factors for hypertension is
evaluated because this helps midwives identify the high-
risk population that need closer antenatal surveillance.
The need to identify risk factors stems from the 7-fold
increase in risk in women with previous preeclampsia,
with recurrence rate as high as 50%.6 Preeclampsia also
has a hereditary predisposition where it is identified in
37% of sisters, and 26% in daughters.7 Women >40 y.o also
had twice the risk.8 Furthermore, the recurrence rate for
obese and overweight women are also higher.9 Likewise,
10% of gestational diabetics will develop preeclampsia,
and the likelihood quadruples if the mother is overtly
diabetic.10,11 Primiparity also carries a 2.4 elevated risk of
preeclampsia, and this risk triples in women with twins.12,13
Furthermore, the BEmONC protocol identifies
generalized selling (pitting edema), headache, epigastric
pain, vomiting, blurring of vision, dyspnea, and convulsion
as danger signs of hypertension.14-16 Missing a danger sign
is a vital opportunity missed to appropriately manage a
patient, thus the need for midwives to be adept in this
aspect of hypertension.
Correct diagnosis is the foundation for decisions
made about treatment. According to a cross sectional
study done by Shimkhada et. al on the misdiagnosis of
obstetrical cases among urban providers in the Philippines,
the prevalence of misdiagnosis was notably high with
an overall rate of 29.8%, where the misdiagnosis rate of
preeclampsia was 33%.17
As first line healthcare providers, it should be a
midwife’s basic knowledge to know the classification
of hypertension in pregnancy so they can correctly
diagnose and appropriately refer a patient at the outset.
For instance, the BEmONC manual states that mild
preeclampsia is diagnosed up to +2 proteinuria; severe
preeclampsia +3. However, the Clinical Practice Guidelines
(CPG) and the American College of Obstetricians and
Gynecologists (ACOG), follows a minimum criteria of +1 for
the diagnosis. In fact, it doesn’t require proteinuria in the
event of symptomatic disease. It is therefore important
to evaluate if the BEmONC protocol is at par with current
guidelines and whether midwives can correctly diagnose
a case to help prevent untoward events.
Furthermore, the BEmONC program has helped train
midwives to administer an intramuscular loading dose of
Magnesium sulfate. The non-BEmONC midwives are not
allowed to give magnesium sulfate without proper training
and certification. Because labor and delivery is a more
likely time for convulsions to develop, magnesium sulfate
is recommended during labor and 24 hours post partum.18
The midwives’ knowledge on proper administration, side
effects and management practices in Magnesium sulfate
administration must be evaluated to ensure safe practice.
Lastly, the midwives’ actual management practices on
hypertension are evaluated to guarantee whether correct
standards are being followed. According to the BEmONC
protocol - gestational hypertension, mild preeclampsia,
should be referred to a physician. Antihypertensive
medications should not be started without physician
prescription. In the setting of preeclampsia-eclampsia,
BEmONC-trained midwives are allowed to administer a 10
gram loading dose of Magnesium sulfate intramuscularly
but should immediately refer the patient to a physician
and facilitate urgent transport. Investigating actual
management practices of midwives in these different
clinical situations is crucial because this ultimately affects
final maternal and fetal outcome.
RESEARCH QUESTION
What are the knowledge and management practices
among public health midwives in the management of
hypertension in pregnancy?
OBJECTIVES
General Objective
To assess the knowledge and management practices
of public health midwives in Cebu City in the management
of hypertension in pregnancy in accordance to the Basic
Emergency Obstetrical and Neonatal Care (BEmONC)
protocol as set by the Department of Health (DOH).
Specific Objectives
1. To determine the following variables related to the
midwives:
a. Public health midwife population in Cebu City
b. Mean age of public health midwives
c. Distribution of public health midwives according
to the following variable characteristics.
c1. BeMONC certification
c2. Mean years of practice of midwives
c3. Average number of prenatal consults seen per
week
2. To determine the proportion of midwives who,
regardless of being certified or not by BEmONC, are
considered knowledgeable on the following:
a. Appropriate functions (based on the BEmONC
guideline)
b. Inappropriate functions (not based on the
BEmONC guideline)
3. To determine the proportion between the
BEmONC trained and non-BEmONC trained midwives who
are considered knowledgeable on the following:
a. Appropriate functions (based on the BEmONC
guideline)
b. Inappropriate functions (not based on the
BEmONC guideline)
4. To determine the proportion of midwives who
correctly identified the following knowledge parameters
according to their perceived correct answers:
a. Risk factors for hypertension in pregnancy
b. Danger signs of hypertension
c. Proper way of checking the blood pressure
d. Correct management protocol of a seizure
episode
5. To determine the proportion among BEmONC-
trained midwives who are knowledgeable on the following
parameters:
a. Proper administration of Magnesium sulfate
b. Side effects of Magnesium sulfate
6. To determine the proportion of midwives who
can identify the correct classification of hypertension in
pregnancy based on the case definition as described in
the:
a. BEmONC protocol.
b. POGS Clinical Practice Guideline.
7. To determine the proportion of non-BEmONC
and BEmONC-trained midwives who agreed to a given
management practice in dealing with the following
diagnosis:
a. Gestational Hypertension
b. Mild Preeclampsia
c. Severe Preeclampsia
d. Eclampsia
DEFINITION OF TERMS
1. public health midwife
- in this study, public health midwives are those
midwives who serve in the different public health centers
in the country.
2. BEmONC
- The Basic Emergency Obstetric and Essential
Newborn Care (BEmONC) is a seven-day training program
that strengthens the basic knowledge, skills and attitude
of midwives in providing essential emergency obstetric
and neonatal care.
3. BEmONC-trained midwife
- a midwife who claims to have undergone BEmONC
training given by the Department of Health
4. Knowledge
- is subdivided and will be determined based
Volume 41, Number 6, PJOG November-December 2017 3
on the following parameters: midwife function, risk
factors and danger signs of hypertension, classification
of hypertension, checking the blood pressure, proper
administration and side effects of Magnesium Sulfate.
5. Management Practice
- will be determined by the proportion of midwives
who correctly answered on the following management
protocols of gestational hypertension, mild preeclampsia,
severe preeclampsia and eclampsia.
6. Functions of a midwife
- will be determined by giving the respondents the
different appropriate and inappropriate functions where
they can either answer agree or disagree only, based on
their perceived correct answer.
7. Appropriate functions
- are functions that are based on the BEmONC
guideline such as:
a. Administration of Magnesium Sulfate intramuscu-
larly
b. Administration of Magnesium sulfate in emergency
situation
8. Inappropriate functions
- are functions that are not based on the BEmONC
guideline such as:
a. Administration Magnesium Sulfate intravenously
b. Administration of Hydralazine in emergency
situation when no physician is available
c. Administration of Diazepam in emergency situation
when no physician is available.
d. Administer Magnesium sulfate, even if not certified,
as long as it is an emergency.
7. Risk factors for hypertension
- will be measured by a given checklist where
respondents can check more than one answer based on
their perceived identified risk factor.
8. Danger signs of hypertension
- will be measured by a given checklist where
respondents can check more than one answer based on
their perceived correct danger sign.
9. Checking for hypertension
- is measured by 2 or 3 item checklist covering the
following concepts (best position in blood pressure
taking, correct arm used, minimum BP requirement
for the diagnosis of gestational hypertension, when to
repeat blood pressure measurement, minimum amount
of proteinuria to diagnose preeclampsia) based on the
BEmONC protocol where the respondents can only choose
1 answer.
10. Classification of hypertension in pregnancy
- will be determined by 7 statements where the
4 Volume 41, Number 6, November-December 2017
midwife identifies the correct diagnosis by checking 1
answer only among the given choices.
11. Management of hypertension in pregnancy
- will be determined by 8 management practices
where the midwife can identify more than 1 answer on
each given diagnosis (Gestational hypertension, Mild
Preeclampsia, Severe preeclampsia, Eclampsia)
12. Management during a seizure episode
- will be determined by 10 knowledge parameters
where the midwife can either answer agree or disagree
only, based on their perceived correct answer.
13. Proper administration of Magnesium sulfate
- will be determined by 7 statements where the
midwife can either answer agree or disagree only, based
on their perceived correct answer.
14. Side effects of Magnesium sulfate
- will be determined by 10 enlisted side effects
that midwives will identify by answering either agree or
disagree only, based on their perceived correct answer.
RESEARCH METHODOLOGY
A. Study Design: Descriptive Study
B. Study Setting: The 69 public health centers under the
Cebu City Health Office
C. Study Population:
A total of 77 public health midwives currently serve
the different health centers in Cebu City. Out of the 77
midwives, 49 (63%) participated in the study.
C1. Inclusion Criteria:
1. All public health midwives who signed the
informed consent, either BEmONC or non-
BEmONC trained.
C2. Exclusion Criteria:
1. Those midwives not present at the time of
survey.
2. Those midwives who refused to be included
in the study.
3. Midwives who belong to the private sector
who have their own private practice.
D. Sample Size and Sampling Method:
Convenience sampling was used. All public health
midwives who were present at the survey were invited to
participate in the study.
E. Data Collection Technique:
A survey questionnaire was used to gather the
needed information regarding knowledge and practice. Table 2. Distribution of public health midwives according to
The questionnaire was constructed in English and variable characteristics.
pretested before final distribution. Informed consent
Table 2.1 BEmONC Certification Centers
was obtained prior to questionnaire distribution.
No. Percent
F. Data Processing and Analysis BEmONC certified 26 26
After the questionnaires were returned, it was Non-BEmONC certified 23 23
checked for completeness. Each survey form was
Total 49 49
assigned its own code number for identification.
Answers to each question were assigned a numerical Table 2.2 Mean years of practice
code, and data entry was done using Microsoft Excel. Less than 5 years 2 4.2
The gathered data were then analyzed using IBM 5-10 years 6 12.5
SPSS statistics version 19. Descriptive statistics was > 10 years 5 10.4
used to summarize the data in proportion and means.
> 20 years 35 72.9
Chi square and Fischer exact test were employed to
compare proportions. Differences between groups Total 48 100
were assessed using percentages. Tables were used to Average numbers of prenatal consults seen
Table 2.3
present the summarized data. per week.
5-10 8 17.4
G. Plan for Utilization of Results
10-20 7 15.2
The findings of this study will be presented and
> 20 12 26.1
submitted to the Cebu- POGS Chapter Annual Residents’
Research Presentation and to the DOH Region 7 first > 30 19 41.3
annual Research Congress. Total 46 100

RESEARCH Functions of a Midwife

Midwife population and other variables
There are a total of 77 public health midwives
serving 69 public health centers in Cebu City where 63%
(49 midwives) of the midwives participated in the study.
Majority of participants were from the North, East, and
South areas (Table 1).
The mean age of midwives was 46 with a SD± 9.98.
Among the participants, more than half (53.1%) were
BEmONC trained (Table 2.1).
The majority (72.9%) of public health midwives
have been in practice for more than 20 years, with only
4.2% having less than 5 years of experience (Table 2.2).
The average number of prenatal consults is more than 30
patients per week (Table 2.3).
In general, majority of the midwives were generally
knowledgeable regarding appropriate and inappropriate
functions, where more than 70% correctly identified
the appropriate function and more than 82% correctly
identified inappropriate function. However, the BEmONC-
trained midwives were found to be 5 to 14x more likely
to correctly identify appropriate function compared to the
non-BEmONC trained midwives (Table 3).
The midwives were then categorized according to
BEMONC training (Table 4). Results showed that more
non-BEMONC trained midwives were able to correctly
disagree on inappropriate practices- such as giving of IV
Magnesium (92 vs. 77.3%), IV Diazepam (100 vs. 91.3%),
and Magnesium sulfate without proper certification
(95.8% vs. 91.3%), although no statistical significance was
noted between both groups (Table 4.3-4.6).

Table 1. Public health midwife population in Cebu City

Area No. of Health Centers No. of midwives/area No. of participants % of participants

North 14 17 12 24.5
West 10 10 6 12.2
East 16 19 12 24.5
South 17 17 12 24.5
Central 12 14 17 14.3
TOTAL 69 77 49 (63%) 100
Volume 41, Number 6, PJOG November-December 2017 5
Table 3. Knowledge of BEmONC midwives and non-BEmONC midwives in identifying appropriate and inappropriate functions
according to the BEmONC guidelines.

Area Correct answer % Correct p value Odds ratio a

APPROPRIATE FUNCTION
3.1 Administration of Magnesium Sulfate Agree 34 .027 5.238
intramuscularly (70.9%) (95% C.I 1.231- 22.282)
3.2. Administration of Magnesium sulfate in Agree 37 .005 14.667
emergency situation provided they are properly (77.1%) (95% C.I 1.695- 126.903)
trained and certified.

INAPPROPRIATE FUNCTION
3.3. Administration of Magnesium Sulfate Disagree 40 .228 .296 (95% C.I .052-2.711)
INTRAVENOUSLY. (85.1%)
3.4 Administration of intravenous Hydralazine in Disagree 38 .699 1.852 (95% C.I .387- 8.871)
emergency situation when no physician is available. (82.6%)
3.5 Administration of intravenous Diazepam in Disagree 45 .234 1.095 (95% C.I .965- 1.242)
emergency situation when no physician is available. (95.7%)
3.6 Administer Magnesium sulfate, even if not Disagree 44 .609 .457 (95% C.I .039-5.409)
certified, as long as it is an emergency. (93.6%)
a. Odds ratio comparing BeMONC to non-BEmONC

Table 4. The proportion of BEmONC and non-BEmONC trained midwives who are considered knowledgeable regarding appropriate
and inappropriate functions.

APPROPRIATE FUNCTION Correct answer % Knowledgeable

4.1. Administration of Magnesium Sulfate intramuscularly
Non-BEmONC certified Disagree 56
BEmONC certified Agree 87
4.2. Administration of Magnesium sulfate in emergency situation provided they are properly trained and certified.
Non-BEmONC certified Agree 60
BEmONC certified Agree 95.7
INAPPROPRIATE FUNCTION Correct answer % Knowledgeable
4.3. Administration of anticonvulsant like Magnesium Sulfate intravenously.
Non-BEmONC certified Disagree 92
BEmONC certified Disagree 77.3
4.4. Administration of intravenous anti-hypertensive like Hydralazine in emergency situation when no physician is available.
Non-BEmONC certified Disagree 78.3
BEmONC certified Disagree 87
4.5. Administration of intravenous anticonvulsant like Diazepam in emergency situation when no physician is available.
Non-BEmONC certified Disagree 100
BEmONC certified Disagree 91.3

4.6. Administer Magnesium sulfate, even if not certified, as long as it is an emergency.

Non-BEmONC certified Disagree 95.8
BEmONC certified Disagree 91.3

6 Volume 41, Number 6, November-December 2017

Risk factors for hypertension in pregnancy Table 5. Distribution of midwives according to their perceived
Among the risk factors strongly identified by midwives risk factors for hypertension in pregnancy.
were history of previous preeclampsia (93.8%), family
Risk Factors No. Percent
history of preeclampsia (87.5%), and advanced maternal
age (81.3%). Likewise, as much 70-75% of midwives Nulliparity 22 45.8
correctly identified obesity and pre-pregnancy diabetes History of previous preeclampsia 45 93.8
mellitus to be risk factors as well. The least identified risk Advanced Maternal Age 39 81.3
factors were nulliparity (46%) and multifetal gestation Multiple previous pregnancies * 40 83.3
(67%) (Table 5). Obesity/BMI >30 34 70.8
Smoking * 31 64.6
Danger signs of hypertension
Multifetal gestation 32 66.7
The most frequent danger sign that the midwives
identified were blurring of vision (93.8%), convulsion Family history of Preeclampsia 42 87.5
(85.4%), and headache (82.3%). Furthermore, 79.2% Pregestational Diabetes Mellitus 36 75
correctly identified vomiting and loss of consciousness, * NOT a risk factor for hypertension
while only 70.8% identified dyspnea as a danger sign
(Table 6). Notably, only few identified right upper quadrant
pain (37.5%) and tea colored urine (33.3%) to be danger Table 6. Distribution of midwives according to their perceived
signs. danger signs of hypertension.

Danger signs No. %

Checking the blood pressure
Overall, less than 70% of the midwives showed Headache 40 83.3
knowledge in this aspect of hypertension. Among the Right upper quadrant pain 18 37.5
respondents, only 69% correctly identified sitting as the Difficulty breathing 34 70.8
best position, 68% correctly answered using the same arm Blurring of vision 45 93.8
for BP taking, while only 6% correctly answered to repeat Convulsion/Upward rolling of eyeball 41 85.4
the BP after one hour of rest (Table 7). Moreover, only
Edema * 38 79.2
57% were knowledgeable of the minimum blood pressure
Vomiting 38 79.2
requirement needed for diagnosis while only 49% were
knowledgeable on the new minimum cut-off of proteinuria Loss of consciousness 38 79.2
needed to diagnose preeclampsia (Table 7). Tea-colored urine 16 33.3
* NOT a danger sign for hypertension

Table 7. Proportion of midwives who correctly answered the

proper way of checking the blood pressure Management of a seizure episode
Overall, the midwives were generally knowledgeable
Correct answer % knowledgeable on the supportive care aspect of a seizure episode,
7.1 Best position Sitting 69.4 where majority correctly agreed to a given appropriate
7.2 Arm used Same arm 68.1 management, where more than 90% will call for medical
help and position the woman to the left and 85% agreed
7.3 When to repeat After 1 hour 6.1 on clearing the airway, administering oxygen and referring
BP measurement of rest
the patient to a hospital.
7.4. Minimum blood 140/90 mmHg 57.2 Furthermore, among the inappropriate practices
pressure requirement given, only a few respondents correctly disagreed about
for diagnosis giving Diazepam (59.6%), about giving a maintenance
7.5. Ask for warning YES 100 dose of Magnesium sulfate and observing the patient in
signs if diastolic BP the health center (43.5%), and to the use soft restraints
persistently >90 (19.1%) (Table 8).
mmHG
7.6. Minimum +1 Proper Administration of Magnesium Sulfate
49.0
amount of protein Overall, majority of the BEmONC-trained midwives
needed for the were generally knowledgeable on the correct route, dosage,
diagnosis and technique of Magnesium sulfate administration (Table
Volume 41, Number 6, PJOG November-December 2017 7
Table 8. The proportion of midwives who correctly answered Table 9. The proportion of BEmONC-trained midwives who
the proper management of a seizure episode. correctly answered the proper administration of Magnesium
Sulfate.
Correct answer % knowledgeable
Correct answer % knowledgeable
1. Call for medical Agree 97.9
help 1. Magnesium Agree 100
sulfate is given
2. Clear airway and Agree 85.4 intramuscularly as
or give oxygen at 10 grams (5 grams
4-6L/ min each buttock),
3. Position woman Agree 95.9 50% solution as
on her LEFT side an initial loading
dose
4. Apply soft Disagree 19.1
restraints to avoid 2. Continue giving Disagree 42.9
undue injuries to maintenance dose
the woman of Magnesium
sulfate of 5 grams
5. Give loading dose Agree 72.3 intramuscularly,
of Magnesium alternating
Sulfate buttocks, every 4
6. Give Disagree 59.6 hours.
anticonvulsant- 3. The preferred Agree 95.2
Diazepam IVTT area for injecting
7. Monitor vital Agree 91.8 magnesium
signs and level of sulfate is in the
consciousness upper outer
quadrant of the
8. Insert a urinary Agree 53.2 buttock, using the
catheter to Z track technique.
monitor urine
output 4. Magnesium Disagree 86.4
sulfate may also
9. Once woman is Disagree 43.5 be given in the
stable, observe deltoid area if
closely and patient requests.
monitor VS every
5. Insert the needle Agree 80
15 minutes in
into the muscle.
the health center
Hold the syringe
until woman
barrel tightly and
delivers. Continue
inject the needle
Magnesium
through the skin
Sulfate.
and into the
10. Refer and arrange Agree 85.4 muscle at a 90
for transport to degree angle.
a hospital once
6. Before injecting, Agree 95.5
stable.
pull on the
plunger a little to
make sure you did
9). However, only 42.9% were knowledgeable that a not hit a blood
maintenance dose of Magnesium sulfate should not be vessel.
continued after a loading dose has been given. (Table 9). 7. If blood comes Disagree 63.6
back after pulling
Side effects of Magnesium Sulfate on the plunger,
Overall, the midwives were generally knowledgeable withdraw the
of the expected side effects of an intramuscular injection, needle a little
except for bleeding at site where only 40% correctly before injecting
the medicine.
8 Volume 41, Number 6, November-December 2017
Table 10. The proportion of BEmONC-trained midwives who identified it (Table 10). Furthermore, majority of the side
correctly identified the side effects of Magnesium Sulfate. effects that needs to be referred to a doctor were all
correctly identified by the midwives such as shortness
Correct answer % knowledgeable of breath (100%), anaphylaxis (85.7%), decrease in urine
AN INTRAMUSCULAR INJECTION CAN CAUSE: output (85.7%), rashes (81%), and decreased DTR (76.2%)
1. Infection Agree 75 (Table 10).
2. Bleeding at site Agree 40
3. Numbness Agree 81 Diagnosis and Classification of Hypertension
4. Pain Agree 90
In the classification of hypertension that is based
SIDE EFFECTS TO BE REFERRED TO A DOCTOR: on the BEmONC protocol, majority of the midwives were
5. Rash or itching Agree Agree unable to identify the correct diagnosis based on the given
may develop case definition, where only 43.5% identified gestational
6. Shortness of Agree Agree hypertension, 30.4% identified preeclampsia, and 46.9%
breath identified eclampsia (Table 11).
In the classification of hypertension that is based
7. Mouth, lips Agree Agree
on the POGS Clinical Practice Guidelines, the majority of
or face swells
(anaphylactic midwives were also unable to identify the correct diagnosis
reaction) – where only 20% correctly diagnosed preeclampsia,
and 38.8% correctly diagnosed eclampsia. Furthermore,
8. Decrease in urine Agree Agree
only 8.9% got a correct diagnosis of superimposed
output
preeclampsia, and only 6.4% got a correct diagnosis of
9. Decrease in DTR Agree Agree chronic hypertension (Table 12).
(Deep Tendon
Reflexes)
Table 12. Proportion of midwives who answered the correct
10. Feeling of Disagree Disagree case definition in the diagnosis of hypertension in pregnancy as
warmth in the defined in the Clinical Practice Guidelines
body
Case Definition Correct answer % knowledgeable
12.1. Elevated BP Preeclampsia 20
Table 11. Proportion of midwives who answered the correct >160/110 with
case definition in the diagnosis of hypertension in pregnancy as headache, blurring of
defined in the BEmONC protocol. vision, and epigastric
pain, after 20 weeks
Case Definition Correct answer % knowledgeable AOG, without
proteinuria
11.1. Elevated blood Gestational 43.5
pressure > 140/90 Hypertension 12.2. Patient is a Superimposed 8.9
mmHg on two known hypertensive Preeclampsia
separate occasions prior to pregnancy,
after 20 weeks AOG, and presents with
in the ABSENCE of worsening blood
proteinuria pressure during
current pregnancy,
11.2. Elevated blood Preeclampsia 30.4
accompanied by new
pressure > 140/90
onset proteinuria
mmHg on two
separate occasions 12.3. Elevated BP Chronic 6.4
after 20 weeks AOG, of >140/90 on two Hypertension
in the PRESENCE of separate occasions
proteinuria before 20 weeks AOG
11.3. In a pregnant Eclampsia 46.9 12.4. Elevated BP, Eclampsia 38.8
woman with elevated with history of
blood pressure and upward rolling of
tonic clonic seizures, eyeball and loss of
the diagnosis is: consciousness
Volume 41, Number 6, PJOG November-December 2017 9
Management Practices
a. Gestational Hypertension
In the management of gestational hypertension, only
48.9% of the respondents correctly answered to refer to
a physician for further management with no statistical
significance noted between both groups of midwives
(Table 13.7).
Furthermore, 45.8% of the respondents answered to
observe and closely follow up the patient only. Moreover,
41.7% of the respondents agreed to give Methyldopa,
while 6.3% agreed to give Nifedipine. Among those who
agreed to give Methyldopa, 45.4% of the BEmONC trained
midwives will give it, while only 38.4% of the non-BEmONC
midwives do (Table 13.2). No statistical significance was
noted between both groups.
b. Mild Preeclampsia
In the management of Mild Preeclampsia, only 46.8%
will correctly refer to a physician for further management,
where 52% of the non-BEmONC midwives will refer and
only 40.9% of the BEmONC midwives do (Table 14.7).
Furthermore, results showed that midwives agreed to
give antihypertensive medications like Methyldopa (53.1%)
and Nifedipine (4.3%). Among those who agreed to give
Methyldopa, 68.1% of the BEmONC midwives will give it while
only 40% of the non-BEmONC midwives do (Table 14.2).
Moreover, the rest will only observe (38%), will refer
the patient to the hospital (12.8%), and will give a loading
dose of Magnesium sulfate (2.1%) (Table 14).
c. Severe Preeclampsia
In the management of severe preeclampsia, result
showed that only 59.6% of the midwives correctly agreed
to refer to a physician, where BEmONC trained midwives
were 4x more likely to refer to a physician for further
management (Table 15.7). Moreover, only 55.3% agreed
to refer and transport the patient to a hospital. Strikingly,
only 36% of the BEmONC trained midwives agreed to
give a loading dose of Magnesium sulfate. (Table 15.6).
Furthermore, results have shown that a number
of midwives agreed to administer Methyldopa (21.3%),
Nifedipine (2.1%), Hydralazine (6.4%), and Diazepam
(2.1%) (Table 16.2-16.5). Among those who agreed to give
Methyldopa and Hydralazine, majority was non-BEmONC
trained, although no statistical significance was noted.
Moreover, 12.8% of the total midwife population will do
observation alone.
d. Eclampsia
In the management of eclampsia, only 61.7%
correctly agreed to refer to a physician while 51% agreed

Table 13. Proportion of non-BEmONC and BEmONC trained midwives who agreed on the following different management practices
in Gestational hypertension.

% % BEmONC %
Management Practice non-BEmONC who Total Midwives p value Odds ratioa
who agreed agreed who agreed

13.1. Observe only. Close 46.15 45.5 45.8 1.000 .972 (95% C.I .311-3.039)
follow up
13.2. Give Methyldopa 38.4 45.4 41.7 .770 1.3 (95% C.I .421-4.222)
13.3. Give Nifedipine 3.8 9.09 6.3 .587 2.5 (95% C.I .211-29.598)
13.4. Give Hydralazine 0 0 0 NA NA
13.5. Give Diazepam 0 0 0 NA NA
13.6. Give loading dose of 0 0 0 NA NA
Magnesium sulfate
13.7. Refer to a physician for 46.1 52.3 48.9 .772 1.4 (95% C.I .448-4.376)
further management *
13.8. Refer to a physician 11.5 4.54 8.3 .614 .365 (95%C.I .035-3.787)
and transport urgently to a
hospital

* correct answer
a. Odds ratio comparing BeMONC to non-BEmONC
10 Volume 41, Number 6, November-December 2017
Table 14. Proportion of non-BEmONC and BEmONC trained midwives who agreed on the following management practices in Mild
Preeclampsia

% % BEmONC %
Management Practice non-BEmONC who Total Midwives p value Odds ratioa
who agreed agreed who agreed

14.1. Observe only. Close 36 40.9 38.2 .771 1.231 (95% C.I. .379-4.000)
follow up
14.2. Give Methyldopa 40 68.1 53.1 .080 3.214 (95% C.I .996-10.695)
14.3. Give Nifedipine 8 0 4.3 .491 .511 (95% C.I .384-.680)
14.4. Give Hydralazine 0 0 0 NA NA
14.5. Give Diazepam 0 0 0 NA NA
14.6. Give loading dose of 0 4.5 2.1 .468 457 (95% C.I .333-.626)
Magnesium sulfate
14.7. Refer to a physician for 52 40.9 46.8 .561 .639 (95% C.I .201-2.032)
further management *
14.8. Refer to a physician 16 9.09 12.8 .670 525 (95% C.I .086-3.190)
and transport urgently to a
hospital

* correct answer
a. Odds ratio comparing BeMONC to non-BEmONC

Table 15. Proportion of non-BEmONC and BEmONC trained midwives who agreed on the following management practices in Severe
Preeclampsia

% % BEmONC %
Management Practice non-BEmONC who Total Midwives p value Odds ratioa
who agreed agreed who agreed

15.1. Observe only. Close 12 13.6 12.8 1.000 1.158 (95% C.I. .209-6.428)
follow up
15.2. Give Methyldopa 28 13.6 21.3 .297 .406 (95% C.I .091-1.817)
15.3. Give Nifedipine 0 4.5 2.1 .457 .511 (95% C.I .333-.626)
15.4. Give Hydralazine 8 4.5 6.4 1.000 .548 (95% C.I .046-6.489)
15.5. Give Diazepam 4 0 2.1 1.000 .522(95% C.I .396-.688)
15.6. Give loading dose of 4 36.3 19.1 .008 13.714 (95% C.I 1.549-
Magnesium sulfate * 121.424)
15.7. Refer to a physician for 44 77.2 59.6 .036 4.327 (95% C.I 1.213-15.439)
further management *
15.8. Refer to a physician 56 54.5 55.3 1.000 .943 (95% C.I .298-2.985)
and transport urgently to a
hospital *

* correct answer
a. Odds ratio comparing BeMONC to non-BEmONC

Volume 41, Number 6, PJOG November-December 2017 11

to transport the patient to a hospital (Table 16.7-16.8).
Moreover, results also showed that only 22.7% of the
BEmONC-trained midwives agreed to give loading dose of
Magnesium sulfate (Table 16.6).
Furthermore, results have also shown that a number
of midwives agreed to give Methyldopa (23.4%), Nifedipine
(8.5%), and Hydralazine (4.25%) (Table 15.2-15.4). Among
those who agreed to give Methyldopa and Hydralazine,
majority were non-BEmONC trained, although no statistical
significance was noted between both groups. Strikingly,
14.9% of the total midwife population will dangerously do
observation alone.
DISCUSSION
Functions of a Midwife
Knowledge is evaluated because it is vital to practice.
Understanding expected competencies will help ensure
patient safety. In general, majority was knowledgeable
regarding their expected functions, where BEmONC-
trained midwives were 5 to 14x more likely to identify
appropriate function compared to their non-BEMONC
counterparts. This finding supports the importance of
undergoing a BEmONC training.
However, although majority was able to correctly
identify inappropriate practice, there were still a number
of midwives, albeit a small percentage, which agreed to
it. Although only a few midwives deviated from correct
practice, the number is real. Statistically, this may be
insignificant, but clinically it counts, because even if only
1 or 2 midwives adhered to wrong practice, this may have
an impact on patient safety. This may also contribute to
additional morbidity if complications arise in the absence
of a physician.
Risk factors for Hypertension
Overall, it is good to know that majority was able to
identify the risk factors for hypertension despite its lack of
emphasis in the BEmONC protocol. This probably reflects
good midwifery training and background. However, it
should be stressed that the risk factors for hypertension
should be more emphasized in their current protocol to
help midwives identify the high-risk population that need
closer antenatal surveillance.
Danger signs of Hypertension
Majority of the midwives were knowledgeable
regarding the danger signs of hypertension that was
mentioned in the BEmONC protocol. However, there are
other danger signs that warrant attention. Notably, only
33-37% of midwives identified right upper quadrant
pain and tea colored urine to be danger signs. However,
the former and latter were not included in the BEmONC
manual, which might explain the poor scores.
Perhaps, significant to the interpretation of these
results are the number of midwives who missed a danger

Table 16. Proportion of non-BEmONC and BEmONC trained midwives who agreed on the following management practices in
Eclampsia.

% % BEmONC %
Management Practice non-BEmONC who Total Midwives p value Odds ratioa
who agreed agreed who agreed

16.1. Observe only. Close 12 18.6 14.9 .690 1.630 (95% C.I. .322-8.246)
follow up
16.2. Give Methyldopa 24 22.7 23.4 1.000 .931 (95% C.I .240-3.612)
16.3. Give Nifedipine 12 4.5 8.5 .611 .349 (95% C.I .034-3.628)
16.4. Give Hydralazine 4 4.5 4.25 1.000 1.143 (95% C.I .067-19.424)
16.5. Give Diazepam 0 0 0 NA NA
16.6. Give loading dose of 12 22.7 17.02 .446 2.157 (95% C.I .451-10.316)
Magnesium sulfate *
16.7. Refer to a physician for 52 72.7 61.7 .229 2.462 (95% C.I .724-8.364)
further management *
16.8. Refer to a physician 48 54.5 51.06 .772 1.300 (95% C.I .412-4.101)
and transport urgently to a
hospital *

* correct answer
a. Odds ratio comparing BeMONC to non-BEmONC
12 Volume 41, Number 6, November-December 2017
sign. This may have a clinical impact because such failure
may result in delayed diagnosis that will likely result in
poor outcome. It must be stressed that failure to detect a
danger sign is a vital opportunity missed, thus the need to
be adept in this aspect of hypertension.
Checking the Blood Pressure
Overall, less than 70% of the midwives were
knowledgeable on the basic tenet of the proper way of
blood pressure measurement. Clearly, basic knowledge on
BP taking needs to be reinforced. The poor scores might
also be due to heavy patient load that pushes midwives to
adhere to incorrect practice to help save time.
Furthermore, the midwives also showed poor
knowledge on the minimum blood pressure requirement
and proteinuria needed to make a diagnosis. According
to the current guidelines in preeclampsia followed by
obstetricians, it only requires +1 proteinuria for the
diagnosis. If we follow the outdated criteria of BEmONC that
requires +3 proteinuria, it may be an avenue for delayed
diagnosis and treatment. In fact, current guidelines do not
require proteinuria in the event of symptomatic disease.
This reflects the growing understanding that preeclampsia
affects multiple organ systems and that renal involvement
is not necessarily required. Results clearly show that
some aspects of the BEmONC protocol, especially on the
diagnosis of preeclampsia, clearly needs to be redefined.
Management of a seizure episode
Although midwives were generally knowledgeable
on the supportive aspect of a seizure episode, incorrect
knowledge on some aspects of management was
uncovered. Results showed that only 59.6% correctly
disagreed to give diazepam and only 19.1% correctly
disagreed to use soft restraints. Furthermore, only
43.5% were knowledgeable that it is incorrect to give
a maintenance dose of Magnesium sulfate and further
observe a woman in the health center after a seizure
episode. Even if only a few midwives agreed to incorrect
practice, this may still pose a threat to patient safety.
Proper administration and side effects of Magnesium
Sulfate.
Results showed that majority of the BEmONC
midwives were generally knowledgeable on the proper
administration and side effects of Magnesium sulfate,
which is a sign of good practice.
However, results have also shown that only 42% of
the BeMONC-trained midwives correctly disagreed in
giving a maintenance dose of Magnesium sulfate. Factors
as to why some midwives agree to continue Magnesium
sulfate, instead of referring these patients to the hospital,
should be explored because it is clearly dangerous to keep
a preeclamptic woman in the health center. Perhaps, the
lack of knowledge or the lack of resources to immediately
transport patients to the hospital may contribute to this
practice.
Diagnosis and Classification of Hypertension
Overall, the midwives showed poor knowledge in the
diagnosis and classification of hypertension based on the
BEmONC protocol and CPG guidelines. This proves that the
BEmONC manual clearly needs to be updated and should
be based on current knowledge principles that guide the
present obstetrical practice.
The poor results are understandable because the
new classification of hypertension in pregnancy is not yet
incorporated into their current BEmONC manual. This is
also consistent with the study of Shimkhada et al. about the
misdiagnosis of obstetrical cases among urban providers
in the Philippines, where the prevalence of misdiagnosis
was notably high. However, critical to any treatment
outcome is, first and foremost, a correct diagnosis. It is
important that midwives are able to classify these patients
correctly so they can appropriately refer them. A wrong
diagnosis is worrisome because of the high maternal and
fetal sequealae of preeclampsia and eclampsia.
Management Practice
There is a trend, although not statistically
significant, that more BEmONC-trained midwives will give
Methyldopa, while more non-BemONC trained midwives
will correctly refer to a physician in the management of
gestational hypertension and mild preeclampsia. Perhaps
the BEmONC-trained midwives were more aggressive in
starting antihypertensive medications, while the non-
BEmONC midwives remained conservative and fearful in
their management.
Furthermore, in the management of severe
preeclampsia and eclampsia, results showed that only 51-
55% agreed to refer and transport patients to the hospital.
This is clinically significant because of the anticipated
morbidity of severe preeclampsia and eclampsia if these
patients are further managed only at the health center.
Strikingly, only 22-36% of the BEmONC-trained
midwives agreed to administer a loading dose of
Magnesium Sulfate in the setting of Severe Preeclampsia
and Eclampsia. The importance of magnesium sulfate
cannot be overemphasized especially in the event of
symptomatic disease. Omitting magnesium sulfate in
these clinical circumstances is dangerous practice. Factors
such as drug availability, personal confidence, fear of side
effects, or the lack of knowledge must be explored as to
why these BEmONC-trained midwives will disagree to give
Magnesium sulfate despite being trained for that purpose.
Furthermore, more non-BEmONC midwives agreed
Volume 41, Number 6, PJOG November-December 2017 13
to give Hydralazine in the setting of severe preeclampsia
and eclampsia, but not in gestational hypertension and
mild preeclampsia. This may probably be attributed to
fact that non-BEmONC midwives lack the competency
to administer Magnesium sulfate, therefore pushing
these midwives to give another drug alternative, like
Hydralazine, especially in the event of symptomatic
disease. Again this emphasizes the importance and need
of proper BEmONC training.
CONCLUSION
In general, majority of the midwives were generally
knowledgeable regarding their expected functions, where
BEmONC-trained midwives were 5-14x more likely to
identify appropriate function. The BEmONC midwives
were also 4x more likely to refer to a physician for further
management in the setting of severe preeclampsia. These
findings support the importance and advantage of a
BEmONC training.
Furthermore, the midwives were also generally
knowledgeable on the risk factors (70-90%), danger
signs (70-90%), proper administration and side effects
of Magnesium sulfate (75-100%), and the supportive
management of a seizure episode (85-97%). However only
few had knowledge regarding unacceptable practices -
such as the use of soft restraints (19%), use of diazepam
(59%), and the danger of observing a woman in the health
center after a seizure attack (43%).
Moreover, several aspects on knowledge clearly need
reinforcement and emphasis, such as the importance of
giving a loading dose of Magnesium sulfate especially
among the BEmONC-trained midwives. Furthermore, the
midwives also showed poor knowledge on the minimum
blood pressure and proteinuria requirement needed for
the diagnosis of preeclampsia. Midwives also showed
poor knowledge on the definition and classification of
hypertension in pregnancy based on their own BEmONC
protocol (only 30-46% knowledge) and that based on the
Clinical Practice Guidelines (only 6-38% knowledge).
In actual management practice, the most common
antihypertensive used by midwives was Methydopa –
where more BEmONC trained midwives agreed to give it
in gestational hypertension and mild preeclampsia, while
more non-BeMONC midwives agreed to give it in severe
preeclampsia and eclampsia. Likewise, the midwives
also agreed to give Hydralazine (4-6%) in the setting of
severe preeclampsia and eclampsia, but not in gestational
hypertension and mild preeclampsia.
Strikingly, only 36% of BeMONC-trained midwives
agreed to administer a loading dose of Magnesium
Sulfate in the management of severe preeclampsia and
only 22% agreed to give it in eclampsia. This is clinically
14 Volume 41, Number 6, November-December 2017
relevant since the importance of Magnesium should not
be overemphasized.
Finally, the midwives are our allies in bringing the
best standard of care to women in the management of
hypertension in pregnancy. By identifying deficiencies,
we can improve and address the setbacks that might have
impeded our progress towards achieving the Millennium
Development Goal.
LIMITATIONS OF THE STUDY
I intended to sample all 77 public health midwives,
but because of the difficulty of locating these midwives,
especially the ones assigned in far-flung barangays, only a
63% participation rate was obtained.
Furthermore, since this is a pilot study on knowledge
and management practice of midwives, those midwives
belonging in the private sector were not yet included in
this study to maintain a more homogenous population.
Lastly, since some inappropriate practices were
explored in this survey, there might be a chance that
midwives might not provide an honest response of their
actual management practice due to fear investigation or
reprimand.
RECOMMENDATIONS
First, the BEMONC manual should be updated, to
keep up with current knowledge at par with the prevailing
obstetrical guidelines in the management of hypertension.
More emphasis on risk factors must be placed and other
danger signs of hypertension must be expanded and
emphasized – such as change in mental status, tea colored
urine and right upper quadrant pain. Likewise, the current
classification of hypertension in pregnancy must be
introduced to the midwives thru revision of their BEmONC
protocol manual.
Furthermore, midwives serve as frontline health care
providers and play a role in referring high-risk pregnancies
at a primary care level. Correct diagnosis is tantamount
to a good outcome. Therefore, it is paramount that
their knowledge be supplemented thru workshops and
conferences to introduce new updates in the management
of hypertension.
Secondly, BEmONC training must be encouraged,
but we must re-evaluate why knowledge is not
translated into actual practice among the BEmONC
trained midwives. Administration of Magnesium sulfate
is lifesaving and its importance should be emphasized
among these midwives.
Third, The DOH must play a vital role in the active
surveillance of public health midwives to ensure that they
stay within the bounds of their expected competencies.
Measures should be taken to ensure that midwives are
certified-proficient, not just trained, so they can take full
advantage of the benefits of BEmONC training.
Lastly, it should be stressed, that high-risk pregnancies
must be referred at all cost. Factors that hinder these
REFERENCES
1. 2015 Annual Report of Cebu City Health Department Epidemiology
Surveillance and Statistics Unit.
2. Philippine Health Statistics Update 2012: Department of Health,
Epidemiology Bureau.
3. UNICEF: Extreme Risks for Pregnant Women and Newborn Babies
in Developing countries
4. WHO, UNICEF, UNFPA and The World Bank estimates. Trends in
maternal mortality: 1990 to 2013.
5. Lohre E, Liljevik S. Evaluation of Knowledge and Management
Practices of Hypertension in Pregnancy among Health Care
Workers (unpublished data).
6. Duckitt K, Harrington D. Risk factors for preeclampsia at antenatal
booking: systematic review of controlled studies. BMJ. 2005;
330:565.
7. Chelsey LC, Cooper DW. Genetics of hypertension in pregnancy:
possible single gene control of preeclampsia and eclampsia in the
descendants of eclamptic women. Br J Obstet Gynaecol. 1996; 93:
898-908.
8. Duckitt K, Harrington D. Risk factors for preeclampsia at antenatal
booking Systematic review of controlled studies. BMJ. 2005;
330:565.
9. Mostello D, Kallogjeri D, Tungsiripat R, Leet T. Recurrence of
preeclampsia: Effects of gestational age at delivery of the first
pregnancy, body mass index, paternity and interval between
births. Am J Obstet Gynecol. 2008; 55e1-55e7.
referrals and ways to address this may be recommended
in other future studies alike. Furthermore, to get an even
better yield of knowledge and management practice, the
number of respondents should be increased to include the
midwives who belong in the private sector.
10. Yogev Y, Langer O, Brustman L, Rosenn B. Preeclampsia and
gestational diabetes mellitus: does a correlations exist in early
pregnancy? J Mat Fet Neo Med. 2004; 15(1):39-43.
11. Duckitt K, Harrington D. Risk factors for preeclampsia at antenatal
booking Systematic review of controlled studies. BMJ. 2005;
330:565.
12. Luo ZL,An N, Xu HR, Larante A, Audibert F, et al. The effects and
mechanisms of primiparity on the risk of preeclampsia: a sytematic
review. Paediatric Perinat Epidemiol. 2007; 21 (Suppl 1).
13. Duckitt K, Harrington D. Risk factors for preeclampsia at antenatal
booking. Systematic review of controlled studies. BMJ. 2005; 330:565.
14. Barbara K, Gomez. Basic Maternal and Newborn Care: A guide for
skilled providers, 2004.
15. BEMONC Modules for Midwives: Second Women’s Health and Safe
Motherhood Project. Department of Health. Sept 20-27, 2010.
16. Managing Complications in Pregnancy and Childbirth: A guide for
Midwives and Doctors. World Health Organization. 2000
17. Shimkhada R, Solon O, Tamandong-Lachica D, Peabody J.
Misdiagnosis of obstetrical cases and the clinical cost consequence
to patients: a cross-sectional study of urban providers in the
Philippines. Glob Health Action 2016; 9:10.3402/gha.v9.32672.
18. Salinger DH, Mundle S, Regi A, et al: Magnesium sulphate for
prevention of eclampsia: are intramuscular and intravenous
regimens equivalent? A population pharmacokinetic study. BJOG.
2013; 120(7):894.
Volume 41, Number 6, PJOG November-December 2017 15
 Awareness on and availment of Philhealth’s maternity care
benefits among the selected patients of a tertiary hospital in
Southern Luzon from February 2015 to February 2016*
By Joeima D. Bernardino, MD and Honorata Lalaine P. Burog, MD, FPOGS, FPSSTD
Department of Obstetrics and Gynecology, Batangas Medical Center

ABSTRACT

Background: In spite of policy changes and government programs aimed to improve maternal health and reduce maternal morbidity,
the Philippines failed to achieve its Millennium Development Goals targets because of several identified factors.

Objective: To determine the relationships of maternal profile and awareness on and availment of PhilHealth maternity care benefits
among the selected patients of a Tertiary Hospital in Southern Luzon Department of Obstetrics and Gynecology were investigated
from February 2015 to February 2016.

Methodology: Descriptive cross-sectional survey method was used in the study involving 365 respondents selected through
convenience sampling. Chi-square test and Cramer’s V was used to determine relationships among the variables. Maternal profile,
which included the patient’s age, educational attainment, employment, family income, health insurance coverage, access to mass
media and the Internet and number of pregnancies were considered as an intervening variable.

Results: The results of the study revealed low level of benefit awareness even for the respondents who have existing PhilHealth
coverage. They also failed to avail most of the benefits. Statistical analyses revealed that age, family income, health insurance
coverage and number of pregnancies were significantly related to awareness while only family income and health insurance
coverage were significantly related to availment. It was established further that pregnant women who were more aware of their
benefits were more likely to avail them.

Conclusion: To achieve optimum availment of benefits, an iterative process of awareness campaign should be instituted starting
from high school education to women’s employment and from initial contact with Barangay Health Workers to their consultation
with health care providers.

Keywords: awareness, availment, PhilHealth

INTRODUCTION about to give birth regardless of social and economic

T
he years to achieve the Millennium Development
Goals (MDGs) have lapsed. The Philippines has
made significant strides towards the achievement
of these goals. Unfortunately, in the area of maternal
health (MDG 5), the country is likely to fail as forecasted
(NSCB 2010). Thus, the Aquino Health Agenda was
issued proclaiming that one of the focuses of public
health programs was improving maternal health in the
country (DOH 2010).
In 2013, the National Health Insurance Act of
1995 or PhilHealth Law that established the Philippine
Health Insurance Corporation was amended. Found in
Section 29-B of the amended version was a provision
guaranteeing financial protection to all women who are
*Finalist, Philippine Obstetrical and Gynecological Society (Foundation),
Inc. (POGS) Research Paper Contest, October 25, 2017, 3rd Floor POGS
Building, Quezon City
16 Volume 41, Number 6, November-December 2017
status. This provision ensured that every pregnant
woman in the country was covered by PhilHealth.
Cognizant of this provision, PhilHealth issued Circular
025-2015 updating and detailing the policies and
mechanisms by which every pregnant woman could
have access to health services during pregnancy, while
in and after delivery, including the necessary healthcare
for her newborn and the subsequent family planning
method she might opt in.
While the effort of the government to improve
health services to pregnant women, it is imperative that
such policies and mechanisms be sustained and refined
to ensure that the country would be on a trajectory
towards achieving Sustainable Development Goal (SDG)
(Gables et al 2015). The policy of insuring health services
to all women who are about to give birth in the country
is indeed a potent tool towards achieving this goal.
Even if the law ensures access to PhilHealth benefits to
every pregnant woman, non-availment of such benefits,
particularly among poor women, could still pose a huge
barrier towards reducing maternal mortality in the
country. The effort of the government, particularly those
in the health service sector, to improve maternal health
and thereby, reduce maternal mortality would simply go
to waste. Thus, it is imperative that a study be conducted
to understand the awareness and availment of PhilHealth
maternal and newborn care benefits among pregnant
women. The ultimate outcome aimed by the study was
the improvement of PhilHealth policies, programs and
mechanisms of benefit availment for pregnant women
that could in turn improve maternal health and reduce
maternal mortality.
OBJECTIVES
General Objective
The study was conducted to determine the
relationships of maternal profile and awareness on and
availment of PhilHealth’s maternity care benefits among
the selected patients of a tertiary hospital in Southern
Luzon Department of Obstetrics and Gynecology from
February 2015 to February 2016.
Specific Objectives
1. To determine the maternal profile of selected patient
in terms of age, educational attainment, employment,
monthly family income, health insurance coverage,
access to mass media and the Internet and number of
pregnancies.
2. To determine their awareness on PhilHealth’s
maternity and newborn care benefits.
3. To determine their availment of PhilHealth’s maternity
and newborn care benefits.
4. To determine if significant relationships exist among
maternal profile, awareness on and availment of
PhilHealth’s maternity and newborn care benefits.
METHODOLOGY
Research Design, Selection of the Subject
Descriptive cross-sectional survey method was used
in the study because it can establish correlation among
variables (Bowling 2014). The computed sample size was
365 at 95% confidence interval with a 5% margin of error
using the Epi InfoTM sample size calculator for Population
Survey based from the 2012 to 2016 annual numbers
of pregnancy-related admissions in the institution.
The subjects were the in-patients of the Department
of Obstetrics and Gynecology of a Tertiary Hospital in
Southern Luzon from February 2015 to February 2016.
Convenience sampling technique was used to select the
respondents of the study.
Instrument
A survey questionnaire was used. It was then
presented on the Institutions Ethical Review Committee,
edited based on their comments and suggestions. The
survey questionnaire was then tested and validated using
Cronbach’s alpha supported by study of Peacock and
Peacock (2011). Survey administration guide were then
formulated to ensure validity and reliability of the results.
The survey questionnaire contained request to participate
in the survey, explanation of the survey purposes,
confidentiality agreement and the survey proper.
Data Gathering Procedures, Analysis Plan and Statistical
Treatment
The survey questionnaire was administered by the
researcher to the respondents who are readily available
and are willing to participate in the study (Latham 2007)
for at least 20 minutes.
The answers on the numbered survey questionnaire
were then encoded in a predesigned MS Excel spreadsheet.
This spreadsheet contained syntaxes and validation rules
to ensure the correctness and accuracy of the encoded
responses.
In this study, chi-square test and Cramer’s V were
used to establish correlation between and among
variables. Table 1 summarizes the data analysis plan and
statistical treatment of variables considered in this study.
RESULTS AND DISCUSSION
The National Demographic and Health Survey
(NDHS) of 2013 provide important and relevant
information regarding the variables investigated in this
study, particularly on maternal profile. It is specifically
mentioned that the data gathered in the survey would
help assess the country’s progress towards achieving
the Millennium Development Goal, including the target
of reducing maternal death to 75% of the 1990 figure by
2015 (PSA 2014).
Table 2 shows the maternal profile of the respondents.
Ninety two percent of the population were 19 years old
and above, 67 % reached high school level, 70 % never
been employed prior to the survey administration and
55 % belong to a family whose income range is ₱4,500
to ₱9,000. Of those who have been employed, 50% had
tenured status. Only seven percent of respondents have
accessed the Internet within the week prior to survey
administration. Nineteen percent of the respondents have
no PhilHealth coverage. Indigent members/beneficiaries,
or those whose PhilHealth premiums are paid for by the
government, constitute 24% of the respondents. Only 23%
of the respondents have PhilHealth coverage while also
simultaneously covered by other social/health insurance,
Volume 41, Number 6, PJOG November-December 2017 17
Table 1. Summary of Statistical Treatment of variables
considered in the study of awareness on and availment of
PhilHealth maternity care benefits among Selected Patients of
a Tertiary Hospital in Southern Luzon from February 2015 to
February 2016
Table 2. Distribution of respondents according to maternal
profile among Selected Patients of a Tertiary Hospital in Southern
Luzon from February 2015 to February 2016
Frequency Percentage

Objectives Statistical Treatment Age

Below 19 years old 32 8
1. To determine the maternal Descriptive Statistics 19 and above 333 92
profile of the selected patients (Frequency and
in terms of age, educational Percentage Tables, Educational Attainment
attainment, employment, monthly average and standard Elementary Level 54 15
family income, health insurance deviation) High School Level 246 67
coverage, access to mass media College and Higher Levels 65 18
and the Internet and number of
pregnancies Employment
Yes 111 30
2. To determine their awareness on Descriptive Statistics No 254 70
the maternity care benefits under (Frequency and Tenured 55 50
the amended Republic Act 7875. Percentage Tables) Non-Tenured 56 50
3. To determine their availment of Descriptive Statistics Family Income
the maternity care benefits under (Frequency and Below 4,500 104 29
the amended Republic Act 7875. Percentage Tables) 4,500 - 9,000 202 55
9,000 and above 59 16
4. To determine if significant
relationships exist among Chi-square test and Access to Mass Media and
maternal profile, awareness on Cramer’s V the Internet
and availment of the maternity
care benefits under the amended Traditional 338 93
Republic Act 7875. Internet 26 7

Health Insurance Coverage

specifically by the GSIS or SSS. Moreover, 39 % of the No PhilHealth Coverage 69 19
respondents experience their first pregnancy, while 23% With PhilHealth Coverage
have already pregnancies at least four times. Paying Member 82 22
The awareness of the respondents on specific Paying Member Beneficiary 43 12
PhilHealth maternity care benefits are numerically Indigent
Member/Beneficiary 86 24
described in Table 3. The only benefit that most of the
And Other Insurance 85 23
respondents are aware of is the Normal Spontaneous
Delivery Package (92%) and the Insertion of Intrauterine Number of Pregnancies
device (IUD) (69%). Only seven percent of the respondents 1 143 39
are aware of the existence of Maternity Care Package, 29 2 87 24
% on Cesarean Section and 16% on Bilateral Tubal Ligation. 3 51 14
For the other six maternal care PhilHealth benefits, the 4 and above 84 23
figures are dismally low since either only one percent or
two percent of the respondents are aware that they can
avail of such benefits. important to ensure maternal and newborn health and
Seven percent and two percent respectively shows may reflect to reduce maternal mortality in the country.
awareness for Maternity Care Package and Antenatal PhilHealth itself explained that these benefits are made
Care Package which are alarmingly low since these distinct from Normal Spontaneous Delivery Package
benefits covers “pre-natal check-ups to screen, detect and because of the low availment (PhilHealth 2012a). However,
manage complications of pregnancy; maternal nutrition; the study shows that this change in the mechanism of
immunizations; and counselling for healthy lifestyle, benefit availment did very little to improve the awareness
breastfeeding, and family planning,” which are very on and availment of such benefits. In spite of the passage

18 Volume 41, Number 6, November-December 2017

Table 3. Awareness on PhilHealth maternity care benefits among Selected Patients of a Tertiary Hospital in Southern Luzon from
February 2015 to February 2016

Benefits Frequency Percentage

1 Maternity Care Package 24 7

2 Normal Spontaneous Delivery Package 337 92
3 Cesarean Section 105 29
4 Breech Extraction 4 1
5 Vaginal Delivery after Cesarean Section 5 1
6 Antenatal Care Package 6 2
7 Intrapartum Monitoring (w/o delivery) 7 2
8 Complicated Vaginal Delivery 5 1
9 Newborn Care Package 172 47
10 Bilateral Tubal Ligation 58 16
11 Insertion of Intra Uterine Device (IUD) 252 69
12 No-scalpel vasectomy – Unilateral or Bilateral 4 1

Level of Awareness on Benefits 73 20

0 or 1 93 25
2 199 55
3 and above

Awareness on Policies/Programs/ Mechanisms

1 Enrollment as indigent through DSWD 20 5
2 Mandatory enrollment of kasambahay 342 94
3 Mandatory enrollment of women about to give birth 23 6
4 No balance billing 20 5
5 No additional professional fee for covered medical services 11 3
6 Mandatory referral to hospital for high-risk pregnancy 13 4
7 Hospitals’ mandatory acceptance of referred patients 19 5
8 Mother’s book 18 5
9 Hospitals’ assistance for patients’ continuous coverage 17 5

Mode of Awareness
Newspaper 8 2
Flyers, pamphlets and other print medium 144 39
Radio 11 3
TV 343 94
Internet 24 7
Explanation of a doctor, nurse, spouse, friend etc. 272 75
Seminar 5 1

of Republic Act 9288 or the Newborn Screening Act of
2004, Department of Health (DOH) newborn screening
test campaign (Gutierrez 2012) and its expansion
(Crisostomo 2014), more effort is still needed to improve
the awareness of mothers on Newborn Care Package since
only 47% of the respondents are aware of this benefit.
Based on this study a dismally low percentage of the
respondents being aware of specific maternal and newborn
care benefits are reflected on the level of awareness as
observed in Table 3. Only 55% of the respondents know at
least three of the 12 specified benefits as shown on Table
3. The figures for the awareness on policies, programs and

Volume 41, Number 6, PJOG November-December 2017 19

availment mechanisms of these benefits are also alarmingly
low. Only on the mandatory enrolment of kasambahay,
are the respondents mostly aware (94%). Even for the
required Mother’s Book, only 5% of the respondents are
aware that they should have one provided by hospitals or
clinics. Mother’s Book is important tool for prenatal check-
ups; it includes follow ups and other specific data which
is needed for maternal care and delivery. For the rest of
the specified policies, programs and mechanisms, only
three percent to six percent of the respondents indicate
awareness. These specified policies were the following,
enrolment as indigent through DSWD (5%), Mandatory
enrolment of kasambahay (94%), Mandatory enrolment
of women about to give birth (6%), No balance billing
(5%), no additional professional fee for covered medical
services (3%), Mandatory referral to hospital for high
risk pregnancy (4%), Hospitals mandatory acceptance of
referred patients (5%), Mothers book (5%) and Hospital
assistance for patients continuous coverage (5%). Evidence
suggests that lack of awareness on this benefit is the
culprit for non-availment, and a barrier in achieving the
sustainable development goal.
Among the ways by which the respondents became
aware of any of the specified benefits, programs,
policies and availment mechanisms, the most popular is
through Television which is 94 %. A campaign, lectures,
announcements or circulars should be broadcasted via
Television in the form of commercials or even interactive
TV programs directed particularly for the poor or those
who belong to the lower-income group to increase
availment of health care services and health insurance
benefits, as a result in the study. A significant majority
about 75% indicate that their awareness is made possible
through the explanation of a doctor, nurse, spouse, friend
and/or others. Based from the result of the research, it is
recommended to expand PhilHealth CARES program that
involves registered nurses assigned to assist members
and beneficiaries regarding their benefit claims (Castillo-
Carandang et. al. 2015) not only placed to the hospital but
also to the Barangay level and involvement of a Barangay
Health Worker. In addition, the research recommended
that Philhealth should work with private and government
organizations to improve benefit awareness among their
female employees. Employers tend to follow the law
requiring them to enroll their employees to Philhealth
but it appears that they are not doing enough so that
their female employees become more aware of their
benefits. Philhealth then, could design awareness drive
that employer could incorporate in their female worker
empowerment programs.
Table 4 summarizes the distribution according to
availment of maternity care benefits of the 296 who
reportedly have existing PhilHealth coverage. Of these
20 Volume 41, Number 6, November-December 2017
respondents, 260 have actually availed at least one of
the benefits while 70% have already availed Normal
Spontaneous Delivery Package while 49% have availed
the Newborn Care Package. A small minority have availed
Maternity Care Package (5%), Cesarean Section (21%),
Bilateral Tubal Ligation (4%) and Insertion of IUD (20%).
For the rest, of the benefits, availment is either 0% or 1%.
The most alarming of these figures is that of the Antenatal
Care Package (2%). No one among the 296 respondents
have availed this benefit in spite of the fact that PhilHealth
has changed a mechanism to promote its availment as
mentioned earlier. Ideally, pregnant women should have
availed at least four of the 12 specified maternity and
newborn care benefits, namely Maternity Care Package,
one of the delivery packages, Antenatal Care Package and
Newborn Care Package. For women with more than two
pregnancies, one of the family planning methods covered
by PhilHealth should be the fifth of this ideal benefit
availment. However, this study revealed that only 25%
of the respondents have availed at least three of the 12
specified benefits. This number poses a serious challenge
to the national goal of improving maternal and newborn
health. The Philippine National Demographic and Health
Survey of 2013 indicates that only 62% of the women
surveyed had received antenatal care in the first trimester
of pregnancy (PSA 2014) while Philhealth benefits cover
four check-ups for the entire duration of pregnancy.
Almost all (98%) of those who have availed one of
PhilHealth maternity care benefits, do so in public hospitals.
Among those who have existing PhilHealth coverage, 169
or 57% have reported instances of non-availment of one or
more benefits. Most of these instances of non-availment,
around 87% occur because these respondents are not
yet PhilHealth members. These figures indicate that
these pregnant women have realized the importance of
PhilHealth maternity care benefits only when they already
needed them but were not able to avail them because
of lack of coverage. Lack of knowledge on filing of claims
and on benefits is identified as a significant culprit of why
there are instances Philhealth benefits are not availed
by members or beneficiaries (Faraon et al 2013). Thus,
the mandatory enrolment to PhilHealth in accordance
to Section 29-B of the National Health Insurance Act of
2013 is indeed a potent policy and campaign towards
ensuring the availability of maternal and newborn care to
all pregnant women in the country. Also it shows that this
study and other studies as mentioned have established
that awareness and availment are significantly related.
That is, women who are more aware are also likely to avail
the benefits they needed.
Shown in Table 5 is the summary of the relationship
between maternal profile and awareness of the
respondents on PhilHealth maternity care benefits.
Table 4. Availment of PhilHealth maternity care benefits among Selected Patients of a Tertiary Hospital in Southern Luzon from
February 2015 to February 2016

Benefits Frequency Percentage

1 Maternity Care Package 16 5

2 Normal Spontaneous Delivery Package 206 70
3 Cesarean Section 61 21
4 Breech Extraction 0 0
5 Vaginal Delivery after Cesarean Section 1 0
6 Antenatal Care Package 0 0
7 Intrapartum Monitoring (w/o delivery) 1 0
8 Complicated Vaginal Delivery 2 1
9 Newborn Care Package 144 49
10 Bilateral Tubal Ligation 11 4
11 Insertion of Intra Uterine Device (IUD) 58 20
12 No-scalpel vasectomy – Unilateral or Bilateral 0 0

Number of Benefits Availed

0 or 1 138 46
2 85 29
3 and above 73 25

Medical Institutions of PhilHealth Availment

Public Hospital 256 98
Others 4 2

Occurrence of Non-Availment
Yes 169 57
No 127 43

Reasons For Non-Availment

Not yet a PhilHealth member/beneficiary 147 87
Discontinued PhilHealth contribution 12 7
Others 13 8

Results of the chi-square test reveals that access to mass
media and the Internet is not related to awareness. On the
other hand, the p-value of 0.030 establishes a statistically
significant relationship between age and awareness while
the computed 0.138 Cramer’s V indicates weak positive
association between these variables. The older, the
respondents are, the more they are aware of PhilHealth
maternity care benefits. Similarly, Olayinka et al (2014)
have established that age is significantly related to the
awareness on maternal health care benefits.
Statistical analysis reveals that there is no sufficient
evidence to support the claim that educational attainment
and employment are significantly related to awareness.
The analysis of Paredes (2015) of NDHS 2008 and 2013
data pointing to lack of benefit awareness, particularly
among Sponsored Program (SP) members could explain
these findings. In this study, 25% of the respondents are
indigent members/beneficiaries or those so called SP
members and another 19% have no PhilHealth coverage
at all who would eventually be enrolled under SP. In other
words, four out of every ten respondents in this study are
SP members, most of whom have relatively lower family
income, lower educational attainment and not been
employed prior to the survey period. It is also important
to note that even among those who had employment
prior to the survey period, having a tenured status does

Volume 41, Number 6, PJOG November-December 2017 21

Table 5. Relationship between maternal profile and awareness Table 6. Relationship between maternal profile and availment
on PhilHealth maternity care benefits among the Selected of PhilHealth maternity care benefits among Selected Patients
Patients of a Tertiary Hospital in Southern Luzon from February of a Tertiary Hospital in Southern Luzon from February 2015 to
2015 to February 2016 February 2016

Chi-Square p-Value Cramer’s V Chi-Square p-Value Cramer’s V

Access to Mass Media and Access to Mass Media and

the Internet 0.01 0.920 -- the Internet 0.71 0.399 NA
Age* 6.98 0.030 0.138 Age 2.31 0.510 NA
Employment Educational Attainment 4.40 0.355 NA
(a) Status 0.68 0.712 -- Employment
(b) Tenure 1.82 0.177 -- (a) Status 2.23 0.328 NA
Family Income* 32.71 0.000 0.212 (b) Tenure 2.45 0.294 NA
Health Insurance Coverage* 23.08 0.003 0.178 Family Income* 18.82 0.001 0.161
Educational Attainment 6.12 0.190 -- Health Insurance Coverage* 27.49 0.000 0.194
Number of Pregnancies* 22.02 0.001 0.174 Number of Pregnancies* 7.39 0.286 NA
n= 365, α = 0.05 *with statistical significance n= 296, α = 0.05 *with statistical significance

not make a difference in terms of benefit awareness.
Results of chi-square analysis reveal that those who have
tenured status are not necessarily more aware on the
benefits than those who have a non-tenured status. This
means that the laws in the country requiring employers to
enrol their employees to PhilHealth and GSIS or SSS might
help to ensure enrolment but is not enough to ensure
that employees would be sufficiently aware of the health/
social insurance benefits.
Test statistic also reveals that family income is
significantly related to awareness. The computed 0.212
Cramer’s V indicates weak positive association. As family
income increases, so too is the level of awareness. The
same results are supported by the studies of Olayinka et
al (2014) and Alvaro and Oducado (2015).
Health insurance coverage also turns out to be
significantly related to awareness as indicated by the
computed 0.003 p-value and 0.178 Cramer’s V. The
indigent members/beneficiaries (SP members) and
those without PhilHealth coverage tend to have lower
level of awareness. A weak positive relationship (0.001
p-value, 0.174 Cramer’s V) is also observed between the
respondents’ number of pregnancies and their awareness
on maternity and newborn care benefits. Those who have
experienced more pregnancies are more aware of the said
benefits.
Table 6 shows the relationship between maternal
profile and availment of PhilHealth maternity benefits.
Access to mass media and the Internet, age, educational
attainment, employment, and the number of pregnancies
turn out to be not significantly related to availment. The
analysis of Paredes (2015) sheds light on these findings.
Table 7. Relationship between awareness on and availment of
PhilHealth maternity care benefits among Selected Patients of
a Tertiary Hospital in Southern Luzon from February 2015 to
February 2016
Chi-Square p-Value Cramer’s V
Awareness 0.71 0.000 0.318
n= 296, α = 0.05
According to this analysis, the significant increase in
PhilHealth membership, particularly of the SP members
does not translate to availment of benefits, which could
be attributed to the lack of benefit awareness among the
members as confirmed in this study.
The p-value of 0.001 indicates that family income
is significantly related to benefit availment. The 0.161
Cramer’s V shows positive weak association between these
variables. The respondents with lower family income have
availed fewer benefits. These respondents are identified
as the indigent members/beneficiaries (SP members)
as confirmed by a related variable, the health insurance
coverage, which also shows significant relationship with
benefit availment at 0.000 p-value. The indigent members/
beneficiaries have the greatest proportion availing fewer
benefits compared to the other groups (paying member,
paying member beneficiary and with other health/social
insurance coverage).
Table 7 shows that awareness on and availment of
PhilHealth maternity care benefits is significantly related.
The Cramer’s V of 0.318 indicates weak positive association

22 Volume 41, Number 6, November-December 2017

between these variables. Similarly, in the study of Faraon
et. al. (2013), it was established that awareness affects
the utilization of PhilHealth benefits while in the study
of Olayinka et. al. (2014), lack of awareness is identified
as a barrier towards utilization of maternal health care
services.
CONCLUSION AND RECOMMENDATIONS
The mandatory PhilHealth enrolment of women
who are about to give birth is expected to deliver better
outcomes in terms of maternal and newborn health in
the country where maternal deaths remain relatively high
resulting to the failure of achieving the country’s MDG 5
targets. However, in spite of the implementation of this
potent policy on a national scale, optimum availment
of PhilHealth maternity care benefits among pregnant
women remains elusive because of the general lack of
benefit awareness. Of the twelve benefits specified in this
study, only Normal Spontaneous Delivery Package and the
Insertion of IUD have come into an acceptable level of
awareness as a result of the information obtained from TV
and from personal explanation of a doctor, nurse, spouse,
friend and/or others.
The result of the study indicates that most women
are not aware that PhilHealth provides Maternity Care
Package and Antenatal Care Package designed to ensure
that they would have the necessary health care services
while having their pregnancy. Even on the essential
Mother’s Book, awareness is dismally low about 5% only.
Furthermore, 47 % of the respondents are not aware
of the Newborn Care Package, which includes newborn
screening test. Consequently, widespread non-availment
of these benefits is observed. Ironically, those who are in
dire need of government support under the SP are the
ones who are not aware of and are not availing PhilHealth
maternity care benefits. These women, constituting four
out of every ten respondents have relatively lower family
income, have lower educational attainment and have not
been employed prior to the survey period.
The results of the study also establish a significant
relationship between awareness on and availment of the
maternity care benefits. In summary, maternal profile is an
intervening variable and has a significant relationship with
the respondents’ awareness on Philhealth maternity care
benefits. Maternal profile has a significant relationship
with the respondent’s availment of Philhealth maternity
care benefits. The respondent’s awareness on Philhealth
maternity care benefits has a significant relationship with
the availment of such benefits.
Based on this and other significant findings, the
following are recommended:
1. Based on this study, pregnant women who have been
employed or have been tenured do not necessarily
become more aware of their maternity and newborn
care benefits. PhilHealth and other concerned
government agencies should work with private and
government organizations to ensure that pregnant
women employees are not only PhilHealth enrolled
but are also aware of their maternity and newborn
care benefits. These organizations could initiate and
sustain an information drive on maternal healthcare as
part of their program to empower female employees.
2. The study reveals that majority of the pregnant women
have reached high school level. However, it is also
established that higher educational attainment does
not necessarily translate to higher level of awareness
on PhilHealth maternity and newborn care benefits.
Thus, it is recommended that lessons on social security
under DepEd’s Social Studies (Araling Pantlipunan)
curriculum be revitalized. The health benefits provided
by PhilHealth should also be introduced to high school
students through the health education curriculum.
3. Mother and Child Book should be revised to include
a checklist of PhilHealth maternity and newborn care
benefits. Included in the checklist is a time framework
(antenatal, labor/delivery and postpartum) of when
to avail the applicable benefits. The attending health
care provider would mark the next benefit to avail and
when to avail it so that pregnant women would be
guided accordingly.
4. Since one of the better modes by which pregnant
women become aware of PhilHealth maternity and
newborn care benefits is thru personal explanation
of a doctor, nurse, spouse, friend and/or others,
it is recommended that Barangay Health Workers
(BHWs) be involved in the current information drive
of PhilHealth through an interagency arrangement.
BHWs would then be at the forefront of informing
women of their rights to be enrolled in PhilHealth as
an SP member if they are not yet enrolled and the
benefits that they can avail. They could also distribute
Mother and Child Books and mark the first benefit
that pregnant women should avail to prevent non-
availment of benefits, particularly the Antenatal Care
Package.
ACKNOWLEDGEMENTS
The researcher extends her deepest garitude to the
continuous guidance and support of the Department’s
consultants who shared their expertise in this study, as
well as the support of family and friends.
Volume 41, Number 6, PJOG November-December 2017 23
REFERENCES
1. Alliance for Health Policy and Systems Research (Alliance HPSR),
World Health Organization and Curatio International Foundation
2012. Medical Insurance for the Poor: Impact on access and
affordability of health services in Georgia. Curatio International
Foundation Policy Brief. http://www.who.int/alliance-hpsr/
projects/alliancehpsr_georgiamedicalinsurancepolicybrief.pdf
(accessed December 29, 2015).
2. Alvaro, J. M. S. and R. M. F. Oducado 2015.Maternal Profile,
Awareness and Utilization of Basic Emergency Obstetrics and
Newborn Care (BEmONC) in a Rural Municipality in Iloilo,
Philippines. Asia Pacific Journal of Education, Arts and Sciences.
2(1):6-13.
3. Bowling A. 2014. Research Methods in Health: Investigating
Health and Health Services. Berkshire, England: Open University
Press Mc-Graw Hill.
4. Castillo-Carandang, N. T., B. A. G. Viray and E. S. Baja 2015.
Assessment of the PhilHealth CARES program in selected areas
of the National Capital Region. PIDS Policy Notes No. 2015-17.
Makati City: Philippine Institute for Development Studies.
5. Department of Health (DOH) 2010. The Aquino Health Agenda:
Achieving Universal Health Care by Enrique T. Ona. Administrative
Order No. 2010 - 0036 of December 16, 2010. Manila: Office of
the Secretary, Department of Health Philippines.
6. Department of Social Welfare and Development (DSWD),
Philippines and World Bank 2006. Pantawid Pamilyang Pilipino
Program. http://siteresources.worldbank.org/ INTPHILIPPINES/
Resources/4PsDSWD.pdf (accessed December 29, 2015).
7. Faraon E.J.A, J. A. G. Estrada, E. L. F Farillas, F. R. D. Mabera, A.
M. P. Paras, M. K. R. Pastrana and A. M. L. Yap 2013. Significant
Predictors of Underutilization of Inpatient Benefits among
PhilHealth Members in Selected Barangays in Manila. Medica
Philippina 47(3):69.
8. Gable, S., H. Lofgren and I. O. Rodarte. 2015. Trajectories for
Sustainable Development Goals: Framework and Country
Applications. Washington, DC: World Bank.
9. Jacobs B.,Ir P. , M. Bigdeli, P. L. Annear and B Van Damme 2011.
Addressing access barriers to health services: an analytical
framework for selecting appropriate interventions in low-income
Asian countries. UK: Oxford University Press and The London
School of Hygiene and Tropical Medicine.
10. Latham B. 2007. Sampling: What is it? Quantitative
Research Methods. http://webpages.acs.ttu.edu/rlatham/
Coursework/5377(Quant))/Sampling_Methodology_Paper.pdf
(accessed December 29, 2015).
24 Volume 41, Number 6, November-December 2017
11. National Economic Development Authority (NEDA). 2014. The
Philippines Fifth Progress Report - Millennium Development Goals
Executive Summary. Pasig City: NEDA.
12. National Statistical Coordination Board (NSCB) 2010. MDG Watch:
Philippine Progress based on the MDG Indicators. Makati: The
National Statistical Information Center.
13. OECD 2011. Health at a Glance 2011: OECD Indicators, OECD
Publishing. http://dx.doi.org/10.1787/health_glance-2011-en.
14. Olayinka O. A., O. T. Achi, A. O. Amos and E. M. Chiedu 2014.
Awareness and barriers to utilization of maternal health care
services among reproductive women in Amassoma community,
Bayelsa State. International Journal of Nursing and Midwifery.
6(1):10-15.
15. Pahw, P. and A. Sood 2013.Existing practices and barriers to
access of MCH services – a case study of residential urban slums
of district Mohali, Punjab, India. Global Journal of Medicine and
Public Health. 2(4):1-8.
16. Paredes K. P. P. 2015. Impact of extending Social Health Insurance
for the poor on facility-based deliveries in the Philippines. Paper
presented at the Global Forum on Research and Innovation for
Health, August 2015, Seoul National University, Seoul, South
Korea.
17. Peacock J. L. and P. J. Peacock 2011. Oxford Handbook of Medical
Statistics. New York: Oxford University Press.
18. Philippine Health Insurance Corporation 2012a. PhilHealth
Circular 24-2012. Entitlement to NHIP Benefits of all Pantawid
Pamilyang Filipino Program Beneficiaries of the DSWD. http://
www.philhealth.gov.ph/circulars/2012/circ24_2012.pdf (accessed
December 29, 2015).
19. Philippine Health Insurance Corporation 2012b. PhilHealth Circular
12-2012. Guidelines for Hospitals Covered by the PhilHealth
CARES Project. http://www.philhealth.gov.ph/circulars/2012/
circ12_2012.pdf (accessed December 29, 2015.
20. Philippine Statistics Authority (PSA) [Philippines], and ICF
International 2014. Philippines National Demographic and Health
Survey 2013. Manila, Philippines, and Rockville, Maryland, USA:
PSA and ICF International.
21. Picazo, O. F., V. G. T. Ulep, I. M. Pantig, and B. L. Ho 2015. A Critical
Analysis of Purchasing of Health Services in the Philippines: A Case
Study of PhilHealth. PIDS Discussion Paper Series No. 2015-54.
Makati City: Philippine Institute for Development Studies.
22. U.S. Department of Health and Human Services, Office of Disease
Prevention And Health Promotion 2010. National Action Plan to
Improve Health Literacy. Washington, DC.
 Carcinoid tumor arising in a mature
cystic teratoma: A case report*
By Katherine Abegail P. Galang, MD and Leo Francis N. Aquilizan, MD, FPOGS
Department of Obstetrics and Gynecology, St. Luke’s Medical Center – Quezon City

ABSTRACT

This report will discuss a case of carcinoid tumor arising in a mature cystic teratoma in a 27-year-old single nulligravid, who
initially consulted for primary amenorrhea and right lower quadrant pain. Pelvic ultrasound was done and revealed an ovarian cyst
on the right, to consider mature cystic teratoma. She underwent right oophorectomy with unremarkable post-operative course.
Furthermore, this case report will tackle the diagnosis, definitive management and prognosis of the condition.

Keywords: Mature cystic teratoma, Carcinoid, Malignant Transformation, Nulligravid

INTRODUCTION small measuring 1.4x1.4cm with normal echotexture.

M
ature cystic teratomas (MCT) are ovarian
tumors that are almost always benign in nature;
the extremely rare coexistence of malignancy
deserves emphasis due to a very small number of published
cases especially in young females. This rarity is of high
clinical interest and poses a challenging dilemma about
the optimal therapeutic strategy especially in women
desiring to preserve fertility. Fertility sparing surgical
approach may be considered in nulliparous women with
favorable pathologic and clinical signs and symptoms.
This case report aims to discuss a case of carcinoid tumor
arising in a mature cystic teratoma in a 27-year-old single
nulligravid patient, its diagnosis, definitive management
and prognosis.
CASE PRESENTATION
This is a case of RR, a 27-year-old, single, nulligravid
who sought consult for right lower quadrant pain. She is
a known asthmatic previously maintained on Salbutamol
as needed for acute attacks and with regular pulmonary
consult. She underwent recto-anal pull through at birth
due to imperforate anus with unremarkable results.
She has family history of diabetes and endometrial
hyperplasia. She reported previous 6-pack year history of
smoking. Since age 14, she undergoes regular gynecologic
check-up due to primary amenorrhea. Initial transrectal
ultrasound at this time showed an infantile anteverted
uterus measuring 2.1x1.7x1.1cm with no myometrial
lesion. Endometrium is thin 0.28cm. The cervix is also
Finalist, Philippine Obstetrical and Gynecological Society (Foundation),
Inc. (POGS) Interesting Case Paper Contest, September 21, 2017, 3rd
Floor POGS Building, Quezon City
42 Volume 41, Number 6, November-December 2017
The right ovary measures 4.1x3.1cm with a portion
containing multiple small follicles <1cm in diameter
consistent with polycystic pattern and a round highly
echogenic portion measuring 2.0x1.9cm which could be
a dermoid component. The left ovary is normal in size
and also polycystic looking (Table 1). She was advised
annual monitoring with transrectal ultrasound and was
prescribed various unrecalled oral-contraceptive pills for
her polycystic ovaries. She sought consult in different
institutions regarding her amenorrhea and underwent
tests such as chromosomal analysis revealing genetically
female with complete set of chromosomes. Furthermore,
serum chemistries and hormone levels were also
requested which revealed normal results. In the interim,
she continuously sought opinion from different doctors
and remained amenorrheic with no other associated sign
and symptom. She denies vaginal spotting, abnormal
vaginal discharge, hypogastric pain, nor was she able to
appreciate a palpable pelvic mass. There were no changes
in urinary and bowel movement either. No weight loss and
anorexia experienced. Monitoring of the right ovarian cyst
revealed slight interval increase in size from 2.0x1.9cm
to 2.9x2.5cm in a span of 10 years. Four months prior to
admission, she experienced right lower quadrant pain
with visual pain score of 2-3/10 initially; this was noted to
increase in intensity to 8-9/10, radiating to the hypogastric
area, not associated with menstruation nor food intake.
She sought consult and underwent transrectal ultrasound
which revealed the following results: small anteverted
uterus measuring 3x1.9x1.5cm, with undefined
endometrium. The left ovary measured 2.3x2.2x1.9cm
with normal echopattern. The right ovary measured
4.2x4.3x3.1cm with a 3.4x3.6x3.2cm well-defined, thick-
walled cystic structure with solid nodules within, could
be a right ovarian complex mass (Table 1). No tumor
Table 1. Ultrasonographic imaging requested yearly for monitoring.

May 10, 2001 Transrectal ultrasound: Small, infantile anteverted uterus measuring 2.1x1.7x1.1cm with no myometrial
lesion. Endometrium is thin 0.28cm. The cervix is also small measuring 1.4x1.4cm with normal
echotexture. The endometrium is thin and intact. The right ovary measures 4.1x3.1cm with a portion
containing multiple small follicles <1cm in diameter consistent with polycystic component and a round
highly echogenic portion measuring 2.0x1.9cm which could be a dermoid component. The left ovary is
normal in size and also with multiple small follicles <1cm in size. No free fuid in cul-de-sac.

August 23, 2003 Transrectal ultrasound: Anteverted small and flat homogenous uterus measuring 1.67x2.32x1.05cm.
Thin hypoechoic endometrium with clean borders. The left ovary is average in size (2.07x1.44x1.11) with
undeveloped follicles. The right ovary is average in size (2.04x1.66x0.73) with a round hyperechoic foci at
the superior pole measuring 1.93x2.25x1.93cm.

April 12, 2004 Transrectal ultrasound: Infantile anteverted uterus measuring 1.86x1.06x1.31cm with thin endometrium
0.14cm, cervix intact and measures 1.11cm. The right ovary is converted into a 2.7x2.7x2.6cm intensely
echoic mass with a hypoechoic rim. The left ovary measures 2.55x1.57x1.56cm.

March 29, 2005 Transrectal ultrasound: Infantile Uterus measuring 1.07x1.97x0.73 with thin, intact endometrium
measuring 0.23cm. cervix intact 1.31cm. The right ovary measurs 4.1x2.16x2.84cm with a wll delineated
hyperechoic refractile echoes measuring 2.5x2.5cm with a thin rim of typical ovarian tissue echoes at
one pole, could be dermoid cyst. Left ovary normal. Cul-de-sac unremarkable.

July 9, 2005 Transrectal ultrasound: Retroverted infantile, small, flat, cordlike uterus measuring 2.46x1.98x1.29cm
with paper thin endometrium 0.20cm. cervix unremarkable and measures 1.47cm. small flat left ovary
measuring 2.23x1.21x1.38cm while right ovary is converted into a small homogeously hyperechoic mass
measuring 2.7x2.22x2.54cm, could be a dermoid cyst.

August 4, 2007 Transrectal ultrasound: Small anteverted uterus measuring 2.5x1.8x1.1cm with no myometrial lesion.
The endometrium is think at 0.22cm and intact. The right ovary measures 2.4x3.3cm and contains an
echogenic structure measuring 2.4x1.7cm, could be a dermoid focus with multiple subcapsular follicle
<1cm in size, >12 in numbers, suggestive of polycystic ovaries. The left ovary measures 2.3x1.7cm also
contains multiple subcapsular follicle <1cm in size, >12 in number, suggestive of polycystic ovaries. No
free fluid in the cul-de-sac.

January 18, 2011 Transrectal ultrasound: Small anteverted uterus measuring 2.9x1.2x1.9cm, with thin endometrium
0.11cm, intact cervix 1.5x1.1cnm the right ovary measures 1.9x1.6cm and is transformed into a cystic
structure with hyperfractile echoes measuring 2.9x2.5cm. Normal left ovary measuring 2.9x2.1cm.

January 29, 2013 Transvaginal ultrasound: Small 3x1.9x1.5cm anteverted uterus with undefined endometrium, margin
is smooth, endometrial echopattern is homogenous without focal lesions demonstrated. Cervix intact.
The right ovary measures 4.2x4.2x3.1cm and showed a 3.4x3.6x3.2cm well-defined, thick walled cystic
structure with solid nodules within. No vascularity is noted. The left ovary is normal and measures
2.3x2.2x1.9.

markers were requested at this time. She was advised to
continue observation however she opted to have the right
ovarian cyst removed. The working impression at this
time is ovarian newgrowth, right probably benign possible
dermoid cyst. On physical examination during admission,
patient was four feet eleven inches tall, weighing 40
kilograms, her BMI is 17.8; she is underweight and her
weight is 10 kilos less than the ideal body weight for
her height. She had stable vitals signs, soft nontender
abdomen. Tanner staging for her breasts and pubic hair
is both at stage 4; this is appropriate for age. On digital
rectal examination, cervix is short, firm closed, uterus
seemed small, and there is a palpable adnexal mass on
the right measuring 3x3cm, movable, cystic. The working
impression at this time is ovarian newgrowth, right
probably benign possible dermoid cyst and the plan is
to do right oophorocystectomy possible oophorectomy.
Intraoperatively, there was minimal peritoneal fluid
noted, the left ovary and both fallopian tubes appeared
grossly normal. The right ovary was cystically enlarged to

Volume 41, Number 6, PJOG November-December 2017 43

Table 2. Serum chemistries requested post-operatively done on Table 4. Histopathologic report and slide review.
June 11, 2013.
April 27, 2013 Right ovarian new growth, poory
SGPT 17.87 U/L differentiated adenocarcinoma (0.4cm) in
SGOT 24.73 U/L a mature cystic teratoma rule out carcinoid
tumor in a teratoma
Sodium 138 mmol/L
Potassium 3.87 mmol/L Pelvic cyst: Mesothelial cyst
Chloride 98.6 mmol/L
May 24, 2013 Right Ovarian new growth: Carcinoid tumor
in a mature cystic teratoma

Table 3. Complete Blood Count prior and after the procedure. Immunohistochemical stain results:
Mammaglobin equivocal, Ber Ep4 positive,
Parameter June 11, 2013 April 18, 2013 Chromogranin equivocal
Hemoglobin 134 g/dL 133 g/dL Pelvic cyst: Mesothelial cyst
Hematocrit 0.38 0.37
Red blood cells 4.5 4.39
Table 5. Whole abdominal CT Scan with intravenous, rectal and
White blood cells 9.36 9.53
oral contrast requested for surveillance.
Neutrophils 41.9% 46.98%
Lymphocytes 48.9%, 45% The liver is normal. No intraluminal lesions seen
Platelets 345,000 345,000 within the normal-sized gallbladder. Pancreas,
spleen and adrenal glands normal unremarkable.
Both kidneys normal in size; renal parenchymal
opacifications at both sides are symmetrical and
Table 3. Tumor markers requested post-operatively done on
simultaneous, several simple cyst measuring
June 11, 2013.
0.7 to 0.8cm seen in both kidneys. The urinary
Ca-125 9.75 June 21, bladder is partially filled and unremarkable.
2014 The stomach and bowels are not unusual. The
AFP 0.89 appendix is not clearly delineated. The mesentery
is not thickened. No enlarged pelvic lymph nodes
and ascites detected. The uterus is normal in size
5x4x6cm, capsule was noted to be smooth and pearl white and anteverted in configuration. No masses seen
in color. The uterus was small with smooth serosal surface. in both adnexa. The L4 and L5 vertebral bodies are
She tolerated the procedure well and the estimated blood fused. The included sections of the lower lungs
loss was 200 ml. Postoperatively, she remained stable reveal no pulmonary nodules nor effusion.
and with good post-op pain control. She was discharged
after 2 days. Grossly, the ovarian newgrowth showed
gray-brown rubbery tissue measuring 4.7x3x1.7cm, on slide-review was done and showed carcinoid tumor arising
cut section it showed a unilocular cyst, thick walled, in a mature cystic teratoma. Immunohistochemical staining
measuring 3cm containing brown pasty material noted to showed the following results: synaptophysin positive, Ber
be sebum along with tufts of hair. Histopathologic report Ep4 positive, mammaglobin and Chromogranin stains
showed the following results: right ovarian new growth, equivocal (Table 4). Working impression at this time is a
poorly differentiated adenocarcinoma in a mature cystic carcinoid tumor, right ovary. The patient was advised to
teratoma rule out carcinoid tumor in a mature cystic undergo transrectal ultrasound and chest x-ray (Tables
teratoma. Serum tumor markers were then requested for 7 and 8) for better visualization of the remaining pelvic
surveillance, results showed CA-125 9.57 U/mL and AFP organs and for metastatis work-up, respectively, however,
0.89 IU/mL, both within normal limits (Table 3). The plan she was lost to follow-up for 3 years. In the interim,
at this time was to do monitoring via Whole Abdomen after more than 1 year after surgery, she remained
Computed-Tomography Scan for surveillance to be done asymptomatic with no gynecologic complaints, except
every 6 months. Initial CT Scan done two months after for persistent amenorrhea. On follow-up check-up,
surgery showed essentially normal abdominal organs, three years after right oophorectomy, she underwent
renal cortical cysts bilateral, physiologic cyst, left ovary, transrectal ultrasound which showed a small cervix with
normal-sized uterus, blocked vertebrae L4-L5 (Table 5). thin endometrium (0.22cm), the right ovary was surgically
The patient and her parents then decided to seek second absent and the left ovary measured 2.8x1.8x2cm with a
opinion at our institution. On consult in our institution, developing follicle (Table 7). In addition, the following

44 Volume 41, Number 6, November-December 2017

blood tests were requested which showed normal results:
Fasting blood sugar 81, Thyroid stimulating hormone
1.69, T3 1.27, T4 8.51, Progesterone 0.34, Serum Prolactin
19.59, Follicle stimulating hormone 6.63, Luteinizing
hormone 4.94, Estradiol 218.2 (Table 9). The plan at this
time is to continue with surveillance with abdominal CT
scan every 6 months. As of this writing, the patient is
asymptomatic, desirous of pregnancy and is planning to
undergo in-vitro fertilization.
CASE DISCUSSION
One of the most common benign tumors of the ovary
is the mature cystic teratoma (MCT), consisting of tissues
from the three germ layers: the ectoderm, endoderm and
mesoderm. This accounts for 15-20% of benign tumors
of the ovary.1 This type of ovarian newgrowth occurs
unilateral and often diagnosed in young females.2 A
malignant tumor that arise from a mature cystic teratoma
is called a teratoma with malignant transformation (TMT),
and this occurs in 1-3% of all mature teratomas. TMTs are
usually unilateral and are mostly seen in perimenopause
and postmenopausal women.3 Malignant transformation
is rarely observed and patients are usually asymptomatic;
the most common form of malignant transformation
in a mature cystic teratoma is squamous cell carcinoma
comprising about 80% followed by adenocarcinoma and
carcinoid tumor. Growth of carcinoid within a teratoma
represents only 5% of all cases with TMT.4 Based from
online literature search, locally, there have been no
published articles discussing about carcinoid tumor arising
from a mature cystic teratoma since it is an extremely rare
case.
Carcinoid tumors are rare, slow-growing,
neuroendocrine malignancies with reported incidence
of 1-2 cases per 100,000 individuals, accounting for only
0.3 % of all carcinoid tumors and less than 0.1 % of all
ovarian cancers.5 They typically arise form the intestine,
or more rarely from the thymus, bronchus, stomach
or pancreas.6 Occasionally they appear with other
teratomas and can be often neglected as part of mature
teratomas. Often times, carcinoid tumors are not properly
diagnosed until the histopathologic results come out.
These malignant tumors are occasionally associated with
metastases and are a majority of cases were associated
with carcinoid syndrome. Carcinoid tumors predispose
an affected patient to experience flushing, wheezing
and diarrhea due to the secretion of a wide variety of
neurohumoral substances and biogenic amines such as
serotonin, histamine, tachykinin, bradykinin, kallikrein,
corticotropin, substance P, motilin, and prostaglandins.
Normally, systemic exposure does not occur with an
intestinal carcinoid until it has metastasized, because of
Table 6. Whole abdominal CT Scan with intravenous and oral
contrast requested for surveillance.
The liver is normal. No intraluminal lesions
seen within the normal-sized gallbladder.
Pancreas, spleen and adrenal glands normal
unremarkable. Both kidneys normal in size;
there is a hypodense, non-enhancing foci at
the upper and mid cortex of the right kidney
and low cortex of both kidneys. The largest
of which measures 0.7x0.7cm is noted at
June 9, the lower pole of the left kidney. The urinary
2015 bladder is partially filled and unremarkable.
The stomach and bowels are not unusual.
The appendix is not clearly delineated. The
mesentery is not thickened. No enlarged
pelvic lymph nodes and ascites detected. The
uterus is not unusual. No masses seen in both
adnexa. The L4 and L5 vertebral bodies are
fused.
Table 7. Ultrasonographic imaging requested for surveillance.
Transrectal ultrasound: Small anteverted
uterus measuring 2.1x2.1x1.1cm with no
myometrial lesions, cervix intact measuring
February 9,
2.5x3x2.2cm, surgically absent right ovary, left
2016
ovary normal easuring 2.8x1.8x2cm. No free
fluid in cul-de-sac.
Table 8. Chest X-ray requested for surveillance.
February 9, Clear lungs, heart not enlarged, diaphragm and
2016 sulci are intact, bony thorax unremarkable.
Table 9. Serum chemistries requested post-operatively done on
June 11, 2013.
Fasting blood sugar 81 mg/dL
Thyroid stimulating hormone 1.69 mmol/L
T3 127 mmol/L
T4 8.51 mmol/L
Progesterone 0.34 mmol/L
Serum Prolactin 19.59 mmol/L
Follicle stimulating hormone 6.63 mmol/L
Luteinizing hormone 4.94 mmol/L
Estradiol 218.2 mmol/L
efficient hepatic metabolism of the secreted substances.
However, primary ovarian carcinoids can cause these
symptoms directly, because their venous drainage by-
passes the portal system.8 In our case, the patient, prior
to the procedure was noted to be asymptomatic with no
Volume 41, Number 6, PJOG November-December 2017 45
reported episodes of flushing, wheezing and diarrhea.
MCTs may be diagnosed preoperatively through
radiologic findings in ultrasound or CT scan indicated by
the presence of fat tissue, hairs, bone and cartilage within
the tumor. In addition, imaging findings of carcinoid tumor
may be of help in diagnosis however there is no sufficient
literature describing the detailed imaging findings of
primary carcinoid tumors. In our case, ultrasonographic
findings of the right ovary revealed round, well delineated,
highly echogenic, cystic, thick walled structure with solid
nodules within. In a study of Ting, et.al (2014) entitled
Primary carcinoid tumor of the ovary arising in a mature
cystic teratoma: a case report, the detailed findings of
carcinoid tumors using various imaging modalities were
discussed and compared showing that vague imaging
findings may be expected since the appearance of ovarian
carcinoid tumor is not characteristic enough. Based on the
study, imaging findings may range from hypervascularity
with intensified enhancement on CT, with isoattenuating
density and solid part. There could also be miniscule
streaks within the solid part and calcification with fat
contents. The study concluded that in cases of ovarian
tumor with solid component and hypervascularity on CT
scan, prompt intraoperative investigation such as frozen
section must be done. Similarly, in the study of Outwater
et. al on ovarian teratomas imaging characteristics, the
imaging appearance of ovarian carcinoid tumors is not well
described. Because these are solid tumors, they would be
expected to be indistinguishable from solid malignancies,
although necrosis is less common in the former. Mucinous
carcinoid tumors have higher signal intensity on T2-
weighted MR images than do most solid tumors because
they contain high-signal-intensity mucin.9 In this case,
ultrasonography was done yearly and nonspecific imaging
findings were always noted.
The treatment for ovarian carcinoid tumors is surgical
excision and surgical staging is not required.3 Moreover,
the optimal therapeutic management in young patients
remains to be a challenge because this condition is
commonly observed in postmenopausal women, in whom
a more extensive surgical treatment such as hysterectomy
and bilateral salpingoophorectomy is a considerable
option. However, in a study by Stamatios et. al. (2013)
entitled Mature Ovarian Teratoma with Carcinoid Tumor
in a 28-Year-Old Patient, fertility sparing surgery among
women wanting to preserve their genital tract is said to be
a reasonable approach. This management is comparable
in our case since the patient is a single nulligravid desirous
of pregnancy in the future. No concensus has been made
yet because of the small number of reported cases,
however, there are case reports in young nulliparous and
childbearing women with this condition wherein fertility
preservation through conservative surgical approach
46 Volume 41, Number 6, November-December 2017
is considered to be more reasonable than prevention
of malignancy progression. Other determinants of
treatment in these rare cases would include clinical and
histopathologic factors. The following are considered
unfavorable: cyst wall invasion, intraoperative rupture of
the ovarian mass, tumor dissemination, and adhesions.2
In carcinoid syndrome as previously discussed in this
case report, the disease may be an aggressive one due
to the large amount of secretion of vasoactive factors
from the neuroendocrine cells. This occurs only in 1/3
of the patients with primary ovarian carcinoid tumor.3
Cardiac involvement is the major cause of death in this
condition.5 In our patient initial working impression is
dermoid cyst, right and was managed conservatively by
doing oophorectomy. Thereafter, a diagnosis of carcinoid
was only made when the histopathologic results came in.
Prior to the contemplated procedure, she was clinically
asymptomatic. Also, intraoperative findings did not show
cyst wall invasion, the right ovary was excised completely
with no noted rupture, there were no adhesions and
tumor dissemination noted making her a good candidate
for fertility sparing surgery and post-operative surveillance
may be done.
According to Davis et. al (1996), if the disease is
limited to one ovary, the prognosis is excellent in primary
ovarian carcinoid tumors and ten year survival rates are
approximately 100%. However, if the disease is in advanced
stage, five year survival rates are approximately 33%. For
our patient, the diseased ovary is unilateral and prognosis
is expected to be excellent.
SUMMARY
In conclusion, a carcinoid tumor arising in an MCT
is very rare in young nulliparous childbearing patients,
especially in those less than 30 years of age, as presented
in our case. Furthermore, preoperative identification
of TMT is not easy because of its nonspecific radiologic
characteristics. Its definitive management remains a
challenge but surgical excision either through laparoscopy
or laparotomy may be regarded as the first approach.
Also since the lesion is unilateral, prognosis is good and is
approximately 100% for the next ten years.
REFERENCES
1. Serinsoz E, Sertcelik A, Atabekoglu C, Dunder I. Carcinoid Tumor
Arising in a Mature Cystic Teratoma. Journal of Ankara Medical
School Vol 24 No 2.
2. Tosuner. Z., Sonmez, F., Arici, D., Dansuk, R. Carcinoid tumor
arising in a mature cystic teratoma: A case report. Departments of
1
Pathology and 2Gynecology, Faculty of Medicine, Bezmialem Vakıf
University, Istanbul, Fatih 34093, Turkey Received July 1, 2014;
Accepted February 2, 2015 DOI: 10.3892/ol.2015.2998.
3. Gokhan B, İlker S, Gunes G, Alp U, Serdar GG. A Primary Insular
Type Carcinoid Tumor Arising in a Mature Cystic Teratoma of the
Ovary: A Case Report. J Clin Case Rep 2:227. doi:10.4172/2165-
7920.1000227.
4. Stamatios P, Ioannis K, Chrysoula MS, et al. Mature ovarian
teratoma with carcinoid tumor in a 28-year-old patient. Case Rep
Obstet Gynecol. 2013; 2013:108582.
5. Kim, Joo-Yeon. A carcinoid tumor arising from a mature cystic
teratoma in a 25-year-old patient: a case study. Kim World Journal
of Surgical Oncology. 2016; 14:120 DOI 10.1186/s12957-016-
0867-8.
6. Levin, M.A. & Flynn, B.C. Primary Ovarian Carcinoid: A Rare Tumor
Causing Unexpected Manifestations in a Previously Undiagnosed
Woman. Anesth Analg. 2011; 112:1158-60.
7. Ting WH, Hsiao SM, Lin HH, Wei MC. Primary carcinoid tumor
of the ovary arising in a mature cystic teratoma: A case report.
uropean journal of gynaecological oncology • March 2014 Impact
Factor: 0.61 • DOI: 10.12892/ejgo23942014.
8. Outwater, E.K., Siegelman, E.S., Hunt, J.L. Ovarian Teratomas:
Tumor Types and Imaging Characteristics. RadioGraphics. 2001;
21:475-490.
9. Davis KP, Hartmann LK, Keeney GL, Shapiro HP. Primary ovarian
carcinoid tumors. Gynecol Oncol. 61:259-265.
Volume 41, Number 6, PJOG November-December 2017 47
 Double trouble: A case of bilateral tubal pregnancy*
By Christine Joy P. Chang, MD and Ma. Regale Noemi O. Sotto, MD, FPOGS, FPSRM, FPSGE
Department of Obstetrics and Gynecology, Quezon City General Hospital

ABSTRACT

Bilateral tubal pregnancy is the rarest form of ectopic pregnancy, and in most cases results from assisted reproductive
techniques. The incidence of simultaneous bilateral tubal pregnancies has been reported to range from 1 per 725 to 1 per 1580
ectopic pregnancies or approximately corresponds to 1 per 200,000 pregnancies. To date, this is the only case reported in our
institution. Bilateral tubal pregnancies are usually diagnosed intraoperatively, but with the advent of diagnostic tools and more
readily available diagnostic modalities, an earlier diagnosis can be made to decrease maternal morbidity and mortality.
This is a case of a 24-year old female, who came in at the emergency room complaining of severe hypogastric pain. She was
admitted as a case of ectopic pregnancy, probably ruptured. Subsequently, emergency exploratory laparotomy was done which
revealed bilateral tubal masses, which on histopathological examination confirmed bilateral tubal pregnancy.

INTRODUCTION CASE REPORT

E
ctopic pregnancy is defined as a pregnancy that
develops after implantation of the blastocyst
anywhere else other than the endometrial lining
of the uterine cavity. The incidence of ectopic pregnancy
ranges between 1-2% of all pregnancies. Nearly 95% of
them occur in the fallopian tubes. Synchronous bilateral
ectopic pregnancy is very rare, and in most cases results
from assisted reproduction techniques. Bilateral ectopic
pregnancy is the rarest form of ectopic pregnancy and one
has been reported in our hospital.
GENERAL OBJECTIVE
To present a rare case of bilateral tubal pregnancy
in a 24-year-old female with no history of assisted
reproductive technology and to recognize its importance
as a life threatening condition.
Specific Objectives
To define ectopic pregnancy.
To state the incidence of bilateral tubal pregnancy.
To identify the risk factors in developing ectopic
pregnancy especially those seen in the patient.
To discuss the pathophysiology of bilateral tubal
pregnancy.
To discuss the diagnosis and management of bilateral
tubal pregnancy.
*Finalist, Philippine Obstetrical and Gynecological Society (Foundation),
Inc. (POGS) Interesting Case Paper Contest, September 21, 2017, 3rd
Floor POGS Building, Quezon City
36 Volume 41, Number 6, November-December 2017
This is a case of K.P., a 24-year-old, Gravida 2 Para
1 (1001), who came in with a chief complaint of severe
hypogastric pain and was admitted for the first time in our
institution on May 4, 2016.
She has unremarkable past medical history. She has a
family history of diabetes mellitus on her paternal side but
denies other heredofamilial diseases such as hypertension,
malignancies, cardiac and thyroid disorders.
She is the second among three siblings, a high school
graduate and is currently unemployed. She has been in a
relationship with a 28-year-old fast food crew for a year.
She is a previous smoker of 0.25 pack years smoker and an
occasional alcoholic beverage drinker.
Her last menstrual period was on February 10, 2016
with a computed age of gestation of 12 weeks, and an
expected date of confinement on November 17, 2016. She
had her menarche at 10 years of age, with regular intervals,
lasting for 5 days, and consumes 2-3 moderately soaked
pads per day. Patient claims to experience dysmenorrhea
every menstrual cycle. She had her coitarche at 14 years
of age and had 4 previous sexual partners. She has no
history of contraceptive use and denies history of sexually
transmitted infections.
She is a gravida 2 para 1 (1001). Her first pregnancy
was delivered alive, term, via spontaneous vaginal
delivery at home, assisted by a midwife. No fetomaternal
complications were noted.
The history of present illness started a few hours
prior to admission, when the patient experienced severe,
sharp, stabbing, hypogastric pain radiating to the lower
back associated with vaginal spotting. No other signs and
symptoms were noted such as passage of meaty materials,
fever or dysuria. Persistence of the above symptoms
prompted patient to seek consult.
 On physical examination, the patient was awake,
coherent, and not in cardiorespiratory distress. Her
blood pressure was 90/60 mmHg, cardiac rate of 102
beats per minute, respiratory rate of 20 cycles per
minute and temperature of 36.5o Celsius. She had pink
palpebral conjunctivae, anicteric sclera, no nasoaural
discharge, no tonsillopharyngeal congestion, or cervical
lymphadenopathies noted.
Her chest expansion was symmetrical and no
retractions were noted on the intercostal space.
Auscultation of the lung area revealed clear breath sounds.
She had a dynamic precordium, her heartbeat had a
normal rate and regular rhythym and no murmurs were
appreciated.
Abdominal examination revealed a rigid, tender
abdomen with muscle guarding.
Her external genitalia was grossly normal.
Speculum exam revealed a pinkish and smooth vaginal
mucosa with no polyps, warts or ulcerations. On internal
examination, her cervix was firm, closed, with cervical
motion tenderness. Uterus was small with bilateral
adnexal tenderness.
Patient had full and equal pulses on all extremities.
No gross deformities noted.
At the emergency room, pregnancy test was positive.
Laboratories such as complete blood count and urinalysis
were done.
She was subsequently admitted as a case of Gravida
2 Para 1 (1001), Ectopic Pregnancy, Probably Ruptured and
the plan was for emergency exploratory laparotomy with
possible salpingectomy.
COURSE IN THE WARDS
Upon admission, patient was venoclysed. Complete
blood count was done which revealed a hemoglobin of
106 g/L, hematocrit of 0.314, and white blood cell count
of 24.15 x 109/L with predominance of neutrophils (Table
1). Urinalysis revealed red blood cell count of 8-10/hpf and
white blood cell count of 10-15/hpf (Table 2). The patient
underwent emergency exploratory laparotomy under
spinal anesthesia. Upon exploration, there was 1.3 liters
of hemoperitoneum. The left fallopian tube was converted
to a 4x4 centimeter cystic, hemorrhagic mass with a 1.5
centimeter point of rupture at the ampullary area. The
right fallopian tube on the other hand was converted into
a 6x6 centimeter cystic, hemorrhagic mass with no point
of rupture. Both ovaries and uterus were grossly normal.
No adhesions were noted (Fig. 1). The surgical team then
proceeded with bilateral salpingectomy. Estimated blood
loss was 2 liters. The patient tolerated the procedure well.
At the post anesthesia care unit, the patient had
stable vital signs and was noted to have adequate and
clear urine output.
On her first post-operative day, the patient had no
subjective complaints. She had stable vital signs and had
already passed flatus. On physical examination, she was
noted to have facial pallor, and abdomen was noted to be
soft and non-tender. Post-operative complete blood count
revealed hemoglobin of 73 g/L, hematocrit of 0.213 and
white blood cell count of 19.46 x 109/L with predominance
of neutrophils. She was started on soft diet. Two units of
packed RBC were transfused. Wound dressing was done
and revealed a well coaptated wound with no discharges.
The rest of the hospital stay was unremarkable. Vital
sign were stable.
Histopathologic report revealed findings of a right
fallopian tube that measures 5.0 x 4.0 x 2.0 cm with a
dilated portion 2.0 cm from the fimbrae measuring 4.0 x
3.0 x 1.0cm and a left fallopian tube which measures 5.0

Table 1: Complete Blood Count

5/4/16 5/4/16(post-op) 5/5/16 5/7/16

RBC x1012/L 3.23 x 10 /L
12 2.56 x 10 /L 12
2.26 x 10 /L
12
3.20 x 1012/L
Hemoglobin 106 g/L 79 g/L 73 g/L 96 g/L
Hematocrit 0.314 0.247 0.213 0.292
MCV 97.1 fl 96.4 fl 94.1 fl 91.1 fl
MCH 32.8 pg 30.9 pg 32.3 pg 30.0 pg
MCHC 338 g/L 320 g/L 343 g/L 329 g/L
Platelet count 363 x 10 L9 198 x 10 L 9
157 x 10 L 9
246 x 109 L
WBC 24.15 x 109 L 19.46 x 109 L 6.77 x 109 L 5.75 x 109 L
Diff ct: Neutrophils 97.3% 93.1% 80.3% 60.9%
Lymphocyte 1.6% 3.2% 11.9% 1.0%
Monocyte 1.0% 3.6% 6.2% 11.1%
Eosinophil 0 0.1% 1.4% 6.2%

Volume 41, Number 6, PJOG November-December 2017 37

Table 2: Urinalysis

Color Dark Yellow

Transparency Hazy
Protein Trace
Glucose Negative
pH Acidic
Specific Gravity 1.025
Red Blood Cells 8-10
White Blood Cells 10-15

Figure 2. Microsection of the Right Fallopian Tube (showing

chorionic villi and decidual tissues). Arrow A shows the lining
epithelium (ciliated columnar epithelial cells.) Arrow B shows
decidual tissues. Arrow C shows luminal projections lined by
ciliated cuboidal cells with immature chorionic villi.

Figure 1. Arrow A shows the 4x4 centimeter cystic, hemorrhagic

mass on the left fallopian tube; Arrow B shows the 1.5 centimeter
point of rupture at the ampullary area; Arrow C shows the 6x6
cystic hemorrhagic mass on the right fallopian tube. Arrow D
shows the uterus.
Figure 3.1. Microsection of the Left Fallopian Tube. Arrow
shows the luminal projections lined by ciliated cuboidal cells
x 3.0 x 2.0 with a dilated portion 2.0 cm from the fimbrae with immature chorionic villi.
measuring 4.0 x 3.0 x 1.0 with a 1.5 cm gross rupture at
the ampullary area. Both have a dark brown to maroon
discoloration, tubular and rubbery. Microscopic sections
of both fallopian tubes show luminal projections lined
by ciliated cuboidal cells with immature chorionic villi
and decidual tissues (Figures 3.1 and 3.2). The final
histopathologic diagnosis was Tubal Pregnancy, Right
Fallopian Tube and Tubal Pregnancy, Ruptured, Left
Fallopian Tube (Fig. 4).

CASE DISCUSSION

Ectopic is derived from the greek word ektopos

meaning out of place. After successful fertilization, the
blastocyst normally implants in the endometrial lining
of the uterine cavity. Implantation anywhere else is Figure 3.2 Microsection of the Left Fallopian Tube. Arrow shows
considered an ectopic pregnancy1. About 1-2 percent of decidual tissues.
38 Volume 41, Number 6, November-December 2017

Figure 4: Copy of the final histopathologic report.
all conceptions are ectopic and these account for 6 percent
of all pregnancy related deaths1. Nearly 95 percent of
ectopic pregnancies are implanted in the segments of
the fallopian tubes and the remaining 5 percent are
implanted in the ovary, peritoneal cavity or cervix1. About
81 percent are ampullary implantations and these are the
most common, 12 percent are in the isthmus, 5 percent in
the fimbrial end and 2 percent in the interstitial region2.
Multifetal pregnancies may implant simultaneously with
either both ectopic or one intrauterine and the other
extrauterine1. Such usually occurs following assisted
reproductive technologies (ART)12. The rate of ectopic
pregnancies continue to increase in the United States and
many European countries due to a number of factors which
include increased rates of sexually transmitted infections,
failed contraception, use of ARTs and tubal surgery2.
According to World Health Organization (2007),
5 percent of maternal deaths in developed countries
are from ectopic pregnancy. These deaths declined
markedly from 1980-1992 due to improved diagnosis
and management. In a review of deaths from ectopic
pregnancy in Michigan, 44 percent of the women who
died were either found dead at home or were dead on
arrival at the emergency department17. In a review of
206 cases of ectopic pregnancy in the Philippines, the
mortality was 7.28 percent. The main causes of death were
secondary anemia due to either preoperative hemorrhage
or both preoperative and postoperative hemorrhage and
infection18.
Bilateral tubal pregnancy, in the absence of preceding
induction of ovulation or assisted reproductive technology,
is an extremely unusual occurrence and the rarest form of
ectopic pregnancy. Worldwide, the estimated incidence
of bilateral tubal pregnancy is 1 in 725 to 1 in 1580 of all
ectopic pregnancies12 which corresponds to an occurrence
of 1 in 200,000 pregnancies3. This is in contrast with the
incidence of the other variants of ectopic pregnancy, with 1
in 9,000 pregnancies for cervical pregnancy, 1 in 2,000 to 1
in 60,000 pregnancies for ovarian pregnancy, 1 in 183,000
pregnancies for abdominal pregnancy and 1 in 16,000 to 1
in 30,000 pregnancies for heterotopic pregnancy2.
Fishback, in 1953, reported a series of 76 cases of
bilateral tubal pregnancy in the Canadian medical associated
journal 8,11. In 1989, Edelstein found 22 more cases7,11.
Andrews, in 2008, reviewed literature and revealed 45
further case reports, 17 of which are associated with
assisted reproductive techniques, and 28 patients are listed
as spontaneous 4,11. De Los Ríos, reviewed and analyzed 42
cases of bilateral tubal pregnancies reported in the last 10
years 9,11. In total, there are about 200 cases of bilateral
tubal pregnancy reported in the literature to date14. Most of
these cases are usually diagnosed intraoperatively.
In 2007, Llovit reported a case of bilateral tubal
pregnancy in a woman with no significant risk factors in the
Philippine Council for Health Research and Development
Library11. At present, there is no reported case of bilateral
tubal pregnancy that has been published in the archives
of the Philippine Obstetric and Gynecologic Society. There
were no cases reported in the hospital census as well. The
incidence of bilateral tubal pregnancy in the Philippines is
not known.
The major risk factor of ectopic pregnancy is
salpingitis2. Its morphologic sequelae account for about
half of the initial episodes of ectopic pregnancy. The
agglutination of the plicae (folds) of the endosalpinx
produced by salpingitis can allow passage of sperm,
but prevent the normal transport of the larger morula.
The morula can be trapped in blind pockets formed by
adhesions of the endosalpinx2. Though not documented,
prior tubal infection, which can distort normal tubal
anatomy, is likely present in our patient. Her sexual history
revealed that the patient had 4 previous sexual partners
which is a risk factor for having tubal infection.
It is also reported that cigarette smoking is associated
with increased risk of ectopic pregnancy2. The number of
cigarettes smoked per day was found to be directly related
to the development of ectopic pregnancy, with a fourfold
increased risk noted among women who smoked 30 or
more cigarettes per day6. In the case of our patient, she
Volume 41, Number 6, PJOG November-December 2017 39
is a 0.25 pack-years smoker consuming 2-3 sticks per day
for 2 years which probably increased her risk of having an
ectopic pregnancy.
There are three possible theories for development
of bilateral tubal pregnancy: 1) simultaneous multiple
ovulation, 2) sequential impregnation or 3) transperitoneal
migration of trophoblastic cells from one extrauterine
pregnancy to the other tube with implantation there16.
Foster stated that bilateral tubal pregnancy
requires multiple ovulations to occur with simultaneous
fertilization and implantation of both oocytes5. Another
possible etiology is sequential impregnation, which implies
fertilization and development of a second oocyte when a
woman is already pregnant16. This is considered to be an
extremely rare event in humans and is inherently difficult
to prove. Tabachnikoff et al stated that transperitoneal
migration of trophoblastic cells from one tube to another
is a plausible explanation for the finding of fetal tissue in
one tube and only villi in the other tube 4,16.
The most possible explanation applicable in our
case is the theory of simultaneous multiple ovulation.
Both ectopic gestations are of approximately the same
age ruling out the theory of sequential impregnation.
Transperitoneal migration of trophoblastic cells is also
not a likely explanation because histopathology revealed
the presence of decidual tissues and chorionic villi in the
lumen of both fallopian tubes.
The most common symptoms of ectopic pregnancy
which are abdominal pain, absence of menses, and
irregular vaginal bleeding often characterized as spotting1
were all present in our patient. In addition, physical
examination of the abdomen revealed a rigid, tender
abdomen with muscle guarding. There was exquisite
cervical motion tenderness, with bilateral adnexal
tenderness on internal examination which gives a high
index of suspicion for a ruptured ectopic pregnancy.
Rupture of an ectopic pregnancy causes intense pain and
exquisite tenderness especially on bimanual examination
and cervical motion which are present in nearly all women
with an advanced or ruptured ectopic pregnancy. Other
symptoms that develop following tubal rupture include
syncope, dizziness and an urge to defecate2.
Diagnostic modalities used to identify ectopic
pregnancies include beta HCG level measurements,
progesterone, transvaginal ultrasound and diagnostic
surgery such as laparoscopy. Identification of an
extrauterine yolk sac, embryo, or fetus in the fallopian
tubes or ovaries through sonography clearly confirms
ectopic pregnancy2. This, however, was not done in our case
since the patient presented with an acute abdomen thus
warranting a direct operation for emergency exploratory
laparotomy. Spontaneous bilateral tubal pregnancy is
rare, therefore preoperative diagnosis is uncommon
40 Volume 41, Number 6, November-December 2017
indicating limitations in ultrasonography. Martinez, in
2009, made an unusual case report of early diagnosis
by ultrasonography of a bilateral tubal pregnancy10. The
most common method of diagnosing the second ectopic
is through direct inspection of contralateral tube in the
operating room or laparoscopic examination. In this case,
it was diagnosed intraoperatively.
Laparoscopic surgical treatment is preferable to
open procedures, because of faster patient recovery2.
However, because of the acute symptoms of the patient,
conservative management, with either laparoscopic
surgery or medical management with methotrexate was
not considered. Tubal surgery is considered conservative
when there is tubal salvage, such as with salpingostomy
or salpingotomy. Salpingostomy was attempted on the
unruptured side of the fallopian tube. However, it was
unsuccessful due to the uncontrolled bleeding from the
implantation site. Some have shown conservative surgery
may increase the rate of subsequent uterine pregnancy but
is associated with higher rates of persistently functioning
trophoblast. Radical surgery is defined by salpingectomy.
Unfortunately, bilateral salpingectomy was done to our
patient due to the size of the mass in both tubes.
Intraoperatively, the left fallopian tube was
converted to a 4x4 centimeters hemorrhagic mass with
a 1.5 centimeter point of rupture at the ampullary area.
The right fallopian tube is converted to a 6x6 centimeters
cystic hemorrhagic mass with no point of rupture. Our
findings in this case are similar to that of Himangini et
al and G.A.AL Quraan et. al who both noted a ruptured
right ectopic with unruptured left ectopic pregnancy in
which decision to undertake bilateral salpingectomy was
also done13. With bilateral salpingectomy, the chances of
having another natural pregnancy is impossible. The only
way for her to have another pregnancy is through assisted
reproductive technology such as in vitro fertilization
which is cannot be afforded by the patient. Thus, a
thorough patient education and counseling regarding the
consequences of bilateral salpingectomy was provided for
this patient. Advise on methods of assisted reproductive
technology that maybe utilized in the event that she
desires to have another child, as well as the expenses it
would incur, was also explained.
CONCLUSION
This is a rare case of spontaneous bilateral tubal
pregnancy. Cases such as this are usually diagnosed
intraoperatively, but with the advent of diagnostic tools
and more readily available diagnostic modalities, an earlier
diagnosis can be made to decrease maternal morbidity
and mortality. Although the incidence of a bilateral tubal
pregnancy is rare, both adnexae and ovaries as well as
the entire pelvis should be thoroughly examined at the
time of exploratory laparotomy when diagnosis of an
ectopic pregnancy is made. Even if patients are at a high
risk of having another ectopic pregnancy, conservative
management is also an important consideration in such
REFERENCES
1. Cunningham F, et al., Williams Obstetrics Twenty Fourth Edition.
USA: McGraw Hill Education, 2014.
2. Katz V, et al., Comprehensive Gynecology Sixth Edition.
Philadelphia: Elsevier Mosby, 2012.
3. Arab M, Kazemi SN, Vahedpoorfard Z, Ashoori A. A Rare Case
of Bilateral Ectopic Pregnancy and Differential Diagnosis of
Gestational Trophoblastic Disease. J Reprod Infertil. 2015;
16(1):49-52.
4. Andrews J, and Farrell S. Spontaneous bilateral tubal pregnancies:
a case report. Journal of Obstetrics and Gynaecology Canada.
2008; 30(1):51-4.
5. Foster HM, Lakshin AS, Taylor WF. Bilateral tubal pregnancy with
vaginal delivery. Obstet Gynecol. 1982; 60:664-6.
6. Shetty J, et al. (2009) A rare case of bilateral tubal pregnancy.
Scientific Medicine 1.
7. Edelstein, et al., Bilateral Simultaneous Tubal Pregnancy, in
Williams Obstetrical and Gynecology 23rd edition. 1989, Lippincott
Williams & Wilkins. p. 227-90.
8. Fishback, H., Bilateral simultaneous tubal pregnancy. Canadian
Medical Associated Journal. 1953; 68(4):397-81.
9. Ríos, J.D.L., J. Castañeda, and A. Miryam, Bilateral ectopic
pregnancy. Journal minim invasive gynecology. 2007; 14(4):419-
27(4).
10. Martinez J, et al., Bilateral simultaneous ectopic pregnancy. South
Medical Journal. 2009; 102(10):055-057.
cases with attempts to save the tubes. Keeping in mind
hopes of having future natural pregnancies, especially
in our setting, where not everybody can afford assisted
reproductive technologies.
11. Llovit, et al, Bilateral tubal pregnancy in a woman with no
significant risk factors. Philippine Council for Health Research and
Development Library. 2007
12. Himangini B, et al. Spontaneous Bilateral Tubal Ectopic Pregnancy.
Pravara Med Rev. 2010; 2(1).
13. G A AL Quraan, et al,. Spontaneous ruptured and intact bilateral
ectopic pregnancy a case report. La Revue de Sante de la
Mediterranee Orientale. July-Aug 2007; 13(4),972.
14. Tadeusz I, Wojciech G, Attur J. Bilateral ectopic tubal pregnancy,
following in vitro fertilization (IVF) Folia Histochemica et
Cytobiologica. 2009; 47:147-148. [PubMed]
15. Stabile I, Grudzinskas JG. Ectopic pregnancy: areview of incidence,
etiology, and diagnostic aspects. Obstet Gynecol Surv. 1990;
45:335-347. [PubMed]
16. Tabachnikoff RM, Dada MO, Woods RJ, et al. Bilateral tubal
pregnancy: a report of an unusual case. J Reprod Med. 1998 Aug;
43(8):707-9.
17. Othman M, Karali S, Badawi K, Mossa H. Bilateral Ectopic Pregnancy:
Case Report. Webmed Central Obstetrics and Gynaecology. 2013;
4(7):WMC004354 doi: 10.9754/journal.wmc.2013.004354.
18. Galang, JS and Acosta H. Ectopic Pregnancy. Philippine Council for
Health Research and Development Library. PCHRDPC934076.
Volume 41, Number 6, PJOG November-December 2017 41
 Severe malaria in a pregnant woman successfully treated with
Artemisinin-based Combination Therapy (ACT)*
By Stephanie Marie S. Aquino, MD and Angela A. Du, MD, FPOGS
Department of Obstetrics and Gynecology, Manila Doctors Hospital

ABSTRACT

Malaria is suspected in pregnant women with fever of unknown origin who come from areas with high transmission of the
disease. Pregnant women are at greater risk of infection due to a weakened immune response and higher parasite burden because
of placental sequestration. A 26-year-old Sudanese primigravid 23 6/7 weeks of gestation presented at our institution with mixed
infection of malaria, with severe features (hypotension and anemia). Malaria was highly suspected due to her country of origin,
which was highly endemic and has high transmission of the disease. Fetal surveillance to monitor fetal well-being was done since
malaria is known to cause perinatal adverse outcomes. Intrauterine growth restriction, preterm labor and stillbirth are the most
common perinatal morbidity from malaria. These are not present in the patient due to the prompt initiation of artemisinin-based
combination therapy, which significantly decreased the parasite load, leading to successful outcome.

Keywords: Malaria, Malaria in Pregnancy, artemisinin combination therapy

INTRODUCTION 30% of preventable low birth weight, 70% of intrauterine

M
alaria is one of the most severe public health
problems worldwide. It occurs most commonly
in the poor, tropical and subtropical areas of
the world. In the Philippines, it has been said that malaria
cases declined to at least 83% reduction from 2005 to
2013 and of the 53 known provinces that are endemic
of the disease, 27 of which have been declared malaria-
free (Cavite, Batangas, Marinduque, Catanduanes, Albay,
Masbate, Sorsogon, Camarines Sur, Iloilo, Aklan, Capiz,
Guimaras, Bohol, Cebu, Siquijor, Western Samar, Eastern
Samar, Northern Samar, Northern Leyte, Southern Leyte,
Biliran, Camiguin, Surigao Del Norte, Benguet, Romblon,
Batanes, and Dinagat Islands).
Malaria is transmitted through the bite of infected
female Anopheles mosquitoes. The problems that malaria
infection causes differ by the type of malaria transmission
area. Persons who live in an area with high transmission of
the infection have developed immunity against it, causing
a lesser degree of morbidity and mortality. Moreover,
those who live in areas with low transmission have no
immunity against it, causing severe and fatal malaria
disease. Pregnant women are at higher risk of having
the infection because of a weakened immune response,
thereby causing fatal disease and contribute to as much as
15% of maternal anemia, 14% of low birth weight infants,
Finalist, Philippine Obstetrical and Gynecological Society (Foundation),
Inc. (POGS) Interesting Case Paper Contest, September 21, 2017, 3rd
Floor POGS Building, Quezon City
48 Volume 41, Number 6, November-December 2017
growth retardation, 36% of premature deliveries and 8%
of infant mortality. Placental sequestration of the parasite,
also known as placental malaria, is the main reason why
these complications happen. Higher parasite burden is
observed in pregnant patients, causing severe disease,
warranting prompt treatment.
This paper presents a case of malaria in pregnancy
seen in a tertiary hospital Obstetrics and Gynecology
Department successfully treated with Artemisinin-Based
Combination Therapy (ACT).
CASE REPORT
This is a case of MT, a 26-year-old, 23 6/7 weeks of
gestation, primigravid resident and citizen of Khartoum,
Sudan, came to the emergency room due to intermittent
fever, associated with one episode of nonbilous and
nonbloody vomiting. It is not associated with chills, cough,
dysuria, hypogastric pain nor diarrhea. Past medical
history, family history and personal/social history were all
unremarkable.
On assessment, patient was febrile at 39˚C,
tachycardic at 142bpm, with BP of 100/60mmHg. She
was initially managed by emergency medicine service,
hydrated and given paracetamol 600mg/IV. Laboratory
tests showed mild anemia with haemoglobin of 101g/L,
hematocrit of 30%, and thrombocytopenia at 107,000,
normal urinalysis results. Patient was tested for Dengue
and showed negative results. Since patient originated
from Sudan, which is highly endemic to malaria, malaria
rapid antigen test was requested and showed positive for
P. falciparum and non-P. falciparum species, suggestive of
mixed infection. For confirmation, malarial blood smear
was requested and showed 7,400,000 ring forms/uL of
blood.
With the patient’s history of recent travel to different
countries, including Dubai, the diagnosis of Ebola, Zika
and MersCoV were considered. She was asked to fill up a
“Triage Screening Form”, which screens for these possible
infections. These were ruled out because the signs and
symptoms of the said disease such as, abdominal pain,
headache, anorexia, bleeding from any site, sore throat,
cough or other respiratory symptoms were absent in
the patient. Also, patient did not come from countries
that are endemic for the disease: Guinea, Liberia, Sierra
Leone, Nigeria, with no exposure to persons or animals
that were infected with the disease. Patient was then
admitted under the service of OBGYN, comanaged with
OBGYN-Infectious Disease, with admitting diagnosis of
G1P0 Pregnancy Uterine 23 6/7 weeks Age of gestation,
not in labor, malarial infection.
Upon admission, patient is still febrile at 38.4˚C,
tachycardic at 142bpm, BP of 100/60mmHg, with
unremarkable physical examination findings. Abdomen
was globular with fundic height of 24 cm and fetal heart
tones of 150 bpm. Patient was hydrated with IV fluids and
was started on the following medications: clindamycin
450mg every 8 hours, hydroxychloroquine 500mg OD
400mg for 3 days (Source: WHO Treatment Guidelines)
and paracetamol 500mg for fever. Fetal heart tones
were monitored closely. Nonstress test was reactive
with category I tracing of FHT 145-150bpm, moderate
variability, with accelerations, no decelerations, with
good fetal movement and no uterine contractions noted.
Ultrasound to ensure fetal well-being was done showing,
“Single live intrauterine pregnancy, 23 5/7 AOG, Breech
presentation, good cardiac (FHR 140 bpm) and somatic
activity, Estimated fetal weight 636 grams (p10-50),
Adequate amniotic fluid volume (SVP=6.57cm), Placenta
posterior, grade II, high lying”, given multivitamins for the
pregnancy. 24 hours later, repeat CBC showed a drop of
haemoglobin from 108 to 81 and haematocrit from 30%
to 23%, still with thrombocytopenia at 60,000. Two units
packed RBC were transfused. Post-blood transfusion
showed hemoglobin of 90 and haematocrit of 25%. CBG
monitoring was done every 6 hours, with no hypoglycemic
episodes noted.
On the 2nd hospital day, patient still had febrile
episodes, with highest temperature of 40˚C, with
hypotensive episodes of 100/40mmHg. Blood pressure
trends were observed, with BP range of 90-100/40-
60mmHg. 24 hours after hydrochloroquine and
clindamycin, repeat peripheral smear showed increase
in ring forms of 13,980,000 ring forms/uL of blood.
Patient was referred to IM-Infectious Disease service,
who recommended artemisinin-combination therapy
(artemether-lumefantrine) based on the National Protocol
for Treatment of Malaria in Khartoum, Sudan. However,
artemisinin combination therapy is not readily available
in the National Capital Region, Philippines, so treatment
was delayed. ACT was only made available through the
Department of Health at the 5th hospital day.
On the fourth hospital day, patient still febrile with
one episode of vomiting, associated with epigastric pain,
with poor appetite, and headache. Patient was put on
small, frequent feedings. Electrolytes were requested with
note of hypokalemia of 2.1mmol/L, correction was started
with KCl drip, with post-correction value of 2.9mmol/L.
She was started on oral KCl once vomiting ceased.
Treatment with ACT (artemether-lumefantrine) was
started at the recommended dosage and frequency at the
5th hospital day. The other medications: hydroxchloroquine
and clindamycin were discontinued. On assessment for
the pregnancy, there were 2 moderate to strong uterine
contractions noted in 15 minute palpation, with good fetal
movement, FHT 160s. Nonstress test showed reactive
with category I tracing, with BFHR of 150-155bpm,
moderate variability, with accelerations, no decelerations,
with uterine contractions every 2-4 minutes, mild to
moderate. On internal examination, cervix is closed, soft,
and 2.5cm long. She was started on nifedipine 10mg every
8 hours. Post-nifedipine tracing was reactive with BFHR of
150-155bpm, moderate variability, with accelerations, no
decelerations, no uterine contractions.
One day after ACT was started, patient was afebrile
with no recurrence of vomiting and no hypotensive
episodes. Daily malarial parasite count showed a significant
decline after one day of therapy from 13,980,000 ring
forms to 4,980,000 ring forms/uL. This suggests that
the parasite was susceptible to ACT. In Sudan where our
patient is from, chloroquine-resistant malaria is present,
hence, artemisinin-based combination therapy is the
treatment of choice.
On the sixth hospital day, patient was afebrile
with no subjective complaints and no perceived uterine
contractions. Malarial parasite count progressively
declined to 785,454 ring forms / uL of blood. Potassium
was normal at 4.9mmol/L. Patient was eventually
discharged on the 3rd day of artemether-lumefantrine,
improved and stable.
CASE DISCUSSION
Malaria is an infection with Plasmodium species with
the female Anopheles mosquito as the vector. Rupture of
red blood cells during the erythrocytic stage of the life cycle
of the parasite is responsible for the clinical symptoms. If
Volume 41, Number 6, PJOG November-December 2017 49
severe, this may cause haemolytic anemia and jaundice,
which are worsened by splenic sequestration of infected
red blood cells. When exposed to the parasite, splenic
macrophages release pro-inflammatory cytokines (TNF-
alpha, IL-1B) which causes nonspecific symptoms, such as
fever, chills, generalized malaise and headache, which are
all similar to any minor viral illness.
Of the four plasmodium species, Plasmodium
falciparum is the specie that can cause the most severe
disease because of its microvascular effects. The falciparum-
infected red blood cells express surface proteins, which
will cause attachment of the RBCs to the adhesion
molecules in the vascular endothelium. This will cause
adherence of infected RBCs to uninfected RBCs forming a
rosette pattern and agglutination. These agglutinated cells
will cause obstruction of the vessels, leukocyte infiltration
in the tissues, thereby local inflammation and edema.
Obstruction of vessels in different organs is the main
pathogenesis of the different complications of malaria,
such as cerebral malaria causing brain edema that can be
fatal, pulmonary edema that can cause acute respiratory
distress syndrome, renal impairment causing metabolic
acidosis and placental malaria that cause pregnancy
complications and poor birth outcomes.
According to Mesbnick, et.al (2008), the adhesion
molecule that is associated with placental malaria is
chondroitin sulphate A (CSA) and hyaluronic acid, which
are expressed by the syncytiotrophoblast that line the
placenta intervillous spaces. There are three specific
changes in the placenta once infected: 1) the mature
trophozoites and schizont parasite accumulate in the
intervillous spaces, 2) intervillous infiltrates of monocytes
and macrophages, some containing with the malarial
pigment (hemozoin), 3) malarial pigments in fibrin
deposits that can persist after resolution of episodes of
infection. These changes are associated with poor birth
outcomes. Placental sequestration of the infected RBCs
will cause obstruction of flow from the maternal to the
fetal circulation, causing fetal hypoxia, decreased nutrient
uptake, impaired growth and vascularization, intrauterine
growth retardation and preterm delivery, thereby causing
low birth weight.
Malaria in pregnancy causes risk to both pregnant
women and baby. It causes more mortality and morbidity
than those of non-pregnant women. This is due to the
reduced immunity during the pregnant state, leading
to more relapses, hyperparasitemia and worse clinical
conditions. The most common manifestations of
malaria in pregnancy are fever, anemia, splenomegaly,
acute pulmonary edema, hyopglycemia and secondary
infections.
For this case, the patient was classified with severe
malaria, with the following clinical signs and symptoms:
50 Volume 41, Number 6, November-December 2017
episodes of circulatory collapse (blood pressure
<90/60mmHg), thrombocytopenia (61,000), severe
anemia (as low as 80g/dL) and hyperparasitemia (>2%
parasitized red blood cells).
The complications of malaria in pregnancy include
algid malaria or shock, anemia, bleeding or coagulopathy,
hemoglobinuria, acute renal failure and acute pulmonary
edema. In the management of severe malaria in
pregnancy, of importance is the management for anemia,
hypoglycaemia and acute pulmonary edema. The patient
only presented with shock, presented with hypotensive
epidoses as low as 80/50mmHg and anemia with a
haemoglobin of 80g/dL. For this, patient was hydrated
and transfused with packed red cells.
Anaemia is a common presentation in malaria and it
may be due to hemolysis of infected erythrocytes, which
may be so significant that it may aggravate folic acid
deficiency, and increased demands during pregnancy.
According to Uneke (2008), anemia increases the risk of
perinatal mortality and maternal morbidity and mortality.
During labor, patients with severe anemia may not be
able to tolerate mild to moderate blood loss, and failure
of compensatory mechanisms may happen which can
lead to maternal morbidity and mortality. Infants may
be at risk for intrauterine growth retardation, stillbirth
and low birth weight. Also, may cause iron deficiency
to the infants, which may affect their behavioural and
cognitive development. Malaria may affect iron status by
decreasing iron absorption in the intestines, sequestrating
iron in the malarial hemozoin, consuming iron for its
metabolism, mobilization of iron stores and releasing it to
the circulation during hemolysis.
In patients with malaria, hypoglycaemia is a
complication of the infection due to the hypercatabolic
state of the infecting parasite. CBG ranges were
maintained to normal and no hypoglycemic episodes
were noted in the patient. According to Ali, et.al (2011),
glucose metabolism during malaria infection is due to
multiple factors, such as drug treatment, fever, parasite
metabolism, hormonal changes, cytokines, fasting and
gastrointestinal disturbances. Patients who present with
hypoglycaemia have higher mortality rates. Therefore,
it is important to monitor glucose levels in patients with
malaria because it can significantly affect its outcome.
Electrolyte disturbances are also common in patients
infected with falciparum malaria. In a retrospective
study made by Thanachartwet, et.al, (2008), 81% of
the study population with uncomplicated malaria had
electrolyte imbalances. The most common disturbance
noted was hypokalemia (<3.4mmol.L), and hyperkalemia
(>5,1mmol.L) in children, especially with those infected
with P.vivax. Most of the patients present as clinically
hypovolemic. They found out that volume depletion
is the most predominant risk factor in hypokalemia.
They concluded that such disturbance in potassium is
multifactorial and could be due to the urinary loss and
shift of potassium from extracellular to intracellular. The
factors that were noted to be associated with hypokalemia
include Plasmodium vivax infection, female gender,
fever before admission, hypovolemia, BUN:Cr ratio >15,
hyponatremia and glucose >100mgdL. It is prudent to
correct potassium concentration since it may cause
increased risk of arrhythmias.
Treating the infection is of utmost importance.
According to the WHO Guidelines for Malaria Treatment,
first line in pregnant patients in all trimesters of pregnancy
is oral quinine. In second and third trimester of pregnancy,
quinine is combined with sulfadoxine-pyrimethamine or a
combination of artesunate tablets. Antimalarial drugs that
are safe in the first trimester of pregnancy include quinine,
cholorquine, clindamycin and proguanil.
In uncomplicated malaria in pregnancy on the
first trimester, seven days of quinine and clindamycin is
recommended. According to WHO, the safest treatment
regimen for pregnant women in the first trimester with
uncomplicated malaria is quinine + clindamycin for 7 days.
In the second or third trimesters, artemisinin derivatives
are recommended. However, in patients with severe
malaria, IV Quinine or IM Artemether is the treatment all
throughout pregnancy. If patient can tolerate oral therapy,
treatment may be completed for 3 days of artemisinin
combination therapy (ACT). Since the patient had a mixed
infection of falciparum and non-falciparum species,
the treatment of choice is still ACT, that is, artemether-
lumefantrine. Also, since the patient is from Sudan where
95% of the parasite is chloroquine-resistant, ACT is still the
treatment of choice.
Artemisinin derivatives are the most effective
antimalarials but are associated with terratogenic effects
in animal studies especially in early pregnancy. However,
according to Kovacs, et.al (2016), there was no increased
pregnancy loss among women who received an artemisinin
compared to women who received no antimalarial drug.
ACT is recommended to be given to women, on the 2nd
and third trimester of pregnancy, infected with malaria.
However, in cases of mixed infection and severe malaria,
it is given in early pregnancy since initiation of treatment
outweighs the risk.
The regimen given to the patient is an artemisinin
combination therapy (ACT). ACT is a combination of a
rapidly acting artemisinin derivative with a longer acting
partner drug. Artemisinin component rapidly clears the
parasites from the blood, significantly decreasing parasite
count. It is also active against the sexual stages of the
parasite. The longer acting partner, which is lumefantrine
in this case, clears the remaining parasites and provides
protection against drug resistance.
It is important to decrease the parasite load of
the mother so vertical transmission to the fetus is less.
Congenital malaria is one of the complications of malaria
in pregnancy where in transmission to the fetus occurs
particularly when there is infection at the time of birth and
the placenta and cord are blood film positive for malaria.
Transplacental spread is deemed to be rare, especially
in high-transmission areas, where immunity has been
established. The placental barrier and immunoglobulin
antibodies, cross the placenta, making the fetus immune
to the infection. All four species of Plasmodium may cause
congenital malaria. The newborn may present with
fever, irritability, feeding problems, hepatosplenomegaly,
anaemia, and jaundice.
The obstetrical dilemma here are, is it advantageous
to tocolyze and control preterm labor? Is there benefit for
induction of labor and termination of pregnancy?
Management of preterm labor in pregnant patients
with malaria is the same as with those not infected with
the disease. One of the main reasons of preterm labor is
infection, so the main management in our case is to treat
the underlying infection. According to Luxemberger et al,
the risk of premature delivery and/or neonatal deaths was
similar for other febrile illnesses such as acute respiratory
infections or urinary tract infections, reflecting an effect
of fever and illness rather than malaria per se. Therefore,
routine obstetric management for preterm labor should
be rendered to the patient. Also, according to the Royal
College of Obstetrics and Gynecology Guideline, malaria
is not a reason for induction of labor. Management of this
case includes: treating the infection, controlling preterm
labor, and surveillance of fetal well-being. Malaria during
pregnancy is not a direct cause of neonatal mortality. It
increases neonatal death indirectly by reducing birth
weight, and low birth weight babies are more likely to die
during the neonatal period.
In areas with high transmission rates of the infection,
where women will have asymptomatic placental
parasitemia, intermittent preventive treatment (IPT) is given
to all pregnant women. According to the Sudan treatment
guidelines, IPT includes therapeutic doses of sulfadoxine-
pyrimethamine (SP), regardless of parasitemia status, under
direct observation of a health care provider. The first dose
is given at the first prenatal check-up after quickening at 16-
20 weeks and the second dose is in the next prenatal visit at
least four weeks apart from the first dose.
WHO updated the recommendation, increasing the
number to three or more SP doses. In practice, women
in areas of moderate to high malaria transmission should
receive SP at each antenatal care visit during the second and
third trimesters (because four visits are recommended),
with 1 month intervals between dose.
Volume 41, Number 6, PJOG November-December 2017 51
 Malaria causes preterm labor, fetal heart rate
abnormalities, fetal compromise or intrauterine growth
restriction. It has been estimated that malaria in
pregnancy in settings with stable malaria transmission, it
is potentially responsible for up to 70% of IUGR and 36% of
preterm delivery. IUGR has been placental infection while
preterm delivery correlates with systemic manifestations
of malaria infection in the mother.
The main management in pregnant patients infected
with malaria is to control the fever and treat the infection.
High fever may induce uterine contractions that may result
to preterm labor, of which antipyretics and hydration may
be given. Fetal distress is the most common complication.
52 Volume 41, Number 6, November-December 2017
Obstetric management involves regular antenatal care
with assessment of fetal growth scans. Perinatal morbidity
may be prevented with prompt diagnosis and treatment.
CONCLUSION
The management of malaria in pregnancy includes:
treating the infection, controlling preterm labor, and
surveillance of fetal well-being. Although the index patient
has not yet delivered upon completion of this report and is
now already in Sudan, the authors can only surmise that the
pregnancy will have a successful outcome because prompt
initiation of the prescribed management was given.
 Cervical pessary in prevention of
preterm birth: A case series*
By Erika Gail G. Hernandez, MD and Mary Anne Tabaquero, MD, FPOGS
Department of Obstetrics and Gynecology, St. Luke’s Medical Center, Quezon City

ABSTRACT

Preterm birth defined as birth between 20-37 weeks age of gestation, poses major concerns as it causes serious health
problems. Across 184 countries, the rate of preterm birth ranges from 5% to 18% of babies born and the Philippines ranks 8th out of
184 countries for the number of babies born prematurely, and ranks 17th for the total number of deaths due to complications from
preterm birth. Management of incompetent cervix as one of the causes of preterm birth is cerclage. However, pessary insertion
is an alternative especially in cases where cerclage may not be employed. To date, there have been no local published reports on
effectiveness of pessary in prevention of preterm birth. Hence this study aims to report on cases supporting the use of pessary in
preterm birth. This is a case series of three patients with short functional cervical lengths (<2.5 cm) seen in ultrasound, managed
with pessary insertion showing its effectiveness in prolonging pregnancy. In conclusion, pessary is an affordable and safe alternative
management of preterm birth which may be employed in our setting. Future clinical trials may be helpful in strengthening this
evidence.

Keywords: Pessary, preterm birth, cervical incompetence

INTRODUCTION this persists as long as the pessary remained in situ.4

P
essary is a device fitted into the vagina to provide
structural support to pelvic organs. It dates back to
the 16th century when the innovative French surgeon
Ambriose Pare (1510-1590) devised a number of oval-
shaped pessaries for uterine prolapse. It was also clearly
described in the year 1701 when Hendrick Van Deventer
(1651-1724) produced pessaries himself for uterovaginal
prolapse. (1)
It has been predominantly used as support for pelvic
organ prolapse until it was first postulated by Vitsky in
1961 that the incompetent cervix is aligned centrally,
with no support except the nonresistant vagina, and a
lever pessary, however, would change the inclination of
the cervical canal deviating it more posteriorly, which in
pregnancy, can thereby direct the weight of the pregnancy
more on to the anterior lower segment.2 (Figure 1). The
cervical pessary has an internal diameter that matches
that of the cervix and an external diameter large enough to
wedge the device against the pelvic floor. This effectively
deviates the cervix towards the posterior vaginal wall
and corrects the cervical angle.3 This is supported by the
observational study performed by Cannie et al which
demonstrated more systematically and objectively, using
magnetic resonance imaging, that the placement of a
pessary led to a more acute uterocervical angle and that
*Finalist, 2016 Philippine Obstetrical and Gynecological Society (POGS)
Interesting Case Paper Contest, August 18, 2016, 3rd Floor POGS Building,
Quezon City
26 Volume 41, Number 1, PJOG January-February 2017
This case series aims to report on three cases in
our institution supporting the effectiveness of pessary in
preventing preterm birth.
THE CASES
This paper presents three cases managed with
pessary insertion for prevention of early preterm birth.
CASE 1
C.A.B. is a 35-year-old Gravida 2 Para 0 (0010)
pregnancy uterine, admitted in our institution at 25 weeks
and 3 days for short cervical length finding on ultrasound.
Early ultrasound at about 12 weeks age of gestation
showed a cervical length of 3.8 cm. Patient then was started
on progesterone vaginal suppository once a day until 14
weeks age of gestation. Patient underwent congenital
anomaly scan with note of decreased cervical length of
2.58 cm, hence dose of progesterone vaginal suppository
was increased to twice a day then eventually thrice a day.
On repeat ultrasound at about 26 weeks age of gestation
showed a further decrease in cervical length to 1.62 cm,
with funnel length of 1.12 cm, 59% funnelling, and internal
cervical os dilated to 2.52 cm. With no history of perceived
contractions nor vaginal bleeding, yet decreasing cervical
length on monitoring, patient was admitted.
Patient was diagnosed gestational diabetes mellitus
at 24 weeks age of gestation and started on metformin.
There are no other known comorbidities.
Figure 1. A. Normal cervix usually points posterior in the last trimester of pregnancy. B. An incompetent cervix usually points
anteriorly in the mid and last trimesters of pregnancy, allowing the membranes to herniate. C. The lever pessary ‘cradles’ an
incompetent cervix, keeping it pointing posteriorly in the last trimester, preventing herniation of membranes. (Javert CT: Further
follow-up on habitual abortion patients. Am J Obstet Gynecol 84:1149, 1962) Lewicky-Gaupp, C, Glob. libr. women’s med., (ISSN:
1756-2228) 2010; DOI 10.3843/GLOWM.10025

First pregnancy was spontaneously aborted at 12
weeks age of gestation one year prior to the present
pregnancy.
On examination, fetal heart tone was 150 bpm,
fundic height of 25 cm, no noted contractions on manual
palpation. Speculum exam showed minimal whitish non
foul smelling discharge. Internal examination revealed a
short cervix dilated to 1 cm and effaced.
Upon admission, betamethasone was immediately
administered intramuscularly and magnesium sulfate drip
started. Patient was referred to perinatology service with
the plan to do cervical cerclage for the incompetent cervix.
However, on repeat ultrasound prior to the contemplated
procedure, cervical length further decreased to 1.3 cm,
also with note of amniotic fluid sludge. Furthermore, with
manipulation of the probe, cervix seemed to close and
lengthen. With these findings, the plan of cervical cerclage
was abandoned for the possibility of iatrogenic rupture
of membranes with such a short cervix and the idea of
pessary placement was entertained. Hence, referral to
urogynecology service for pessary insertion was done. At
26 weeks age of gestation, a hodge pessary (Figure 2) was
then inserted. Patient was placed on complete bed rest
and maintained on daily oral and intravaginal and weekly
intramuscular progesterone to support pregnancy. With
deranged blood sugar values on monitoring, patient was
started on insulin.
Regular ultrasound monitoring was done. (Table 1)
Patient stayed in the hospital, placed on complete
bed rest, maintained on oral nifedipine to maintain
uterine quiescence. At 34 weeks 3 days age of gestation,
patient complained of low back pain, and with moderate
contractions occurring every 2-4 minutes appreciated
on manual palpation, prompted internal examination
revealing cervix 4 cm dilated 70% effaced station -2 intact
bag of water, pessary in place. Pessary was removed and
labor was allowed to progress. Patient delivered to a live
preterm male apgar score 9,9 birth weight 2085g birth
length 50cm Ballard’s score 35 weeks AGA via normal
spontaneous vaginal delivery. On inspection, placenta was
noted to be small with no calcifications.

Table 1. Serial Ultrasound Monitoring of Case 1

Age of Sonographic Sonographic Functional

gestation age weight Cervical length
28 weeks 27 weeks 1093 +/-164g 2.68cm
30 weeks 29 weeks 1400+/-204g 1.65cm
32 2/7 weeks 31 2/7 weeks 1781 +/- 267g 1.30 cm
34 weeks 32 2/7 weeks 2050 +/- 308g 1.00 cm
Figure 2. Hodge pessary

Volume 41, Number 1, PJOG January-February 2017 27

CASE 2
M.J.C. is a 34-year-old gravida 2 para 1 (0101)
pregnancy uterine, admitted in our institution at 31
weeks age of gestation for an incidental finding of short
cervix on ultrasound. During her regular prenatal check-
up, ultrasound revealed cervical length of 2.7 cm without
funneling, prompting an internal examination revealing
cervical dilation of 1-2 cm. Patient was asymptomatic with
no perceived contractions or vaginal bleeding. Patient was
admitted.
Patient is a gravidocardiac with a history of open heart
surgery for mitral valve repair for congenital severe mitral
valve regurgitation, asymptomatic after the operation
with no maintenance medications.
Patient had a previous pregnancy 5 years prior to the
present, delivered preterm at 33 weeks age of gestation
after preterm labor.
On examination, vital signs were stable, abdomen
gravid with fetal heart tone of 130 bpm, fundic height
of 26 cm, with no noted contractions on admitting
cardiotocogram. Speculum examination showed a
violaceous smooth cervix with whitish non foul smelling
discharge. Internal examination revealed a short cervix
dilated to 1-2 cm dilated.
Upon admission, intramuscular betamethasone
was immediately administered and oral tocolytics,
Nifedipine 10 mg every 8 hours, were started. Work up
was done showing no evidence of infection as possible
cause of preterm labor. Nevertheless, oral antibiotic was
started. Patient was referred to perinatology service. Oral
progesterone was started to support pregnancy.
On the fourth hospital day, ultrasonographic cervical
scoring was done showing a U-shaped cervix with a further
decrease in cervical length to 1.79 cm. This prompted
urogynecology service referral for pessary placement.
At 31 4/7 weeks age of gestation, a hodge pessary was
then inserted and patient was placed on complete bed
rest and maintained on intravaginal progesterone. There
were no appreciated uterine contractions until the 16th
hospital day when the patient had vaginal discharge and
upon internal examination, the cervix was 3-4 cm dilated
Table 2. Serial Ultrasound Monitoring of Case 3
Age of gestation Sonographic age
17 6/7 weeks 17 4/7 weeks
18 weeks 17 3/7 weeks
18 1/7 weeks 17 3/7 weeks
18 3/7 weeks ---
18 4/7 weeks ---
18 6/7 weeks ---
28 Volume 41, Number 1, PJOG Januay-February 2017
80% effaced station 0 with intact bag of water, pessary
displaced, with mild to moderated contractions noted.
Expectant management was then employed.
On the 22nd hospital day, 17 days after pessary
insertion, patient at 34 weeks age of gestation, delivered
via normal spontaneous vaginal delivery to a live preterm
male apgar score 9,9 birth weight 2010g birth length 44 cm
Ballard’s score 34 weeks AGA.
CASE 3
S.B. is a 34-year-old gravida 4 para 3 (3003) admitted in
our institution at 17 weeks and 6 days for vaginal bleeding.
It was prior to admission in our institution that the patient
started to have vaginal bleeding consuming approximately
2 pads with no perceived contractions. Consult was done
at a local hospital and patient was prescribed tranexamic
acid, antibiotics, and started on magnesium sulfate drip.
Pelvic ultrasound done at that time showed a low lying
placenta with a distance of 2cm from the cervical os.
Patient still with vaginal bleeding then transferred to our
institution.
Patient was diagnosed with Hypertension at 4 weeks
age of gestation when blood pressure elevated to 140/100.
There were no medications given for hypertension.
Patient had 3 previous pregnancies all carried to term.
She initially delivered via normal spontaneous delivery
but underwent cesarean section for the subsequent
pregnancies with oligohydramnios as reason for the
primary cesarean section.
On examination, vital signs were stable, fetal heart
tone at 140 beats per minute, no contractions on manual
palpation and internal examination showed a short but
closed cervix with minimal blood on examining finger.
Upon admission, work up showed no infection.
Patient, in threatened abortion, with low lying placenta,
was started on magnesium sulfate drip and isoxuprine
tablet. On repeat ultrasound, placenta was 5.1 cm from
the cervical os but the cervix was noted to be Y-shaped
with functional length of 1.1 cm and 50% funnelling. Serial
ultrasound scans were done thereafter. (Table 2)
On the third hospital day, the patient who was
Functional Cervical Cervical Funneling
Sonographic weight
length Percentage
210 +/- 31 g 1.1 cm 50 %
182 +/- 27 g 1.32 cm 66 %
203 +/- 30 g 2.1 cm 32 %
--- 0 cm 100%
--- 0.87 cm 99.7 %
--- 0.58 cm 87 %
previously asymptomatic, complained of hypogastric pain.
Urinalysis requested showed urinary tract infection for
which oral cefuroxime was started, and maintained on
isoxuprine drip. On repeat cervical scoring the following
day, functional cervical length was 0 cm with 100%
funnelling. Patient was referred to urogynecology for
pessary insertion. Plan was to complete the oral antibiotics
for urinary tract infection prior to pessary insertion.
Meanwhile, transvaginal monitoring of the cervix was
done regularly.
On the 12th hospital day, at 19 3/7 weeks age of
gestation, a hodge pessary was placed intravaginally and
the patient was discharged the following day.
At 33 2/7 weeks age of gestation, patient had watery
vaginal discharge. With an internal examination of cervix
4 cm 70% effaced, floating presenting part but ruptured
bag of water, breech presentation, the patient underwent
repeat cesarean section with bilateral tubal ligation and
delivered to a live preterm female Apgar score 8,9 birth
weight 1950g birth length 44 cm Ballards score 35 weeks
AGA.
Tabulation of patients’ characteristics summarized in
Table 3.
DISCUSSION
The American College of Obstetricians and
Gynecologists (ACOG) defines preterm birth as birth
between 20-37 weeks age of gestation.5 Our local society,
the Philippine Obstetrical and Gynecological Society
adapts the same definition.
Preterm birth poses major concerns as it causes
serious health problems upon birth and even up to
adulthood. Underdeveloped organs in infants born
prematurely lead to a number of complications,
namely, respiratory distress syndrome, patent ductus
arteriosus, intraventricular hemorrhage, hydrocephalus,
hypothermia, necrotizing enterocolitis, anemia, jaundice,
hypoglycaemia, infection upon birth; and cerebral palsy,
impaired cognitive skills, visual and hearing problems,
behavioural and psychological problems as long term
effects.6
According to the World Health Organization, an
estimated 15 million babies are born preterm every
year and almost 1 million children die each year due to
complications of preterm birth while many survivors face
a lifetime of disabilities.7 Across 184 countries, the rate
of preterm birth ranges from 5% to 18% of babies born.7
Philippines ranks 8th out of 184 countries for the number
of babies born prematurely, and ranks 17th for the total
number of deaths due to complications from preterm
birth.8 According to the Department of Health of the
Philippines data, disorders of short gestation and low birth
weight are among the top ten leading causes of infant
mortality in the years 2000-2010.9 Its economic impact
is an approximate healthcare cost of seven thousand to
fifteen thousand pesos per day for preterm newborn in
the intensive care unit.10

Table 3. Summary of Patients’ Characteristics

Case 1 Case 2 Case 3

Maternal Age (years) 35 34 34

OB Score G2P0 (0010) G2P1 (0101) G4P3 (3003)
Ultrasonographic Cervical Functional 1.3 1.79 0.58
Length at Pessary Insertion (cm)

Type of Pessary hodge hodge hodge

AOG at Pessary Insertion 26 weeks 31 4/7 weeks 19 3/7 weeks
AOG at Delivery 34 3/7 weeks 34 weeks 33 2/7 weeks
Number of weeks of pregnancy 7 4/7 2 3/7 13 6/7
prolonged by pessary

Fetal Outcome AS 9,9 AS 9,9 AS 8,9

BW 2085g BW 2010g BW 1950
BL 50 cm BL 44 cm BL 44
BS 35 weeks AGA BS 34 weeks AGA. BS 35 weeks AGA

AS- apgar score; BW- birth weight; BL- birth length; BS- Ballard’s score; AGA- appropriate for gestational age

Volume 41, Number 1, PJOG January-February 2017 29

 One of the causes of preterm birth is incompetent posteriorly, and redirects the weight of pregnancy away
cervix. The American College of Obstetricians and from the vaginal axis, as opposed to cerclage which does
Gynecologists (ACOG) defines cervical incompetence as not. In addition, pessary is a cheap device that can be made
the inability of the uterine cervix to retain pregnancy in the readily available in low resource areas in the country.
second trimester, in the absence of uterine contractions, In all three cases, the hodge pessary was used. (Figure 2)
characterized as painless cervical dilatation. This definition It is a type of pessary that is manually shapeable and its
applies to all three cases in this series. The incidence of anterior bar is applied behind the pubic arch, redirecting
incompetent cervix has been highly variable and it has the cervix posteriorly and repositioning the weight of the
been described in various reports in the literature as growing fetus thereby reducing direct pressure on the
ranging from 1%-8%.11 ACOG recommends cerclage in cervical os in an incompetent cervix whose axis generally
cervical insufficiency, as in case 2, with prior spontaneous points forward in the axis of vagina. (Figure 1) Different
preterm birth and short cervical length less than 2.5cm.12 models of pessaries have been used in previous studies.
However, women whose cervical length is determined to (Figure 3) Presently, there are no studies showing the
be short and who have not previously had a preterm single advantage of one type of pessary over another in the
birth, such as in cases 1 and 3, are poor candidates for prevention of preterm birth.
cerclage.12 Also, according to the Society of Obstetricians There is increasing survival rates with increasing
and Gynecologists of Canada (SOGC), there is no benefit to age of gestation and weight at birth. According to
cerclage in women with incidental finding of short cervix by the Philippines Obstetrical and Gynecological Society
ultrasound but no prior risk factors, such as in cases 1 and (POGS), the percentage survival rates based on age of
3.13 Furthermore, the use of cerclage has been assessed gestation (AOG) and birth weight at delivery are: at least
in two Cochrane reviews wherein data do not allow a firm
conclusion on the use of cerclage in prevention of preterm
birth because of contradicting review results.14 Another
form of mechanical prevention of preterm birth in women
where cerclage may not be considered such as in the three
cases above, may be in the form of nonsurgical pessary.
In a systematic review carried out by Liem et al in 2013,
all cohort studies included, namely Quaas et al, Arabin
et al, Acharya et al, Sieroszewski et al, Antczak-Judycka
et al, and Kimber-Trojnar et al, all indicated potential
effectiveness of pessary in preventing preterm birth.14 One
among the two randomized trials in the same review also
showed promising results. The Pesario Cervical para Evitar
Prematuridad (PECEP) trial, with a study population of 385
women with a short cervix, is the first randomized study of
the use of cervical pessary for prevention of preterm birth,
whose result confirm the benefit of pessary use in such
population.15 To date, there are no published studies on
pessary as management for preterm birth locally.
The reported success rates of vaginal pessaries
closely mirror those observed with cerclage and nominal
success rates are in the 80-90% range.16 However, there
are a number of advantages favoring pessary over cerclage.
Unlike the surgical cerclage, pessary is noninvasive with
no anesthesia needed during placement, and with no Figure 3z. Different models of pessaries used to prevent
needles involved, least likely to cause iatrogenic rupture spontaneous preterm birth. (a) Ring pessary (top left), Hodge
of membranes, bleeding, or cervical laceration. Pessary pessary (top right) and donut pessary (bottom left), all originally
designed to prevent genital prolapsed or uterine retroflexion,
is easy to apply, reposition if dislodged, and remove once
and butterfly – shaped pessary to support the cervix according
indicated, with little expertise needed. In an extremely to Jorde and Hamann (bottom right). (b) Arabin cervical pessary,
short cervix wherein cerclage may be difficult to perform, design to enclose, incline and possibly rotate the cervix as high
a pessary may be placed instead. All these advantages as possible. (Arabin B. And Alfirevic Z. Cervical pessaries for
are evident in our three cases. Also, the mechanism of prevention of spontaneous birth: past, present and future. Wiley
the pessary, as desbribed above, displaces the cervix online library. Ultrasound Ostet Gynecol 2013; 42:390-399)

30 Volume 41, Number 1, PJOG Januay-February 2017

60% between 28-31 weeks AOG and greater than 85%
between 32-36 weeks AOG, and at least 50% between
1000-1499 grams and more than 70% at 1500-1999
grams at birth.10
The present trend for management of preterm labor
is tocolysis to facilitate administration of steroids for
lung maturity. However, for our three cases, the simple
placement of pessary did not just limit our intervention
to steroid administration but even increased the chances
of survival by prolonging the pregnancy up to about 34
weeks age of gestation wherein survival rate is reported
at 85%, as evidenced by good outcome of babies born all
in three cases.
Pessary in pregnancy is well tolerated. Only a few
complications have been reported which is most likely
due to the relatively short duration of use and proper
REFERENCES
1. Farell, Scott A. Chapter 1: The History of Pessaries for Uterovaginal
Prolapse by Thomas F. Baskett. Pessaries in Clinical Practice.
London: Springer-Verlag London; 2007.
2. Abdel-Aleem H, Shaaban OM, Abdel-Aleem MA. Cervical pessary
for preventing preterm birth (Review). Copyright 2010 The
Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
3. Arabin B, Halbesma JR, Vork F, Hübener M, van Eyck J. Is treatment
with vaginal pessaries an option in patients with a sonographically
detected short cervix? J Perinat Med 2003; 31:122-133.
4. Cannie MM, Dobrescu O, Gucciardo L, Strizek B, Ziane S, Sakkas E,
Schoonjans F, Divano L, Jani JC. Arabin cervical pessary in women
at high risk of preterm birth: a magnetic resonance imaging
observational follow-up study. Ultrasound Obstet Gynecol 2013;
42:426-433.
5. American Congress of Obstetricians and Gynecologists. Frequently
Asked Questions Preterm (Premature Labor and Birth. USA. July
2014. Available from: http://www.acog.org/Patients/FAQs/
Preterm-Premature-Labor-and-Birth#labor.
6. Mayo Clinic. Premature Birth.USA: Mayo Foundation for Medical
Education and Research. November 2014. Available from: http://
www.mayoclinic.org/diseases-conditions/premature-birth/
basics/complications/con-20020050.
7. World Health Organization Media Centre. Preterm Birth.
USA; November 2014. Available from: http://www.who.int/
mediacentre/factsheets/fs363/en.
8. UNICEF Philippines.Time to focus on more than 350,000
preterm births in the Philippines every year. Manila: November
2012. Available from: http://www.unicef.org/philippines/
mediacentre_19960.html#.VaEQi_mqqko.
9. Republic of the Philippines Department of Health. Infant Mortality
Ten (10) Leading Causes. Philippines: May 2014. Available from:
http://www.doh.gov.ph/kp/statistics/infant_deaths.html.
antenatal care.2 Increase in vaginal discharge may be
one complication as shown in the study of Arabin et al in
2003.2 However, the study by Havlik et al in 1986 reports
that there is no change in vaginal flora in women with
pessary.2 Discomfort or minor bleeding due to erosions
or lacerations may be observed.17 In all these cases, the
pessary may be removed and cleaned with running water
before reinsertion and repositioning.
CONCLUSION
In the search for strategies to prevent preterm birth,
pessary has promising results. It is an affordable and safe
alternative management of preterm birth which may
be employed in our setting. Future clinical trials may be
helpful in strengthening this evidence.
10. Guinto, Valerie and Festin, Mario. Epidemiology and Impact of
Preterm Labor. Philippine Obstetrical and Gynecological Society,
Inc. Clinical Practice Guidelines on Preterm Labor and Preterm
Prelabor Rupture of Membranes. 2nd Ed. Philippines: November
2010.
11. Kofinas, Alexander D. Cervical Insufficiency-Preterm Labor Continu-
um. Cornell University, College of Medicine. Available from:http://
www.kofinasperinatal.org/files/dmFile/Cervicalinsufficiencypre-
termlaborcontinuum.pdf.
12. American Congress of Obstetricians and Gynecologists. Practice
bulletin no. 142: cerclage for the management of cervical
insufficiency. Obstet Gynecol. 2014 Feb. 123(2 Pt 1):372-9.
[Medline]. Cerclage.
13. Society of Obstetricians and Gynecologists Canada. Cervical
Insufficiency and Cervical Cerclage. Canada: December 2013.
Available from: http://sogc.org/wp-content/uploads/2013/11/
December2013-CPG301-ENG-REV-Dec-13-13.pdf.
14. Liem, Sophie M., Van Pampus, Marielle G., Mol, Ben Willem
J., Bekedam, Dick J. Cervical Pessaries for the Prevention of
Preterm Birth: A Systematice Review. Obstetrics and Gynecology
International Volume 2013 (2013), Article ID 576723, 10 pages
http://dx.doi.org/10.1155/2013/576723.
15. Bello-Munoz Juan Carlos, Llurba Elisa, Cabero, Lluis, et.al.Cervical
Pessary in Pregnant Women with a Short Cervix (PECEP): An Open-
Label Randomised Controlled Trial. The Lancet. April 2012. Volume
379, No. 9828, p1800-1806, 12 May 2012.
16. Newcomer J, Pessaries for the treatment of incompetent cervix
and premature delivery. Obstet Gynecol Surv 2003; 55:443-448.
17. Arabin B. And Alfirevic Z. Cervical pessaries for prevention of
spontaneous birth: past, present and future. Wiley online library.
Ultrasound Ostet Gynecol 2013; 42:390-399.
Volume 41, Number 1, PJOG January-February 2017 31
 Comparative efficacy of oral lactobacillus rhamnosus (protexin)
against metronidazole (flagyl) in the treatment of bacterial
vaginosis: A ramdomized clinical trial*
By Marianne Rose L. Go, MD and Rosendo R. Roque, MD, FPOGS
Department of Obstetrics and Gynecology, University of Santo Tomas Hospital

ABSTRACT

Background: Bacterial vaginosis (BV) is a very common gynecologic infection associated with a vast number of complications both
in gynecologic and obstetric patients. One of the major concerns in its treatment is a high recurrence rate which was multifactorial
and the choice of the suitable antimicrobial is important to decrease the treatment failure.

Methods: All gynecologic patients aged 18 years old and above in a tertiary hospital diagnosed with bacterial vaginosis according to
Amsel’s criteria. A total of 80 patients were randomly assigned into two groups; one group to receive oral Probiotics (Protexin) while
the other group to receive Metronidazole. The patients will be followed up accordingly on Days 1, 3, 7 and 30 and will be graded
according to Amsel’s criteria. The primary endpoint of the study is the treatment of bacterial vaginosis based on the mentioned
criteria. (Anukam, 2006)

Results: The results showed that there was a significant improvement in the character of the vaginal discharge based on the Amsels
criteria on Day 1 of treatment for the Metronidazole group (0/40; 100%, p value <0.001) and Day 3 for Oral Lactobacillus arms.
(7/40; 20%, p value 0.01). The Metronidazole arm showed a significant improvement in the fishy odor on vaginal examination with
addition of 10% KOH on day 1 (0/40; 100%, p value <0.001) and Day 3 for oral Lactobacilus (0/40; 100%, p value 1.00). Then vaginal
pH was noted to be more acidic in the Metronidazole compared to the Protexin arm on Day 1 of treatment (0/40; 0% and 40/40;
100% p value <0.001 respectively). However, both groups had no significant difference of vaginal pH in Days 3-30 (0/40; 100% p
value 1.0). There was a note of less number of recurrence rate under the Protexin arm after 30 days of treatment (5/40; 12.5%
p value <0.001 ) as reflected in the decreased number of clue cells.

Conclusion: The Metronidazole remains to be the standard treatment for Bacterial vaginosis. There was also faster recovery and
clinical improvement in the character of the vaginal discharge, amount and smell based on the Amsel’s criteria as early as Day 1
of follow-up; however, there was a small number of population with poor compliance resulting to higher recurrence rate which
was evident on the 30th day of follow-up. The oral lactobacillus rhamnosus showed advantage over Metronidazole due to lower
recurrence rate of BV as noted on Day 30 of follow up.

Keywords: Bacterial vaginosis, oral lactobacillus, metronidazole

INTRODUCTION weeks.1 There seems to be an association between the

B
acterial vaginosis (BV) results from the breakdown of
the physiological equilibrium that exists between the
local Lactobacillus microenvironment and a pool of
other resident anaerobic or facultative anaerobic bacteria
in the vagina. Bacterial vaginosis has been shown to be
a risk factor in the development of pelvic inflammatory
disease, progression of squamous intraepithelial lesion
(SIL), chorioamnionitis and high incidence of preterm
delivery in pregnancy. The recurrence rate of BV is up to
30% after traditional antimicrobial therapy as early as 2
*3rd Place, 2017 Philippine Obstetrical and Gynecological Society
(POGS) Research Paper Contest, April 6, 2017, Citystate Asturias Hotel,
Puerto Princesa City, Palawan
18 Volume 41, Number 1, PJOG January-February 2017
absence of, or low concentrations of vaginal lactobacilli
and the development of BV. Many studies have suggested
that the presence of H2O2-producing vaginal lactobacilli
may protect against BV. The importance of the microflora
of the vagina is important in that there exists a balance,
which could either lead to a healthy and diseased state.
Factors, such as hormone levels, douching, sexual
practices, innate immunity, as well bacterial interactions
and host defenses all play a role in this delicate balance.2
The role of innate immunity cannot be stressed enough.
Bacterial vaginosis was also said to be associated with
apparent reduced expression of host antimicrobial factors
especially apparent in post-menopausal women.
Lactobacilli are the most common organisms used
as probiotics. In medicine, they have been used orally to
alleviate gastroenteritis and in this study, as a modality immunocompromised patients and use of contraceptive
to prevent BV. Since the vaginal microbiota of women methods were excluded from the study. Using OpenEpi,
with BV has been found to contain diminished levels of Version 2 software program to compute the sample size, it
lactobacilli in comparison with healthy women, it has was computed that a minimum number of 80 subjects are
been theorized that lactobacilli administered orally or required for 80% power (alpha of 0.05). In a study done
intra-vaginally can be an effective means in the restoration by Anukam in 2006, those who received oral Lactobacillus
of the normal flora of the vagina and in effect, curing showed 64.7% clinical and microbiological cure as
women with BV, or at least preventing its recurrence.3 measured by a normal Nugent score, more pronounced
When probiotic L. rhamnosus GR-1 was administered to after the 30 day follow up, while those who received
the vagina of premenopausal women, it resulted in 3536 Metronidazole had 33.3% cure. These data are reflective
gene expression changes and increased expression levels of the possible beneficial outcomes of Oral Lactobacillus
of some antimicrobial defenses against pathological flora. particularly in preventing recurrent Bacterial Vaginosis.
The organisms associated with BV are theorized to form According to their per-protocol analysis, 11 of the 17
dense biofilms on the vaginal epithelium which lead (64.7%) women in the probiotic arm had normal Nugent
to increased resistance to lactobacilli-produced lactic scores on day 30 compared to 6 out of 18 (33.3%) in the
acid and hydrogen peroxide (H2O2) which are normally metronidazole arm: OR 0.27 (95% CI 0.07 to 1.10).
antagonistic to them.4 The biofilms are also able to induce
host expression of certain inflammatory factors, such as
IL-1 and IL-8 which lead to a decreased immune response
against them.
Among 10 strains of lactobacilli being evaluated for
use in a probiotics tablet, (Mastromarino et al) found,
in vitro, that Lactobacillus gasseri 335 and Lactobacillus
salivarius FV2 were able to coaggregate with G. vaginalis.
When these strains of lactobacilli were combined with
Lactobacillus brevis in a vaginal tablet, adhesion of G.
vaginalis was reduced by 57.7%, and 60.8% of adherent
cells were displaced. Boris et al. found that the adherent
properties G. vaginalis were similarly affected by
Lactobacillus acidophilus.5
The purpose of this study therefore is to compare in a
randomized clinical trial, the effectiveness in terms of cure
and prevention of recurrence of BV using Oral Probiotics
(Protexin) VS Metronidazole (Flagyl) in the treatment of
Bacterial Vaginosis.

METHODOLOGY

The randomized clinical trial will be carried out on 80

female patients with sexual contact aged 18 years old and
above, diagnosed with Bacterial vaginosis based on the
Amsel’s criteria with a scoring system of 4: (1. Fluid with
pH >4.5, 2. Thin, homogeneous, grayish-white adherent
discharge, 3. Fishy odor on addition of potassium hydroxide
10% w ⁄ v to the discharge (positive amine test or sniff
⁄ whiff test), 4. Clue cells on saline wet mount). Number
of patients will be divided equally according to the group
A (Oral probiotics-Protexin) and group B (Metronidazole)
which would serve as the control. They will be monitored
based on follow up re-evaluation of the BV. Women who
underwent antimicrobial therapy for conditions other
than BV, pregnancy, presence of urogenital infections,
sexually transmitted diseases, co-morbid conditions,
Figure 1. Flowchart of Methodology
The participants will receive either Oral Lactobacillus
rhamnosus (Protexin) or Metronidazole (Flagyl) as per
the instructions in the sealed white envelopes that will
be opened upon recruitment of the patient to the study.
Group A will be the treatment group and Group B as the
comparator group. Group A will be given Oral Probiotics
(Protexin) tablet once a day for one week. Group B will
be given Metronidazole 500 mg/tab (Flagyl), 1 tab twice
daily for one week. Follow up will be assigned as Day 1,
which is the onset of treatment, Day 3, Day 7 and Day

Volume 41, Number 1, PJOG January-February 2017 19

30 and will be re-evaluated based on the resolution of With initiation of treatment, as shown in Table 2,
BV based on the Amsel’s criteria (0-2/4). During their there was a significant difference in the proportion of
scheduled visits, an unmoistened sterile speculum was subjects with discharge on days 1 and 3 as shown by the
inserted into the vagina so that vaginal walls, fornices, p values <0.001 and 0.01 respectively. Significantly more
and the cervix could be evaluated for erythema, color, and proportion of subjects given oral Lactobacillus rhamnosus
viscosity of discharge. The pH value of the vaginal walls (Protexin) had discharge with 100% and 20% on days 1 and
and of the lateral fornices was measured by colorimetric 3 respectively. However, there was no significant difference
paper with 8 comparison colors for pH values between noted in the proportion of subjects with discharge at
3.6 and 6.1. Vaginal samples were collected from lateral days 7 and 30 as reflected by all p values >0.05. It can
fornices by a wooden Ayre’s spatula; the samples were be seen from the table that vaginal discharge significantly
mixed with saline and 10% potassium hydroxide on two improved on day 7 in both groups.
different slides and then immediately observed under a
microscope. The identification of clue cells will be from Table 2. Comparison of the Amount of Discharge Between the
the obtained vaginal smear and will be studied under the Two
microsope under the supervision of a medical staff from
Metronidazole Protexin p-value*
the Pathology Department of a tertiary hospital. Overall, Follow-up
(n=40) (n=40)
the respone to treatment for Bacterial vaginosis as the
endpoint and goal of both study groups will be based Day 1 0 (0%) 40 (100%) <0.001 (S)
on Amsel’s criteria point system from which a minimum
Day 3 0 (0%) 7 (20.0%) 0.01 (S)
of 3 out of 4 of the criteria is needed for the diagnosis
of Bacterial vaginosis and a score of 1 to 2 out of 4 Day 7 0 (0%) 0 (0%) 1.00 (NS)
would mean recovery from the infection. The treatment Day 30 0 (0%) 0 (0%) 1.00 (NS)
endpoint is to attain a score of 0-2 out of 4 which means
* p>0.05- Not significant; p ≤0.05-Significant
disease improvement/treatment. A persistent score of 3-4
out of 4 signifies disease persistence or treatment failure.
Differences between groups determining association Grossly, the appearance of the discharge in majority
will be analyzed using the T student test, chi2 and fisher of the subjects are comparable during examination
exact tests. The difference between the two groups will particularly on day 7 and 30 of the follow up. Below are
be considered significant if P<0.05 after intention to-treat representative pictures of the vaginal smear added with
analysis. 10% KOH solution.

RESULTS

Table 1 shows the comparison of the demographic

characteristics between the two groups. The results
showed that there was no significant difference noted as
proven by all p values >0.05.

Table 1. Comparison of the Demographic Characteristics

Between the Two Groups

Metronidazole Protexin p-value*

(n=40) (n=40)

Age
Mean ± SD 34.05 ± 10.03 34.05 ± 13.19 0.70 (NS)
Gravida
Primigravida 24 (60.0%) 23 (57.5%) 0.82 (NS)
Multigravida 16 (40.0%) 17 (42.5%)
Amsel’s Scoring 40 (100%) 40 (100%) 1.00 (NS)
4 Figure 1. Day 1 post treatment. Demonstration of vaginal
discharge of a patient with BV on Day 1 of treatment. It has a
* p>0.05- Not significant; p ≤0.05-Significant
characteristic yellowish mucoid fishy like smelling disharge upon
addition of KOH
20 Volume 41, Number 1, PJOG January-February 2017
Figure 2. Day 3 post treatment. Demonstration of vaginal dis-
charge of a patient with BV on Day 3 of treatment showing a
significant decrease in the amount of vaginal discharge and with
improvement in the fishy-like odor of the discharge on addition
of KOH
Figure 3. Day 7 of treatment. Shows further decrease in the
amount of whitish mucoid with complete resolution of the
foul smelling vaginal discharge when mixed with 10% KOH
solution

table that pH of vaginal flora was significantly improved in

acidity on day 3 in both groups.

Table 3. Comparison of the Proportion of Subjects According to

pH of Vaginal Flora Between the Two Groups

Metronidazole Protexin p-value*

Follow-up
(n=40) (n=40)

Day 1 0 (0%) 40 (100%) <0.001 (S)

Day 3 0 (0%) 0 (0%) 1.00 (NS)
Day 7 0 (0%) 0 (0%) 1.00 (NS)
Day 30 0 (0%) 0 (0%) 1.00 (NS)

* p>0.05- Not significant; p ≤0.05-Significant

Figure 4. Day 30 after treatment. Shows further decrease in the
amount of whitish mucoid with complete resolution of the foul
smelling vaginal discharge when mixed with 10% KOH solution
Table 3 shows the comparison of the proportion of
subjects according to pH of vaginal flora between the two
groups. The results showed that there was a significant
difference in the proportion of subjects at day 1 (p<0.001).
Significantly more proportion of subjects given protexin
had alkalinepH of vaginal discharge with 100%. However,
there was no significant difference noted in the proportion
of subjects with acidic pH of vaginal flora at days 3, 7 and
30 as proven by all p values >0.05. It can be seen from the
Table 4 shows the comparison of the proportion
of subjects with presence of clue cells between the two
groups. The results showed that there was a significant
difference in the proportion of subjects with clue cells at
day 1 (p<0.001). Significantly more proportion of subjects
given protexin had clue cells with 87.5%. However, there
was no significant difference noted in the proportion of
subjects with pH of vaginal flora at days 3, and 7 as proven
by all p values >0.05. It can be seen from the table the
number of clue cells significantly decreased on day 3 in
both groups. On day 30, there was a re-appearance of cells
among those given Metronidazole with 12.5% which was
statistically significant (p=0.05).
Volume 41, Number 1, PJOG January-February 2017 21
Table 4. Comparison of the Proportion of Subjects with Presence
of Clue Cells Between the Two Groups

Metronidazole Protexin p-value*

Follow-up
(n=40) (n=40)

Day 1 0 (0%) 35 (87.5%) <0.001 (S)

Day 3 0 (0%) 0 (0%) 1.00 (NS)
Day 7 0 (0%) 0 (0%) 1.00 (NS)
Day 30 5 (12.5%) 0 (0%) 0.05 (S)

* p>0.05- Not significant; p ≤0.05-Significant

Figure 7. Demonstration of Vaginal smear with Bacterial

vaginosis (Day 7 of treatment). The gram negative coccobacilli
were very scant in number and intermediate cells becomes
more visible

Figure 5. Demonstration of Vaginal smear with Bacterial

vaginosis (Day 1 of treatment) Squamous cells have been
identified surrounded by gram negative cocobacilli

Figure 8. Demonstration of Vaginal smear with Bacterial

vaginosis (Day 30 of treatment). The gram negative coccobacilli
discretely exists surrounding the intermediate cells.

Table 5 shows the comparison of the proportion

Figure 6. Demonstration of Vaginal smear with Bacterial
vaginosis (Day 3 of treatment). The gram negative coccobacilli
was noted to be decreased in number and intermediate cells
becomes more apparent
of subjects with fishy odor on KOH between the two
groups. The results showed that there was a significant
difference in the proportion of subjects at day 1 (p<0.001).
Significantly more proportion of subjects given protexin
had persistence of the fishy odor on KOH with 100% with
no significant difference on days 3, 7 and 30 as proven all
p values >0.05 with disappearance of the foul smelling
vaginal discharge. It can be seen from the table that fishy
odor on KOH already gone on day 3 in both groups. For

22 Volume 41, Number 1, PJOG January-February 2017

the metronidazole group, there was complete resolution Table 7 shows the comparison of scores at different
of the fishy odor starting on day 1 of treatment until days follow-up between the two groups. The results showed
3, 7 and 30. that there was a significant difference in the proportion of
subjects according to Amsel’s scoring at days 1, 3 and 30
Table 5. Comparison of the Proportion of Subjects with Fishy as shown by all p values <0.05. Significantly higher scores
Odor on KOH Between the Two Groups were noted among subjects given protexin. However, there
was no significant difference noted in the score at days 7
Metronidazole Protexin p-value* (p=1.00). On day 30, there was a recurrence noted in the
Follow-up
(n=40) (n=40) presence of clue cells among those given Metronidazole
with 12.5% which was statistically significant (p=0.05).
Day 1 0 (0%) 40 (100%) <0.001 (S)
Table 8 shows the comparison of recurrence between
Day 3 0 (0%) 0 (0%) 1.00 (NS) the two groups. The results showed that there was a
Day 7 0 (0%) 0 (0%) 1.00 (NS) significant difference in the proportion of subjects with
Day 30 0 (0%) 0 (0%) 1.00 (NS) recurrence among those given Metronidazole with 12.5%
which was statistically significant (p=0.05).
* p>0.05- Not significant; p ≤0.05-Significant Table 9 shows the comparison of the days before
complete resolution of signs and symptoms between
Table 6 shows the comparison of the days before the two groups. The results showed that there was
complete resolution of the different criteria between the a significant difference in the proportion of subjects
two groups. The results showed that there was a significant according to days before complete resolution (p<0.001).
difference noted (p<0.001). The day of resolution was The day of resolution was significantly shorter in the
significantly shorter in the Metronidazole group than the Metronidazole group than the protexin group. However,
protexin group. However, the recurrence was significantly the recurrence was significantly noted only among those
noted only among those given Metronidazole. given Metronidazole.

Table 6. Comparison of the Days Before Complete Resolution Between the Two Groups

Metronidazole Protexin p-value*

(n=40) (n=40)

Amount of Discharge
<1 day 40 (100%) 0 (0%)
1 day 0 (0%) 33 (82.5%) <0.001 (S)
3 days 0 (0%) 7 (17.5%)

pH of Vaginal Restoration
<1 day 40 (100%) 0 (0%) <0.001 (S)
1 day 0 (0%) 40 (100%)

Presence of Clue Cells

<1 day 35 (87.5%) 5 (12.5%)
1 day 0 35 (87.5%) <0.001 (S)
Recurrence 5 (12.5%) 0

Fishy Odor with KOH

<1 day 1 (2.5%) 0
1 day 39 (97.5%) 0 <0.001 (S)
3 days 0 40 (100%)

* p>0.05- Not significant; p ≤0.05-Significant

Volume 41, Number 1, PJOG January-February 2017 23
Table 7. Comparison of the Score Between the Two Groups

Metronidazole Protexin p-value*

Follow-up
(n=40) (n=40)

Day 1 Amsels score

0 40 (100%) 0
3 0 5 (12.5%) <0.001 (S)
4 0 35 (87.5%)

Day 3 Amsels score

0 40 (100%) 33 (82.5%) 0.01 (S)
1 0 7 (17.5%)

Day 7 Amsels score

0 40 (100%) 40 (100%) 1.00 (NS)

Day 30 Amsels score

0 35 (87.5%) 40 (100%) 0.05 (S)
1 5 (12.5%) 0

* p>0.05- Not significant; p ≤0.05-Significant

Table 8. Comparison of Recurrence Between the Two Groups Table 9. Comparison of the Days Before Complete of Resolution
of Signs and Symptoms Between the Two Groups
Metronidazole Protexin p-value*
(n=40) (n=40) Metronidazole Protexin p-value*
Follow-up
(n=40) (n=40)
Recurrence
Over-all
(+) 5 (12.5%) 0 0.05 (S)
Resolution
(-) 35 (87.5%) 40 (100%)
<1 day 35 (87.5%) 0

1 day 0 33 (82.5%) <0.001 (S)

DISCUSSION
The mechanisms whereby lactobacilli function as
anti-infective defenses are still not fully understood.
This may involve production of antimicrobial factors and
maintenance of a vaginal pH of ≤4.5. It could also be due to
bio-surfactants that alter the surrounding surface tension of
the vagina which leads to reduced adhesion of pathologic
bacteria. This might explain the relative lack of exposed
epithelial cells noted in healthy women. (8) In addition,
lactobacilli have been shown to bind and aggregate with
some pathogens, interfering with their adhesion, and
directly killing them through production of antimicrobials
thus limiting their effect and spread to other organs.
Studies have also shown that production of H2O2
by lactobacilli has a clinically protective role against BV
3 days 0 7 (17.5%)
Recurrence 5 (12.5%) 0
* p>0.05- Not significant; p ≤0.05-Significant
such that it is believed to have a protective role against
colonization of other flora. Studies have shown that an
oral dose of over one billion organisms per day was found
to maintain a lactobacilli-dominated vaginal presence
leading to a decreased incidence of BV. The onset of effect
is obviously longer than direct vaginal instillation, and will
depend on viability of the strains as they pass through
the stomach and gut. However, an advantage of the oral
approach may be the ability of the lactobacilli to reduce the
transfer of yeast and pathogenic bacteria from the rectum

24 Volume 41, Number 1, PJOG January-February 2017

to the vagina, which could potentially lower the risk of
infection. It is highly recommended that in comparing
the treatment outcome for Bacterial vaginosis, a 3rd arm
can be utilized which will include Metronidazole and
oral Lactobacillus rhamnosus combined as the standard
treatment for Bacterial vaginosis. The Oral lactobacillus
rhamnosus will serve as an adjunct in the treatment of
BV to help prevent recurrence which is proven to be its
significant effect in the treatment of BV together with
Metronidazole, the standard drug.
.
REFERENCES
1. Valentina, Marcone, et al. Long-term vaginal administration
of Lactobacillus rhamnosus as a complementary approach to
management of bacterial vaginosis. Journal on Vaginal Microflora.
Volume 8 (2004) pages 8,10-11.
2. M.E. Falagas, et al. Probiotics for the Treatment of Women with
Bacterial Vaginosis. Clinical Microbiology and Infection. Volume
13, Number 7 (July 2007) page 658-659.
3. Brown, Donald. Oral Probiotic Combination for the Treatment of
Bacterial Vaginosis Herbal Prescriptions for Health and Healing.
4th edition. (2006) page 278.
4. Hillier, Sharon, et al. Association Between Bacterial Vaginosis and
Preterm Delivery of a Low-birth-weight Infant. The New England
Journal of Medicine. Volume 33, No 26 (1995) page 1737-1738.
5. Cribby, et al. Vaginal Microbiota and the Use of Probiotics. Journal
of Interdisciplinary Persperctives on Infectious Disease Volume.
157, Pages 2-4. (2008).
CONCLUSION
The Metronidazole remains to be the standard
treatment for Bacterial vaginosis. There was also faster
recovery and clinical improvement in thecharacter of
the vaginal discharge, amount and smell based on the
Amsel’s criteria. The advantage of the Oral Lactobacillus
rhamnosus is evident in the lowering of the recurrence
rate of BV for Protexin arm (0 out of 40 on the 30 fo the
follow-up).
6. Jeavons, Heather S. Prevention and Treatment of Vulvovaginal
Candidiasis Using Exogenous Lactobacillus. JOGNN Journal.
Volume 32. Pages 1-3 (2003).
7. Ray A, et al. Intervention and treatment of vulvovaginal candidiasis
in women with HIV Infection. The Cochrane Collaboration. (2011).
Pages 8-9, 31.
8. Antonio, May, et al. Colonization of Rectum by Lactobacillus
Species and Decreased Risk of Bacterial Vaginosis. Journal of
Infectious Diseases. Volume 7, (2005) page 397.
9. Senok AC. et al. Probiotics for the treatment of bacterial vaginosis
(Review) The Cochrane Collaboration. Copyright 2009, Issue 4,
page 21.
Volume 41, Number 1, PJOG January-February 2017 25
 Evans syndrome complicated by chronic
hypertension with superimposed pre-eclampsia with
HELLP syndrome in pregnancy: A case report*
By Maria Cecilia C. Ching, MD and Maria Czarina Mendoza, MD, FPOGS
Department of Obstetrics and Gynecology, Quirino Memorial Medical Center

ABSTRACT

The case of a pregnant woman initially presenting with low platelets and low haemoglobin and subsequently diagnosed
as a case of Evans Syndrome is presented. Owing to its extremely low incidence, little research exists investigating pregnancies
complicated by Evans Syndrome. Although diagnosis is simple and straightforward, management of a pregnancy of this nature has
proven to be complex and challenging. Further complicating the case and its management is the concurrent diagnosis of Chronic
Hypertension with Superimposed Pre-eclampsia, in complete HELLP Syndrome. Pre-eclampsia in the background of Evans Syndrome
makes this case a truly interesting case. The individual effects of the two disease entities in a single patient are discussed in this
report.

Keywords: Autoimmune hemolytic anemia, evans syndrome, HELLP syndrome, idiopathic thrombocytopenic purpura, pre-eclampsia

INTRODUCTION This patient was first admitted at 15 weeks and 3 days

E
vans Syndrome is an extremely rare, chronic,
relapsing and remitting hematologic condition
characterized by the sequential or simultaneous
diagnosis of Autoimmune Hemolytic Anemia (AIHA) and
Immune Thrombocytopenic Purpura (ITP) in a patient.
Evans Syndrome in the setting of pregnancy has not
been well-documented and research largely involves the
pediatric age group.
First described in 1951, Evans Syndrome has been
largely considered as a diagnosis of exclusion, often
clinched only when other more common clinical entities
are ruled out. In terms of incidence, it is diagnosed in
only 0.8% to 3.7% of all patients with either ITP or AIHA
at onset.1 Evans Syndrome is mostly diagnosed in the
pediatric age group and Evans Syndrome among adults
has not been well-documented.2
CASE REPORT
O. L. is a 37-year-old, G3P2 (2002) Catholic,
married, housewife from Quezon City. Her two previous
pregnancies were both uncomplicated, delivered vaginally
at term. She was admitted at a tertiary hospital with an
admitting diagnosis of G3P2 (2002) Pregnancy Uterine 30
weeks and 6 days AOG by LMP; Chronic Hypertension with
Superimposed Pre-eclampsia, Evans Syndrome.
*Finalist, 2016 Philippine Obstetrical and Gynecological Society (POGS)
Interesting Case Paper Contest, August 18, 2016, 3rd Floor POGS Building,
Quezon City
age of gestation for decreased hemoglobin and platelet
count. Over the course of her 23-day stay, the patient
was transfused with 38 units of platelet concentrate
which raised her platelet count to 156,000. She was also
transfused with 7 units of packed RBC to correct anemia
with Hemoglobin of 76 g/L. Patient underwent a series
of laboratory tests to investigate the possibility of a pre-
existing autoimmune disorder or bleeding dyscrasia,
which yielded the following results: peripheral blood
smear showed mildly hypochromic, microcytic red
blood cells with ovalocytes, there is rouleaux formation,
leucopenia, no blast cells seen, platelets are inadequate;
ANA Autoantigen Screen was equivocal at 0.8, PNH
panel with FLAER negative for Paroxysmal Nocturnal
Hemoglobinuria. On bone marrow aspiration and biopsy,
findings were mildly hypercellular marrow with trilineage
hematopoiesis, moderate to marked erythroid hyperplasia
and mild to moderate megakaryocytic hyperplasia—
morphologic findings consistent with Idiopathic
Thrombocytopenic Purpura. Coombs Test done on the
patient revealed positive Direct and Indirect Coombs
results. Reticulocyte count was also found to be increased
at 2.25, indicative of hemolytic anemia. Over her 3-week
stay, patient developed blood pressure elevations as high
as 170/100 mmHg. Diagnosis was G3P2 (2002) Pregnancy
Uterine 18 weeks and 5 days AOG by LMP, Not in Labor,
Chronic Hypertension, Evans Syndrome. Patient was
started on Prednisone and Methyldopa 250 mg 2 tablets
every 8 hours and was subsequently discharged.
Patient was readmitted at 30 weeks age of gestation

32 Volume 41, Number 1, PJOG January-February 2017

for swelling of the right side of the face. Blood pressure
was 160/110 mmHg, patient was noted to have swelling
on the right side of the face, generalized petechiae on the
abdomen and extremities (Figures 1, 2, 3). CBC showed
normal hemoglobin and thrombocytopenia of 18,000.
SGPT and SGOT were both significantly elevated. LDH was
also significantly elevated. Renal function test was normal.
Diagnosis was G3P2 (2002) Pregnancy Uterine 30 weeks
AOG by LMP, Chronic Hypertension with Superimposed
Pre-eclampsia, Evans Syndrome, Maxillary Cellulitis, Right.
Specialists in Hematology, OB-Infectious Diseases
(OB-IDS), Perinatology and Otorhinolaryngology were
involved in the management of this patient.
Figure 1. On admission, swelling of the face
Figure 3. Multiple Petechiae on abdomen
Biophysical profile and non-stress test were still
reassuring. However, estimated fetal weight was 1122g,
which falls below the 10th percentile. Doppler velocimetry
study was contemplated. Antenatal corticosteroids were
given for fetal lung maturity.
Methyldopa and Prednisone were continued. Despite
increasing Prednisone dose to 60mg/day and transfusion
of thirteen units of platelet concentrate, platelet count
further decreased to 9,000, complete HELLP Syndrome
was considered. Termination of pregnancy by vaginal
delivery was decided. Cervical ripening agents were
started. On Electronic Fetal Monitoring, fetal heart rate
pattern showed a Category III trace (Figure 4), prompting
Figure 2. Hematoma and petechiae on extremities
Figure 4. Multiple Petechiae on abdomen Category III Tracing—
absent variability with spontaneous deceleration
Volume 41, Number 1, PJOG January-February 2017 33
an Emergency Cesarean Section under General Anesthesia.
Intraoperatively, patient was transfused with 2 units of
platelet concentrate and 2 units of Fresh Whole Blood.
Estimated blood loss for the procedure was 1000mL.
Patient delivered to a live preterm baby boy Apgar Score
8, 9 (Figure 5).
On the 2nd post-operative day, patient had
uncontrolled blood pressure reaching up to 200/110
despite antihypertensive treatment. Patient went into
a generalized tonic-clonic seizure and went into cardiac
arrest.
The baby was admitted at the Neonatal Intensive
Care Unit for observation. Hemoglobin and platelet count
were normal. The baby demised on the third day of life
due to prematurity.

CASE DISCUSSION

The clinical picture presented above is most

compatible with the diagnosis of Evans Syndrome. Evans
Syndrome is considered a rare hematologic condition that
is diagnosed when a single patient presents with Immune
Thrombocytopenic Purpura and Autoimmune Hemolytic
Anemia simultaneously or in sequence.3
Idiopathic Thrombocytopenic Purpura or Primary
Immune Thrombocytopenic Purpura is diagnosed
when a patient presents with thrombocytopenia or
low platelet count (less than 150,000) of unidentifiable
etiology.1 Thrombocytopenia in pregnancy must be
throroughly investigated (Figure 6). Common causes of
thrombocytopenia include infection, drug intake, blood
dyscrasia, or it may be secondary to a disease. When
none of these are identified, diagnosis of ITP is made.1
In the patient’s case, an extensive battery of laboratory
tests effectively ruled out other possible causes of
thrombocytopenia. In addition, the patient’s blood picture
consistently showed decreases platelet counts.
Autoimmune hemolytic anemia (AIHA) is diagnosed
when a patient presents with decreased hemoglobin
level (level) and evidence of Red Blood Cell hemolysis not
attributable to other causes.3 In AIHA, both the direct
and indirect antiglobulin (Coombs) tests are positive. The
positive result of the patient’s Direct and Indirect Coombs
test confirms AIHA. Along with this, the patient’s history of
low hemoglobin that required transfusion and the increased
LDH support the diagnosis of AIHA in the patient.
The pathophysiology of Evans syndrome is not clearly
understood, but likely involves two major mechanisms3.
The presence of autoantibodies directed against a base
protein of Rh blood group leads to destruction of red blood
cells (hemolysis) and a separate group of autoantibodies
directed against platelet GPIIb/IIIa destroys platelets
(thrombocytopenia)4.
Figure 5. Baby delivered via “E” LTCS I
Clinical signs and symptoms for Evans Syndrome
typically include the usual features of hemolytic anaemia:
pallor, lethargy, jaundice, and in severe cases, heart failure.
Clinical manifestations of thrombocytopenia include:
petechiae, bruising, and mucocutaneous bleeding.4 Its
chronic course is characterized by recurrent relapses
and remissions.1 This is consistent with our patient who
presented with generalized petechiae and bruising on the
extremities and the abdomen.
With only seven reports documenting Evans
Syndrome in Pregnancy based on an exhaustive search
for available literature in PubMed, this disease in relation
to pregnancy remains largely understudied. However,
when taking into consideration ITP and AIHA, possible
maternal and fetal complications may be identified.
For the Immune thrombocytopenic purpura, possible
consequences include maternal and fetal hemorrhage
from thrombocytopenia.4,5 For the Autoimmune hemolytic
anemia, possible risks include life-threatening anemia,
stillbirth or severe postpartum hemolytic anemia in
infants.5,6
Possible complications during pregnancy include:
spontaneous bleeding episodes4, stroke and with the

34 Volume 41, Number 1, PJOG January-February 2017

Figure 6. Algorithm for differential diagnosis of thrombocytopenia in pregnancy
Reference: Bergmann, F, Rath, W. “The Differential Diagnosis of Thrombocytopenia in Pregnancy”, Deutsches Arzteblatt International, 2015.
patient’s hypertension, one should always watch out
for placental abruption. For the gravid patient with
Evans Syndrome, goals of managing the Immune
Thrombocytopenic Purpura are to minimize hemorrhage
and to restore normal platelet count if possible.7 During
pregnancy, the goal is to maintain platelet count of at
least 30,000. When approaching term, platelet count of
at least 50,000 is recommended. Normal spontaneous
delivery is still the preferred mode of delivery, but
Cesarean section may still be considered if there is an
identified obstetric indication. If the patient is to undergo
Cesarean Section, achieving a platelet count of at least
80,000 is recommended.7 In our patient, administration
of steroids and transfusion of platelet concentrate were
done in an attempt to improve the patient’s platelet
count prior to delivery. However, platelet count did not
increase.
For Evans Syndrome in pregnancy, risks to the fetus
include bleeding, intrauterine growth restriction because
of the possible life-threatening anemia, fetal distress
and ultimately, intrauterine fetal demise.8 Neonatal
thrombocytopenia may also develop as a complication of
the patient’s ITP, and this is observed in 9 to 15% of fetuses
delivered to mothers with ITP regardless of the severity
of the mother’s thrombocytopenia. In the current case,
the neonate underwent a complete blood count to check
platelet count. This was done to investigate the possibility
of neonatal thrombocytopenia, which is common among
newborns of mothers with ITP. Another complication to
watch out for is Intracranial Hemorrhage, observed in 1-3%
of cases, which may lead to death or severe neurologic
sequelae.7
When the diagnosis of Evans Syndrome is reached,
first-line treatment given to the patient is corticosteroids,
alone or in combination with intravenous immunoglobulin
(IVIG).8 Corticosteroids are considered the first-line
Volume 41, Number 1, PJOG January-February 2017 35
treatment option; it works to increase platelet production
and decrease the production of platelet antibodies thereby
decreasing platelet destruction.8 If the patient is refractory
to corticosteroids, IVIG may be given. Intravenous
immunoglobulin helps to block the macrophages that
work to destroy platelets prematurely, and improves
platelet survival time. Second-line treatment options
include rituximab and splenectomy.7 In our patient, she
was given Prednisone and received platelet concentrate
transfusions. The latter may be done but this is only done
as a temporizing measure. Owing to its extreme rarity,
long-term survival data of patients with Evans Syndrome
are limited, cited causes of death were mostly related
to hemorrhage or sepsis. It is important to note that
no clinical practice guidelines currently exist for Evans
Syndrome, and that management is usually targeted on
the patient’s active problems—ITP and/or AIHA.
Along with the patient’s diagnosis of Evans
Syndrome, further complicating this case is the diagnosis
of Chronic Hypertension with Superimposed Pre-
Eclampsia with HELLP Syndrome. Initially diagnosed as
a case of Chronic Hypertension at 15 weeks AOG, the
patient developed Superimposed Pre-eclampsia later in
pregnancy, which is a common finding among pregnant
patients with autoimmune disorders. According to a
study done by Lecarpentier, et al, pregnant women with
Essential Chronic Hypertension have a 23.3% chance of
eventually developing Superimposed Pre-eclampsia.9 This
is consistent with other previous studies that found the
risk to be 17% to 34.9%.8 Although no direct link between
Evans Syndrome and development of Pre-eclampsia exists
in literature, other autoimmune diseases have been shown
to increase a woman’s risk for developing pre-eclampsia.
A study by Barnabe, Faris and Quan (2011) found that
preeclampsia occurred in 18.4% of pregnancies of women
with rheumatoid arthritis (7.3% for the control group) and
16.8% of pregnancies of women with lupus (9.3% for the
control group).10 For Evans Syndrome, its autoimmune
nature gives cause to think that these patients may be at
increased risk as well.
Once diagnosed with pre-eclampsia, termination of
pregnancy is ideally done at 34 weeks age of gestation,
unless emergency indications are identified.11 HELLP
Syndrome, when present, indicates poor maternal
condition, prompting termination of pregnancy.11
When HELLP Syndrome was observed in our
patient as a complication of the Pre-eclampsia, the
thrombocytopenia could have been already present
due to her Evans Syndrome, and only aggravated by the
presence of HELLP Syndrome. However, because the
patient is already being treated with steroids and platelet
concentrate transfusions to correct the thrombocytopenia,
the current thrombocytopenic state of the patient at this
36 Volume 41, Number 1, PJOG January-February 2017
time may be more attributable to the HELLP Syndrome
rather than the Evans Syndrome. In addition, the
exacerbation of the thrombocytopenia, now refractory to
both steroids and platelet concentrate transfusion, may
be due to the combination of Evans Syndrome and HELLP
Syndrome, but this is not supported by data.
When managing a patient with pre-eclampsia,
the safety of both mother and fetus is of paramount
importance.11 Mother should be stabilized, length
of gestation confirmed and fetal well-being must be
assessed.11 Possible fetal complications that should be
watched out for in pre-eclampsia are perinatal death,
placental abruption and development of non-reassuring
fetal status. On the maternal side, HELLP Syndrome,
pulmonary edema, eclampsia and acute renal failure are
the commonly reported complications and patients must
be watched out for the development of any of these. Of
the complications, the development of HELLP syndrome
is the most commonly documented complication,
accounting for 4.1 to 27.1% of cases according to POGS.11
This is applicable to our patient who developed complete
HELLP Syndrome.
Fetal surveillance in this setting is highly recommended.
Biophysical profile scoring is recommended every 3
days, daily non-stress test, regular monitoring of the fetal
heart tones and perception of fetal movement.11 All these
were done in the current case to confirm viability and well-
being of the fetus. Without an emergency indication, the
management plan for the fetus is to deliver at term and
to continue medical management as long as both patient
and fetus remain stable.
The decision to terminate pregnancy at 31 weeks
age of gestation proved to be a diagnostic dilemma.
With the patient’s thrombocytopenia not responding
to Prednisone and platelet concentrate transfusions,
spontaneous vaginal delivery was initially preferred to
avoid blood loss, and Cesarean section was reserved only
for obstetric indication. On one hand, the mother is noted
to be deteriorating, having developed HELLP syndrome
which should prompt immediate termination of delivery.
On the other hand, terminating the pregnancy at this
point would be disadvantageous to the baby, who, at 31
weeks age of gestation and with an estimated fetal weight
of 1100 grams, has a poor prognosis in terms of outcome
if delivered. However, upon hooking to electronic fetal
monitoring, the baby was noted to have a Category III fetal
tracing. With both mother and fetus in critical condition,
the decision to proceed with an emergency cesarean
section despite the severe thrombocytopenia was made.
Preparations in the counselling and prognosticating the
family regarding the conditions of the mother and the
baby, as well as the securing of adequate blood products
were done before proceeding with the operation. Ethical
issues may be discussed in this setting, primarily the
principles of beneficence, non-maleficence and double
effect. Ultimately, the decision to proceed with a cesarean
section in this case became a necessity when both patients
were noted to be deteriorating, and immediate action--
termination of pregnancy—had to be taken to improve
chances of a favourable outcome for both mother and
baby despite the maternal thrombocytopenia and the
fetal prematurity.
Because the baby was born to a mother with
thrombocytopenia, it was imperative to obtain a blood
picture of the baby to investigate the possibility of neonatal
thrombocytopenia. Complete blood count, particularly
the platelet count, was normal. However, on the third
day of life, baby demised due to extreme prematurity.
The possibility of an intracranial bleed may be considered
given the maternal history, but a cranial ultrasound was
not done to confirm this.
Despite aggressive management and close
monitoring, patient demised 2nd post-operative day
after developing elevated blood pressure readings
now refractory to antihypertensive medications, and
generalized tonic-clonic seizure. Cause of death was
cardio-respiratory arrest secondary to Uncal Herniation
probably secondary to Cerebrovascular Bleed.
REFERENCES
1. Jaime-Pérez, J, Guerra-Leal, L., López-Razo, O. “Experience with
Evans syndrome in an academic referral center”, Brazilian Journal
of Hematology and Hemotherapy, March 28, 2015.
2. Michel, M, Chanet, V, Dechartres, A et al. “The spectrum of Evans
syndrome in adults: new insight into the disease based on the
analysis of 68 cases”, Blood Journal, October 2009, Volume 114
Number 15.
3. Longo, Fauci, Kasper et al. Harrison’s Principles of Internal
Medicine, 18th Edition, 2013.
4. Roxana Ghashghaei, Remus Popa, and John Shen. “Evans
Syndrome”, American Journal of Medicine, November 2013,
Volume 126 Number 11.
5. Chao S., Zeng, CM, Liu, J. ”Thrombocytopenia in pregnancy and
neonatal outcomes”, Zhongguo Dang Dai Er Ka Zhi, October 2011,
13, 790-93.
6. Tuncer, Z., Buyukasik, Y., Demirtas, E., Tuncer, R., Zarakolu, P.
“Pregnancy complicated by Evans Syndome”, European Journal
of Obstetrics and Gynecology and Reproductive Biology, Vol 100,
December 2001.
7. Mendoza, C., “Idiopathic Thrombocytopenic Purpura”, Clinical
Practice Guidelines on Medical Complications in Pregnancy,
Philippine Obstetrics and Gynecology Society (Foundation), Inc.,
2015.
SUMMARY
In this report, the case of a thirty-seven year old
diagnosed with Evans Syndrome, Chronic Hypertension
with Superimposed Pre-eclampsia in HELLP syndrome was
presented. Diagnosis is simple but management remains
complex and challenging, warranting future research.
Although it is an uncommon hematologic condition
that is rarely diagnosed and not widely studied, Evans
Syndrome must be considered by clinicians when
confronted with a patient who has a Coombs positive
anemia and thrombocytopenia on Complete Blood Count,
especially since prognosis for Evans syndrome largely
depends on its early recognition and timely management.
With the presence of Pre-eclampsia complicating the
case, close monitoring particularly blood pressure and
fetal heart tones, regular laboratory work-ups and fetal
surveillance are warranted.
A multi-disciplinary approach involving specialists
from Obstetrics, Pediatrics, and Internal Medicine,
specifically Hematology, is recommended. Sufficient
preparation for eventual delivery, close fetal and maternal
surveillance and early management during pregnancy
are imperative to increase the possibility of a favorable
pregnancy outcome in these women.
8. Norton, Alice and Roberts, Irene. “Management of Evans
Syndrome”, BJH British Journal of Haematology, 2005, Volume 132,
125-137.
9. Lecarpentier, E., et al. “Risk Factors of Superimposed Preeclampsia
in Women with Essential Chronic Hypertension Treated before
Pregnancy”, Public Library of Science, May 2013.
10. Barnabe, C., Faris, P. And Quan, H. “Canadian Pregnancy Outcomes
in Rheumatoid Arthritis and Systemic Lupus Erythematosus”,
International Journal of Rheumatology, Volume 2011, August
2011.
11. Bernardino, M and Olivar, J. “Preeclampsia with Severe Features”,
Clinical Practice Guidelines on Hypertension in Pregnancy 3rd
edition, Philippine Obstetrics and Gynecology Society (Foundation),
Inc., 2015.
12. Porcaro, Valenzise, M., G. Candela, et al. “Evans Syndrome: A case
report” Pediatric Medicine Journal, 2014, Volume 36.
13. Ahmedul Kabir, Jayanta Banik, Ratan Das Gupta, et al. “Evans
Syndrome”, Journal of Medicine, 2010 Volume 11 Number 1.
14. Bergmann, F, Rath, W. “The Differential Diagnosis of
Thrombocytopenia in Pregnancy”, Deutsches Arzteblatt
International, 2015.
Volume 41, Number 1, PJOG January-February 2017 37
 Knowledge, attitude, and practice on
human papillomavirus vaccination among obstetrics
and gynecology residents in Metro Manila*
By Katrina Immaculada F. Decena, MD and Doris R. Benavides, MD, FPOGS
Department of Obstetrics and Gynecology, Philippine General Hospital, University of the Philippines-Manila

ABSTRACT

Background: Human Papilloma Virus (HPV) has been known to be an important factor in the development of cervical cancer. In
2006, two vaccines were made available in the Philippines, one covering two subtypes (HPV 16 and 18) and the other covers four
subtypes (HPV 6, 11, 16 and 18) of the virus.

Objectives: This study aimed to determine the current knowledge, attitude, and practices of obstetrics and gynecology residents
from both government and private sector regarding HPV vaccination as well as determine barriers to vaccination. It also aimed
to determine if there is any disparity between the private and government setting, and between residency year levels which may
create a discrepancy in the vaccination coverage of their patients.

Methods: Data will be collected through a self-administered questionnaire. The survey to be used in this study was adapted
from the form used in a similar study done in Hong-Kong. The questionnaire will consist of five sections: 1) items regarding the
respondents’ demographics (age; sex; institution type; residency training year level; number of patients seen in a typical week;
number of patients seen in a week aged 10-17, 18-26, and 27-45; number of pap smears performed in a typical week), 2) Knowledge
on human papillomavirus infection, 3) Attitude towards HPV vaccine, 4) HPV vaccination practice, and 5) Perceived barriers in HPV
vaccination.

Results: This study found that the knowledge of residents about human papilloma virus was generally poor to fair with no significant
difference between the knowledge of residents from government institutions compared to those from the private sector. Majority
of the residents believe that the vaccine should be administered to 10-17 years old, prior to sexual debut and exposure to the human
papilloma virus but were not able to prescribe vaccination for this age group. The perceived barriers of residents in prescribing and
vaccinating their patients differ between age groups. For 10-17 years old, parental refusal for vaccinating their children is due to
the notion that in doing so, their child is being singled out as being at risk for sexually transmitted diseases. For patients 18-26
years old, residents believe that their reluctance to discuss and talk about issues of sexuality are likely to hinder them from getting
vaccinated. For the 27-45-year-old age group, the residents believe that the patient’s belief that they do not have HPV infection is
likely to hinder them being vaccinated.

Conclusion: Proper education and good communication skills among residents and patients should be developed to properly
employ and promote vaccination.

Keywords: Human Papilloma Virus

INTRODUCTION Worldwide, cervical cancer remains one of the top

H
uman Papilloma Virus has been known to be an
important factor in the development of cervical
cancer. Several subtypes of the virus have been
identified to cause the malignant transformation of the
cervical epithelium, also known as the high-risk subtypes.
The identification of and the development of a vaccine
against these subtypes has led to the possibility of
preventing some cervical cancers through vaccination.
*1st Place, 2017 Philippine Obstetrical and Gynecological Society (POGS)
Research Paper Contest, April 6, 2017, Citystate Asturias Hotel, Puerto
Princesa City, Palawan
malignancies ailing women. It is ranked fourth among
the most common cancers in women and seventh
overall. In 2012, there were 528,000 new reported cases
of cervical cancer causing an estimated 266,000 deaths
worldwide. It is the second most commonly diagnosed
cancer and the third leading cause of death in women
in the less developed countries. Approximately
February 90% of
cervical cancer mortalities occurred in the developing
parts of the world, with Asia accounting for 144,400
deaths.1
Among Filipino women, it is ranked second as the
most common malignancy and is the most common cause
Volume 41, Number 1, PJOG January-February 2017 1
of cancer related mortality.2,3 The ICO Information Center
on HPV and Cancer published in June 2016 that in the
Philippines, there are 6670 documented new cases with
2832 reported deaths annually.3
Infection with the human papilloma virus (HPV)
oncogenic types, most frequently HPV 16 is the most
significant risk factor in the development of cervical
cancer. The International Biological Study on Cervical
Cancer has shown that 93% of invasive cervical cancers had
infection with HPV.4 Reports indicate that in squamous cell
carcinoma, HPV types were present in 93.8% and 90.9%
in adenocarcinoma2. HPV infection is now considered a
necessary prerequisite for the genesis of cervical cancer.4,5
The recent understanding of the causal connection
between infection and the so called highrisk or oncogenic
types of HPV and cervical cancer, has led to a paradigm
shift geared towards not only detection but also to the
prevention of CIN and cervical cancer. Research on HPV has
led to the technology for the development of candidate
vaccines to prevent HPV infection and subsequently,
cervical cancer.5
Two pharmaceutical companies have been the major
players in research and development in prophylactic HPV
vaccines to date.5 Two vaccines, the bivalent, targeting HPV
16/18 and a quadrivalent, targeting HPV 6/11/16/18 have
been developed. Early data from randomized control trials
have consistently showed that prophylactic vaccines are
effective in preventing infection and lesions caused by the
targeted HPV types and thus substantially reducing HPV
-related morbidity and mortality.6 Both have undergone
phase 3 trials and have been approved for sale in the US
and UK since 2006. The use of either quadrivalent or the
bivalent vaccine for the prevention of cervical cancer has
been approved in the Philippines and has been gaining
popularity among Filipinos.2
Long lasting protection against HPV 16 may translate
into the prevention of at least half of all cervical cancers.5
Currently, Center for Disease Control (CDC) and American
College of Obstetricians and Gynecologist (ACOG) guideline
states that the ideal population for vaccination are girls at
age 11-12 years old prior to sexual activity. However, they
also recommend giving it to girls 9-26 years old and those
who have not been vaccinated.7,8
Published literature of studies done worldwide have
shown low levels of public knowledge about HPV and its
links to cervical cancer but have shown that the people are
generally in favor of vaccination.
Several cross sectional studies have been undertaken
in different parts of the world to examine the gynecologists’,
pediatricians’ and other healthcare providers’ knowledge,
attitudes, acceptance and practices regarding the use of
HPV vaccine.13-14 These studies have demonstrated that
HPV vaccine acceptability among healthcare providers
2 Volume 41, Number 1, PJOG January-February 2017
is positive. However, most of the studies were done in
developing countries.14
According to a study on HPV vaccine acceptability
among Filipino women conducted last 2010, acceptance
for vaccination is mostly influenced by price. In the
Asia pacific region, price has been cited as a major
barrier for the enactment of HPV vaccination programs.
In addition, exposure to vaccine-promoting media
and suggestion from health-care providers to obtain
protection from genital warts, were significant influences
in the acceptance of vaccination.11 The effectiveness
of HPV vaccine acceptance by the general population
might be related to several factors such as price and
whether or not healthcare providers advise females
to be vaccinated.12-14 In addition to this, a high rate of
reception also requires accurate information from
healthcare providers by answering questions from
parents or patients. Thus, a good implementation of
communication should reduce barriers to vaccination,
and create and sustain a favorable response in the target
population.12-13 Therefore, healthcare providers play a
key role in influencing the populations’ acceptability of
HPV vaccination and decision to be vaccinated.
One study found that for physicians, their professional
organization or society recommendations were the most
influential variable in recommendation of the vaccine to
their patients.15 On the other hand, another recent study
showed that the strongest predictor of HPV vaccination
was the type of practice of the physician, with those on
private practice reporting higher vaccination rates than
those in another type of practice such as ambulatory care
clinics or urgent care clinics.16
This study aims to determine the current knowledge,
attitude, and practices of obstetrics and gynecology
residents from both government and private sector
regarding HPV vaccination as well as pinpoint barriers
to vaccination. The study will also be able to determine
if there is any disparity between the knowledge, attitude
and practices of residents in the private and government
setting which may create a discrepancy in the coverage of
their patients with the vaccine.
The results of this study could contribute to identify
and address key aspects in terms of strengthening practice
of HPV vaccination both in the government and private
setting to be able to increase coverage.
OBJECTIVES
The general objective of this study is to determine
the knowledge of, the attitude towards and the practice
regarding HPV vaccination among obstetrics and
gynecology residents in Metro Manila both in private and
government setting.
SPECIFIC OBJECTIVES:
1. To determine the knowledge of obstetrics and
gynecology residents regarding HPV infection.
2. To determine the attitude of obstetrics and
gynecology residents regarding HPV vaccination.
3. To determine the practices and perceived barriers
of obstetrics and gynecology residents regarding
recommendation and administration of HPV
vaccination among their patients.
4. To determine if there are differences between
the knowledge, attitude, practices and perceived
barriers regarding HPV vaccination among
obstetrics and gynecology residents from private
and government hospitals.
5. To determine if there are differences between
the knowledge, and practices regarding HPV
vaccination among the residency year levels.
MATERIALS AND METHODS
A. Research Design
A descriptive cross-sectional survey design will be
used to determine the level of knowledge of obstetrics
and gynecology residents in Metro Manila regarding HPV
infection, as well as their attitude towards vaccination
against HPV infection. A descriptive study design will also
be used to determine the percentage of OB GYN residents
who recommend and administer HPV vaccination including
the perceived barriers in giving the vaccine.
B. Study Cohort
Inclusion Criteria
The study population will include board certified
physicians currently undergoing obstetrics and gynecology
residency training in the different training hospitals in
Metro Manila.
Exclusion criteria
1. Residents who are involved in research on
HPV Vaccination, as this may give them undue
advantage of having extra knowledge regarding
the topic.
2. Residents who have ties with any of the two
manufacturers of the HPV vaccine which will
create bias in the recommendation and practice
of HPV vaccination.
C. Sample Size
For 2016, there are 550 residents undergoing
obstetrics and gynecology training in accredited hospitals
in Metro Manila. Using a conservative and pioneering
survey response or turn out rate of 50%, allowing +/-6.7%
margin of error estimated at CI 95%, then, this study will
need a minimum of 154 respondents in order to represent
the 550 total population of residents undergoing obstetrics
and gynecology training in accredited hospitals in Metro
Manila.
A list of Metro Manila hospitals with accredited
obstetrics and gynecology training program will be
obtained from the Philippine Obstetrics and Gynecology
Society. Multi-stage cluster sampling will be used in
determining the hospitals whose residents will be asked
to participate in the study. The hospitals will be clustered
according to their location, by city (example: Manila,
Quezon City, Pasay City, Makati City, Valenzuela, Caloocan,
Pasig, Muntinlupa, Marikina, San Juan). In alphabetical
order of the name of the hospitals per cluster, all the
residents from the first two of every three hospitals will
be included in the study (example: Manila- H1, H2, H3, H4,
H5, H6 study will include H1,H2, H4, H5).
D. Materials and Methods
Data will be collected through a self-administered
questionnaire.
The survey to be used in this study was adapted
from the form used in a similar study done in Hong-Kong.
The survey was designed by an academic physician and
validated by an expert panel consisting of epidemiologists,
public health specialists, family physicians, microbiologists
and academic professionals. The survey was pilot tested
by 20 physicians for face-validity and comprehensibility.
The questionnaire will consist of five sections: 1)
items regarding the respondents’ demographics (age; sex;
institution type; residency training year level; number of
patients seen in a typical week; number of patients seen
in a week aged 10-17, 18-26, and 27-45; number of pap
smears performed in a typical week), 2) Knowledge on
human papillomavirus infection, 3) Attitude towards HPV
vaccine, 4) HPV vaccination practice, and 5) Perceived
barriers in HPV vaccination.
Questions that address the attitude of the participants
towards HPV vaccination and the perceived barriers in
vaccination are close-ended with possible responses
including “extremely important”, very important”,
“important”, “somewhat important”, and “not at all”
All data gathered from the respondents will be
treated as confidential information.
E. Description of the study procedure
Data will be collected through a self-administered
questionnaire.
The researcher will send a letter of request to the
chairperson and the chief resident of the Department of
Obstetrics and Gynecology of each hospital for permission
Volume 41, Number 1, PJOG January-February 2017 3
to conduct the study in their institution, and meet with
them personally. Once allowed to conduct the study, the
questionnaires will be distributed and will be collected
after 5-7 days.
F. Definition of the Outcomes
This study would investigate the following outcomes
of interest:
1. Level of knowledge regarding HPV infection among
obstetrics and gynecology residents in Metro Manila
will be computed by the obtaining the number of
participants that answered the items correctly,
divided by the number of items, and multiplied by
100.
2. A positive or negative attitude towards HPV
Vaccination of obstetrics and gynecology residents
in Metro Manila will be computed by taking the
number of participants that answered 1, for
“Not at all important”; 2, somewhat important’;
3, “important”; 4, for “very important” or 5, for
“extremely important” for each of the items, divide
by number of participants multiplied by 100.
3. Practice regarding HPV vaccination among obstetrics
and gynecology residents in Metro Manila will be
computed by obtaining the tally of participants who
answered the corresponding choices of each item,
divide by the number of participants who answered
each item, multiplied by 100. Mean scores will also be
computed and grouped as follows: 1-2.33 “negative”,
2.34-3.67 “neutral” and 3.68-5 “positive”
4. Perceived barriers of obstetrics and gynecology
residents in Metro Manila to vaccination of patients
will be computed by obtaining the tally of participants
who answered the corresponding choices of each
item, divide by the number of participants who
answered each item, multiplied by 100
G. Data analysis
Data will be entered and analysed using the IBM-
Statistical Package for Social Sciencesver 21. Descriptive
statistics, frequencies and percentages will be calculated
for each item in the questionnaire. Knowledge will be
presented in the form of frequency and percentage in
each item while the overall knowledge will be presented
by mean and standard deviation. Attitude assessment will
be categorized on a 5-level Likert scale that ranges from 1,
for “Not at all important” to 5, for “extremely important”.
Each item of attitude will be presented in percentage,
mean and standard deviation. Level of attitude will be
4 Volume 41, Number 1, PJOG January-February 2017
calculated by mean scores and grouped as follows: 1-2.33
“negative”, 2.34-3.67 “neutral” and 3.68-5 “positive”.
The practices and perceived barriers will be presented as
frequency and percentage.
To test whether there are significant overall average
differences between obstetrics and gynecology residents
from private and government hospitals’ knowledge,
attitude, practices and perceived barriers regarding HPV
vaccination, Chi-square test with appropriate contingency
tables will be utilized.
To determine if there are differences in the knowledge
and practices regarding HPV vaccination as stratified by
the respondents’ residency year levels, One-way analysis
of variance will be performed. Also, associations between
respondents’ year level and their categorical levels
knowledge, and practices regarding HPV vaccination will
be tested using Chi Square test of independence with
correspondents’ contingency tables.
Any associated p-values lesser than 0.05 alpha will be
considered significant.
H. Ethical Considerations
The protocol for this research will be submitted to the
University of the Philippines-Manila Research Ethics Board
(UPMREB) PGH Review Panel, and the commencement of
data gathering will begin after approval by the board is
obtained.
Informed consent will be obtained from the
participants invited to accomplish the survey. The informed
consent form will be in English because it is assumed that
all the study subjects have a good grasp of the English
language. Demographic and personal information will be
kept confidential. The names of the participating obstetrics
and gynecology residents will not be disclosed during the
reporting of the study.
The study has no direct benefit to the participants
but this study may help determine the knowledge, attitude
and practice regarding HPV vaccination. This will be able to
aid the Department of Health and the Philippine Obstetrics
and Gynecology Society in their efforts to improve HPV
vaccination coverage in the country.
The investigators will strictly observe the following:
1. Personal information and research data collected
from each subject will be kept confidential. Their
names will not appear in the analysis and reporting
of the study.
2. The investigators will relay correct and factual results.
3. All sources of information, journals, publications and
unpublished studies will be provided for review.
I. Disclosure of Conflict of Interest Table 1. Characteristics of the Study Population
The investigators are not affiliated with any
organization, committee or company that could affect Respondents’ profiles Descriptive [n=157]
the results and conclusions of the study. They also have
co competing financial interest that could reasonably be Age, years
viewed as a conflict of interest. mean[sd] 29.16 ±2.49
Gender
J. Risk and Benefits
M 13 8.3
The study has no direct benefits to the participants
F 144 91.7
but may assist the Department of Health and Philippine
Obstetrics and Gynecology Society in their efforts to Residency year level
increase HPV vaccination coverage. There are no perceived 1 24 15.5
risks for the participants as the investigators will keep all 2 41 26.1
their answers confidential so as not to affect their training, 3 45 28.6
practice and social standing. 4 47 29.8
The participants will not be receiving any form of Institution
incentive or compensation for taking part in this research. Private 43 27.4
Government 114 72.6
RESULTS
Number of patients seen in
a typical week
This study was conducted in October 2016. A total
1-10 13 8.3
of 157 residents have been surveyed and have completed
11-20 27 17.2
the questionnaire. Mean age of respondents is 29.16
years old (SD + 2.49). The majority of the residents were 21-30 4 2.5
females at ninety-two percent (92%) and eight percent 31-40 20 12.7
(8%) were males. Seventy-three percent (73%, n= 114) 41-50 93 59.2
of the respondents were from government hospitals and Aged 9-17
twenty-seven percent (27%, n= 43) from private hospitals. 10-20 91 58.0
More than half or 59.2%, of the surveyed residents see an 30-40 43 27.4
average of 41-50 patients in a typical week. By age group 50-60 11 7.0
of patients, majority or fifty-eight percent (58%) of the 70-80 2 1.3
residents surveyed do not have patients aged 9-17 years 90-100 2 1.3
old, sixty percent (60%) see around 10-20 patients aged
None 8 5.1
18-26 years old, and forty-five percent (45%) see around
10-20 patients aged 27-45 years old. Most of the surveyed Aged 18-26
residents, 41%, perform an average of 6-10 pap smears 10-20 35 22.3
per week while 33.9% only perform 1-5 pap smears per 30-40 95 60.5
week (Table 1). 50-60 20 12.7
70-80 2 1.3
Knowledge 90-100 5 3.2
Knowledge among residents regarding the Human Aged 27-45
Papilloma Virus was poor to fair. Majority, 33%, have fair 10-20 33 21.0
knowledge getting 50-60% of the questions right while 30-40 70 44.6
twenty-seven percent (27%) had poor knowledge getting 36 22.9
50-60
less than 50% of the questions right. Only 17% of the 8.9
70-80 14
residents were able to answer more than 3 questions 2.5
90-100 4
correctly. Less than half (47.8%) of the population was
able to determine the correct prevalence of HPV infection Number of pap smears
in sexually active adolescents and young women, and less performed in a typical week
1-5 36 22.9
than half (28.7%) know the prevalence of genital warts in
sexually active adolescent and young women. However, 6-10 64 40.8
more than half (55.4%) know that 75-100% of cervical 11-15 33 21.0
cancers are caused by infection with HPV, and a high 16-20 24 15.3

Volume 41, Number 1, PJOG January-February 2017 5

percentage (96%) of the residents were able to determine
the disease caused by the 4 most common HPV subtypes
– HPV 6 and 11 causing genital warts and HPV 16 and 18
causing cervical carcinoma.
There is a significant association between the
respondents’ year level and level of knowledge. Ten of 24
first year residents had fair knowledge, 14 of 41 second
year residents had poor knowledge, 14 of 45 third year
residents had fair knowledge, as well as 16 of 47 fourth
year residents had fair knowledge. Third year and fourth
year residents had higher proportion of those with average
and high levels of knowledge compared to the rest of the
year levels. This association implies that higher level of
knowledge is associated with the higher level of residency
training of the respondents (p<0.001).
On the other hand, among 43 respondents from
the private institution, 14 had average knowledge, while
from the government sector 39 out of 114 had fair level
of knowledge. This showed that the association between
the type of institution where the residents are training,
whether private or government, and their level of
knowledge was not statistically significant (p=0.196).
Attitude
The surveyed residents identified the most important
factors that they consider when prescribing HPV
vaccination across all age groups (10-17, 18-26, and 27-45
years old) as: (1) the ability of the vaccine to be efficient in
demonstrating reduction in cervical intraepithelial lesions,
(2) vaccination leading to long lasting immunity and
(3) the vaccines’ ability to protect against genital warts
or condylomata. It was also important to the residents
that recommendation of vaccination is able to provide
them with a venue to discuss sexuality issues with the
patients. It was equally an important factor to consider
for the respondents that the vaccines are available at a
reasonable price. For age group 10-17 years, the vaccines’
ability to eliminate the need for future annual pap smears
and eliminating the increase in the likelihood of their
patients having sex are only of neutral importance among
the residents (Table 2).
In the assessment of respondents’ attitude, none of
the attitude indicators for patients 10-17 years old, 18-26
years old, and 27-45 years old differ significantly when
stratified by the respondents’ year level of residency.
Thus, respondent’s attitude towards vaccination were not
influence by their year level of residency.
The residents deemed that HPV vaccination is as
equally important as the other vaccines such as the vaccines
for genital herpes (56.1% of respondents), hepatitis B
(65% of respondents), chlamydia 55.4% of respondents),
tuberculosis (59.9 % of respondents), influenza (48.4% of
respondents) and chickenpox (50.3% of respondents).
6 Volume 41, Number 1, PJOG January-February 2017
In assessing towards the attitude on Genital
Herpes, Hepatitis B, Chlamydia, Tuberculosis, Influenza,
Chickenpox, and ideal age range for HPV vaccination, the
attitude of the respondents were also not influenced by
their residency year level.
Majority, 62.4%, of the residents think that the ideal
age range for vaccination is 10-17 years old while, 36.3%
think that the ideal age would be 18-26 years.
Practices
In the past 3 months, more than half of the residents,
55% and 60.5%, were able to prescribe HPV vaccination
to an average of 1-25 patients aged 18-26 years old and
27 years and older, respectively. On the other hand, for
patients aged 10-17 years, majority of the residents
(63.7%) did not prescribe HPV vaccination.
The quadrivalent vaccine was the popular choice
of vaccine at 91.1%, amongst residents. There were,
7.5% (n=12) of the respondents that did not have any
preference. The most important influences for choice
of vaccination were: (1) due to the broader coverage of
HPV subtypes (59.2%), (2) a perceived lower price of the
vaccine (31.8%), (3) ability to protect against genital warts
(28.7%), (4) safety profile (28.7%) and (5) ability to infer
stronger protection (27.4%).
Among the indicators of practices, it was shown that
higher proportion of third and fourth year level residents’
choice of vaccine was based on perceived safety (p=0.031)
and according to patients’ choice (p=0.025). This implies
that higher residency level promotes higher practices
towards the said indicators.
In comparison, residents from government hospitals
significantly recommended HPV vaccination to a lesser
number of their 18-25 year old clients compared to
residents from private hospitals, at 25 patients or less in
the past 3 months (p<0.001).
Barriers to Vaccination
For the perceived barriers to prescribing HPV
vaccination, the residents identified several factors that
might hinder their ability to immunize their patients.
For patients aged 10-17, 40.1% of the residents
perceived that the parents will somewhat likely refuse
to have their children be immunized with HPV vaccine
because they think that their child is being singled out be at
risk for an STD. Almost thirty-seven (36.9%) percent of the
residents also believe that the parents’ concern regarding
the vaccine’s safety is a barrier to immunization. Other
perceived barriers to immunization include: (1) the parents
think that their child is receiving too many vaccinations
already (33.8%), (2) the parents pay less attention to
vaccination of their children once they are over 5 years
old (35.7%), and (3) the parents’ reluctance to have their
Table 2. Attitude of obstetrics and gynecology residents HPV vaccination of patients 10-17 years old, 18-26 years old, and 27-45
years old

10-17 yr old
Attitude
Mean Std. Deviation

Would be efficient (demonstrating reduction in cervical intraepithelial lesions) 4.52 0.64

Would not cause adverse effects 4.27 0.75
Would also protect against condylomata (genital warts) 4.51 0.60
Would allow patients to receive other vaccines at the same visit 4.11 0.93
would lead to long lasting immunity 4.36 0.83
Would eliminate the need for future annual Pap tests 3.60 1.31
Would not increase the likelihood of my patients having sex 3.58 1.26
Would not decrease condom use in my patients 3.82 1.20
Would provide an opportunity for me to discuss sexuality issues with my patients 4.52 4.17
Would have regulatory approval from local authority for the client’s age 3.92 1.15
Would have regulatory approval in other countries for the client’s age 3.97 1.15
Would be available at a reasonable price 4.39 0.88

18-26 yr old
Attitude
Mean Std. Deviation

Would be efficient (demonstrating reduction in cervical intraepithelial lesions) 4.55 0.61

Would not cause adverse effects 4.26 0.78
Would also protect against condylomata (genital warts) 4.47 0.71
Would allow patients to receive other vaccines at the same visit 4.17 0.97
would lead to long lasting immunity 4.30 0.94
Would eliminate the need for future annual Pap tests 3.82 1.28
Would not increase the likelihood of my patients having sex 3.78 1.27
Would not decrease condom use in my patients 3.79 1.19
Would provide an opportunity for me to discuss sexuality issues with my patients 4.20 0.89
Would have regulatory approval from local authority for the client’s age 4.06 0.99
Would have regulatory approval in other countries for the client’s age 4.06 1.01
Would be available at a reasonable price 4.33 0.81

27-45 yr old
Attitude
Mean Std. Deviation
Would be efficient (demonstrating reduction in cervical intraepithelial lesions) 4.51 0.67
Would not cause adverse effects 4.34 0.67
Would also protect against condylomata (genital warts) 4.50 0.63
Would allow patients to receive other vaccines at the same visit 4.18 0.93
would lead to long lasting immunity 4.28 0.89
Would produce similar antibody response as observed in young adults 4.24 0.79
Would eliminate the need for future annual Pap tests 3.82 1.27
Would not increase the likelihood of my patients having sex 4.11 4.26
Would not decrease condom use in my patients 3.89 1.16
Would provide an opportunity for me to discuss sexuality issues with my patients 4.11 0.96
Would have regulatory approval from local authority for the client’s age 4.08 1.02
Would have regulatory approval in other countries for the client’s age 4.03 1.02
Would be available at a reasonable price 4.35 0.82

Volume 41, Number 1, PJOG January-February 2017 7

Table 3. Barriers to vaccination of patients aged 10 -17 years old

extremely unlikely somewhat unlikely neither somewhat likely extremely likely

Barrier - 10-17 years old
Frequency Percent Frequency Percent Frequency Percent Frequency Percent Frequency Percent

too many vaccines 16 10.2 27 17.2 44 28 53 33.8 17 10.8

safety of the vaccine 1 0.6 40 25.5 48 30.6 58 36.9 10 6.4
don’t believe in 16 10.2 22 14 62 39.5 34 21.7 23 14.6
vaccines
pay less attention to 7 4.5 34 21.7 50 31.8 56 35.7 10 6.4
vaccination status
once child is over 5
years of age
reluctance to have 6 3.8 40 25.5 34 21.7 53 33.8 24 15.3
their children
immunzed against STD
reluctance to discuss 18 11.5 49 31.2 30 19.1 42 26.8 18 11.5
issues of STI
singling out their child 16 10.2 32 20.4 25 15.9 63 40.1 20 12.7
as one who is at risk
for an STD
increase risky 18 11.5 28 17.8 50 31.8 38 24.2 21 13.4
behavior
Time pressure during 20 12.7 28 17.8 39 24.8 51 32.5 19 12.1
well child visit
recommendations 25 15.9 51 32.5 40 25.5 32 20.4 9 5.7
change too often
reluctance to 21 13.4 36 22.9 47 29.9 31 19.7 22 14
administer multiple
vaccines
reluctance to tallk to 18 11.5 43 27.4 39 24.8 35 22.3 22 14
adolescents about
issues of sexuality
and STI
Acquisition and 22 14 44 28 41 26.1 34 21.7 16 10.2
administration cost
ability to get older 4 2.5 33 21 39 24.8 54 34.4 26 16.6
children to show up
for well visits

Table 4. Barriers for vaccination of patients aged 18-26 years old

extremely unlikely somewhat unlikely neither somewhat likely extremely likely

Barrier - 18-26 years old
Frequency Percent Frequency Percent Frequency Percent Frequency Percent Frequency Percent

Need to pay vaccines 3 1.9 46 29.3 45 28.7 29 18.5 34 21.7

safety of the vaccine 10 6.4 39 24.8 50 31.8 42 26.8 16 10.2
doesn’t believe in 12 7.6 14 8.9 65 41.4 40 25.5 26 16.6
vaccines
doesn’t believe she 20 12.7 33 21 58 36.9 37 23.6 9 5.7
will have cervical
cancer
Doesn’t believe she 17 10.8 37 23.6 51 32.5 34 21.7 18 11.5
will have HPV
reluctance to be 27 17.2 47 29.9 48 30.6 28 17.8 7 4.5
immunized against
an STD
Reluctance to discuss 26 16.6 29 18.5 39 24.8 51 32.5 12 7.6
issues of sexuality
Singling her out as 29 18.5 29 18.5 51 32.5 32 20.4 16 10.2
one who would be at
risk for an STD
Time pressure during 29 18.5 40 25.5 59 37.6 24 15.3 5 3.2
a well visit
Reluctance to talk 30 19.1 29 18.5 44 28 46 29.3 8 5.1
about issues of
sexuality
Acquisition and 30 19.1 30 19.1 53 33.8 30 19.1 14 8.9
administration cost of
another vaccine

8 Volume 41, Number 1, PJOG January-February 2017

children immunized against sexually transmitted diseases
(33.8%). The residents also feel that time pressure during
well child visits (32.5%) and their ability to get older
children or adolescents to come in for a well visit (34.4%)
are somewhat likely to hinder their ability to vaccinate
patients within this age group (Table 3).
For patients 18-26 years old, 32.5% and 29.3% of
residents believe that their reluctance to discuss and talk
about issues of sexuality are somewhat likely to hinder
them from prescribing HPV vaccination, respectively. The
rest of the issues were only deemed to be neither likely or
unlikely to prevent them from immunizing their patients
(Table 4).
For the 27-45 year-old age group, 29.3% of the
residents believe that the belief of patients that they do not
have HPV infection somewhat likely to hinder them from
prescribing HPV vaccination. Almost thirty percent (29.9%)
of the residents believe their reluctance to discuss issues
of sexuality, while 28% believe that the added burden of
acquisition and administration cost of another vaccine are
all somewhat likely to hinder them from prescribing HPV
vaccination. The rest of the issues were only deemed to be
neither likely or unlikely to prevent them from immunizing
their patients (Table 5).
Comparing residents from the private hospitals
and residents from government hospitals, there are no
significant differences in their perceived barriers for
vaccination of patients at ages 10-26 years old. However,
for their patients aged 18-26 years old, residents from
government hospitals had higher ratings on the barrier
of “not believing in vaccines” than those in the private
setting (3.48 vs 2.98, p=0.009). For patients aged 27-45
years old, residents in government setting had higher
ratings on the barrier of “reluctance in discussing issues of
sexuality”(2.81vs 2.35, p=0.030).
DISCUSSION
This study found that the knowledge of residents
about human papilloma virus was generally poor to fair.
There was no significant difference between the knowledge
of residents from government institutions compared to
those from the private sector although relating between
year levels, the knowledge of senior residents (3rd and
4th years) were significantly higher. The knowledge on
HPV prevalence was indeed low yet, the knowledge on
the role of the HPV types in cervical cancer and genital
warts was high. The residents were able to identify that
HPV types 6 and 11 are responsible for genital warts while
types 16 and 18 are the high risk types – associated with
cervical carcinoma. In comparison with international
data involving obstetrics and gynecology specialists, the
resident’s knowledge on the etiologic agents were at par
with theirs. On the other hand, compared to studies that
involved general practitioners and physicians from other
specialties who have shown that they have low knowledge
regarding the etiology of cervical cancer, the residents
surveyed had a higher level of knowledge10.

Table 5. Barriers for vaccination of patients aged 27-45 years old

extremely unlikely somewhat unlikely neither somewhat likely extremely likely

Barrier - 27-45 years old
Frequency Percent Frequency Percent Frequency Percent Frequency Percent Frequency Percent

Need to pay vaccines 13 8.3 32 20.4 47 29.9 45 28.7 20 21.7

safety of the vaccine 12 7.6 38 24.2 55 35 45 28.7 7 4.5
doesn’t believe in 12 7.6 17 10.8 72 45.9 42 26.8 14 8.9
vaccines
doesn’t believe she 16 10.2 27 17.2 59 37.6 50 31.8 5 3.2
will have cervical
cancer
Doesn’t believe she 15 9.6 33 21 45 28.7 46 29.3 18 11.5
will have HPV
reluctance to be 26 16.6 50 31.8 45 28.7 30 19.1 6 3.8
immunized against
an STD
Reluctance to discuss 24 15.3 33 21 40 25.5 47 29.9 13 8.3
issues of sexuality
Singling her out as 22 14 43 27.4 48 30.6 28 17.8 16 10.2
one who would be at
risk for an STD
Time pressure during 16 10.2 40 25.5 49 31.2 34 21.7 18 11.5
a well visit
Reluctance to talk 30 19.1 40 25.5 49 31.2 26 16.6 12 7.6
about issues of
sexuality
Acquisition and 22 14 30 19.1 44 28 44 28 17 10.8
administration cost of
another vaccine

Volume 41, Number 1, PJOG January-February 2017 9

 The residents regarded HPV vaccination to be
equally important for adolescent women’s health same
as with other vaccines such as for genital herpes, hepatitis
B, chlamydia, tuberculosis, influenza and chicken pox.
Majority of the residents also believe that the vaccine
should be administered preferably at the age range of 10-
17 years old, prior to sexual debut and exposure to the
human papilloma virus. However, a number of the surveyed
residents were not able to prescribe vaccination for this
age group probably owing to the fact that majority of them
are also not able to see patients within this age bracket.
A number of the residents also believe that the 18-26
year old population should likewise be vaccinated against
human papilloma virus. Both ideals are in keeping with the
recommended age group to receive HPV vaccination by the
CDC and other governing bodies which is 9-26 years old.7,8
The quadrivalent vaccine was the preferred vaccine
with the major factors for choice being (1) the ability of
the vaccine to be efficient in demonstrating reduction
in cervical intraepithelial lesions, (2) vaccination leading
to long lasting immunity and (3) the vaccines’ ability to
protect against genital warts or condylomata.
The perceived barriers of residents in prescribing
and vaccinating their patients differ between age groups.
For the younger age group (10-17 years old), parental
refusal for vaccinating their child or children is due to the
notion that in doing so, their child is being singled out as
being at risk for sexually transmitted diseases. Parents are
also concerned regarding safety of the vaccine. According
to a survey among pediatricians, they anticipated that
emphasizing cervical cancer prevention more strongly
than other vaccines may lessen concerns about vaccine
acceptance. Research indicated that parental resistance to
HPV vaccination is linked to their concern that this would
promote risky sexual behavior. However, it is impossible
to evaluate whether those who are vaccinated against
HPV will participate in a riskier behavior.17
On the other hand, for patients 18-26 years old,
residents believe that their reluctance to discuss and talk
about issues of sexuality are somewhat likely to hinder
them from vaccinating their patients.
For the 27-45 year-old age group, the residents
believe that the patient’s belief that they do not have HPV
infection somewhat likely to hinder them from prescribing
HPV vaccination. Similar to a study conducted in China, the
most common arguments against vaccination included
worries about the safety of the vaccine and low perceived
personal risk for cervical cancer. Both concerns should
both be responsive to education efforts.18
In comparison with other studies siting cost of
vaccine, provider’s and parental concerns regarding safety
and efficacy, and communication related to sexuality as
barriers of HPV vaccine prescription, these are also shown
10 Volume 41, Number 1, PJOG January-February 2017
in our study to be major barriers.10 Healthcare practitioners
provide patients with important information, and parents
value advice about preventive measures, such as vaccines.
Since obstetrician – gynecologists are not able to see
patients within the 10-17-year age bracket the responsibility
of vaccinating this population falls upon Pediatricians.
Therefore, efforts pertaining to HPV vaccination should not
only involve obstetrician – gynecologists, but also Pediatricians
and Family Physicians as well. One study found that women
with higher levels of HPV knowledge were significantly more
open to vaccination for both themselves and their daughters
which reinforces the importance of public education in the
success of an HPV vaccination program.18 Unfortunately,
counselling of patients also seemed to be a concern among
healthcare workers. This could be due to time constraints,
the inability to discuss the merits of the vaccine with
adolescents and their parents, cost issues, or simply that
even tough healthcare workers are aware that a HPV vaccine
exists, they are not counselling patients about it.13 The HPV
vaccination programme’s success relies largely on healthcare
providers’ willingness and ability to recommend vaccination
against HPV to their patients as well as effective education
regarding HPV and HPV vaccine.
CONCLUSION
Our study has shown that more educational
initiatives should be organized for both government and
private obstetrics and gynecology residents to enhance
their perceived importance of prescribing HPV vaccine to
their patients. There should be focus on the epidemiology
of HPV infection and genital wart. Educational initiatives
should emphasize the ability of the HPV vaccine to achieve
strong protection and long lasting immunity, as well as
its ability to have cross protection against the important
oncogenic subtypes which has been perceived by our
respondents as important factors in their choice of vaccine.
For barriers that hinder effective vaccination of
children, since parental refusal is due to concerns regarding
safety and concerns of their children being singled out as
having STD, parents would be particularly reassured about
the low rates of adverse effects and the vaccine’s many
health benefits. Likewise, good communication skills
among residents should be developed to allay concerns
on discussing sexuality and sexuality transmitted diseases
from the older age group. To enhance vaccine uptake rate
among women, the government should consider at least
partial subsidy to eligible clients to overcome vaccine cost
which is one of the important barriers.
In light of the present findings, future research can
evaluate interventions which could effectively enhance
residents’ as well as the target populations’ knowledge
regarding HPV vaccination and if there will be improvement
in the uptake of the vaccines among the target population
after enhancing their knowledge.
LIMITATIONS OF THE STUDY
To our knowledge, this is the first study to evaluate
the knowledge, attitude, practices and perceived barriers
REFERENCES
1. Torre, Lindsey A. MSPH, Freddie Bray PhD, et. Al. Global cancer
statistics, 2012. CA: A Cancer Journal for Clinicians. March/April
2015. Vol 65. Issue 2. Pg 87-108.
2. Domingo, Efren J. MD, Ana Victoria V. Dy Echo, MD. Epidemiology,
prevention and treatment of cervical cancer in the Philippines.
Journal of Gynecologic Oncology. March 2009. Vol 20. No 1: 11-16.
3. ICO Information Center on HPV and Cancer Fact sheet 2016.
Institut Catala d’Oncologia.
4. Walboomer, Jan M.M. , Marcel V. Jacobs, et.al. Human Papilloma
Virus is a necessary case of invasive cervical cancer worldwide.
Journal of Pathology. 1999. 189: Pg 12-19.
5. Franco, Eduardo L. and Diane M. Harper. Vaccination against
human papillomavirus infection: a new paradigm in cervical cancer
control. Vaccine 23. 2005. Pg 2388-2394.
6. Koutsky, Laura A. and Diane M. Harper. Chapter 13: Current
findings from prophylactic HPV vaccine trials. Vaccine 21. August
2006. Vol 24: S114-S121.
7. American College of Obstetrics and Gynecology. Committee
Opinion: Human Papillomavirus Vaccination. Number 641. Sept
2015.
8. Center for Disease Control and Prevention. Fact Sheet: HPV
Vaccine information for young women.
9. Aljuwaihel Anoud, Alaa Al-Jaralla, et al. Awareness of HPV and
Cervical Cancer vaccine among PHC Physicians in Kuwait. Greener
Journal of Medical Science. 2012.
10. Wong, Martin C.S., Albert Lee, et al. Knowledge, Attitude, Practice
and Barriers on Vaccination against Human Papillomavirus
Infection: A Cross Sectional Study among Primary Care Physicians
in Hong-Kong. PLOS ONE. August 2013. Vol 8. Issue 8.
towards HPV vaccination among obstetrics and gynecology
residents from both private and government institutions
in Metro Manila.
The primary limitation of this study is that the actual
uptake of the vaccine was not studied. Correlates with
healthcare providers’ practices and attitude towards
vaccination may be dissimilar to those of uptake.
11. Young, April M., Richard A. Crosby, et. al. HPV Vaccine Acceptability
among Women in the Philippines. Asian Pacific Journal of Cancer
Prevention. Vol 11. 2010.
12. Voidazan, Septimiu, Monica Tarcea, et al. Knowledge Practices and
Barriers to Vaccination Against Human Papillomavirus Infection:
Addressing a group of Doctor in Romania. Management in Health
XIX. 3/2015. Pg 32-37.
13. Allie, Naseera. Knowledge awareness and utilization of the
human papillomavirus vaccine in Durban. South African Journal of
Gynecologic Oncology. Vol 14. No 1. 2012. Pg 6-10.
14. Songthap, Archin, Punnee Pitisuttihtum, et a. Knowledge,
attitudes and acceptance of a human papillomavirus vaccine
among healthcare providers. Southeast Asian Journal on Tropical
Medicine and Public Health. Vol 40. No 5. September 2009. Pg
1048-1056.
15. Raley, Janice C., Kristen A. Followwill, et al. Gynecologists’ attitudes
regarding human papilloma virus vaccination: a survey of Fellows
of the American College of Obstetrics and Gynecologists. Infectious
Disease in Obstetrics and Gynecology. 2004. 12: Pg 127-133.
16. Vadaparampil, Susan T. PhD. Stephanie A.S. Staras, PhD. Et
al.Provider Factors Associated with Disparities in Human
Papillomavirus Vaccination Among Low-income 9- to 17- year old
girls. Cancer. 2013; 119: Pg 621-628.
17. Daley, Matthew F. MD. et. al. A National Survey of Pediatrician
Knowledge and Attitudes Regarding Human Papillomavirus
Vaccination. Pediatrics. Volume 118. Number 6. December 2006.
Pg.2280-2289.
18. Fang-Hui Zhao, et al. A multi-center Survey of HPV Knowledge and
Attitudes Toward HPV Vaccination among Women, Government
Officials, and Medical Personnel in China. Asian Pacific Journal of
Cancer Prevention. Vol 13. 2012. Pg 2369-2378.
Volume 41, Number 1, PJOG January-February 2017 11
 Ovarian new growth creating a
cutaneous fistula: A case report*
By Glaiza S. de Guzman, MD and Margaret Joyce C. Limson, MD, FPOGS
Department of Obstetrics and Gynecology, Philippine General Hospital, University of the Philippines-Manila

Ovarian new growths are among the most common tumors in women. Their presentation at time of diagnosis vary and
are often incidental findings on ultrasound examination. Complications of ovarian masses include torsion, rupture, infection,
hemorrhage, and malignant degeneration. These masses have also been known to create fistulous tracts to other organs of the
body. Entero-adnexal communications have been reported in literature. However, fistula formation to the skin has not yet been
reported. Here, we present an adult woman diagnosed to have ovarian new growth and a one-year history of serous discharge from
a skin lesion. Imaging studies show a fistulous connection to the abdominopelvic mass. She underwent excision of the mass with
fistulectomy. This is the first reported case of an ovarian new growth which created a cutaneous fistula.

Keywords: cutaneous, fistula, ovarian new growth, teratoma

INTRODUCTION

O
varian new growths complicated by fistula
formation are an uncommon entity but have
occasionally been described. There have been
reported cases of entero-ovarian fistula after surgery or
chemotherapy.1,2 However, formation of a fistulous tract
directly to the skin has not been identified in literature.
We report a case of a woman with an ovarian new growth
complicated by a cutaneous fistula who underwent
complete surgical resection of the mass with fistulectomy

CASE REPORT

The patient is AD, a 42-year-old G3P3 (3003), who

presented with a one year history of yellowish discharge
from an infraumbilical skin lesion. She is a known
hypertensive and diabetic for one year maintained on
Amlodipine and Metformin with good compliance. She
has adequate sugar control with HbA1c of 5.3%. Her family
medical history is unremarkable. She denies smoking or
use of alcohol and illicit drugs.
Four years prior to consult, she noted a 3 x 3 cm
fluctuant infraumbilical mass, with erythematous borders
diagnosed to be a carbuncle. She underwent incision and
drainage of this lesion with note of good post-operative
healing. She was apparently well until three years ago
when she started to experience intermittent abdominal
pain associated with gradual abdominal enlargement. She
did not have any weight loss, fever, anorexia, urinary or
bowel movement changes. No consult was done and no
*Finalist, 2016 Philippine Obstetrical and Gynecological Society (POGS)
Interesting Case Paper Contest, August 18, 2016, 3rd Floor POGS Building,
Quezon City
38 Volume 41, Number 1, PJOG January-February 2017
Figure 1. An infraumbilical wound with a defect draining
yellowish serous discharge.
medications were taken by the patient. One year prior
to consult, there was gradual sinus formation on the
site of the previous carbuncle resulting in a skin defect.
From this opening, yellowish serous discharge would
drain spontaneously throughout the day aggravated by
movement.
Persistence of symptoms prompted consult. She had
stable vital signs. On abdominal examination, there is a
4 x 4 cm healed wound on the infraumbilical area with
a 0.5 x 0.5 x 2 cm fistula (Figure 1). On palpation, there
was no fluid wave. There was an 18 x 18 x 10 cm cystic,
movable, nontender abdominopelvic mass. Yellowish
serous discharge would drain from the site of the fistula
upon palpation and manipulation of the said mass. The
rest of the systemic physical examination was essentially images show opacification of a multilobulated structure
normal. There were no non-healing wounds elsewhere located midline and posteroinferior to the radiopaque
in the body. On internal examination, she had normal marker, adjacent to the soft tissue density which likely
external genitalia, parous vagina, and the cervix was represents the abdominal mass. Her CA 125 was 7.64. The
smooth measuring 2 x 2 cm. The corpus and adnexae were wound aspirate was sent for AFB and culture. There was
difficult to assess due to the abdominopelvic mass. no AFB seen. Culture showed heavy growth of diphtheroid
Transvaginal-transabdominal ultrasound showed an species. HIV testing was negative.
intraabdominal fluid collection measuring 4.4 x 4.3 x 1.8 She underwent exploratory laparotomy, adhesiolysis,
cm (volume 17.81 cc) bounded by the fascia anteriorly and right salpingooophorectomy, left salpingectomy, and
the abdominopelvic mass posteriorly. The fluid collection fistulectomy under regional anesthesia. Intraoperatively,
seemed to be connected to the skin by a fistulous tract the mass was densely adherent to the anterior abdominal
measuring 2.8 x 0.8 cm. Occupying the abdominopelvic wall, omentum, and surrounding bowel loops (Figure 3).
cavity was a unilocular cystic mass measuring 19.6 x 20.4 x
14.0 cm with low level echo fluid and echogenic stipplings
within. There were echogenic cores at its inferior pole
measuring 2.1 x 1.8 and 2.3 x 1.8 cm each, casting posterior
acoustic shadows. Color flow mapping showed absent
vascularity. The uterus and left ovaries were normal.
Abdominal computerized tomography scan showed
a large, well-defined predominantly cystic focus with
enhancing rim measuring 20.4 x 15.3 x 16.2 at the
abdominopelvic region. It exhibited fat attenuation
with lobulated coarse calcifications. Anteriorly, the
mass seemed to cause the clinically apparent anterior
abdominal bulge at the region of the umbilicus. A column
of hypodensity is seen extending from the mass to the
adjacent extracutaneous region through a small defect in
the overlying soft tissue (Figure 2).
A fistulogram showed initial pooling of contrast
material into the clinically apparent ulceration with
eventual opacification of a tract approximately 2.5 cm long
coursing posteriorly with abrupt cutoff distally. Delayed

Figure 2. An axial cut on abdominopelvic computed tomography

scan at the level of the fistula. A column of hypodensity is seen
extending from the mass to the adjacent extracutaneous region Figure 3. The abdominopelvic mass was densely adherent to
through a small defect in the overlying soft tissue (box). the wound scar making adhesiolysis difficult at the area.
Volume 41, Number 1, PJOG January-February 2017 39
Intraoperative referral to general surgery service was done
for enterolysis. Once freed from surrounding adhesions,
we excised the abdominopelvic mass together with a
portion of the adherent abdominal wall and fistulous
tract. The mass was cystic and unilocular measuring 20
x 19 x 10 cm arising from the right ovary (Figure 4). On
cut section, there was note of teeth located at the inferior
border (Figure 5). The capsule was thickened at 0.5 cm.
Assisted by the plastic surgery service, we were able to
close the abdominal layers with no fascial defect. There
was good postoperative wound healing. Histopathologic
study showed a mature teratoma.
Figure 4. The abdominopelvic mass arose from the right ovary.
It measured 20 x 19 x 10 cm with thickened capsule.
DISCUSSION
Ovarian new growths are a diverse group of tumors
classified as sex cord-stromal, surface epithelial, germ
cell, and metastatic tumors.3 Most ovarian masses are
benign and occur mostly during the reproductive years.3,4
Symptoms usually vary among patients. They may
experience abdominal enlargement, abdominal pain,
and urinary or gastrointestinal symptoms. If the mass is
hormonally active, patients may also complain of vaginal
bleeding.4 Transvaginal examination is the investigation of
choice in the detection of ovarian masses and assessment
for its potential for malignancy.5 Management largely
depends on symptoms produced by the mass, the
likelihood that the mass is malignant, and the chance of
spontaneous resolution.3,5
Accounting for about 33% of ovarian masses,
mature cystic teratomas are the most common germ
40 Volume 41, Number 1, PJOG January-February 2017
Figure 5. Cut section of the mass showed teeth formation at its
inferior border.
cell tumor.3 Thesedevelop from a totipotential germ
cell and thus contain an admixture of all three germ cell
layers on histopathologic examination. The characteristic
sonographic findings of an ovarian teratoma include
a dense echogenic area within a larger cyst, a cyst with
bands of mixed echoes, and an echoic dense cyst. Cysts
are commonly unilocular with smooth, shiny, opaque
white capsule. On cut section, they contain masses of hair,
teeth, and cartilage with sebaceous fluid.3
Operative treatment of mature cystic teratoma is
cystectomy or oophorectomy depending on the amount
of normal ovarian tissue left and the patient’s reproductive
goals. The goal of surgical management is to preserve as
much ovarian tissue as possible while minimizing adhesion
formation. In this case, the right ovary was converted to
the large mass with no normal ovarian stroma. As such,
excision along with the fallopian tube was performed.
There was difficulty separating the ovarian new growth
from the surrounding peritoneal structures possibly due to
a previous rupture and subsequent inflammatory changes.
Careful adhesiolysis should be done in such cases so as
not to injure any adjacent structures and prevent further
spillage of the contents.
Teratomas may undergo complications which include
rupture, torsion, infection, hemorrhage, and malignant
degeneration.3 Cyst rupture is particularly uncommon
because of its thick capsule.6 Reported sites of rupture
include the urinary bladder, vagina, and bowel. Rarely,
they form fistulous tracts with other organs of the body.
Shai and colleagues reported a case an entero-adnexal
fistula as initial presentation of an advanced ovarian
carcinoma. Their patient underwent a combination of
chemotherapy, antibiotics, and delayed surgery. They were
able to perform optimal debulking without the necessity
of bowel resection.1 A similar case of entero-ovarian fistula
of a benign ovarian teratoma was also reported by von-
Walter and Nelken.2
Recognition of clinical and radiologic findings
is important in managing cases of ovarian masses
complicated by fistula formation to other organs of the
body. Symptoms vary and are nonspecific. Fistula formation
may be caused by diverse factors which include radiation
exposure, immunosuppression, infection, malnutrition,
poorly controlled diabetes mellitus, and cyst rupture with
subsequent inflammation and necrosis. In this patient,
REFERENCES
1. Shai A, Grikshtas E, Segev Y, Moskovitz M, Bitterman A, Steiner M,
Lavie O. Conservative management for an entero-adnexal fistula
at initial presentation of advanced ovarian carcinoma. Current
Oncology. 2013; 20(1).
2. Von-Walter AR and Nelken RS. Benign cystic ovarian teratoma with
a fistula into the small and large bowel. Obstetrics & Gynecology
2012; 119(2):434-436.
3. Lentz GM, Lobo RA, Gerhenson DM, Katz Comprehensive
Gynecology, 6thed. USA: Elsevier Mosby, 2012.
predisposing factors for fistulization to the skin may
include previous rupture with resulting adhesion to an
already weakened anterior abdominal wall. Inflammation,
ischemia, and necrosis of the cyst wall may have caused
further breakdown of the abdominal wall creating a direct
communication between the ovarian new growth and the
skin. Adequate sugar control and daily wound care was
emphasized to the patient to achieve good postoperative
wound healing. On literature search, there have been no
reported cases of an ovarian new growth creating a fistula
to the skin.
SUMMARY
In summary, we presented a case of an ovarian new
growth complicated by a fistulous tract to the skin. The
patient was successfully managed via surgical resection of
the mass along with fistulectomy.
4. Jerek JS (ed). Berek& Novak’s Gynecology, 14th ed. Lippincott
Williams & Wilkins. USA, 2007.
5. Monaghan JM, De Barros Lopes A, Naik R (ed). Bonney’s
Gynaecological Surgery 10th ed. Blackwell Publishing, 2004.
6. Giustini FG, Sohn S, and Khosravi H. Pelvic abscess and perforation
of the sigmoid colon by a segment of benign cystic teratoma: an
unusual complication of induced abortion. Journal of Reproductive
Medicine. 1978; 20(5):291-292.
Volume 41, Number 1, PJOG January-February 2017 41
 Tubal ligation and salpingectomy and the risk of
epithelial ovarian cancer: A case-control study*
By Cyriel Anthony I. Tingne, MD and Jean Anne B. Toral, MD, MSCE, FPOGS
Department of Obstetrics and Gynecology, Philippine General Hospital, University of the Philippines-Manila

ABSTRACT

Background: Epithelial ovarian carcinoma is the most lethal of the gynecologic malignancies. Recent theories on the etiopathogenesis
of epithelial ovarian carcinoma supported the presence of occult, early stage neoplasms in the fimbriated end of the fallopian tube
even before development of ovarian carcinoma. This study is interested in correlating opportunistic salpingectomy or tubal ligation
as a possible effective prevention strategy in the occurrence of epithelial ovarian carcinoma.

Objective: To determine the association between the occurrence of epithelial ovarian carcinoma and a previous history of tubal
ligation and/ or salpingectomy

Methods: This is a case-control study involving chart review of patients who underwent total hysterectomy with bilateral
salpingoophorectomy with a histologically verified epithelial ovarian cancer (cases) and patients who underwent same surgical
procedure for benign gynecologic conditions specifically myoma uteri and adenomyosis with normal ovaries on final histology
report (controls). The association between the occurrence of epithelial ovarian carcinoma and previous tubal ligation and/or
salpingectomy was determined using appropriate statistical methods.

Results: A total of 558 patients were included in this review. They were divided into 158 post-surgical patients with histologically
verified epithelial ovarian cancer (cases) and 400 post-surgical patients for benign gynecologic conditions with normal ovaries on
final histology report (controls). Adjusted for age, parity and obesity the odds of developing epithelial ovarian carcinoma in subjects
without previous tubal ligation and/or salpingectomy is 29%.

Conclusion: The result of the study showed that tubal ligation and/or salpingectomy reduces the risk of developing epithelial
ovarian carcinoma hence for patients at average risk of ovarian cancer, risk-reducing salpingectomy should be discussed and at
the time of abdominal or pelvic surgery. It must also be included in the counseling of women planning a hysterectomy for benign
indications to conserve ovarian function and prevent ovarian epithelial carcinoma.

Keywords: epithelial ovarian carcinoma, tubal ligation, prevention

INTRODUCTION and immunohistochemical studies categorizes epithelial

E
pithelial ovarian carcinoma is the most lethal of the
gynecologic malignancies. The American Cancer
Society estimates that 21,980 women will be
diagnosed with ovarian cancer in the United States, and
14,270 will die of the disease in 2015.1 At present, there
has been no effective screening test, and treatment of
advanced stage ovarian carcinoma has yielded marginal
survival rates. Therefore, the development of prevention
strategies may prove to be the only modality that will give
favorable impact on this dreadful disease.
Recent theories on the etiopathogenesis of epithelial
ovarian carcinoma supported by molecular, morphological
*2nd Place, 2017 Philippine Obstetrical and Gynecological Society
(POGS) Research Paper Contest, April 6, 2017, Citystate Asturias Hotel,
Puerto Princesa City, Palawan
ovarian carcinoma into Type I and Type II based on a dualistic
model of carcinogenesis. Type I ovarian malignancies
progress in a step-wise fashion beginning as a low grade
lesion and later on developing into a malignancy. They are
usually indolent, genetically stable and harbors specific
mutation including KRAS, BRAF, ERBB2, CTNNB1, PTEN,
PIK3CA, ARID1A, and PPP2R1A. Type I tumors comprise
low-grade serous, low-grade endometrioid, clear cell and
mucinous carcinomas, and Brenner tumors. Type II ovarian
malignancies on the other hand is characterized to have
high genetic instability, aggressive, present in an advanced
stage and have a high frequency of TP53 mutations.
Type II tumors comprise high-grade serous, high-grade
endometrioid, malignant mixed mesodermal tumors
(carcinosarcomas), and undifferentiated carcinomas. In
women with BRCA1 and BRCA2 mutations, for which
adnexal surgery was done, histopathologic results

12 Volume 41, Number 1, PJOG January-February 2017

showed the presence of occult, early stage neoplasms
in the fimbriated end of the fallopian tube even before
development of ovarian carcinoma. These so called serous
tubal intraepithelial carcinomas (STIC) are early tubal
lesions mostly found in the fimbriated end of the fallopian
tube specifically in the secretory type cells. Shedding of this
precursor lesions on the ovarian surface therefore suggest
the pathogenesis of ovarian carcinoma. Serous tubal
intraepithelial carcinoma (STIC) lesions in the fallopian
tubes have not only been found in women with known
BRCA mutations but they also in 50% to 60% of sporadic
serous ovarian cancers. Furthermore, these serous tubal
intraepithelial carcinomas are known to harbor the same
TP53 mutations found in concomitant ovarian carcinomas
implicating a clonal relationship.2
In light with the current findings on the origin of
ovarian carcinoma, opportunistic salpingectomy or tubal
ligation may therefore be an effective prevention strategy.
Several studies have shown that tubal ligation and
salpingectomy reduces the risk of developing epithelial
ovarian carcinoma. In a study by Madsen et al in 2015,
a nationwide registry-based case control study which
involved 13,241 Danish women diagnosed with epithelial
ovarian cancer and 3,605 women with borderline ovarian
tumor from 1982-2011, results have shown that tubal
ligation reduced overall epithelial ovarian cancer risk
(odds ratios 0.87; 95% confidence interval 0.78-0.98)
with significant variation according to histology with the
strongest risk reduction associated with endometrioid
cancer (odds ratios 0.66; 95% confidence interval 0.47-
0.93).3 In a population-based cohort study by Falconer
et al in 2015, which involved 251,465 Swedish women
with previous surgery for benign gynecologic condition
comparing it to the 5,449,199 unexposed women from
1973 to 2009, results showed that there was a statistically
significant lower risk for ovarian cancer among women
with previous salpingectomy (HR=0.65, 95% CI=0.52)
when compared to the unexposed population. In the
same study, bilateral salpingectomy was associated with
a 50% decrease in risk of ovarian cancer compared with
the unilateral procedure (HR= 0.35, 95% CI= 0.17 to 0.73).4
Two meta-analysis have also shown that tubal ligation
reduces the risk of epithelial ovarian carcinoma. In 2012,
a meta-analysis done by Rice et al. on 30 studies on tubal
ligation and 24 studies on hysterectomy from 1969 to
2011 was done. The analysis found out that tubal ligation
decrease the risk of ovarian carcinoma with a relative risk
of 0.70 (95% CI: 0.64, 0.75). In secondary analysis of the
study, the association between tubal ligation and ovarian
cancer risk was stronger for endometrioid tumors (RR=
0.45, 95% CI: 0.33, 0.61) compared to serous tumors. This
study also concluded that observational epidemiologic
evidence supports that tubal ligation and hysterectomy
are associated with a decrease in the risk of ovarian cancer
by approximately 26-30%.5 In a 2011 meta-analysis, Cibula
et al concluded that previous tubal ligation in women at
average risk for ovarian cancer was associated with a 34%
overall risk reduction; however, no significant risk reduction
was found for women with mucinous or borderline tumors
who had undergone previous tubal ligation.6
 
OBJECTIVES
The purpose of this study is to determine the
association between the occurrence of epithelial ovarian
carcinoma and a previous history of tubal ligation and/ or
salpingectomy
SPECIFIC OBJECTIVES:
1. To determine the sociodemographic profile of
both cases and controls.
2. To determine the odds ratio in developing
epithelial ovarian carcinoma with history of tubal
ligation and/ or salpingectomy.
3. To analyze the association of previous history
of tubal ligation and/ or salpingectomy in the
occurrence of epithelial ovarian carcinoma.
4. To determine which histologic subtype of epithelial
ovarian cancer is associated with highest risk
reduction rate for patients with a history of tubal
ligation and salpingectomy.
5. To determine the interval time and age of patient
from bilateral tubal ligation or salpingectomy to
diagnosis of ovarian cancer.
METHODS
This is a case-control study conducted from
September to October 2016. The study involved chart
review of patients who underwent total hysterectomy
with bilateral salpingoophorectomy with a histologically
verified epithelial ovarian cancer (cases) and patients who
underwent same surgical procedure for benign gynecologic
conditions specifically myoma uteri and adenomyosis with
normal ovaries on final histology report (controls).
Medical records of the eligible cases and controls
from January 2012 to December 2015 were retrieved
and reviewed. The principal investigator retrieved
patient information and data checklist documenting
demographics (age, height and weight), risk factors
(gravidity, parity, obesity, pelvic endometriosis, and
polycystic ovarian syndrome) and history of tubal ligation
and salpingectomy and the year and age of the patient
when it was performed. A master list was utilized as a
guide during data collection with the subjects included
in the study being assigned to their corresponding study
Volume 41, Number 1, PJOG January-February 2017 13
number. The indication and complete surgical procedure
were also documented. The complete histologic diagnosis
was obtained including the specific histologic subtype of
epithelial ovarian cancer. The association between the
occurrence of epithelial ovarian carcinoma and a previous
tubal ligation and/ or salpingectomy was determined using
appropriate statistical methods.
 
STATISTICAL ANALYSIS
After the data has been extracted by the investigator
from the patient charts, all the information were manually
entered into an electronic spreadsheet file and subsequent
data processing and analysis was carried out using the
software Stata 13.0.
Descriptive statistics such as mean and standard
deviation for continuous variables such as age, BMI,
gravidity and parity; or frequency and percentage were
used for the categorical data variables such as disease
status, presence of PCOS, and obesity to provide an
overview of the study population. A Chi-square test of
association or independent t-test, whichever is applicable,
was done to determine if there is a significant difference
in the baseline clinico-demographic variables between the
study groups. Proportion per categories of the qualitative
variable such as presence of PCOS, obesity, etc. was also
described. Point and interval estimates of the proportion
for those who underwent tubal ligation or salpingectomy
were also determined. In order to determine procedure-
specific proportions, those participants who previously
had the procedures were further divided among those
who underwent tubal ligation and salpingectomy.
The exposure odds was computed to determine
the association of the performance of said procedures
among cases and controls; and subsequently determine
the odds ratio for the exposure and outcome of interest.
Logistic regression was done mainly with the adjustment
for probable confounders to be conducted using select
clinical variables based on literature through the backward
elimination process. An arbitrary cut-off change in
p-value of less than 0.25 was used to screen for probable
confounders, and significant confounders were identified
based on the change in estimation criterion where in the
cut-off value is 10%. If the change in estimate is greater
than 10%, it will be included in the final model, otherwise
it will be removed.
The level of significance for all sets of analysis was
set at p<0.05 using two-tailed comparisons. Significance
levels were adjusted for multiple comparisons performed,
if applicable.
RESULTS
Data collection of this study identified a total of
14 Volume 41, Number 1, PJOG January-February 2017
158 eligible cases with epithelial ovarian cancer and 400
eligible controls. Table 1 shows the characteristics of both
cases and controls. For both cases and controls majority of
women at the time of diagnosis of the disease were ages 41
to 50 years old, 58 (36.71%) and 286 (71.5%) respectively.
Socio demographic profile also shows that majority of
both cases and controls are women who have had two
or more pregnancies. At the same time, it can be noted
that there were more nulliparous women among the cases
than otherwise. Among controls, 63 out of 400 (67.02%)
were identified to have pelvic endometriosis while 58
out of 400 (57.79%) have history of polycystic ovarian
syndrome and most surgeries were done for myoma uteri,
347 (98.58%). Among cases, the epithelial subtype most
commonly identified was serous carcinoma, 51 (32.28%)
followed by mucinous type, 43 (27.22%), endometrioid,
40 (25.32%) and clear cell, 24 (15.19%). Of the eligible
cases, 16 out of 158 (10.13%) with history of tubal ligation
while 41 out of 400 (10.25%) controls with prior tubal
ligation. Table 2 shows the association of tubal of ligation
and subtype of epithelial ovarian carcinoma and the time
and age since the procedure was done, it can be seen that
for patients with mucinous, serous, endometrioid and
clear cell epithelial ovarian carcinoma, 10 out of the 43, 4
out of the 51, 1 out of 40 and 1 out of 24 had a history of
tubal ligation respectively. The table also shows that most
tubal ligation was performed when the patient’s age was
less than 35 and that the time elapsed since tubal ligation
until the development of the disease was 10 to 19 years.
Table 3 shows the regression analysis of epithelial ovarian
carcinoma and history of tubal ligation and salpingectomy,
adjusted for age, parity and obesity it is shown that the
odds of developing epithelial ovarian carcinoma increases
by 29% in the absence of previous tubal ligation and/or
salpingectomy.
DISCUSSION
Epithelial ovarian carcinoma is the most lethal of
the gynecologic malignancies.7 Despite holistic scientific
innovations in surgical technique and chemotherapy,
including targeted therapy and antiangiogenic agents, the
overall survival rate has not improved over recent decades.
To reduce the impact of ovarian cancer on women’s
health, there is a need to detect it in an early stage and also
prevent it from occurring. Options to detect it early include
periodic clinical examination, transvaginal sonography
and estimation of serum CA-125 level, but these have not
been found to be uniformly effective.7 Ovarian cancer has
been called a ‘silent abdominal tumor’ because symptoms
such as abdominal distension, nausea and early satiety
due to the presence of ascites, and peritoneal/omental
metastases occur late in the course of the disease.
Table 1. Characteristics of both cases and controls

Cases Controls p-value

Characteristics
(n=158) (n=400)

Age in years
21 to 30 6 (3.80%) 2 (0.50%)
31 to 40 22 (13.92%) 12 (3%)
41 to 50 58 (36.71%) 286 (71.50%) 0.00**
51 to 60 55 (34.81%) 94 (23.50%)
61 to 70 14 (8.86%) 6 (1.50%)
71 to 80 3 (1.90%) -

Parity
None 42 (26.58%) 76 (19.10%)
Uniparous 18 (11.39%) 48 (12.06%) 0.05*
Two and above 98 (62.03%) 274 (68.84%)
Obese 27 (17.09%) 139 (34.75%) 0.00**
Tubal Ligation 16 (10.13%) 41 (10.25%) 0.97
Endometriosis - 63 (67.02%)
Polycystic ovarian syndrome - 58 (59.79%)
Myoma uteri - 347 (98.58%)
Adenomyosis - 115 (78.23%)

Histologic Subtype
Clear cell 24 (15.19%) -
Endometrioid 40 (25.32%) -
Mucinous 43 (27.22%) -
Serous 51 (32.28%) -

Table 2. The association between tubal ligation and the risk of epithelial ovarian cancer and histologic subtype by the time since
tubal ligation and age at tubal ligation

Characteristics Endometrioid Endometrioid Mucinous Serous p-value

No tubal ligation 23 (95.83%) 39 (97.50%) 33 (76.74%) 47 (92.16%) 0.01*

Age during procedure
<35 1 (100%) 1 (100%) 7 (70%) 4 (100%) 0.68
≥35 - - 3 (30%) -

Time since tubal ligation

1 to 9 - - - -
10 to 19 - - 8 (80%) 1 (25%) 0.09
20 and above 1 (100%) 1 (100%) 2 (20%) 3 (75%)

Volume 41, Number 1, PJOG January-February 2017 15

Table 3. Regression analysis of epithelial ovarian cancer and history of tubal ligation or salpingectomy

Unadjusted Odds Adjusted Odds

Characteristics
OR (95% CI) p-value OR (95% CI) p-value

No history of the procedure 1 (0.19 to 6.94) 0.99 1.29 (0.25 to 6.78) 0.76
Age in years 1.03 (0.95 to 1.11) 0.48 1.03 (0.95 to 1.12) 0.44
Obesity 2.11 (0.14 to 30.89) 0.46 2.32 (0.27 to 19.79) 0.44

Parity
None 1.00 1.00
Uniparous 0.75 (0.12 to 4.66) 0.76 0.64 (0.10 to 4.15) 0.64
Two and above 0.88 (0.22 to 3.54) 0.85 0.75 (0.17 to 3.26) 0.69

Recent data suggest that some ovarian cancers are CONCLUSION

actually initiated in the fallopian tubes, thus removal of
the fallopian tubes or cutting a segment of it (bilateral The result of this paper showed that tubal ligation
salpingectomy and tubal ligation) may be a risk-reducing and/or salpingectomy reduces the risk of developing
strategy in both high-risk and average-risk women. Pre- epithelial ovarian carcinoma hence for patients at average
invasive lesions in the distal fallopian tubes [serous tubal risk of ovarian cancer, risk-reducing salpingectomy/
intraepithelial neoplasia (STIN)] have been identified in 1 tubal ligation should be discussed and at the time of
to 6% of high-risk women undergoing risk reducing BSO8. abdominal or pelvic surgery. It must also be included in the
Serous tubal intraepithelial carcinoma (STIC), and invasive counseling of women planning a hysterectomy for benign
serous carcinomas are also identified in the distal fimbrial indications to conserve ovarian function and prevent
end of the fallopian tubes in women with non-familial or ovarian epithelial carcinoma. Additional studies preferably
sporadic ‘ovarian’ cancer. These lesions originating in the prospective follow up and a larger sample size must be
tubal fimbria may spread to the peritoneum and result employed in the future to find out the role of risk-reducing
in apparent primary peritoneal carcinoma without an salpingectomy as a current primary prevention strategy
ovarian lesion. Thus, serous ovarian, fallopian tubal and for women against ovarian cancer.
peritoneal carcinomas are regarded as a single entity
and designated as ‘pelvic serous carcinoma’. Based upon
these findings, it is proposed that tubal neoplasia is the
primary lesion in high-grade serous pelvic carcinomas
and that these lesions subsequently spread to the ovary
and peritoneum. Results of this study showed that the
odds of developing epithelial ovarian carcinoma increases
by 29% in subjects without previous tubal ligation and/
or salpingectomy. This extrapolation is consistent with
several published literatures as cited in this paper on the
role of tubal ligation and salpingectomy in reducing the
risk of developing epithelial ovarian carcinoma. Although
this study is limited because of its small sample size and
retrospective method, a larger sample size and prospective
data collection of at least 10 years may be employed in
future studies to determine long term impact of risk-
reducing salpingectomy as a current primary prevention
strategy for women against ovarian cancer.

16 Volume 41, Number 1, PJOG January-February 2017

REFERENCES
1. Walker JL, Powell CB, Chen LM, Carter J, Bae Jump VL, Parker
LP, Borowsky ME, Gibb RK. Society of Gynecologic Oncology
recommendations for the prevention of ovarian cancer. Cancer.
2015. July 1; 121(13):2108-20.
2. Kurman RJ, Shih IM. Molecular pathogenesis and extraovarian
origin of epithelial ovarian cancer – shifting the paradigm. Human
Pathology. 2011. Jul 31; 42(7):918-31.
3. Madsen C, Baandrup L, Dehlendorff C, Kjær SK. Tubal ligation
and salpingectomy and the risk of epithelial ovarian cancer and
borderline ovarian tumors: a nationwide case – control study. Acta
Obstetricia et Gynecologica Scandinavica. 2015. Jan 1; 94(1):86-94.
4. Falconer H, Yin L, Grönberg H, Altman D. Ovarian cancer risk after
salpingectomy: a nationwide population-based study. Journal of
the National Cancer Institute. 2015. Feb 1; 107(2):dju410.
5. Rice MS, Murphy MA, Tworoger SS. Tubal ligation, hysterectomy
and ovarian cancer: a meta-analysis. Journal of Ovarian Research.
2012. May 15; 5(1):1.
6. Cibula D, Widschwendter M, Májek O, Dusek L. Tubal ligation
and the risk of ovarian cancer: review and meta-analysis. Human
Reproduction Update. 2011. Jan 1; 17(1):55-67.
7. Woodward ER, Sleightholme HV, Considine AM, Williamson
S, McHugo JM, Cruger DG. Annual surveillance by CA125 and
transvaginal ultrasound for ovarian cancer in both high-risk and
population risk women is ineffective. BJOG: An International
Journal of Obstetrics & Gynaecology. 2007. Dec 1; 114(12):1500-9.
8. Bagga R. Remove the Fallopian Tubes and save the Ovaries: The
Emergence of Opportunistic Salpingectomy to reduce Ovarian
Cancer Risk.
Volume 41, Number 1, PJOG January-February 2017 17
 A retrospective study on the accuracy of sassone, lerner and
IOTA simple rules in determining malignancy of ovarian masses
in a tertiary hospital ob-gyn ultrasound diagnostics unit*
By Arriane R. Morales, MD and Filomena S. San Juan, MD, FPOGS
Department of Obstetrics and Gynecology, Manila Doctors Hospital

ABSTRACT

Background: Ultrasonography has been established as one of the important diagnostic tools in detecting and classifying ovarian
masses. Several studies have been made in determining the sensitivity and specificity of the different scoring systems as to
determining the malignancy of ovarian masses. In a tertiary hospital ultrasound diagnostic unit, three scoring systems are utilized
namely Lerner, Sassone and IOTA simple rules.

Objective: To determine and compare the sensitivity and specificity on the most utilized ultrasound scoring systems in determining
malignancy of ovarian masses.

Methods: A single center observational, analytical, cross-sectional study utilizing review of the transvaginal or pelvic ultrasound
results of women with ovarian masses that were scored using Sassone, Lerner and IOTA Simple Rules in a tertiary hospital ultrasound
diagnostics unit from January 2013 to June 2016 was done. The sensitivity, specificity, positive and negative predictive values of
each scoring system utilized was determined and compared with the histopathologic result.

Results: Out of the 111 ovarian masses that were included in the study, 44 ovarian masses were scored using Lerner Scoring system
with a sensitivity, specificity, positive and negative predictive values of 100%, 65% 22.2% and 100%. 105 ovarian masses screened
using Sassone Scoring System showed a sensitivity, specificity, positive and negative predictive values of 100%, 68%, 20.5% and
100%. A total of 33 out of the 111 ovarian masses were scored using the IOTA scoring system with a sensitivity, specificity, positive
and negative predictive values of 100%, 85.6%, 55.5% and 100%.

Conclusion: IOTA simple rules had a high sensitivity and specificity compared to Sassone or Lerner Scoring System. However, we
cannot fully conclude that individual specificity will be better than combined tests since there is limited number of ovarian masses
analyzed.

Keywords: malignancy, ovary, ultrasonography, sensitivity, specificity

INTRODUCTION Society of Ultrasound in Obstetrics and Gynecology

U
ltrasonography has been established as one of
the important diagnostic tools in detecting and
classifying ovarian masses. It is widely used because
of its non-invasiveness and cost-effectiveness in producing
quality imaging that can aid clinicians in diagnosing masses.
Several scoring systems have been developed through
the years in helping sonologists in determining whether
a mass is benign or malignant. The scoring systems have
utilized morphological characteristics of the masses and
color flow in some cases. In the latest International Society
of Ultrasound in Obstetrics and Gynecology (ISUOG), they
have recommended the use of IOTA Scoring system in
classifying adnexal masses. While the latest Philippine
*Finalist, 2017 Philippine Obstetrical and Gynecological Society (POGS)
Research Paper Contest, April 6, 2017, Citystate Asturias Hotel, Puerto
Princesa City, Palawan
(PSUOG) guideline recommends assessment of tumors be
initially done by pattern recognition using the ten simple
rules in determining benign or malignant tumors. Further
assessment of the tumors can be employed using IOTA
which now includes color flow assessment. However, in
the absence of color flow capability, Sassone scoring may
be used instead. Despite ultrasound being a necessary
diagnostic modality, the gold standard in identifying
malignancy among ovarian masses still is histopathology.
Several studies have been made in determining the
sensitivity and specificity of the different scoring systems
as to determining the malignancy of ovarian masses.
However locally, several sonologists may still use different
scoring systems based on their comfort and availability of
color flow in their respective institutions. With this reason,
it is important to determine and compare the sensitivity
and specificity on the most utilized ultrasound scoring
systems in determining malignancy of ovarian masses.
Volume 41, Number 2, PJOG March-April 2017 5
Review of Related Literature:
Precise diagnosis of ovarian masses is important
in clinical decision making in the practice of gynecology.
Currently, ultrasonography is the widely utilized diagnostic
modality in identifying adnexal masses because of its
relative simplicity and non-invasiveness. According to
the Royal College of Obstetricians and Gynaecologists
Green-top Guidelines, a pelvic ultrasound is the single
most effective way of evaluating an ovarian mass with
transvaginal sonography being preferable due to its
increased sensitivity over a transabdominal ultrasound.1
Some studies show that an ultrasound can accurately
characterize about 90% of adnexal masses and the
reported sensitivity and specificity of ultrasound for
detecting ovarian malignancies is 88%-96% and 90%-96%,
respectively.2
In the past, several morphological scoring systems
have been utilized in determining benign and malignant
adnexal masses. These scoring systems classify ovarian
masses based on several characteristics, namely, wall
thickness, inner wall structures, echogenicity and presence
or absence of solid areas. In a study done by Sassone
et al in 1991, it provided promising results when their
study yielded a specificity of 83% and sensitivity of 100%,
positive and negative predictive values of 37 and 100%
respectively. Moreover, since they were able to rigidly and
explicitly define each characteristic of the adnexal mass,
their approach was more sensitive compared to other
morphologic scoring system.3 Sassone scoring system
describes adnexal masses based on inner wall structure,
wall thickness, septum thickness, and echogenicity.
The maximum score for an adnexal mass is 15 while the
minimum score is 4. A score of greater than or equal to 9 is
considered malignant. This scoring system may be useful
particularly in countries with low resources since it relies
on 2D scans and it doesn’t need the use of color flow.
In a prospective study done by Shende V. et al (2016) in
India, where they utilized the Sassone scoring system in 56
patients with adnexal masses in determining benign from
malignant adnexal masses, they concluded that there is a
highly significant association between the Sassone score
and type of adnexal masses (P value is <0.000001).4
Over time, several other morphological scoring
systems have been developed. However, these scoring
systems were found to be subjective since some of them
failed to show a systematic description of the lesions and
would require extra effort to properly classify each lesion
into the scoring system.5
In the advent of new technology, doppler flow has
been used to further classify ovarian masses as benign
or malignant. In a study done by Tantipalakorn C. et al
(2014) where the International Ovarian Tumor Analysis
(IOTA) group, proposed simple ultrasound-based rules in
6 Volume 41, Number 2, PJOG March-April 2017
predicting ovarian malignancy. The rules were based on
the simple demonstration of certain sonographic findings,
some of which are indicative of malignancy (M-features)
and others of benignity (B-features).6 In addition to the
morphological characteristics, they also accounted for the
blood flow within the adnexal masses, utilizing color flow
parameters. The IOTA Group has published the largest study
to date looking into the use of ultrasound in distinguishing
benign and malignant ovarian masses. Utilizing the data
derived from the IOTA Group, simple ultrasound rules were
developed to help classify the masses as benign (B-rules)
or malignant (M-rules). The B-rules included the following
characteristics such as unilocular cysts, presence of solid
components where the largest component measures < 7
mm, presence of acoustic shadowing, smooth multilocular
tumor with a largest diameter of < 100 mm, and no blood
flow. The M-rules on the other hand included irregular
solid tumor, presence of ascites, presence of at least four
papillary structures, Presence of irregular multilocular
soild tumor with largest diameter > 100 mm and a very
strong blood flow. Using this rules, the reported sensitivity
was 95%, specificity 91%, positive likelihood ratio of 10.37
and a negative likelihood ratio of 0.06.7
In a study done by Valentin in 2000, it determined
the sensitivity and false positive rate of Lerner’s score
and Doppler variable utilizing time average maximum
velocity. The study tested prospectively earlier defined
cut-off values for Lerner’s score and Doppler variables
and verified whether the combination of Doppler variable
and Lerner’s score had better sensitivity and specificity in
determining malignancy than the use of each alone. The
study compared the ultrasound examinations with those
of the histologic examinations of the specimens. The study
defined the best diagnostic method as the one who can
detect the most malignancy with the lowest false positive
rate. The study concluded that a combination of Lerner’s
score and measurement of time averaged velocity were
best diagnostic tests with a sensitivity of 92% and a false
positive rate of 19%.8 A study done by Lerner et al in 1994
tried to simplify the determination of ovarian malignancy
by Sassone. The group removed the determination of
wall thickness and replaced it with shadowing in order
to differentiate the features of Dermoid cyst from
ovarian malignancy. The cut off value for Lerner was 3 in
determining malignancy with a specificity of 77% and a
sensitivity of 96.8%.9
The Philippine Society of Ultrasound in Obstetrics
and Gynecology (PSUOG) recommends that assessment of
ovarian tumors be initially done using the ten simple rules
for identifying a benign from a malignant tumor. Further
assessment should then be done by IOTA scoring which
includes color flow assessment. In the absence of color
flow capability, Sassone Scoring may be used instead.10
 In the advent of technology, ovarian masses can be
diagnosed earlier. At present, there are a lot of morphological
scoring systems that are utilized in determining the malignant
potential of ovarian masses. Several studies made on these
different scoring systems have established different sets of
sensitivity and specificity in diagnosing ovarian masses as
benign or malignant. Moreover, some ovarian masses may
be classified as borderline malignant histopathologically
while exhibiting benign features on ultrasound. Some
borderline characteristics include unilocular cysts with
cresent sign and extensive papillations or a cyst with a
well-defined multilocular nodule.11 Locally, in a tertiary
hospital setting, three scoring systems are being utilized in
determining malignant potential of ovarian masses, namely
Sassone, Lerner and IOTA simple rules. These three scoring
systems have different sensitivities and specificities as
seen in the different studies worldwide. The study will be
helpful in determining the accuracy of each scoring system
utilized by OB-GYN sonologists in a local tertiary ultrasound
diagnostics unit in terms of sensitivity, specificity and
predictive values. The determination and comparison of the
sensitivity and specificity of the three scoring systems done
in the local setting will help in determining the best scoring
system to be utilized in the tertiary hospital ultrasound unit.
Further recommendation can be given as to which among
the three scoring systems can be utilized better or if the
specificity or sensitivity will be increased if they are utilized
together. Moreover, this study helped identify the possible
ultrasound features of benign ovarian masses which turn
out to be borderline masses on histopathology. This can
help clinicians in accurately diagnosing borderline ovarian
tumors pre-operatively.
OBJECTIVES
General Objective: To find out the accuracy of 3
scoring systems namely Sassone, Lerner and IOTA Simple
Rules in determining malignancy of ovarian masses.
General Objective: To find out the accuracy of 3 scoring
systems namely Sassone, Lerner and IOTA Simple Rules in
determining malignancy of ovarian masses.
SPECIFIC OBJECTIVES:
1. To determine the sensitivity, specificity, positive
predictive value, negative predictive value of
Sassone Scoring System, Lerner Scoring System
and IOTA Simple Rules in detecting malignancy in
patients with ovarian mass using histopathology
as gold standard.
2. To determine whether use of 2 or more scoring
systems will have greater sensitivity, specificity,
positive and negative predictive values compared
to use of a single scoring system.
Materials
Study Design:
This is was a single center observational, cross-
sectional study utilizing review of the transvaginal or
pelvic ultrasound results of women with ovarian masses
that were scored using Sassone, Lerner and IOTA Simple
Rules by OB-GYN Sonologists who are fellows of Philippine
Society of Ultrasound in Obstetrics and Gynecology in a
tertiary hospital ultrasound diagnostics unit from January
2013 to June 2016. The sensitivity, specificity, positive and
negative predictive values of each scoring system utilized
for the ovarian masses in determining malignancy will be
computed. The ultrasound findings of the ovarian masses
will be compared to the final histopathological results.
Inclusion Criteria:
All transvaginal or pelvic ultrasound results of
unilateral or bilateral ovarian masses that were scored
using Sassone Score, Lerner Score and IOTA Simple Rules
from January 2013 to June 2016 in a tertiary hospital
ultrasound diagnostic unit and had undergone exploratory
laparotomy or laparoscopic surgery with or without frozen
section which have been done within 2 months of the
performance of the scan. The final histopathology should
show the result of one or both ovaries scored by the said
scoring system.
Exclusion Criteria:
Ovarian masses that were scanned in the tertiary
hospital OB-GYN ultrasound diagnostic unit but were not
classified as benign or malignant using any of the following
scoring systems, Sassone, Lerner or IOTA Simple Rules.
Masses that were not operated on or was operated after
2 months from the time of scan. Masses that do not have
any histopathologic report will be excluded.
METHODOLOGY
This was a single center observational, analytical,
cross-sectional study utilizing review of the transvaginal or
pelvic ultrasound results of women with ovarian masses
that were scored using Sassone, Lerner and IOTA Simple
Rules by OB-GYN Sonologists who are fellows of Philippine
Society of Ultrasound in Obstetrics and Gynecology in
a tertiary hospital ultrasound diagnostics. Review of
transvaginal and pelvic gynecologic ultrasound reports
with ovarian masses done at a tertiary hospital OB-GYN
ultrasound unit using Voluson E6 machine from January
2013 to June 2016 was done. The reports with ovarian
masses that were classified as benign or malignant using
Lerner, Sassone and IOTA Simple rules were tabulated
and the sensitivity, specificity, positive and negative
Volume 41, Number 2, PJOG March-April 2017 7
predictive values of Sassone, Lerner and IOTA Simple rules Table 1. Demographics
will computed. The results were compared to the final
histopath result to determine malignancy. Demographics Mean + SD or n (%)

Sample Size: Mean Age in Years 41.18 (+ 11)

The study utilized the Epi Info Version 7, in determining Gravidity 52 (46%)
the minimum sample size requirement and was estimated 0
to be at least 101 based on sensitivity of IOTA in detecting 1-2 31 (27.93%)
malignancy in patients with ovarian mass = 82 % 6, with 3-4 20 (18.02%)
95% confidence interval and 7.5% margin of error.
>5 8 (7.20%)
Statistical Analysis: Parity 58( 52.25%)
Data was analyzed using Stata SE Version 12. 0
Quantitative variables were summarized as mean average 1-2 27 (24.32%)
and standard deviation, while qualitative variables were 3-4 18 (16.21%)
tabulated as frequency and percentage. Sensitivity, >5 8(7.20 %)
specificity, positive predictive value and negative predictive
Symptoms
value of Sassone, Lerner and IOTA scoring system in
detecting malignancy in patients with ovarian masses with Abdominal mass 44 (39.64%)
histopathology result as gold standard. Abdominal pain 22 (20%)
Increase in abdominal girth 4 (3.77%)
RESULTS Irregular menses 14 (12.61%)
Vaginal Bleeding 4 (3.64%)
A total of 111 ovarian masses were scanned in the
Ultrasound Diagnostics Unit from June 2013 until June 2016 Urinary Symptoms 0
that were scored using Lerner, Sassone and IOTA Simple Pelvic Heaviness 0
Rules with histopathologic reports from surgeries done
within 2 months of the scan. The total mean (+ SD) age of
the women with ovarian masses is 41 + 11.4 years (range scoring system and are shown in Table 3.
13-77 years). Among the gravidity and parity, majority of Out of the 111 ovarian masses that were included
the subjects were nulligravid and nulliparous. Among the in the study, 44 ovarian masses were scored using Lerner
symptoms reported, 39 % of subjects noted a palpable Scoring system. The test was able to score correctly all
abdominal mass, 22% complained of dysmenorrhea, ovarian cysts that were malignant on histopath. However,
20% complained of abdominal pain, 13 % complained of out of the 40 ovarian cysts that were benign, there
irregular menses, 4% noted increase in abdominal girth, were 14 ovarian cysts that were false positive. These 14
4 % complained of vaginal bleeding, 2% complained of ovarian masses were interpreted as malignant using the
pelvic heaviness as seen in Table 1. Lerner scoring system although they were benign on final
The final histopathology results of the 111 ovarian histopath. Among the 14 ovarian cysts, majority were
masses screened using the three different scoring systems mature cystic teratomas and endometriotic cysts.
showed 10 (9%) malignant findings and 101 (90%) benign Almost all ovarian masses were scored using Sassone
findings (Table 2). There were no borderline malignant scoring system. Out of the 105 ovarian masses screened,
findings seen. The majority of the benign masses were the test was able to identify correctly all malignant ovarian
endometriomas (44.14%) and mature cystic teratomas masses. Among the 97 ovarian masses that were benign,
(21.62%). There were also 15 (13.5%) mucinous one third were identified as malignant and were false
cystadenomas and 10 (9%) serous cystadenomas as positive hence giving a specificity of only 68%.
shown in Table 2. A total of 33 out of the 111 ovarian masses were scored
Lerner, Sassone and IOTA Simple Rules were utilized using the IOTA scoring system. All 5 malignant ovarian
in determining the malignancy of the 111 ovarian masses cysts were correctly identified hence the high sensitivity
and was compared to the histopathologic result. In of the scoring system. Out of the 28 ovarian masses that
addition, those ovarian masses screened using combined were benign on final histopath, 4 were classified by IOTA
scoring system were also identified and compared to the simple rules as malignant hence the specificity of 85.6%.
final histopath result. The sensitivity, specificity, positive A combination of the scoring systems were utilized in
and negative predictive values were computed for each order to determine the malignancy of the ovarian masses.

8 Volume 41, Number 2, PJOG March-April 2017

Table 2. Histological Diagnosis mostly dermoid and endometriotic cysts.
Among the 7 ovarian masses scored using combined
Histological Diagnosis N= 111 n(%) Lerner and IOTA simple rules, there was 1 malignant ovarian
cyst on histopath and this was correctly identified by both
Benign Lesions scoring systems. Half of the ovarian masses interpreted as
Endometrioma 49 (44.14%) benign on histopath were scored as malignant using both
Mature Cystic Teratoma 24 (21.62%) Lerner and IOTA hence decreasing the specificity of the
combined test to 50%.
Mucinous Cystadenoma 15 (13.51%)
There were 27 ovarian masses screened using
Serous Cystadenoma 10 (9%) both Sassone Score and IOTA simple rules. All malignant
Struma Ovarii 1 (0.9%) ovarian masses were correctly interpreted by both scoring
Fibroma 1 (0.9%) systems. Out of the 23 benign masses, there were 4
masses that were read as malignant. The specificity of
the combined Sassone and IOTA was higher than utilizing
Malignant Lesions
Sassone alone but slightly lower than using IOTA simple
Papillary Serous (0.9%) rules alone. The 4 masses showed histopathologic finding
Cystadenocarcinoma of mature cystic teratoma.
Ovarian New Growth Malignant 1 (0.9%) IOTA Simple Rules, Lerner and Sassone Scoring was
used in 7 ovarian masses. The combination of the three
High grade Serous Papillary 2 (1.8%)
showed a high sensitivity since there was only 1 malignant
Carcinoma ovarian mass and it was detected by all three scoring
Adenocarcinoma 1 (0.9%) systems. However, half of the benign masses were scored
Clear Cell Adenocarcinoma 1 (0.9%) as malignant hence decreasing the specificity to 50%.
Endometriod Adenocarcinoma 1 (0.9%) The specificity of all three combined is lower than the
specificity of the individual tests alone.
Granulosa Cell Tumor 1 (0.9%)
Comparing the specificity of combined tests, the
Signet Ring Adenocarcinoma 1 (0.9%) combination of IOTA and Sassone had higher specificity
than the combination of IOTA Simple rules and Lerner as
The outcomes showed that there were 44 ovarian masses well as Lerner and Sassone. This can be attributed to the
that were scored using both Lerner and Sassone. When increase in the number of ovarian masses analyzed with
both tests were utilized, the specificity of the test was at IOTA and Sassone compared with the other combination
65% which was similar to utilizing Lerner score alone but tests with only 7 samples.
slightly lower than using Sassone alone. The sensitivity of
the tests in combination was similar to when used alone. DISCUSSION
Both tests were able to identify all malignant ovarian
masses. Among the 40 benign ovarian masses, 14 out of In this present study, we determined the accuracy
40 were scored by both as malignant. These masses were of detecting ovarian malignancy in the ultrasound

Table 3. Summary of Sensitivity, Specificity, Positive and Negative Predictive Values

Ultrasound Scoring Positive Predictive Negative Predictive

Sensitivity Specificity
N= 111 GZZZ’ Value Value
Lerner (n=44) 100% 65% 22.22% 100%
Sassone (n=105) 100% 68% 20.5% 100%
IOTA Simple Rules (n=33) 100% 85.6% 55.5% 100%
Lerner + Sassone (n=44) 100% 65% 22.2% 100%
Lerner + IOTA (n=7) 100% 50% 25% 100%
Sassone + IOTA Simple Rules 100% 82.61% 50% 100%
(n=27)
Lerner + Sassone + IOTA Simple 100% 50% 25% 100%
(n=7)
Volume 41, Number 2, PJOG March-April 2017 9
department of a tertiary hospital utilizing three scoring
systems namely Lerner, Sassone and IOTA Simple Rules.
Several studies have showed various sensitivity and
specificity of the different tests. The ultrasound machine
utilized in the study was Voluson E10 and E8 which are
both capable in providing clear and resonant ultrasound
images. Both machines are also capable of color flow
as well as Doppler studies. Most of the sonologists in
the tertiary hospital ultrasound diagnostics unit were
all fellows of the PSUOG and have experience years of
scanning from 3 to 25 years.
The study done by Lerner et al in 1994 modified
the previously devised morphologic system by removing
variables which they deemed unnecessary and added
another variable called shadowing. The parameters tested
were wall structure, shadowing, septal thickness and
echogenicity. It established a cut-off of 3 for malignancy.
This study yielded a sensitivity of 96.8% and a specificity
of 77%. It also had a positive and negative predictive
value of 96.8% and 77%. Conversely, our study yielded a
higher sensitivity but slightly lower specificity. The positive
predictive value was slightly lower and the negative
predictive value were also the same. In another study
by Klangsin et al, which studied the comparison of five
sonographic scoring systems in malignant ovarian tumors
among 146 patients, the sensitivity of Lerner score was
82.2 % and specificity of 68.3%.12 Among the 44 ovarian
masses screened by Lerner’s scoring system, there were
14 ovarian masses that were scored to be malignant
but were benign on final histopath result. These masses
were dermoid cysts, endometriotic cyst and mucinous
cystadenoma. The ovarian cysts that were mature cystic
teratomma on histopathology were described as having
mixed echoes with hyperechoic focus, thick wall (1.17
cm) and thick capsule (0.71 cm). Another had a reticular
pattern with medium level echoes, thick capsule (0.37)
and septum (0.83 cm) and an irregularity measuring
0.4x0.4 cm. Another mass was described as a complex
mass predominantly cystic with scanty flow at the inferior
pole and high resistance index. There were 2 ovarian
masses that were endometriotic cysts on histopath but
was scored as 7 using lerner scoring system and was
interpreted as malignant. The masses were described as
mixed echogenicity with thick capsule (0.3 cm) and thick
septum (0.4 cm), with no solid areas but with multiple
echogenic stipplings and posterior shadowing.
The study done by Sassone et al in 1991, provided
promising results when their study yielded a specificity
of 83% and sensitivity of 100%, positive and negative
predictive values of 37 and 100% respectively. Moreover,
since they were able to rigidly and explicitly define each
characteristic of the adnexal mass, their approach was
more sensitive compared to other morphologic scoring
10 Volume 41, Number 2, PJOG March-April 2017
system.3 Sassone scoring system describes adnexal masses
based on inner wall structure, wall thickness, septum
thickness, and echogenicity. The maximum score for an
adnexal mass is 15 while the minimum score is 4. A score
of greater than or equal to 9 is considered malignant. This
scoring system may be useful particularly in countries with
low resources since it relies on 2D scans and it doesn’t
need the use of color flow.
Most of the sonologists in this study utilized the
sassone scoring system compared with that or IOTA and
Lerner. The cut off size of the wall thickness, papillarities
and irregularities was 3 mm. Those greater than 3 mm
received a higher score. The sonolucency on the other
hand was graded according to echogenicity. Those with
higher echoes scored greater compared to the anechoic
masses. Since the cut off for malignancy is 9, there
were several ovarian cysts that were scored malignant
despite showing benign results on histopathology.
Other masses that scored 7 or 8 were interpreted as
borderline malignant. 14 out of 105 ovarian masses
were interpreted as borderline malignant with a sassone
score of 7 or 8. These masses exhibited the following
characteristics, first, the wall thickness were more than
3 millimeters, second they were characterized as having
mixed echogenicity or low echogenicity with echogenic
cores. Third, some masses were solid. The final
histopathologic results of these borderline masses were
endometriotic cyst, mucinous cystadenoma and mature
cystic teratoma which are all benign. Similarly, our study
had higher sensitivity than specificity making sassone a
good screening tool in detecting malignancy in adnexal
masses. In the study of Sassone, although other studies
identified tumor size as a risk factor for malignancy, they
concluded that it’s addition in their scoring system did
not improve the test’s sensitivity since there are large
benign tumors. They also noted the source of their large
false positive test were the benign teratomas since their
characteristics overlapped with that of malignant tumors.
In this study, 24 of the ovarian masses were mature cystic
teratomas.
The International Society of Ultrasound in Obstetrics
and Gynecology (ISUOG), they have recommended the use
of IOTA Scoring system in classifying adnexal masses. While
the latest Philippine Society of Ultrasound in Obstetrics and
Gynecology (PSUOG) guideline recommends assessment
of tumors be initially done by pattern recognition using
the ten simple rules in determining benign or malignant
tumors. Further assessment of the tumors can be
employed using IOTA which now includes color flow
assessment. In this study, the sensitivity and specificity of
IOTA Simple rules was at 100% and 85% respectively. The
sensitivity was higher in IOTA compared to that of Sassone
and Lerner. It also has a higher positive predictive value
compared to the other scoring system. Comparing it to
the study done by Tantipalakorn in 2014, IOTA was found
to have higher specificity in their study as compared to the
sensitivity. Out of the 34 ovarian masses scored using IOTA
Simple Rules, only 4 ovarian masses were interpreted as
having malignant features but with benign final histopath
result. The masses exhibited irregular multilocular solid
tumor and with presence of at least 4 papillarities.
The histopathologic result was mature cystic teratoma.
Current recommendation for classifying ovarian or adnexal
masses utilize pattern recognition the n application of the
IOTA simple rules. Timmerman et al in 2014 established
there set of ultrasound simple rules in order to be more
practical and make the assessment more simplified. Due
to the relative novelty of this scoring system, many of the
sonologist in the study were more comfortable in utilizing
other scoring systems such as Sassone and Lerner scoring
System.
In the study of Jung in 2015, described ultrasound of
ovarian masses using pattern recognition approach. The
study described the classical features of endometrioma are
homogenously low level echoes in the cyst commonly called
as ground glass appearance which signifies hemorrhages
within the cyst. However some atypical findings of
endometriomas include fluid – fluid level, hyperechoic
mural heterogeneity or calcification. In this study there
were several ovarian masses that were endometriomas
on histopath. Mature cystic teratoma, usually shows focal
high echogenic nodules, heterogeneous internal echoes in
the cyst with acoustic shadows, and multiple hyperechoic
fine lines and dots, which are due to reflection by clumps
of hair, sebum, or fat component within the mass. The
hyperechoic area is not usually as intensely echogenic
as calcification and may be confused with the echo of
adjacent bowel gas.
A study done by Tongsson et al in 2008 determined
the validity of pattern recognition in diagnosing ovarian
mature cystic teratomas. They concluded that ultrasound
pattern recognition using transabdominal ultrasound with
color extended-flow mapping can accurately diagnose
mature cystic teratoma with a sensitivity of 94% and
a specificity of 98%. Moreover, they concluded that,
subjective evaluation of an adnexal mass by an experienced
sonographer is a highly accurate method for diagnosis of
cystic teratomas. Also, training should be done to focus
on recognizing the morphologic features of a mass, rather
than on any particular scoring system.13
CONCLUSION
In conclusion, the ultrasound diagnostic unit of the
tertiary hospital can accurately determine benign ovarian
masses utilizing any of the three scoring systems. All
three scoring systems had high sensitivity. However, in
determining malignancy, use of IOTA Simple rules has a
higher specificity (85%) compared to Sassone and Lerner
Scoring. Borderline interpretation of ovarian masses may
vary depending on the scoring system used. Combination
of the scoring system (double and triple) showed
persistently high sensitivity. Moreover, the combination
of Sassone and IOTA simple rules had higher specificity
than combination of Lerner and Sassone or Lerner and
IOTA. When all three scoring systems were combined, it
showed lower specificity compared to the sensitivity of
the individual scoring systems. However, we cannot fully
conclude that individual specificity will be better than
combined tests since there is limited number of ovarian
masses analyzed.
LIMITATIONS OF THE STUDY
This study was limited to a retrospective single
center study. The data gathered was limited to review
of transvaginal and pelvic ultrasound results of ovarian
masses that were scanned from January 2013 to June
2016 in a tertiary hospital OB-GYN ultrasound diagnostic
unit. The final histopathologic results were limited to
those surgeries done within the same tertiary hospital
within 2 months of the date of the ultrasound result. The
histopathologic report should classify the ovarian mass as
benign or malignant. This study was limited to determining
the sensitivity, specificity, positive predictive and negative
predictive values of Sassone, Lerner and IOTA Simple Rules
scoring systems of ovarian masses. This study tackled
some descriptions of the ovarian masses in determining
benign or malignant features.
RECOMMENDATION
Due to the limited number of ovarian masses
analyzed, further study should be done with increased
number of ovarian masses. We recommend that at least
101 ovarian masses be analyzed by Sassone, Lerner and
IOTA simple rules individually so as to come up with a
greater number of sample size. We also recommend to
determine the experience years of the sonologists and
find out how it affects the accuracy of the ultrasound
unit in determining the malignant potential of ovarian
masses utilizing Sassone, Lerner and IOTA Simple rules. A
prospective study can be done in order to ensure that the
sampled ovarian masses will be scored utilizing all three
scoring systems to be able to compare the accuracy of
each test. A detailed examination of the ovarian masses
can also be done to describe the differences in the features
of the most commonly mistaken masses as malignant.
Volume 41, Number 2, PJOG March-April 2017 11
REFERENCES
1. RCOG/BSGE Joint Guideline Management of Suspected Ovarian
Masses in Premenopausal Women. Green-Top Guideline No. 62
(2011) .
2. Jung, S. Ultrasonography of ovarian masses using a pattern
recognition approach. Ultrasonography. 2015; 34:173-182.
3. Sassone AM, Timor-Tritsch IE, Artner A, et al. Transvaginal
sonographic characterization of ovarian disease: evaluation of a
new scoring system to predict ovarian malignancy. Obstet Gynecol.
1991; 78:70-76.
4. Shende V, Kamat A, Raut S, Jagtap P, Bobade P, Kuthe S. Sassone
Scoring System in Differentiating Benign and Malignant Adnexal
Masses. Indian Journal of Applied Research. Volume 6 Issue: 3
March 2016; 59-62.
5. Ferrazzi E1, Zanetta G, Dordoni D, Berlanda N, Mezzopane R,
Lissoni AA. Transvaginal Ultrasonographic Characterization
of Ovarian Masses: Comparison of five scoring systems in a
multicenter study. Ultrasound Obstet Gynecol. 1997; 10:192-197.
6. Tantipalakorn C, Wanapirak C, Khunamornpong S, Sukpan K,
Tongson T, IOTA Simple Rules in Differentiating between Benign
and Malignant Ovarian Tumors. Asian Pacific Journal of Cancer
Prevention. 2014; 15:5123-5126.
7. Timmermann D, Valentin L, Bourne TH, Collins WP, Verrelst
H, Vergote I. definitions and measurements to describe the
sonographic features of adnexal tumors: a consensus opinion
from the International Ovarian Tumor Analysis (IOTA) Group.
Ultrasound Obstet Gynecol. 2000; 16-500-5.
12 Volume 41, Number 2, PJOG March-April 2017
8. Valentin L. Comparison of Lerner Score, Doppler Ultrasound
Examination, and their combination for discrimination between
benign and malignant adnexal masses. Ultrasound of Obstetrics
and Gynecology. 2000; 15:143-147.
9. Lerner JP, Timor-Tritsch IE, Federman A, Abramovich G.
Transvaginal ultrasonographic characterization of ovarian masses
with an improved, weighted scoring system. Am J Obstet Gynecol.
1994; 170:81-85.
10. Philippine Society of Ultrasound in Obstetrics and Gynecology
Guidelines (2012).
11. Yazbek J, Raju KS, Ben-nagi J, Holland T, Hillaby K, Jurkovika, J.
Accuracy of ultrasound subjective pattern recognition for diagnosis
of borderline ovarian tumors. Ultrasound Obstet Gynecol. 2007;
29: p 489-495.
12. Klangsin S, Suntharasaj T, Suwanrath C, Kor-anantakul O,
Prasartwanakit V. Comparison of the Five Sonographic Morphology
Scoring Systems for the Diagnosis of Malignant Tumors. Gynecol
Obstet Invest. 2013; 76:248-253.
13. Tongson T, Luewan S, Phadungkiatwattana P. et al Pattern
recognition using transabdominal ultrasound to diagnose ovarian
mature cystic teratoma. International Journal of Gynecology and
Obstetrics. 2008; 103:99-104.
 Assessment of climacteric symptoms among
Filipino women ages 40 years and above seen
at a tertiary hospital in Metro Manila*
By Krystle R. Calimbas, MD and Catherine Irene L. Maceren-Medina, MD, FPOGS
Department of Obstetrics and Gynecology, Manila Doctors Hospital

ABSTRACT

Background: The common climacteric symptoms experienced by women 40 years and above can be classified into vasomotor,
physical, psychological and sexual complaints. This may be associated with sociodemographic factors. The timing of menopause is
also believed to be associated with sociodemographic factors.

Objectives: To determine the prevalence and associated factors of climacteric symptoms experienced by women ages 40 years and
above seen at a Tertiary Hospital in Metro Manila.

Methods: By using Modified Menopause Rating Scale questionnaire (Rahman, et al.), 360 Filipino women aged 40 years and above
were interviewed and were asked of their sociodemographic data and presence of climacteric symptoms (divided into somatic,
psychological and urogenital domain).

Results: Majority of the participants had menopause at age 51, with mean age at menopause of 48.4 + 3.58 (SD) years. The most
prevalent symptom reported was joint and muscular discomfort (65-75%) and this was more common among perimenopausal
women. This was also the most common reason for absence at work of the participants. There was no significant association found
between sociodemographic factors and climacteric symptoms, as well as with the timing of menopause.

Conclusions: Unlike other studies in different countries, no significant association was found on this study between sociodemographic
factor and climacteric symptoms. Sociodemographic factors also did not show any significant association with the timing of
menopause.

Keywords: climacteric, menopause, menopause rating scale, menopausal symptoms

INTRODUCTION The age of menopause is believed to be a significant

O
ne of the turning points in a woman’s life is when
they reach the middle age, as it comes along with
many changes not only physically, but also changes
that affects the quality of their lives. Menopause is a phase
in every woman’s life that is inevitable and can occur
either spontaneously or secondary to other conditions.1
It is defined as complete cessation of menstruation for
12 months or more.2 The average age of menopause on
western countries is at 51 years.3 On the other hand,
based on the latest study regarding the average age of
menopause among Filipino women, (done > 20 years
ago) the estimated age is at 48 years.4 The average life
expectancy of Filipino women is 72 years-old (WHO,
2015). With those average ages of menopause, more than
a third of a woman’s life will be spent after menopause.3
*Finalist, 2017 Philippine Obstetrical and Gynecological Society (POGS)
Research Paper Contest, April 6, 2017, Citystate Asturias Hotel, Puerto
Princesa City, Palawan
factor in a woman’s health because reproductive health
is considered as a reflection of overall health. For that
reason, women with early menopause are expected to be
less healthy than those with late menopause. Due to its
limited studies to prove this theory, the National Institute
of Health has conducted a study entitled “The SWAN Song:
Study of Women’s Health Across the Nation’s Recurring
Themes”, which aimed to assess how menopause per se
and the process of the menopause transition may affect
future health risks and outcomes. This study started
in 1994 and it has contributed a remarkable insights
regarding many determinants and interactions that predict
health and also disease risk in midlife women. It was found
out in this study that the major factors that influence risk
include race/ethinicity, socioeconomic status and adverse
life events and body mass index, particularly metabolically
unhealthy obesity.
As a woman enters menopause state, ovarian
hormone production eventually ceases and the nature
of relationships between hormones, body size, ethnicity,
Volume 41, Number 2, PJOG March-April 2017 13
metabolic status and cardiovascular diseases symptoms
risk differ.5 Many symptoms can be attributed to loss of
ovarian reproductive function such as physical symptoms
that may be debilitating. It includes hot flushes, night
sweats, urogenital atrophy, sexual dysfunction, mood
changes, bone loss and metabolic changes that predispose
to cardiovascular disease and diabetes.1
REVIEW OF RELATED LITERATURE
THE PHYSICAL AND BEHAVIORAL EFFECT OF MENOPAUSE
The common climacteric symptoms experienced
by menopause women can be classified into vasomotor,
physical, psychological and sexual complaints. Another
health issues to be addressed in the menopausal women
especially those with long-term estrogen deficiency are
cardiovascular changes and bone mineral content changes
that would lead to osteoporosis.7
Women entering menopause usually experience
vasomotor symptoms. Usually, in late perimenopause and
first postmenopausal years, hot flushes occur in which a
woman experience sudden episode of vasodilation in the
face and neck lasting for 1-5 minutes followed by profuse
sweating. But there are some women who still experience
hot flushes and other vasomotor symptoms even after
years of menopause. These symptoms are associated with
the declining levels of estrogens and inhibin B, as well as
increasing FSH levels. However, these can only partially
explain the disturbed thermoregulation. Other symptoms
include sleep disturbance, mood disorders, muscles and
joint pains.1
Another climacteric symptoms that seemingly affect
the quality of life of a woman are the genitourinary
symptoms. These include vaginal dryness, dyspareunia,
vulvar pruritus and recurrent urogenital infections. Such
symptoms are associated with vulvovaginal and urinary
tract atrophy, which are due to estrogen deficiency.1
In menopause, moisture content in the vagina is low
and the pH increases (>5). The mucosa may exhibit
inflammation and small petechiae.3 On the other side,
unlike vasomotor symptoms such as hot flushes and night
sweats, the genitourinary symptoms mentioned above
which are experienced by menopause persist throughout
postmenopausal years. In addition, a menopause woman
cannot get away from osteoporosis due to estrogen
deficiency resulting indirectly to increased bone resorption
and decreased bone formation.1 It can be noted for the
first time when menstrual cycle becomes irregular in the
perimenopause from 1.5 years before the menopause to
1.5 years after menopause.3
WOMEN’S AWARENESS OF MENOPAUSE
Many women enter into this phase without
14 Volume 41, Number 2, PJOG March-April 2017
having sufficient knowledge about the various symptoms
they may have to deal with. That is why some women
perceive menopause as a nightmare. A lot of women
faces menopause with basic fears, confusion and
discouragement due to lack of understanding of the
physical changes in their body. They do not have the idea
about the options available to prevent the debilitating
complications of menopause. On the other hand, there
are some communities or societies where women are
well educated and have adequate knowledge about
menopausal symptoms. These women are able to tolerate
the complications of menopause with positive approach
and with the use of appropriate treatments.
In general, women living in rural areas can complicate
the menopause experience due to several reasons
such as geographical isolation, lack of confidentiality
and anonymity, stress from multiple roles, poverty and
limited health care and support services.7 Easy access
to health care and support system is very important in
addressing the issues of women regarding menopause.
Adequate information and education on menopause may
help the community prepare themselves for the physical
and behavioral changes in women entering the period
of menopause. With sufficient knowledge regarding
menopause, the attitudes and practices of women towards
menopause will be positive.
FACTORS AFFECTING THE TIMING OF MENOPAUSE
Based on Berek and Novak’s Gynecology (2007), the
age at menopause is genetically determined and is not
affected by race, socioeconomic status, age at menarche or
number or prior ovulations. One factor that is consistently
associated with early menopause is smoking due to its
toxic effect on the ovaries. Moreover, women who are
exposed to chemotherapy or radiation are also likely to
have early menopause.10 On the other hand, based on the
study of S. Davis et al. (2015), the timing of menopause
is affected by a complex interplay of genetic, epigenetic,
socioeconomic and lifestyle factors. In fact, approximately
50% of the interindividual variability in age at menopause
is related to genetic effects. It has been found that women
with mothers or other first-degree relatives were 6-12 fold
more likely to also undergo early menopause.1
Socioeconomic Status
According to the SWAN study, socioeconomic status
is a factor in the early occurrence of menopause. Women
of low socioeconomic status are believed to more likely
experience early menopause. Moreover, increased
depressive symptoms and menopausal symptoms can
be associated with low socioeconomic status. The
economic well being, educational background and
financial security of women are related to the outcomes
and risks.5 This was also observed in the study of Gold
(2011). The socioeconomic status was measured by the
woman’s educational attainment or by her husband’s
occupation. But it is believed that education was more
strongly associated with age at natural menopause than
occupation.11
Parity
Increasing parity has been associated with later age
at menopause, which is associated with the theory that
natural menopause occurs after depletion of oocytes. This
is particulary among women of higher socioeconomic
status.11
Physical activity
Few studies have examined the effect of exercise
on age at menopause. Physical activity is associated with
decreased concentrations of reproductive hormones
and it also affects the frequency of ovulation. Therefore,
later age at natural menopause is expected with women
who are physically active compared to women who live a
sedentary life.11
Smoking
Berek et. al (2007) mentioned that factors which
are toxic to the ovary often result in an earlier age of
menopause and this includes smoking.10 Several studies
have observed this finding and one of those was the
study conducted in Norway (Mikkelsen et. al, 2007). A
cross-sectional study was done which primarily aimed to
investigate the association between early menopause and
current, past active and passive smoking. The subjects
included a sub-sample of 2123 postmenopausal women
born in 1940-41. Study showed that early menopause,
defined as menopause at age of less than 45 years, has
a strong association with current smoking. Cessation of
smoking for more than 10 years before menopause has
significant reduction of risk of early menopause. Therefore,
the study suggested that the earlier a woman quits
smoking, the more protected she is from early menopause.
In addition, early menopause was significantly associated
with passive smoking.14
FACTORS AFFECTING THE PREVALENCE OF MENOPAUSAL
SYMPTOMS
Body Mass Index
In SWAN study, it was proven that body weight is
correlated to hormone levels and can be associated with
the outcome experienced by the menopause women.
Based on this study, higher body mass index (BMI) is
associated with worse vasomotor symptoms as women
traverse the menopause. However, this may vary as a
woman becomes postmenopausal. Obese women have
a lesser decline in estradiol even as they transition to
menopausal state. It is due to the peripheral conversion of
fats or adipose tissue to estrogen. BMI is also associated
with the mood, symptoms and hormones, as well as the
metabolic syndrome and cardiovascular risk factors.5
Marital status
In the study of Tsehay (2014), findings have shown
no significant difference in the prevalence of menopausal
symptoms across marital status. This lack of significant
difference among Ethiopians may be attributed to the fact
that the culture they have adapted may have influenced
them relatively in the same way and pattern regardless of
their marital status. On the other hand, this contradicted
the previous study conducted in Saudi Arabia, where in
married women has shown almost 4x more symptoms
than single women. This was somehow attributed to a
different life history, including sexual activity, use of birth
control and cultural differences.13
Intake of Pills
Oral contraceptive pills are beneficial for non-
smoking, healthy perimenopausal women. It has been
found to relieve vasomotor symptoms in perimenopausal
women and also decrease the risk of postmenopausal hip
fractures, and regularize menses in women with abnormal
uterine bleeding. Hence, it enhances the quality of life of
perimenopausal women.16
MENOPAUSAL SYMPTOMS PREVALENT AMONG DIFFERENT
NATIONS
Across nations, there were various menopausal
symptoms that are more prevalent. In Pakistan and Saudi
Arabia, the most prevalent symptoms experienced by
the menopausal women were hot flushes and excessive
sweating. These women were 45 years and above of
age.2,15 On the other hand, among Filipino women, with an
average age of menopause at 48 years, the most prevalent
symptom was headache while the least prevalent was
hot flush.4 In Malaysia, the most prevalent menopausal
symptoms were joint and muscular discomfort. The age
of menopause of Malaysian women was higher compared
to other Asian countries, which was 51.3 years old.9 Other
signs and symptoms experienced by menopausal women
across nations were sleep disturbances, urinary frequency,
vaginal dryness, poor memory, anxiety and depression.2
OBJECTIVES
To determine the prevalence and associated factors
of climacteric symptoms experienced by women ages
Volume 41, Number 2, PJOG March-April 2017 15
40 years and above seen at a Tertiary Hospital in Metro
Manila
SPECIFIC OBJECTIVES:
1. To determine the prevalence of climacteric
symptoms among the respondents
2. To determine the socio-demographic factors
associated with climacteric symptoms
3. To determine the average age at menopause of
the respondents
4. To determine the socio-demographic factors
associated with timing of menopause
5. To determine the incidence of loss of productivity
among the respondents suffering from climacteric
symptoms
MATERIALS AND METHODOLOGY
A. Materials
1. Study design
Cross-sectional study
This study involved data collected from the
questionnaire or survey form to assess the prevalence
of climacteric symptoms among middle age women
subclassified into 2: (1) Premenopause (2) Perimenopause,
(3) Menopause.
This study also involved analysis of correlation of
climacteric symptoms and different variables that may
affect or contribute to the prevalance of such symptoms
and timing of menopause.
Sampling design - Simple Random Sampling
Women ages 40 years and above seen at the waiting
area of outpatient department in our institution were
chosen randomly and entirely by chance.
Data collection was in questionnaire/survey form.
2. Inclusion criteria
Included in this study were women between ages
40 years and above seen in the waiting area of our
institution’s out-patient department (OPD) who gave
consent to participate in the survey. These included
patients with or without specific gynecologic complaints
and also companions of patients.
3. Exclusion criteria
Excluded in this study are pregnant and breastfeeding
women, menopause women induced by surgery (bilateral
oophorectomy), chemotherapy or radiation and who are
currently taking hormonal replacement therapy.
16 Volume 41, Number 2, PJOG March-April 2017
4. Definition of terms
a) Menopause means cessation of menses for a full
12 months without a specific cause such as pregnancy or
breast-feeding according to the standards of the world
health organization (WHO)5
b) Perimenopause refers to a variable time beginning
a few years before and continuing after the event of
menopause.10 It also refers to a state prior to menopause
in which a woman had menstruation in the previous/
last 2-12 months but not in the previous/last 2 months,
OR a when a woman experiences increasing menstrual
irregularity but without skipping menstrual period (7 days
difference from the beginning of a given cycle to the next,
experienced after the previously regular cycle).7
c) Premenopause refers to a state in which there
are minor changes in cycle length, particularly decreasing
length of the cycle.7 In other study, it refers to a time
when menses had occurred in the past 3 months with no
decreased predictability.10
d) Climacteric refers to a phase in the women’s life,
which marks the transition from the reproductive phase
to the non-reproductive state. This phase includes the
perimenopause by extending for a longer variable period
before and after the menopause.8
Limitations of the study
This study assessed whether the participant
experienced the symptoms asked or not. The severity of
the symptoms experienced by the participants were not
measured or assessed.
6. Informed consent
B. Methodology
This was a descriptive study that was conducted
from months of October to November 2016. Participants
were given a consent form and the content of the form
was explained to them in Filipino language to make sure
that they have understood it. After signing the consent
form, a code was assigned to each participant. Before
the interview, the height and weight of the participant
was measured to compute for the body mass index. The
primary investigator did one-on-one interview with each
participant in a cubicle where privacy was observed. The
survey or questionnaire used was adapted from different
studies. This was the “Modified Rating Scale”, which was
validated and proven to be a valuable tool for assessing
health related quality of life of women in the menopausal
transition and was used worldwide. This was also
translated into different languages.16 The questionnaire
included questions regarding sociodemographic data,
menopausal status and symptoms experienced by the
participants.
 Questionnaires were divided into two sections such
as follows:
(1) Socio-demographic data of the participants, which
include age, body mass index, marital status,
socioeconomic status (educational level), history of
smoking and history of intake oral contraceptive pills,
menopausal status
(2) Assessment of menopausal symptoms composed of
11 items and divided into three subscales:
a. Somatic, which includes hot flushes, heart
discomfort/palpitation, sleeping problems and
muscle and joint problems.
b. Psychological-depressive mood, irritability,
anxiety ad physical and mental exhaustion
c. Urogenital-sexual problems, bladder problems
and dryness of the vagina7
This questionnaire was translated to Filipino
language so that those respondents who were unable or
had difficulty understanding English language were able to
answer the questions correctly and accurately. Informed
consent was given. The name of the participant was not
written in the questionnaire/survey form and a code was
assigned to each participant.
Data Analysis
Data analysis was performed in Stata SE version
13. Quantitative variables were summarized as mean
and standard deviation for quantitative variables, while
qualitative variables were tabulated as frequency and
percentage. Age of menopause was estimated with 95%
confidence level. Association between different factors
and menopausal symptoms were analyzed using Fisher’s
exact test. The level of significance was set at 5%.
C. Sample size
Using Epi Info Version 7, the minimum sample
size requirement is 360 based on percentage of
postmenopausal = 37.4% (Rahman et. al, 2010) with alpha
level = 5% and margin of error = 5%.
RESULTS
There were 360 women aged 40 years and above
who completed the survey. Graph 1 showed that among
these women, 39 (10.8%) were premenopausal, 140
(39.6%) were perimenopausal and 169 (46.9%) were
postmenopausal. Among the group of postmenopause/
menopause, majority had menopause at 50 years (23.7%).
The average age at menopause was 47-48 years
with 95% confidence interval. To be exact, the mean age at
menopause was 48.4 + 3.58 (SD) years and median of 48 years.
Graph 1. Age at menopause of the participants
Table 1 showed that most of the participants were
married that comprised 253 (70.1%) while only 36 (10%)
were single. Meanwhile, in terms of body mass index, 120
(33%) had normal weight, 93 (25.8%) were overweight
and 95 (26.4%) were obese. Majority was high school
graduate (42.5%) while 35% graduated from college. In
addition, 11% were elementary graduate and 8% finished
post-graduate course and the rest of 3% had no formal
education.
Mostly, 272 (75.6%) had 2 or more children. A greater
part of the respondents, 223 (61.9%) were non-smoking,
40 (11%) were currently smoking, but 4(1.1%) of them
already stopped smoking for more than 10 years and
the rest were passive smokers. The ages of participants
at menopause who stopped smoking for more than 10
years were 49, 51 (2) and 52. Meanwhile, almost 2/3 of all
had a sedentary lifestyle and 1/3 claimed to have regular
exercise. There were only 57 (15.8%) who were currently
taking oral contraceptive pills.
Prevalence of climacteric symptoms among the
respondents
The frequency of climacteric symptoms among all the
participants was shown on Table 2. Among premenopause
(n=39), physical and mental exhaustion was the most
prevalent symptom, followed by sleeping problem.
Women at this age group rarely experienced the rest of
the climacteric symptoms. Meanwhile, joint and muscular
discomfort was the most frequent symptom experienced
by perimenopause and menopause. In fact, almost 75%
of the perimenopause suffered from joint and muscular
discomfort while more than 65% of menopause suffered
from it. Irritability was also a common problem among
60% of perimenopause. On the other hand, half of the
menopausal women experienced physical and mental
exhaustion. Most of the somatic subscale symptoms
especially joint and muscular discomfort occurred in
the perimenopausal women compared to pre- and
postmenopausal women. Moreover, there were also more
psychological subscale symptoms especially irritability
found on perimenopausal compared to pre- and post
menopausal. Sexual problem was also affecting 48-50% of
the perimenopausal and menopausal women.
Volume 41, Number 2, PJOG March-April 2017 17
Table 1. Sociodemographic data of respondents obese group experienced hot flushes and sweating, and
also sexual problems.
Sociodemographic Data To further see if there is association between
Mean + SD or n (%)
(N=360) BMI and climacteric symptoms, the respondents
were grouped according to menopausal status. It was
Age (years) 48.4 + 3.58
shown in Table 3.1.1. that among premenopause, joint
Body Mass Index and muscular discomfort was still the most prevalent
Underweight (<18.5) 24 (6.7)
symptom experienced by the respondents regardless
of the BMI. But it was most frequent in the group of
Normal (18.5-22.9) 120 (33.3)
obese. On the other hand, it was noticeable that 50%
Overweight (>23) 93 (25.8)
of the premenopausal women who were underweight
Obese I (>25) 95 (26.4)
experienced hot flash or sweating. Actually, hot flash was
Obese II (>30) 28 (7.8) found on all premenopause. But it was found more on the
Marital status morbidly obese, comprising 58.3 % of all the morbidly
Single 36 (10) obese premenopause. Results also showed that there
Married 253 (70.1) were only two symptoms found on the underweight
Widow 46 (12.8) group and those were hot flash and irritability.
Separated 25 (6.9) On the other side, it was shown in Table 3.1.2
Educational level that somatic and psychological symptoms were more
No formal education 11 (3.1) prominent among perimenopause who were underweight.
Elementary 41 (11.4) Meanwhile, no significant association between BMI and
High school 153 (42.5) climacteric symptoms were found among obese women.
College 126 (35) But overall, it can be noticed that all climacteric symptoms
Post-graduate 29 (8.1)
were mostly found in the group of menopause.
Number of children Table 3.1.3 showed that among the group of
None
menopause, joint and muscular discomfort was still the
53 (14.7)
most prevalent symptom regardless of the body mass
1 35 (9.7)
index. But among obese women, the other two prominent
2 or more 272 (75.6) symptoms aside from joint and muscular discomfort were
Smoking history
physical and mental exhaustion, sexual problem and
Non-smoking 223 (61.9) irritability.
<10 years 16 (4.4) However, there were no significant association found
≥10 years 24 (6.7) between BMI and climacteric symptoms with regards to
Stopped smoking for >10 years 4 (1.1) menopausal status.
Passive smoker 93 (25.8) On Table 3.2, it was shown that the marital status has
History of intake of OCPs also not shown a significant difference in the climacteric
No intake of OCPs 303 (84.2) symptoms experienced by the respondents. But among
Currently taking OCPs 57 (15.8) married women (n=253), more than 65% suffered from
joint and muscular discomfort.
On Table 3.3, it was also shown that regardless
The association between the socio-demographic and of the history of oral contraceptive pills (OCP) intake,
climacteric symptoms the most prevalent climacteric symptom experienced
The climacteric symptoms experienced by the by the respondents was joint and muscular discomfort
participants were correlated with selected variables (63%). Among those who were currently taking pills,
such as body mass index, marital status and intake of another prevalent symptom was physical and mental
pills. Results showed in Table 3.1 that body mass index exhaustion followed by heart discomfort, sexual problem
(BMI) has no significant association with the climacteric and irritability. But results did not show any statistical
symptoms experienced by the respondents. But based on significance.
this study, it was shown that regardless of the BMI, 60-
70% experienced joint and muscular discomfort. Among The association between the sociodemographic factors
the underweight group, half of them experienced heart and timing of menopause
discomfort. Meanwhile, symptom of irritability affected Different characteristics or sociodemographic factors
50-60% of obese. In addition, more than 50% of morbidly were also correlated with the timing of menopause, which

18 Volume 41, Number 2, PJOG March-April 2017

Table 2. Frequency of climacteric symptoms among the total number of respondents

Premenopause Perimenopause Menopause

Somatic p value
(n = 39) (n= 140) (n= 169)

Hot flushes, sweating 1 (2.6) 76 (50) 64 (30.9) < 0.001

Heart discomfort 4 (10.3) 79 (52) 65 (38.5) < 0.001
Sleeping problems 7 (18) 83 (54.6) 81 (48) < 0.001
Joint and muscular discomfort 6 (15.4) 110 (72.4) 112 (66.3) < 0.001
Psychological
Depressive mood 1 (2.6) 64 (42.1) 52 (30.8) < 0.001
Irritability 3 (7.7) 92 (60.5) 78 (46.2) < 0.001
Anxiety 0 45 (29.6) 51 (30.2) < 0.001
Physical and mental exhaustion 8 (20.5) 87 (57.2) 86 (50.9) < 0.001
Urogenital
Sexual problems 1 (2.6) 76 (50) 82 (48.5) < 0.001
Bladder problems 1 (2.6) 29 (19.1) 42 (24.9) 0.002
Dryness of vagina 0 41 (27) 53 (31.4) < 0.001

Table 3.1. Correlation of symptoms experienced by the respondents with body mass index (BMI)

Characteristics Body mass index

Underweight Normal Overweight Obese I Obese II

Somatic p value
(n=24) (n=120) (n=93) (n=95) (n=28)

Hot flushes, sweating 9 (37.5) 43 (35.8) 32 (34.4) 41 (43.2) 16 (57.1) 0.214

Heart discomfort 12 (50) 44 (36.7) 40 (43) 40 (42.1) 12 (42.9) 0.735
Sleeping problems 9 (37.5) 54 (45) 49 (52.7) 45 (47.4) 14 (50) 0.682
Joint and muscular discomfort 15 (62.5) 71 (59.2) 58 (62.4) 66 (69.5) 18 (64.3) 0.644
Psychological
Depressive mood 7 (29.2) 37 (30.8) 31 (33.3) 29 (30.5) 13 (46.4) 0.578
Irritability 10 (41.7) 51 (42.5) 45 (48.4) 50 (52.6) 17 (60.7) 0.348
Anxiety 7 (29.2) 30 (25) 27 (29) 21 (22.1) 11 (39.3) 0.423
Physical and mental exhaustion 9 (37.5) 53 (44.2) 53 (57) 48 (50.5) 18 (64.3) 0.126
Urogenital
Sexual problems 6 (25) 53 (44.2) 42 (45.2) 42 (44.2) 16 (57.1) 0.238
Bladder problems 5 (20.8) 26 (21.7) 16 (17.2) 20 (21.1) 5 (18.9) 0.941
Dryness of vagina 5 (20.8) 28 (23.3) 26 (28) 25 (26.3) 10 (35.7) 0.680

included body mass index, marital status, educational
attainment, history of smoking, number of children or
parity and physical activity.
Table 4 showed the correlation of timing of menopause
with selected variables. Among the respondents who had
early menopause at age 40-44 years, 7 out of 23 (30%) were
overweight but did not show significant difference from
normal weight and obese. On the other hand, about 65%
of this group was married. History of smoking among these
women also did not show significant difference, although
majority (56.5%) were non-smokers. On this study, early
menopause at ages 40-44 years were found more on
multiparous women. In fact, 87% of the respondents ages
40-44 were had 2 or more children.
On the other side, most of the respondents who
had age at menopause at 45-49 years were high school
graduate. Meanwhile, women who had late menopause
at age 55-59 years were either college graduate or had
finished a post-graduate course.
Lastly, results showed that more than 70% of the

Volume 41, Number 2, PJOG March-April 2017 19

Table 3.1.1. Correlation of symptoms experienced by the respondents with BMI among group of premenopause

Characteristics Body mass index among premenopause

Underweight Normal Overweight Obese I Obese II

Somatic p value
(n=10) (n=40) (n=43) (n=47) (n=12)

Hot flushes, sweating 5 (50) 19 (47.5) 21 (48.8) 24 (51.1) 7 (58.3) 0.982

Heart discomfort 0 1 (7.1) 1 (11.1) 1(10) 1(50) 0.451
Sleeping problems 0 3 (21.4) 2 (22.2) 2 (20) 0 1.000
Joint and muscular discomfort 0 3 (21.4) 1 (11.1) 2 (20) 0 1.000
Psychological
Depressive mood 0 1 (7.1) 0 0 0 1.000
Irritability 1 (25) 1 (7.1) 0 1 (10) 0 0.604
Anxiety 0 0 0 0 2 (100) 0
Physical and mental exhaustion 0 3 (21.3) 1 (11.1) 4 (40) 0 0.470
Urogenital
Sexual problems 0 0 0 1 (10) 0 0.641
Bladder problems 0 0 0 1(10) 0 0.641
Dryness of vagina 0 0 0 0 0 0

Table 3.1.2. Correlation of symptoms experienced by the respondents with BMI among group of perimenopause

Characteristics Body mass index among perimenopause

Underweight Normal Overweight Obese I Obese II

Somatic p value
(n=10) (n=66) (n=41) (n=38) (n=14)

Hot flushes, sweating 5 (50) 19 (47.5) 21 (48.8) 24 (51.1) 7 (58.3) 0.982

Heart discomfort 8 (80) 22 (55) 22 (51.2) 21 (44.7) 6 (50) 0.375
Sleeping problems 7 (70) 23 (57.5) 22 (51.2) 23 (48.9) 8 (66.7) 0.649
Joint and muscular discomfort 7 (70) 29 (72.5) 30 (69.8) 35 (74.5) 9 (75) 0.984
Psychological
Depressive mood 5 (50) 16 (40) 18 (41.9) 20 (42.6) 5 (41.7) 0.988
Irritability 7 (70) 22 (55) 27 (62.8) 28 (59.6) 8 (66.7) 0.895
Anxiety 5 (50) 11 (27.5) 11 (25.6) 14 (29.8) 4 (33.3) 0.641
Physical and mental exhaustion 6 (60) 19 (47.5) 28 (65.1) 26 (55.3) 8 (66.7) 0.537
Urogenital
Sexual problems 0 0 0 1 (10) 0 0.641
Bladder problems 2 (20) 10 (25) 5 (11.6) 8 (17) 4 (33.3) 0.344
Dryness of vagina 3 (30) 11 (27.5) 8 (18.6) 15 (31.9) 4 (33.3) 0.618

respondents who had early menopause live a sedentary
life while those menopause who exercise regularly had
menopause at 45-54 years of age (30-40%).
On the other hand, those women who had menopause
at 50 years and above were of normal weight (44.3%).
Most of them were also married (69.6%). But unlike those
women with early menopause, most of the respondents
with late menopause belonged to higher socioeconomic
status. Results showed that parity of more than 2 were
found mostly in women with late menopause. In fact, 61
out of 79 (77.2%) women who had menopause at age 50-
54 were multipara.
The incidence of loss of productivity among the
respondents suffering from menopausal symptoms
The response to work of women suffering from

20 Volume 41, Number 2, PJOG March-April 2017

Table 3.1.3. Correlation of symptoms experienced by the respondents with BMI among group of menopause

Characteristics Body mass index among menopause

Underweight Normal Overweight Obese I Obese II

Somatic p value
(n=4) (n=14) (n=9) (n=10) (n=2)

Hot flushes, sweating 4 (40) 24 (36.4) 10 (24.4) 17 (44.7) 9 (64.3) 0.085

Heart discomfort 4 (40) 21 (31.8) 17 (41.5) 18 (47.4) 5 (35.7) 0.596
Sleeping problems 2 (20) 28 (42.4) 25 (61) 20 (52.6) 6 (42.9) 0.129
Joint and muscular discomfort 8 (80) 39 (59.1) 27 (65.9) 29 (76.3) 9 (64.3) 0.412
Psychological
Depressive mood 2 (20) 20 (30.3) 13 (31.7) 9 (23.7) 8 (57.1) 0.231
Irritability 2 (20) 28 (42.4) 19 (43.9) 21 (55.3) 9 (64.3) 0.185
Anxiety 2 (20) 19 (28.8) 16 (39) 7 (18.4) 7 (50) 0.130
Physical and mental exhaustion 3 (30) 31 (57) 24 (58.5) 18 (47.4) 10 (71.4) 0.236
Urogenital
Sexual problems 2 (20) 29 (43.9) 24 (58.5) 18 (47.4) 9 (64.3) 0.148
Bladder problems 3 (30) 16 (24.2) 11 (26.8) 11 (28.9) 1 (7.1) 0.551
Dryness of vagina 2 (20) 17 (25.8) 18 (43.9) 10 (26.3) 6 (42.9) 0.224

Table 3.2. Correlation of symptoms experienced by the respondents with marital status

Characteristics Marital status

Single Married Widow Separated

Somatic p value
(n=36) (n=253) (n=46) (n=25)

Hot flushes, sweating 15 (58.3) 102 (40.3) 16 (34.8) 8 (32) 0.789

Heart discomfort 13 (36.1) 109 (43.2) 16 (34.8) 10 (40) 0.685
Sleeping problems 15 (41.7) 119 (47) 25 (54.4) 12 (48) 0.714
Joint and muscular discomfort 18 (50) 169 (66.8) 29 (63) 12 (48) 0.084
Psychological
Depressive mood 9 (25) 83 (32.8) 16 (34.8) 9 (36) 0.754
Irritability 15 (41.70) 126 (49.8) 19 (41.3) 13 (52) 0.596
Anxiety 5 (13.9) 67 (26.5) 16 (34.8) 8 (32) 0.165
Physical and mental exhaustion 13 (36.1) 125 (49.4) 28 (60.9) 15 (60) 0.114
Urogenital
Sexual problems 6 (16.7) 120 (47.4) 21 (45.7) 12 (48) 0.004
Bladder problems 8 (22.2) 45 (17.8) 14 (30.4) 5 (20) 0.257
Dryness of vagina 3 (8.3) 71 (28.1) 15 (32.6) 5 (20) 0.036

menopausal symptoms was shown in Table 5. DISCUSSION

Among perimenopause and menopause, more than
10% miss work due to different climacteric symptoms,
especially joint and muscular discomfort. Actually, 19
(12.5%) among perimenopause while 21 (12.4%) among
menopause women were absent at work when climacteric
symptoms occur.
There were 360 women aged 40 years and above
who completed the survey, 169 of those were menopause
already. Majority of the respondents who are menopause
had their menopause at age 50 years. More than 20 years
ago, in the study of Jalbuena (1994), the average age at
menopause was 47-48 years. This implies that among

Volume 41, Number 2, PJOG March-April 2017 21

Table 3.3. Correlation of symptoms experienced by the respondents with history of intake of oral contraceptive pills

Characteristics History of intake of OCPs

No intake of OCPs Currently taking pills

Somatic (n=303) (n=57) p value

Hot flushes, sweating 119 (39.3) 22 (38.6) 0.524

Heart discomfort 117 (38.6) 31 (54.4) 0.029
Sleeping problems 143 (47.2) 28 (49.1) 0.451
Joint and muscular discomfort 192 (63.4) 36 (63.2) 0.544
Psychological
Depressive mood 98 (32.3) 19 (33.3) 0.498
Irritability 143 (47.2) 30 (52.6) 0.271
Anxiety 78 (25.7) 18 (31.6) 0.224
Physical and mental exhaustion 145 (47.9) 36 (63.2) 0.024
Urogenital
Sexual problems 128 (42.2) 31 (54.4) 0.061
Bladder problems 62 (20.5) 10 (17.5) 0.381
Dryness of vagina 77 (25.4) 17 (29.8) 0.293

our study population, the average age of Filipinos at
menopause was now closer to Western countries’ age
at menopause, which is 51 years. It was also found out
that on this study that the most prevalent climacteric
symptom now among the participants was joint and
muscular discomfort (65-75%). This was also the most
common reason why the affected women missed their
work. Moreover, almost 75% of these women belong
to perimenopause group who were still active at work.
Hence, this concern is relevant to address especially in
women who are working to support their family. It was also
noted that half of the menopausal women experienced
physical and mental exhaustion. This finding on this study
is important not only for the women themselves, but also
for the people they live with. Being aware that physical
and mental exhaustion is common symptom among
menopausal women would prepare the family also to
become more understanding, more patient and more
caring for the women on menopausal years.
Each woman experiences different climacteric
symptoms. In fact, there are some who do not
experience any symptom at all even if they have reached
perimenopausal years already. This study aimed to
correlate the factors that may affect the prevalence of
symptoms. In SWAN study, it was stated that the higher
body mass index (BMI), the worse vasomotor symptoms
could occur in women on perimenopausal years. It was
explained that the relationship of BMI with climacteric
symptoms especially vasomotor symptoms varies as a
woman completes the transition into menopause due
to increased peripheral production of estrogen from
hormone precursors of adipose tissue. Prior to menopause,
there is only minimal contribution of adiposity to the
total body estrogen pool until the tiime comes when the
ovary becomes inactive after menopause. Vasomotor
symptoms becomes more prominent in obese wome
perhaps due to increased insulation of the body by fat.
On this study, it also showed that the higher body mass
index, the worse vasomotor symptoms, as manifested
by hot flushes or sweating. It showed that the group of
morbidly obese women were the most number of women
who experienced vasomotor symptom. But surprisingly,
the group of menopause who were morbidly obese
were the ones who experienced more of the vasomotor
symptoms compared to perimenopause. However, these
results showed no statistical significance.
Regarding marital status, there were various studies
with different views such as in the study of Tsehay (2014),
in which, no significant difference in the prevalence of
menopausal symptoms among menopausal women. But
there was also a study in Saudi Arabia that has shown a
significant increase in the prevalence of symptoms among
married women. On this study, 253 (70%) were married
but statistics showed no significant difference in the
prevalence of climacteric symptoms.
History of intake of pills was one of the selected
variables to correlate with climacteric symptoms because
it has been found to improve the quality of life among
perimenopausal women, by providing relief of vasomotor
symptoms and decreasing the risk of postmenopausal

22 Volume 41, Number 2, PJOG March-April 2017

Table 4. Correlation of Timing of Menopause with selected variables

Characteristics Age at menopause

40-44 45-49 50-54 55-59

Body mass index p value
(n=23) (n=64) (n=79) (n=4)

Underweight 1 (4.4) 4 (6.3) 6 (7.6) 0 0.413

Normal 6 (26.1) 25 (37.5) 35 (44.3) 1 (25)
Overweight 7 (30.4) 17 (26.6) 15 (19) 2 (50)
Obese I 6 (26.1) 12 (18.8) 20 (25.3) 0
Obese II 3 (13) 7 (11) 3 (3.8) 1 (25)
Marital status
Single 2 (8.7) 7 (10.9) 7 (8.9) 0 0.971
Married 15 (65.2) 41 (64.1) 55 (69.6) 4 (100)
Widow 6 (26.1) 13 (20.3) 14 (17.7) 0
Separated 0 3 (4.7) 3 (3.8) 0
Educational attainment
No formal education 1 (4.4) 2 (3.1) 4 (5.1) 0 0.524
Elementary 3 (13) 5 (7.8) 15 (19) 0
High school 11 (47.8) 34 (53.1) 29 (36.7) 2 (50)
College 8 (34.8) 20 (31.3) 26 (32.9) 1 (25)
Post-graduate 0 3 (4.7) 5 (6.3) 1 (25)
History of smoking
Non-smoking 13 (56.5) 38 (59.4) 49 (62) 4 (100) 0.985
<10 years 1 (4.4) 2 (3.1) 4 (5.1) 0
≥10 years 2 (8.7) 8 (12.5) 7 (8.9) 0
Stopped smoking for >10 years 0 1 (1.6) 1 (1.3) 0
Passive smoker 7 (30.4) 15 (23.4) 18 (22.8) 0
Parity
None 1 (4.35) 11 (17.2) 11 (13.9) 0 0.083
1 2 (8.7) 5 (7.8) 7 (8.9) 1 (25)
2 or more 20 (87) 48 (75) 61 (77.2) 2 (50)

Table 5. Response to work of women suffering from menopausal symptoms

Response to Work Menopausal status

Premenopausal Perimenopausal Menopause

(n=39) (n=152) (n=169)

Does not miss work 39 (100) 133 (87.5) 148 (87.6)

Absent at work 0 19 (12.5) 21 (12.4)

fracture. However, it was found on this study that there
was no statistical significance that may support this
theory. But this could be further studied because on this
study, only 16% of the total participants were taking OCPs.
Therefore, this could not perfectly explain the correlation
between intake of pills and the symptoms.
The timing of menopause was still controversial.
Although it was already proven that it is genetically
determined, 10 there are lots of studies nowadays
that strive to prove that there are various factors that
may affect it. This study has selected variables such as
educational attainment, parity, physical activity and
smoking to correlate it with the timing of menopause.
Most of the respondents who had age at menopause

Volume 41, Number 2, PJOG March-April 2017 23

at 45-49 years were high school graduate. Meanwhile,
women who had late menopause at age 55-59 years were
either college graduate or had finished a post-graduate
course. But there was no significant difference found on
this variable. Parity has also been associated with later
age of menopause. However, there was no statistical
significance found on this study.
History of smoking is significant to know because it
was already proven in previous studies that factors such
as smoking which are toxic to the ovary often result in
an earlier age of menopause.10 Ironically, present study
showed that early menopause at ages 40-44 years were
mostly found among those who were non-smoking, and
those also who had late menopause were mostly non-
smoking. Therefore, there was no significant association
found. In contrast to the previous studies saying that
cessation of smoking for more than 10 years decreases
risk of early menopause, this was not found on this study.
The ages at menopause of the respondents who stopped
smoking for >10 years were 49, 51 and 52, which belong
to average age at menopause among Filipinos. Therefore,
no significant association was found between history of
smoking and timing of menopause. As mentioned above,
smoking has long been proven already that it can cause
earlier cessation of menses due to its toxic effect to the
ovary. The findings on this study was different may be
because the data gathered regarding smoking history
were not sufficient. The findings could be more significant
if the data obtained were regarding how many pack years
(cigarette sticks per day), not just the number of years of
smoking. Some participants may have smoked for more
than 10 years but not every day or may be they were just
consuming 1-2 sticks per day. And some may be smoking
for less than 10 years but consuming 10 sticks per day.
Therefore, the number of pack years could give more
significant results.
Lastly, the incidence of loss of productivity of women
suffering from climacteric symptoms was only 12% each
among perimenopausal and menopausal women. Although
by looking at statistics, 12% seems to be a small number,
it is still significant to address this concern to help these
women to face this transition in their lives. It was found
that the most common climacteric symptom causing their
absence at work was joint and muscular discomfort. As
mentioned, this was found more on the perimenopausal
women who are still actively working whether on their
profession or at home. Thus, addressing this symptom as
early as premenopause period would help women to avoid
missing their work or prevent possible complications. This
study would help Filipino middle age women be aware
of the common climacteric symptoms they have to face
so they can seek help or consult with physicians who are
experts on this significant transition in life.
24 Volume 41, Number 2, PJOG March-April 2017
CONCLUSION
The assessment of climacteric symptoms among
Filipino women ages 40 years and above showed that
the mean age of menopause was 48.4 + 3.58 (SD) years.
Majority of the participants who were menopause had
their menopause at age 51 years. The most prevalent
climacteric symptom experienced by them was joint and
muscular discomfort, but this was more common among
perimenopausal women. This was also the most common
symptom that could not be endured by those women who
miss their work. The somatic and psychological symptoms
were found more on the perimenopausal group than
the menopausal, while urogenital symptoms were
experienced more by the menopausal group.
On the other hand, there were no significant
association between sociodemographic factors and
climateric symptoms, as well as with the timing of
menopause.
In terms of productivity, it has shown that only more
than 10% of the respondents were affected to a point
of missing their work when they experience climacteric
symptoms.
RECOMMENDATIONS
There were various factors used to associate with
timing of menopause such as body mass index, marital
status, educational attainment, history of smoking and
parity. But genetics was not included on this study.
Although it was already proven in previous studies that
timing of menopause is genetically determined, it could
still be included in this study by adding question on the
survey regarding the age at menopause of their mother or
1st degree relative.
Socioeconomic status has been one of the significant
factors used in different countries to assess if it has
significant association with the timing of menopause. It
was measured by educational attainment, household
income or husband’s income. Most of the studies
used educational attainment as a measure for the
socioeconomic status and that was the reason why
educational attainment was chosen to use in this study.
But here in the Philippines, there are Filipinos who were
not able to finish college degree or post-graduate course
but was still able to succeed and became rich. On the other
hand, there were also Filipinos who finished college but
did not succeed and chose to live a simple life. Therefore,
educational attainment is not a sufficient measure for the
socioeconomic status of a person. This paper recommends
including household income as a measure to assess the
real socioeconomic status of the participant.
On the other hand, as mentioned above, the number
of pack years is more important than the number of years
the participant is smoking. Therefore, this paper also
recommends including the number of cigarette stick per
day in the questionnaire.
Lastly, the assessment tool used was translated
REFERENCES
1. Susan. S. Davis, et al. (2015). Menopause. Nature Reviews Disease
Primers 1, Article number: 15004.
2. Shazia Khokhar. (2013). Knowledge, Attitude and Experience of
Menopause. Pakistan Journal of Medical Research, 2013 (April-
June), page 42.
3. Roger Lobo.(2012). Menopause and Care of the Mature Woman.
Comprehensive Gynecology, Sixth edition, page 273.
4. Ramoso-Jalbuena. (1994). Climacteric Filipino women:
preliminary survey in the Philippines. 1994 Oct; 19(3):183-90.
5. Nanette Santoro, MD, et al. (2011) The SWAN Song: Study of
Women’s Health Across the Nation’s Recurring Themes. Obstet
Gynecol Clin North Am. 2011. September; 38(3):417-423.
doi:10.1016/j.ogc.2011.05.001.
6. Eun Kyung Kwak, et al. (2014). Menopause Knowledge, Attitude,
Symptom and Management among Midlife Employed Women.
Journal of Menopausal Medicine. pISSN: 2288-6478, eISSN: 2288-
6761 http://dx.doi.org/10.6118/jmm.2014.20.3.118;20:118-125.
7. Rahman et al.: Assessment of menopausal symptoms using
modified Menopuase Rating Scale (MRS) among middle age
women in Kuching, Sarawak, Malaysia. Asia Pacific Family
Medicine 2010 9:5.
8. Baber, R. (2016). Menopause terminology. Internation Menopause
Society. Promoting education and research on midlife women’s
health. http://www.imsociety.org/menopause_terminology.php.
9. Shakila. P, et al. (2014). An Assessment of Women’s Awareness and
Symptoms in Menopause (A Study with Reference to Academic
Women’s at Sri Lanka). Journal of Business & Economic Policy ISSN
2375-0766 (Print) 2375-0774 (Online) Vol. 1, No. 2; December 2014
to different languages and was validated in different
countries. This paper recommends making the said tool to
be validated in our country so other researchers can also
use it. Translation of questionnaire to Filipino language
should be done by the experts and be validated.
10. Berek, et. al (2007). Menopause. Lippincott Williams & Wilkins
14th edition. Section VII, p1324.
11. Ellen Gold. (2011). The Timing of the Age at Which Natural
Menopause Occurs. Obstet Gynecol Clin North Am. 2011.
September; 38(3):425-440. doi:10.1016/j.ogc.2011.05.002.
12. Ensieh Noroozi, et al. (2013). Knowledge and attitude toward
menopause phenomenon among women aged 40-45 years.J Educ
Health Promot. 2013; 2:25.
a
13. Al-Sejari M. Age at natural menopause and menopausal symptoms
among Saudi Arabian women in Alkhobar. [Electronic Version].
Journal of Menopause in Arab World. 2005; 9:45-74.
14. Mikkelsen, et al. (2007). Early menopause, association with
tobacco smoking, coffee consumption and other lifestyle
factors: a cross-sectional study. BMC Public Health. 2007; 7:149
doi:10.1186/1471-2458-7-149.
15. Al-Olayet, et al. (2010). Severity of menopausal symptoms, and
knowledge attitude and practices towards menopause among
Saudi women. Scientific Research and Essays Vol. 5 (24), pp. 4077-
4079, 18 December, 2010. http://www.academicjournals.org/SRE.
ISSN 1992-2248 ©2010 Academic Journals.
16. Kaunitz AM (2001). Oral contraceptive use in perimenopause. Am
J Obstet Gynecol. 2001 Aug; 185(2 Suppl):S32-7.
17. Heinemann, et al. (2003). Health and Quality of Life Outcomes.
International versions of the Menopause Rating Scale (MRS).
2003; 1:28.
Volume 41, Number 2, PJOG March-April 2017 25
 Embolization in abdominal
pregnancy: A case report*
By Jay Ian R. Argel, MD and Ma. Cristina P. Crisologo, MD, FPOGS
Department of Obstetrics and Gynecology, Philippine General Hospital, University of the Philippines-Manila

ABSTRACT

Abdominal pregnancy is a rare form of ectopic pregnancy. This type of pregnancy poses a difficult situation since it can
incur high morbidity to mother and the fetus. Diagnosis is often difficult and surgical management should be multidisciplinary
in approach. This paper presents a case 29-year-old who presents as missed abortion, subsequently diagnosed with abdominal
pregnancy. Embolization of major vessels prior to evacuation of products of conception in abdominal pregnancy is a management
option to prevent catastrophic complications such as hemorrhage.

Keywords: Abdominal pregnancy, abortion, ectopic, embolization, laparotomy, hemorrhage

INTRODUCTION laparotomy, salpingectomy. Her family medical history

Ectopic pregnancy is defined as pregnancy
implantation elsewhere than in the lining of the uterine
cavity.1 Pregnancies of ectopic origin comprise about 1-2%
of all pregnancies with majority of cases occurring at the
fallopian tube.1,2 Even rarer, are abdominal pregnancies
which comprise about 1% of all pregnancies.3,4
In recent years there have been an increase incidence
of ectopic pregnancies due to increased incidence in
salpingitis caused by sexually transmitted infections
like Chlamydia infection, and in part due to improved
diagnostics wherein unruptured ectopic pregnancy are
detected earlier.2
Ectopic pregnancies in general are the most common
cause of maternal mortality in the first half of pregnancy.2
Blood loss is the major cause of mortality in ectopic
pregnancies.1,2 Maternal morbidity and mortality are high
largely due to the hemorrhage as a consequence of the
detachment of the extrauterine placenta which may be
near to any major vessels in the pelvic cavity. Cornual and
abdominal pregnancies have five times greater risk of
being fatal.1,3
CASE
A 29-year-old gravida 2 para 0 (0010) sought consult
at the emergency room of tertiary hospital for abdominal
pain. She has no known co-morbidities and was operated
on for a previous ectopic pregnancy 5 years prior, at
the same hospital, where she underwent exploratory
*2nd Place, 2017 Philippine Obstetrical and Gynecological Society
(POGS) Interesting Case Paper Contest, April 6, 2017, Citystate Asturias
Hotel, Puerto Princesa City, Palawan
was unremarkable. She is a high school graduate with a
5-pack year smoking history with occasional alcoholic
beverage intake. She is currently unemployed. She had
her first coitus at 20 years-old with 1 sexual partner with
unknown sexual history.
She had her menarche at 14 years-old, with
subsequent menstrual periods coming at irregular
intervals, lasting for 5 days and soaking 2 pads per day with
no associated dysmenorrhea. Her last menstrual period
was on October 20, 2015 giving her an amenorrhea of 42
weeks at the time of consult since menses are irregular
and unsure.
This is her second pregnancy, her first pregnancy was
on 2011 which is a tubal pregnancy and she was operated
on in the same hospital.
History started 2 months prior to consult when
patient had missed menses. She did not have any prior
prenatal consults nor any examinations. A transvaginal
ultrasound was done which revealed an intrauterine
gestation of about 24 2/7 weeks with findings consistent
with an intrauterine fetal demise. She consulted at a
local hospital wherein work-up such as blood tests were
done which allegedly revealed normal result and she
was sent home. She was advised to follow-up and await
spontaneous passage of products of conception.
In the interim, patient was lost to follow up and had
occasional abdominal pain but otherwise an unremarkable
course. There was no vaginal bleeding nor passage of any
placenta-like tissues.
She decided to seek consult because of prolonged
undelivered fetal death in utero. At the obstetric admitting
section, she had a blood pressure of 110/80, heart rate of 84
and respiratory rate of 20 with essentially normal systemic
findings. Focusing on the abdomen, the fundic height is

Volume 41, Number 2, PJOG March-April 2017 33

24 cm with an estimated fetal weight of 1.0-1.2 kg. Her
abdomen is soft and nontender. On internal examination,
she had normal external genitalia, nulliparous vagina,
cervix is closed and firm, corpus seemed to be enlarged
to 24 weeks’ size, with no adnexal masses and tenderness
appreciated.
The patient was initially managed as a case of
abortion and was admitted for induction of labor to allow
spontaneous passage of products of conception. Due
to failed induction and high index of suspicion, a repeat
transvaginal ultrasound was done.
On transvaginal ultrasound, the sonographic
impression showed the possibility of an extra-uterine
pregnancy probably abdominal with normal sized uterus
with thin endometrium, and normal ovaries. (Figures 1
and 2). The fetus had no cardiac activity, and biometric
parameters were consistent with 23 4/7weeks’ age of
gestation.
An abdominal computed tomography scan with
triple contrast was also done which was signed out as
extrauterine pregnancy. Findings were described as an
extrauterine pregnancy described large complex mass in
Figure 1. Transvaginal Ultrasound showing the empty uterus
alongside the fetal head.
Figure 2. Transvaginal Ultrasound showing bilateral ovaries to
rule out ovarian pregnancy.
34 Volume 41, Number 2, PJOG March-April 2017
the right abdominopelvic region measuring 14.7 x 13.1 x
10.4 cm with a single extrauterine fetus demonstrating
overlapping calvarial sutures. A heterogenously-enhancing
soft tissue component with a maximum thickness of
3.6 cm was seen at the superior wall of the mass likely
representative of the placenta. It appeared to be supplied
by the uterine vessels as well as distal branches of the
right internal iliac artery. The uterus and adnexae were
unremarkable.
Further description of the mass is that it is intimately
related to but maintains a clear plane of differentiation
from the right aspect of the uterine fundus and corpus,
and the right fallopian tube inferiorly. Superiorly, it
displaces the adjacent bowel loops without subsequent
bowel obstruction. Posteriorly, it compresses the inferior
vena cava and intimately related to the abdominal aorta.
Anteriorly, it abuts muscular layer of the abdominopelvic
wall. The final impression by CT scan is extrauterine
pregnancy.
A multidisciplinary consultation was done with other
services and the plan for the patient is for pre-operative
embolization to be followed by exploratory laparotomy,
adhesiolysis, and evacuation of products of conception.
The patient was referred to Thoracovascular surgery
service for the involvement of the major vessel. She was
also seen by the Interventional Radiology service for pre-
operative embolization to minimize blood loss prior to
the evacuation of the products of conception through
laparotomy.
Patient underwent pre-operative embolization of
feeding vessels a day prior to exploratory laparotomy. The
patient was under intravenous sedation of midazolam
and fentanyl. Abdominal aortogram was performed to
assessed all the possible feeding vessels to the placenta
using a pigtail French 5 catheter. Lumbar 4 on the right
was embolized using contour embolization particles 355-
500 microns mixed with Ultravist 370 mg and gel foam
injection. (Figure 3)
After embolization of the right Lumbar 4 artery,
another abdominal aortogram was done and right ovarian
artery was assessed to be involved. The right ovarian
artery was embolized using Contour size 355-500 microns
followed by gelfoam. Additional vortex pushable coil size
4 x 4 millimeter inserted through Progreat microcatheter
advanced to the depth of the right ovarian artery. (Figure 4).
Total operative time during embolization was 4 hours
and pressure dressing and sandbag was applied to the left
femoral artery for several hours post procedure. Patient
tolerated procedure well and there were no bleeding or
hematoma noted.
Preoperatively blood products were made available,
a total of 6 units of packed red blood cells were prepared.
Surgery was performed under general anesthesia a day

Figure 3. Lumbar 4 on the right was embolized using contour
embolization particles 355-500 microns mixed with Ultravist
370 mg and gel foam injection.
Figure 5. Grossly normal bilateral ovaries and encapsulated
mass at the right broad ligament.
completely separated. There was a 13 x 12 x 9 cm well-
circumscribed encapsulated mass (Figure 6) at the right
broad ligament which on cut section revealed a stillbirth
macerated baby boy, 624 grams. The placenta measured
12 x 10 x 7 centimeter with a 3 vessel umbilical cord
measuring 23 x 1 cm. (Figure 7)
The right fallopian tube was surgically absent. The
left fallopian tube had an obstructed fimbriated end
which was surgically corrected by doing left fimbrioplasty
by everting the edges of the obstructed fimbriated end
and doing simple interrupted sutures on the edge using
Chromic 4-0 sutures. Patient tolerated procedure well and
estimated blood loss was only 300 milliliters.

Figure 4. Right ovarian artery was embolized using Contour

size 355-500 microns followed by gelfoam. Additional vortex
pushable coil was also used.

after the embolization. The procedure was exploratory

laparotomy, evacuation of products of conception, left
fimbrioplasty under general anesthesia. Intraoperatively
there was no hemoperitoneum and both ovaries were
grossly normal. (Figure 5)
Double Kelly clamping of the right tuboovarian
ligament was performed to separate the right ovary from
the uterus and products of conception. The product of
conception was removed from the broad ligament by
opening up the broad ligament and doing series of double Figure 6. Encapsulated mass at the right broad ligament
Kelly clamping and suture ligation circumferentially until measuring 13 x 12 x 9 cm.

Volume 41, Number 2, PJOG March-April 2017 35

 Patient had an unremarkable course at the wards and
was discharged on day 3 post-operative day.
Figure 5. Cut section of the encapsulated mass showed
macerated stillbirth baby boy.
Figure 5. Postsurgery showing the normal bilateral ovaries,
surgically absent right fallopian tube, and normal uterus.
DISCUSSION
Ectopic pregnancy is a rare event with most occurring
at the fallopian tube. Since the site of fertilization is the
fallopian tube various tubal pathologies such as salpingitis
can cause agglutination of the folds of the endosalpinx
thereby allowing passage of sperm, but prevents the
normal transport of the larger morula.1 Abdominal
36 Volume 41, Number 2, PJOG March-April 2017
pregnancy is a rare event with an estimated incidence of
about 1 in 402 pregnancies in developing countries and
1 in 10,000 pregnancies in industrialized countries.5 The
higher incidence in non-industrialized countries can be
explained by reduced diagnostic options.6
Abdominal pregnancies can be classified as primary
when the pregnancy occurs as a direct implantation on
the peritoneum, and is associated with normal fallopian
tubes, normal ovaries, and no tubal fistula. It may, more
commonly, be a secondary abdominal pregnancy wherein
the pathology occurs either as a result of tubal abortion or
rupture.1
The clinical symptoms of an uncomplicated abdominal
pregnancy described in literature are rather unspecific,
among which the most frequently encountered: persistent
abdominal or suprapubic pain (100%), no delay in
menstruation, bloody vaginal discharge, gastrointestinal
symptoms like nausea and vomiting (70%), painful fetal
movements (40%), general malaise (40%), altered bowel
movements.6 In this case, the presenting symptom is only
non-specific abdominal pain which occurs intermittently.
Thus, the suspicion of an abdominal pregnancy based on
these non-specific signs may be missed out in the early
part of the pregnancy.
With the advent and easy access to imaging
procedures, ultrasound in particular, such abnormal
pregnancies should be more readily picked up. In our
index case, although a second trimester ultrasound was
done, it may have been missed because the sinologist just
concentrated on the measurement of the fetus, without
correlation to the other pelvic and abdominal structures.
With the aid of various diagnostics, exact location of
the pregnancy can be described, in our case, the location
is in the the right aspect of the uterine fundus and corpus,
and the right fallopian tube and closely related to the
inferior vena cava and aorta.
Numerous implantation sites have been encountered
in literature among which are uterine, omental, vital
organs, large vessels, cul de sac, bowel, appendix, broad
ligament, pelvic sidewall, peritoneum and spleen.6
Diagnosis can be confirmed by imaging, and it can
show details like vascularization, placental attachment
and its relationship to adjacent organs. On ultrasound,
findings of abdominal pregnancy include the following: (1)
presence of fetus outside the uterus, (2) absence of the
uterine wall between the bladder and the fetus, (3) extra
uterine location of the placenta, (4) poor visualization of
the placenta, (5) pseudo-placenta previa appearance,
oligohydramnios, fetal parts adjacent to the mother’s
abdominal contents, abnormal fetal presentation, and
the absence of amniotic fluid volume.8 In this index case,
the suspicion of an abdominal pregnancy was made
on the basis of the finding of an empty uterus with thin
endometrium lateral to the fetus.
More advanced imaging such as magnetic resonance
imaging and computed tomographic scan are now readily
available. These imaging techniques provide the advantage
of giving clearer appearances of the subject of focus in
multiple planes. More importantly, it provides a clearer
definition of the placenta and its vascularization and its
relationship to the adjacent organs in the abdominal
cavity.8
Management option is surgical through laparotomy
due to the risk of hemorrhage. It is for this reason
that surgery should be carefully planned and properly
crossmatched blood products should be readily available
for blood transfusion.
Removal of the placenta poses a big challenge.
The question whether to remove it or not depends
whether preoperatively its blood supply can be secured.
Removing the placenta results in less morbidity such
as fewer complications like septicemia, fewer repeat
hospitalizations and surgery, bowel obstruction, fistula
or disseminated intravascular coagulation, however it
is associated with increased mortality rate.4,5 If placenta
is not removed, it is recommended to monitor human
chorionic gonadotrophin.4
Preoperatively angiography is done is to identify all
sources of blood supply to the placenta and to embolize
vessels that could be difficult to ligate during surgery.
Routine angiographic evaluation should include abdominal
aortography with renal evaluation, selective celiac and
superior mesenteric arteriography, and selective internal
iliac arteriography including the hypogastric vessels.8
Embolization can play a great role before and after
REFERENCES
1. Lentz GM, Lobo RA, Gershenson DM, and Katz, VL. Comprehensive
Gynecology, 6th ed. USA: Elsevier Mosby, 2012.
2. Cunningham F, Leveno K, Bloom S, Hauth J, Rouse D, Spong C.
Williams Obstetrics. 23d edition. McGrawHill; 2010.
3. Nwobodo EI. Abdominal pregnancy. A case report. Ann Afr Med.
2004; 3(4):195-196.
4. Baffoe P, Fofie C, Ganau BN. Term Abdominal Preganancy with
Healthy Newborn: A Case Report. Ghana Med J. 2011 Jun; 45(2):
8183.
5. Ombelet W, Vendermerve JV, Van Assche FA. Advanced
extrauterine pregnancy: description of 38 cases with literature
survey. Obstet Gynecol Surv. 1988; 43(7):386-97.
6. Bohlitea R, Radoi V, tufan C, Horhoianu IA, Bohlitea C. Abdominal
pregnancy - Case presentation. J Med Life. 2015 Jan-Mar; 8(1): 49-
54.
exploratory laparotomy. Embolization can be defined
as any endoluminal procedure, vascular or nonvascular,
to occlude a vessel to obtain therapeutic benefit.
Angiographic arterial embolization is a technique that
can be utilized to manage abdominal pregnancy which
involves blockage of feeding blood vessels using synthetic
materials such as microcatheter and gelfoam or coils.9
For this particular case, embolization is warranted
since there are major feeding vessels seen on abdominal
CT scan that may cause hemorrhage and would likely
to reduce the vascularity of the placenta, hence it will
facilitate complete removal of the placenta and products
of conception during surgery. Postoperative embolization
can also be done using same technique to prevent bleeding
of retained placenta.8 Data on morbidity and mortality of
pre or post operalive embolization is limited, however,
complications include vessel puncture causing hematoma,
pseudoaneurysm, arteriovenous fistula, dissection,
intraluminal thrombosis and embolus which can be
attributed to the use of microcatheters, microguides, and
use of embolization agents such as coils and polymerizing
materials.9
Methotrexate therapy could be added to surgical
treatment. It can be used in postoperative period to aid
in absorption of the retained placenta. It might increase
infectious complications because of rapid tissue necrosis,
but some authors argue for complete regression of the
placenta. Methotrexate provides the advantage since it
can quickly reduce the HCG level, however using it directly
after surgery can lead to rapid placental lobular necrosis
and likely cause intraabdominal bleeding.10
7. Nkusu Nunyalulendho D, Einterz EM. Advanced abdominal
pregnancy: case report and review of 163 cases reported since
1946. Rural Remote Health. 2008 Oct-Dec; 8(4):1087.
8. Nkusu Nunyalulendho D, Einterz EM. Advanced abdominal
pregnancy: case report and review of 163 cases reported since
1946. Rural Remote Health. 2008 Oct-Dec; 8(4):1087.
9. Bilbao JI, Martínez-Cuesta A, Urtasun F, Cosín O. Complications
of Embolization. Seminars in Interventional Radiology. 2006;
23(2):126-142. doi:10.1055/s-2006-941443.
10. Agarwal N, Odejinmi F. Early abdominal ectopic pregnancy:
challenges, update and review of current management. The
Obstetrician & Gynaecologist. 2014; 16:193-8.
Volume 41, Number 2, PJOG March-April 2017 37
 Idiopathic central precocious
puberty: A case report*
By Mariel Anne C. dela Rea, MD and Marian C. Dichoso, MD, FPOGS
Department of Obstetrics and Gynecology, De La Salle University Medical Center

ABSTRACT

Central precocious puberty is characterized by early pubertal changes, acceleration of growth velocity, and rapid bone
maturation. It is a relatively rare disorder, with an incidence rate of about 1 : 5000 – 1 : 10 000 individuals in the general population;
it is more frequent in girls than in boys. This is a case of a 7 year-old female complaining of onset of menstruation. Physical
examination revealed advanced pubertal changes of Tanner stage 4-5 for breast and stage 3 for pubis. Diagnostic evaluation
revealed well developed internal genitalia, markedly elevated LH levels, advanced bone aging and a normal cranial MRI. Based on
clinical and diagnostic evaluations, a diagnosis of idiopathic central precocious puberty was made and the patient was started on
GnRHa therapy. It is important to initiate therapy early in patients with central precocious puberty so as to prevent compromised
adult height and psychosocial embarrassment.

Keywords: Precocious puberty, central precocious puberty, idiopathic central precocious puberty

INTRODUCTION

P
hysical changes during puberty are controlled by the
hypothalamic pituitary gonadal axis which increases
its activity before the onset of clinical puberty. The
pulsatile secretion of gonadotropin releasing hormone
(GnRH) increases and stimulates the pulsatile release of
luteinizing hormone (LH) and to a lesser extent follicle
stimulating hormone (FSH). This initially occurs at night
and then later also during the day with consequential rise
in gonadal steroid levels. Signs of pubertal maturation are
described by Tanner staging. In girls, breast development
is rated from 1 (preadolescent) to 5 (mature), and stage
2 (appearance of the breast bud) marks the onset of
pubertal development. Pubic hair stages are rated from
1 (preadolescent, no pubic hair) to 5 (adult), and stage Figure 1. In girls, breast development is rated from 1 (preadoles-
2 marks the onset of pubic hair development.1 (Figure 1) cent) to 5 (mature) and stage 2 (appearance of the breast bud)
The onset of puberty in girls is marked by breast budding marks the onset of pubertal development. Pubic hair stages are
rated from 1 (preadolescent, no pubic hair) to 5 (adult), and
(Tanner stage 2) followed by appearance of pubic and
stage 2 marks the onset of pubic hair development.
axillary hair then maximal growth velocity and finally Source: Jean-Claude Carel, MD and Juliane Leger, MD. Precocious Puberty. The N
menarche.2 Engl K Med 2008; 358:2366-77
Precocious puberty is classically defined as the onset
of secondary sexual characteristics before the age of 8 years the median age of menarche remains unchanged.
in girls and 9 years in boys. The prevalence of precocious New guidelines have been set to help in determining
puberty is about 10 times as high in girls as in boys.1 There which girls should be evaluated. These guidelines state
are controversies on the age threshold for precocious that Caucasian girls older than 7 years old and African
puberty. Pubertal changes and sexual maturation were American girls older than 6 years-old, with early breast
noted to occur earlier in African American girls however and/or pubic hair development, should be investigated
further in the following condition 1) rapid progression
of skeletal maturation (bone age >2 SD of chronological
*3rd Place, 2017 Philippine Obstetrical and Gynecological Society (POGS)
age), 2) new central nervous system (CNS) findings and
Interesting Case Paper Contest, April 6, 2017, Citystate Asturias Hotel, 3) psychosocial disturbances related to pubertal changes.3
Puerto Princesa City, Palawan Precocious puberty can be divided into central or
38 Volume 41, Number 2, PJOG March-April 2017
gonadotropin dependent precocious puberty wherein
there is early activation of pulsatile GnRH secretion. This
could be due to hypothalamic lesions but in most cases
the cause is idiopathic. Management is medical and often
directed to halting the maturation of the hypothalamic
pituitary gonadal axis. Peripheral or gonadotropin
independent precocious puberty results from sex steroid
exposure independent of hypothalamic-pituitary gonadal
activation. It may be due to gonadal or adrenal tumors
secreting exogenous sex steroids and genetic disorders
such as McCune-Albright syndrome. Surgery is indicated Uterus Endometrium
for GnRH independent precocious puberty due to
gonadal tumors. Peripheral precocious puberty can lead
to activation of pulsatile GnRH secretion and to central
precocious puberty.1

CASE REPORT

The index patient is a 7 year-old gravida 0 who

presented at the clinic with the chief complaint of vaginal
bleeding of 2 days duration, using 4 moderately soaked
pads per day with no associated pelvic pain. Breast Left Ovary Right Ovary
budding was noted at 5 years of age and pubic hair Figure 2
growth at 6 years-old. The patient was born at around 28
weeks age of gestation and was admitted for 3 months
at the neonatal intensive care unit due to prematurity.
Her mother was 19 years-old at that time. Her mother’s
menarche was at 10 years of age. There was no family
history of menstrual disorder or congenital malformations.
Her parents are separated and she is being raised by her
paternal grandparents. The patient has no other siblings.
The patient denies any sexual contact. She is right handed.
On physical examination, the index patient had
Tanner staging 4 for breast (secondary mound of areola
and papilla above the breast), Tanner stage 3 for pubis
(labial hair spreads over mons pubis) and note of axillary
hair. She weighed 36kg and had a height of 137cm which
was at the 94th percentile for girls at her age. She was not
pale and had pink palpebral conjunctiva. She had a soft
flat abdomen with no palpable mass or tenderness. Pelvic
examination revealed normal appearing external genitalia
and an intact vaginal canal with passage of minimal
amount of menstrual like fluid. As the patient was a virgin,
a bimanual rectal examination was done revealing good Figure 3
sphincteric tone, smooth rectovaginal septum and no
palpable masses. stimulating hormone (FSH) and luteinizing hormone (LH)
Initial working impression was precocious puberty. were elevated with LH/FSH ratio of 3:1 (Figure 4). Serum
At the third day of menstruation, transrectal androgens levels were within normal range. Her estradiol
ultrasound showed the presence of normal sized uterus level was within pubertal range (Figure 5). An x-ray of the
with a length of 3.53 cm and endometrial thickness of patient’s non-dominant hand revealed a bone aging of 11
1.15 cm. Both ovaries were normal in size with presence years old using the Greulich-Pyle method (Figures 6 & 7).
of follicles (Figures 2 & 3). Serum thyroid function Cranial magnetic resonance imaging (MRI) with contrast
tests were within normal range. Both levels of follicle revealed a normal result (Figure 8).

Volume 41, Number 2, PJOG March-April 2017 39

 Figure 7
Figure 4

Figure 5

Figure 8

At this time, the impression was idiopathic central

precocious puberty.
After the initial cycle of menstruation which lasted for
5 days, the patient had another 2 cycles of menstruation
occurring at 35-52 days interval, lasting for 5 days. After
her third cycle and prior to initiation of therapy, the index
Figure 6 patient weighed 39 kg and had a height of 139cm (height
40 Volume 41, Number 2, PJOG March-April 2017
increase of 2 cm in 3 months). Tanner staging of the breast
had progressed to stage 5 while the pubis remained at
stage 3 (Figures 9, 10 & 11).
The patient was started on gonadotropin releasing
hormone agonist (GnRHa), leuproride acetate, 3.75 mg
given at 28 days interval. Psychosocial counseling was also
offered to the patient and her family.

CASE DISCUSSION

This is a case of a 7 year-old complaining of onset of

menstruation. Physical examination revealed advanced
pubertal changes of Tanner stage 4-5 for breast and stage
3 for pubis. Diagnostic evaluation revealed well developed
internal genitalia, markedly elevated LH levels, advanced
bone aging (>2SD of chronological age) and normal
cranial MRI. Based on clinical and diagnostic evaluation,
a diagnosis of idiopathic central precocious puberty was
made and the patient was started on GnRHa therapy.
Central precocious puberty is characterized by
hypothalamic-pituitary-gonadal axis activation leading to Figure 9
progressive pubertal development, acceleration of growth
velocity, and rapid bone maturation that often results in
reduced adult height. It is a relatively rare disorder, with
an incidence rate of about 1 : 5000 – 1 : 10 000 individuals
in the general population; it is more frequent in girls
than in boys, with the female : male ratio estimated to
be between 3 : 1 and 23 : 13. It is more common than
peripheral precocious puberty and accounts for up to 90%
of published cases4. Idiopathic central precocious puberty
is sometimes familial and occurs more frequently than
organic central precocious puberty. It is more common in
girls (74%) than in boys (60%).3 The onset of organic central
precocious puberty is earlier usually before the age of 3
in girls.3 On the other hand, organic central precocious
puberty is more common in boys than girls (40-90% vs.
8-33%).
A search for local data revealed a total of 11 reported
cases of precocious puberty, only 2 of which were central
precocious puberty - a case of hypothalamic hamartoma
and a case of 3 year-old with idiopathic central precocious
puberty.5-15
Many environmental, endocrine and genetic factors
affect the onset of puberty: 1) race 2) early maternal Figure 10
menarche 3) low birth weight 4) excessive weight gain in
infancy and early childhood 5) after international adoption
6) when no father is present in the household1.However,
these factors are associated with only a fraction of causes
of early puberty and are not considered as main etiology
of the disease. Factors noted in the index patient include
prematurity at birth (low birth weight) and the absence of
a father in the household.
Examination of a child with precocious puberty should Figure 11

Volume 41, Number 2, PJOG March-April 2017 41

start with accurate family and personal medical history,
physical examination and pubertal staging. A complete
personal history is necessary, including the age at onset of
puberty and progression of pubertal manifestations which
is often more rapid in precocious puberty. There also
should be note of any evidence suggesting possible central
nervous system dysfunction, such as headache, increased
head circumference, visual disturbances, or seizures.
Family history should include the age at onset of puberty
in parents and siblings. Growth should be evaluated since
progressive precocious puberty is associated with a high
growth velocity. The stage of pubertal development should
be classified as described by Tanner. Careful assessment
is needed in obese girls to avoid overestimating breast
development. The development of pubic hair results
from the effects of androgens, which may be produced
by functioning ovaries in central precocious puberty. In
girls, pubic hair in the absence of breast development is
suggestive of adrenal disorders, premature pubarche, or
exposure to androgens.1 It would be helpful to assess
signs of specific causes of precocious puberty, such as
hyperpigmented skin lesions suggesting neurofibromatosis
or the McCune-Albright syndrome.
Diagnosis of central precocious puberty is based
on the signs of activation of the hypothalamic-pituitary-
gonadal axis in girls younger than 8 years-old. This includes
breast tanner stage of >1, uterine volume (longitudinal
diameter >3.5cm), increased height velocity, bone age
>2 SD above chronological age, menstrual bleeding and
increased basal or stimulated LH3. The course of precocious
puberty is considered progressive or accelerated when
tanner stage 3 is reached before 10 years of age. In the index
patient, breast budding was noted at 5 years-old and pubic
hair growth at 6 years of age. Upon initial examination
tanner staging was 4 and 3 for breast and pubis, respectively
but there was progression to tanner stage 5 for breast after
2 months indicating possible rapid progression. Further
diagnostic tests revealed uterine length of 3.53 cm, markedly
elevated LH levels and increased height velocity, all of which
are associated with progressive precocious puberty.
It is necessary to establish the degree of skeletal
maturation. In precocious puberty, skeletal maturation
and statural growth are accelerated (the former more than
the latter), so the child is mature more than they grow.
The child with precocious puberty is deprived, according
to the age of onset, of a certain period of normal pre-
pubertal growth and thus final adult height is shorter than
the target height. A reference atlas such as the one by
Greulich and Pyle can be used to evaluate the effect of
sex steroids on epiphyseal maturation; the bone age of
patients with precocious puberty is consistently greater
than their chronologic age (> 2 SD above chronological
age). In the index patient, bone aging of the non dominant
42 Volume 41, Number 2, PJOG March-April 2017
hand revealed a skeletal age of 11 years-old, much greater
than her chronological age.
The gold standard for evaluation of precocious
puberty is the measurement of gonadotropins at 0,
15, 30, 45, 60 and 90 minutes after stimulation by
intravenous GnRH (which is unavailable in many countries
including the United States and the Philippines).3 Early
activation of hypothalamic-pituitary-gonadotropin axis is
demonstrated by maximal luteinizing hormone level after
GnRH stimulation. In an attempt to simplify the GnRH test,
a single determination of basal LH of > 0.3 IU/L or an LH
peak ≥ 5 IU/L at 30 to 60 minutes after GnRH stimulation
suggest progressive central precocious puberty.3,23 Onset
of puberty starts with increased LH secretion compared to
FSH and so an increased LH/FSH ratio may be indicative of
central precocious puberty. In the absence of intravenous
GnRH, basal LH and FSH levels were obtained from the
index patient on her 3rd day of menstruation. Basal LH level
was at 15.03mIU/ml and her LH/FSH ratio was 3:1. Both
results established the diagnosis of central precocious
puberty. (IU/L=mIU/ml)
Gonadotropin levels in children younger than 3
years old should be interpreted with caution, because
gonadotropin levels are normally high in this age group.
Random measurements of follicle-stimulating hormone
are not useful, since they vary little throughout pubertal
development.1
In all cases of central precocious puberty, MRI of the
brain should be performed to rule out any hypothalamic
lesion. The prevalence of such lesions is higher in boys (40
to 90%) than in girls (8 to 33%) presenting with precocious
puberty and is much lower when puberty starts after
the age of 6 years in girls (<2%).1 The most frequent CNS
lesion associated with precocious puberty is hypothalamic
hamartoma. Small and pedunculated hypothalamic
hamartomas are often associated with central precocious
puberty while large and sessile ones are associated with
seizures. The younger the child (<4 years-old), the higher
the possibility of a CNS lesion in central precocious puberty.
Cranial MRI of the index patient revealed normal result.
In at least 50% of cases of precocious puberty, pubertal
manifestations will regress or stop progressing, and no
treatment is necessary.1 The decision to treat depends on
the child’s age, the rate of pubertal progression and height
velocity. Pubertal progression is considered slow if there
is no choice in Tanner staging of breast and pubis during
a 6 month observation. Height velocity is accelerated if
it is more than 6 cm per year. In a 3 month observation
of the index patient, tanner stage for breast progressed
from 4 to 5 and height was increased by 2 cm. For cases
in which precocious puberty progresses, concerns include
early menarche in girls and short adult stature due to early
epiphyseal fusion and adverse psychosocial outcomes.1
Thus, the two main reasons for treating patients with
idiopathic central precocious puberty is to improve
psychosocial well being and to prevent compromised
adult height.
GnRH agonists are the gold standard in the
management of progressive central precocious puberty.
They provide continuous stimulation of the pituitary
gonadotrophs, leading to desensitization and decrease in
the release of LH and, to a lesser extent, FSH. This leads to
decreased sex steroid production. Factors affecting height
gains include baseline bone age (markedly advanced
bone age associated with shorter adult height) and
duration of treatment (onset of treatment at a younger
age and a longer duration of treatment associated with
greater height gain). Normal adult height can be achieved
if treatment is started before bone maturation is too
advanced and if gonadal suppression is maintained for
several years.
Most common GnRH agonist used for the treatment
of central precocious puberty is the monthly 3.75 mg
intramuscular injection. Dose can be increased depending
on the response of the patient to the therapy. Other
forms/dosage of GnRH agonist have also been used for
central precocious puberty-3-month depot formulations
(11.25 and 30 mg) and the once-yearly histrelin
subcutaneous implants. Although these formulations
have not been studied as extensively as the 1 month
depot leuprolide acetate formulation, they have proven
to be as effective and with better compliance due to the
less frequency of administration.16,17,18 Higher LH and FSH
levels were seen with the 11.25 mg 3-month leuprolide
acetate dose but no differences in final growth velocity
and bone age progression was noted. However, during
monitoring of treatment higher dosing was required in
some circumstances.18 The index patient was offered both
the 1 month (3.75 mg) and 3 month (11.25 mg) dosing but
her family opted to start the monthly leuprolide acetate
administration.
Several methods have been proposed in monitoring
pubertal suppression during GnRH agonist therapy.
Traditionally, LH level of < 2 IU/L obtained 30-60 minutes
after GnRH stimulation indicate adequate pubertal
suppression.3,19,20 Other methods have been investigated
and appear more applicable to the Philippine setting
since GnRH is unavailable. A study done by Zung et al
compared basal, post GnRH agonist and first voided
urinary LH as alternative methods to GnRH stimulation
test in assessing pubertal suppression during treatment.21
The study concluded LH levels obtained 24 hours after the
GnRH agonist injection was accurate enough to determine
adequate pubertal suppression. Basal LH, urinary LH and
estradiol levels did not correlate well with the degree of
suppression.21 In another study, LH level ≤ 2.5 mIU/ml
obtained 90 minutes after GnRH agonist administration
indicates adequate suppression with a sensitivity of 100%
and specificity of 88%.22 A study by Brito et al indicated
LH level of < 6.6 IU/L obtained 2 hours after GnRH agonist
administration was consistent with adequate pubertal
suppression.20 Repeat LH level was determined in the index
patient 90 minutes after her 3rd monthly GnRH (3.75 mg)
administration. The result was 1.83 mIU/ml (basal LH level
was at 15.03mIU/ml).
Aside from laboratory evaluation, the patient must
be monitored clinically to assess gonadal suppression.
The patient’s BMI, tanner staging and growth velocity
should be evaluated every 3-6 months. Bone age should
be evaluated every 6 months. Successful therapy would
indicate arrest or regression of tanner staging and
bone aging nearing chronological age.22 At the time of
submission of this paper, the index patient had completed
6 months of treatment. Her height remained unchanged
after her third GnRHa injection at 141 cm. Tanner staging
of the breast regressed to tanner stage 3 after the fourth
GnRHa injection and to tanner stage 2 after the sixth
injection. There was no progression of tanner staging for
her pubis.
The optimal time to stop treatment has not been
established, but most studies suggest that treatment
beyond the age of 11 years is not associated with significant
further height gain.1 Pubertal manifestations reappear
within months after discontinuing GnRH agonist treatment.
Follow up 6 months after completion of treatment is
recommended to ensure puberty subsequently progresses
normally.
For cases in which precocious puberty is caused by a
central lesion (e.g., a mass or malformation), management
of the lesion generally has no effect on the course of
pubertal progression. Initial management of hypothalamic
hamartomas include the use of GnRH agonist since
significant risk is associated with surgery and removal of
the lesion does not guarantee pubertal regression.23
No adverse effects on reproductive development
or fertility have been found to be associated with GnRH
agonist therapy. There was reversibility of hypothalamic
pituitary ovarian axis suppression after cessation of GnRH
agonist treatment.24 In a prospective study involving
long term follow-up and adult callback after completion
of treatment with 1 month leuprolide acetate depot, all
patients achieved pubertal hormonal response within 1
year after cessation of treatment and no impairment of
reproductive function was observed in adulthood.25
In contrast to adults, hypoestrogenic state induced
by the long term use of GnRH agonist in early pubertal
stage does not result in deterioration of the bone mineral
density.26 Pituitary-ovarian suppression by GnRH agonist
does not reverse or prevent bone mass acquisition.27
Volume 41, Number 2, PJOG March-April 2017 43
 The negative psychosocial implications of early sexual
development should not be underestimated. Precocious
pubertal changes have been associated with adverse
psychosocial outcomes and psychological evaluation may
be useful. However, there is limited available data that are
specific to patients with precocious puberty. A study done
by Baumann et al in 2001 showed that patients with history
of precocious puberty had behavioral problems including
neuroticism and feelings of insecurity.28 Patients suffering
from precocious puberty are at risk for depression, anxiety,
difficult socialization, early sexual activity at a young age
and sleep disturbances.
REFERENCES
1. Jean-Claude Carel, MD and Juliane Leger, MD. Precocious Puberty.
The N Engl K Med. 2008; 358:2366-77.
2. Lobo R, Lentz G, Gershenson D and Katz V: Comprehensive
Gynecology, 6th ed. USA: Elsevier Mosby, 2012.
3. Franco Antoniazzi and Giorgio Zamboni. Central Precocious
Puberty Current Treatment Options. Pediatr Drugs. 2004; 6
(4):211-231.
4. Martin Chalumeau, MD, Wassim Chemaitilly, MD, Christine Trivin
PhD, Luis Adan, MD, Gerard Breart, MD and Raja Brauner, MD.
Central Precocious Puberty in Girls: An Evidence-Based Diagnosis
Tree to Predict Central Nervous System Abnormalities. Pediatrics
Vol. 109 No. 1 January 2002.
5. Christine Marie Caligagan-Bucad. Precocious Puberty: A Case
Report. Philippine Scientific Journal. 2002; 35(2):44-58.
6. Ouano MML, Gamuac RC, Ortiz MH. Isosexual Precocious Puberty
and Gelastic Seizure with Hypothalamic Mass – Case Report and
Review of Literature. The PCMC Journal. 1992; 0.
7. Mercado-Asis LB, Gallardo LT, Reyes-Rivera CT, Araza LA. McCune-
Albright Syndrome. Congress Programme and Book of Abstracts.
1996; 0.
8. Torres, JRS. Precocious Puberty in a Child with an Ovarian Sex Cord
Tumor. Philippine Journal of Obstetrics and Gynecology. 1999; 0.
9. Madona Victoria Calderon-Domingo, Ina S. Irabon, Pure Sertoli Cell
Tumor of the Ovary, A Rare Cause of Isosexual Pseudoprecocious
Puberty in a Two Year Old Girl. Philippine Journal of Reproductive
Endocrinology and Infertility. January 2009; Vol. 6 (2): p. 68-79.
10. Carmela Lapitan, Liemer R Miranda. Precocious Puberty as
the Presenting Feature of Leydig Cell Tumor of the Testis.
PCHRDPC051089.
11. Enrico Gil C. Oblepias, Margaret Joyce A. Cristi-Limson. A Rare
Case of Isosexual Pseudoprecocious Puberty in a Patient with
Mixed Germ Cell Malignancy of the Ovary with Endodermal Sinus
Tumor and Dysgerminoma. Philippine Journal of Obstetrics and
Gynecology. October 2012; Vol. 36 (4): p. 166-174.
44 Volume 41, Number 2, PJOG March-April 2017
CONCLUSION
The onset of precocious puberty has important
physical and psychological consequences for affected
children and induces anxiety in their families. However,
not all girls with early signs of puberty require treatment.
It is necessary to make a rapid, correct diagnosis as well
as to form a judgment concerning the progression of the
condition based on a combination of clinical signs and
diagnostic evaluation thus providing the appropriate
treatment to prevent psychosocial embarrassment and
poor height prognosis in these patients.
12. Helen Valenzona Madamba, Ma. Cristina Palaez-Crisolongo. An
Ovarian Sex Cord Tumor with Annular Tubules. Philippine Journal
of Obstetrics and Gynecology. July 2012; Vol. 36 (3): p. 144-148.
13. Arlene Tiong-Samonte. Precocious puberty. Philippine Journal of
Pediatrics; Vol. 36 (1) : p. 65-77.
14. Cyriel Anthony I. Tingne, Agnes L. Soriano-Estrella. Juvenile
Granulosa Cell Tumor of the Ovary Presenting as Isosexual
Precocious Puberty: A Case Report. Philippine Journal of Obstetrics
and Gynecology. July 2015; Vol. 39 (3): p. 28-33.
15. Manish Gutch, Sukriti Kumar, Keshav Kumar Gupta, Abhinav
Kumar Gupta, Syed Mohd Razi. McCune-Albright Syndrome with
Hypophosphatemic Rickets. Journal of the ASEAN Federation of
Endocrine Societies. May 2015; Vol. 30 (1) : p. 40-43.
16. Lee PA, Klein K, Mauras N, Neely EK, Bloch CA, Larsen L, Mattia-
Goldberg C, Chwalisz K. Efficacy and safety of leuprolide acetate
3-month depot 11.25 milligrams or 30 milligrams for the
treatment of central precocious puberty. J Clin Endocrinol Metab.
2012 May; 97(5):1572-80. Epub. 2012; Feb 16.
17. Silverman LA, Neely EK, Kletter GB, Lewis K, Chitra S, Terleckyj O,
Eugster EA. Long-Term Continuous Suppression With Once-Yearly
Histrelin Subcutaneous Implants for the Treatment of Central
Precocious Puberty: A Final Report of a Phase 3 Multicenter Trial.
J Clin Endocrinol Metab. 2015 Jun; 100(6):2354-63. Epub. 2015
Mar 24.
18. Fuld K, Chi C, Neely EK. A randomized trial of 1- and 3-month
depot leuprolide doses in the treatment of central precocious
puberty. J Pediatr. 2011; 159(6):982.
19. Nurgun Kandemir, Huseyin Demirbilek, Zeynep Alev Ozon, Nazli
Gonc, Ayfer Aliasifoglu. GnRH Stimulation Test in Precocious
Puberty: Single Sample is Adequate for Diagnosis and Dose
Adjustment. J Clin Res Ped Endo. 2011; 3(1):12-17.
20. Vinicius N. Brito, Ana C Latronico, Ivo J.P. Arnhold and Bernice
B. Mendonca. A Single Luteinizing Hormone Determination 2
Hours After Depot Leuprolide is Useful for Therapy Monitoring
of Gonadotropin-Dependent Precocious Puberty in Girls. The
Journal of Clinical Endocrinology & Metabolism. Novemver 2009;
89(9):4338-4342.
REFERENCES
21. Amnon, Zung, Ella Burundukov, Mira Ulman, Tamar Glaser and Zvi
Zadik. Monitoring Gonadotropin-Releasing Hormone Analogue
(GnRHa) Treatment in Girls With Central Precocious Puberty: A
Comparison of Four Methods. Pediatr Endocr Met. 2015; 28(7-
8):885-893.
22. Huseyin Demirbilek, Ayfer Alikasifoglu, Nazli E. Gonc, Alev Ozon
and Nurgun Kandemir. Assessment of Gonadotrophin suppression
in Girls Treated with GnRH Analogue for Central Precocious
Puberty; Validity of Single Luteinizing Hormone Measurement
After Leuprolide Acetate Injection. Clinical Endocrinology. 2012;
76, 126-130.
23. Stewart L, Steinbok P, Daaboul J. Role of surgical resection in
the treatment of hypothalamic hamartomas causing precocious
puberty. Report of six cases. Journal Of Neurosurgery [J
Neurosurg]. 1998 Feb; Vol. 88 (2), pp. 340-5.
24. Thornton P, Silverman LA, Geffner ME, Neely EK, Gould E, Danoff
TM. Review of outcomes after cessation of gonadotropin-releasing
hormone agonist treatment of girls with precocious puberty.
Pediatric Endocrinology Reviews: PER [Pediatr Endocrinol Rev].
2014 Mar; Vol. 11 (3), pp. 306-17.
25. E. Kirk Neely, Peter A. Lee, Clifford A. Bloch, Lois Larsen, Di Yang,
CynthiaMattia-Goldberg, Kristof Chwalisz. Leuprolide Acetate
1-Month Depot for Central Precocious Puberty: Hormonal
Suppression and Recovery International Journal of Pediatric
Endocrinology. Volume 2010, p. 1-9.
26. Hong K. Park, Hae S. Lee, Jung H. Ko, Il T. Hwang, Jung S. Lim and
Jin S. Hwang. The effect of gonadotrophin-releasing hormone
agonisttreatment over 3 years on bone mineral density and body
composition in girls with central precocious puberty. Clinical
Endocrinology. 2012; 77:743-748.
27. Jung Hee Ko, Hyo Sung Lee, Jung Sub Lim, Shin Mi Kim, Jin Soon
Hwuang. Changes in Bone Mineral Density and Body Composition
in Children with Central Precocious Puberty and Early Puberty
Before and After One Year of Treatment with GnRH Agonist. Horm
Res Paediatr. 2011; 75:174-179.
28. D.A. Bauann, M.A. Landolt, R. Wetterwald, J.M. Dubuis, P.C.
Sizonenko, E.A. Werder. Psychological Evaluation of Young Women
After Medical Treatment for Central Precocious Puberty. Horm
Res. 2001; 56:45-50.
29. Gonul Catli, Pinar Erdem, Ahmet Anik, Ayhan Abaci, Ece Bober.
Clinical and Laboratory Findings in the Differential Diagnosis
of Central Precocious Puberty and Premature Thelarche. Turk
Pediatri Arsivi. 2015; 50:20-6.
30. John S. Fuqua. Treatment and Outcomes of Precocious Puberty:
An Update. J Clin Enocrinol Metab. June 2013; 98(6):2198-2207.
31. Melinda Chen and Erica A. Eugster. Central Precocious Puberty:
Update on Diagnosis and Treatment. Pediatr Drugs. 2015; 17:273-
281.
32. P.S.N. Menon, M. Vijayakumar. Precocious Puberty – Perspectives
on Diagnosis and Management. Indian J Pediatr. January 2014;
81(1):76-83.
33. Wassim Chemaitilly, Christine Trivin, Luis Adan, Valerie Gall,
Christian Sainte-Rose and Raja Brauner. Central Precocious
Puberty: Clinical and Laboratory Features. Clinical Endocrinology.
2011; 54:289-29.
Volume 41, Number 2, PJOG March-April 2017 45
 Mullerianosis of the urinary bladder:
First case report in the Philippines
By Jane Karla Garcia Cadavedo, MD; Marian C. Dichoso, MD, FPOGS
and Ernesto V. Arada III, MD, FPOGS
Department of Obstetrics and Gynecology, De La Salle University Medical Center

ABSTRACT

Mullerianosis is a rare, benign, and morphologically complex, tumor-like lesion that consists of an organoid structure with
normal Müllerian tissue. The diagnosis requires the presence of at least two of the three mullerian tissues: endometriosis,
endosalpingiosis, and endocervicosis. There are only less than twenty (20) cases reported in literature. At present there is no
published case report of mullerianosis here in the Philippines. This is a case report of a 30-year old Filipino woman who presented
predominantly with lower urinary tract symptoms of severe dysuria, hematuria, and lumbar pain and was evaluated for a urologic
problem secondary to a posterior bladder mass. Subsequent evaluations revealed the diagnosis of mullerianosis. This is where the
interest in mullerianosis sets, its potential to mimic a neoplastic lesion of the urinary tract from clinical and diagnostic viewpoints.
The clinical importance to diagnose this case correctly is of grave importance for appropriate management.

Keywords: Mullerianosis, endometriosis, endosalpingiosis, endocervicosis

INTRODUCTION The patient underwent hormonal treatment and had

M
ullerianosis is a very rare and complex tumor-like
lesion, first described by Young and Clement in
1996, composed of at least two (2) out of three
(3) mullerian tissues such as endometrial- endometriosis,
cervical-endocervicosis, and tubaric-endosalpingiosis.1
Up to present, this entity is very rare with fewer than 20
cases reported in English literature1-15. Currently there
is no published case report of this rare condition here in
the Philippines. Most of the published literature reports
presence of mullerianosis in the urinary bladder.1-8 It occurs
in nulliparous and multiparous women under the age
group, ranging from 23-53 years old in most literature.1-8
The rarity of this lesion may cause misdiagnosis;
its correct identification is tremendously important for
appropriate management, since patients may benefit
from hormonal therapy and surgical management may
perhaps be avoided.2
This paper presents the first case report of
mullerianosis of the urinary bladder here in the
Philippines. A 30-year old nulligravida who presented
with hematuria, dysuria, and lumbar pain, she underwent
computed tomographic urography which revealed a
bladder mass, probably a malignant neoplasm, suggestive
of a transitional carcinoma. Cystoscopy and transurethral
biopsy, however, revealed a probable case of mullerianosis.
Histochemical staining confirmed a case of mullerianosis.
*1st Place, 2017 Philippine Obstetrical and Gynecological Society (POGS)
Interesting Case Paper Contest, April 6, 2017, Citystate Asturias Hotel,
Puerto Princesa City, Palawan
26 Volume 41, Number 2, PJOG March-April 2017
clinical improvement after three (6) months of therapy.
Awareness of this lesion is necessary for proper diagnosis
and appropriate management.
CASE REPORT
This is a case of P.M., 30 years old, married,
nulligravida, Filipino, Catholic, from Indang, Cavite, and
works as an Information Technologist in Kuwait. She
consulted in the Philippines on October 16, 2015 with the
chief complaint of hematuria.
The patient was apparently well until one year prior
to admission when the patient started having severe
dysuria, and hematuria with note of passage of blood clot
per urine, associated with lumbar pain. The patient sought
consult with a private physician in Kuwait, a bimanual
examination revealed a palpable bladder mass, which was
confirmed by ultrasound. No further evaluation, follow up
and medications were started.
Six months prior to present consultation, the patient
sought another consult due to persistence of symptoms.
She then underwent computed tomographic urography
which revealed a large well-defined enhancing soft tissue
intraluminal growth in the antero-superior aspect of the
urinary bladder at the midline level, measuring 3.9 x 3.5 x
2.5 cm, with mild homogenous enhancement after contrast
administration, suggestive of neoplastic etiology, most
likely a transitional carcinoma, hence patient underwent
cystoscopy and transurethral biopsy. The cystoscopy
revealed that the mass forms a bridge in the middle of the
urinary bladder at the base separating bladder into two
halves. The growth at the dome of the urinary bladder On the same day of the consultation the patient was
extends to the right lateral wall. There were multiple blue requested by the obstetrician-gynecologist to undergo a
domed cysts with different sizes. Several biopsies were transvaginal ultrasound, which revealed a mass anterior
taken. Histologic report revealed the following results; the and separated from the uterine body measuring 3.51 x
lamina propria and the muscularis shows multiple tubular 3.07 x 2.81 cm (Figure 1). It is seen within the posterior
and glandular spaces lined by ciliated tubal like and wall of the urinary bladder. The sonologic diagnosis was a
non-ciliated columnar epithelium and a focal area lined bladder mass versus a parasitic subserous myoma.
by mucinous epithelium. A focus of hemosiderin laden The primary impression was mullerianosis of the
macrophages surrounding a strip of surface endometrial urinary bladder based on the histopathologic report and
like epithelium, some of the fragments is lined by an histochemical staining done in Kuwait, subsequently;
admixture of urothelium and mullerian epithelium. Some patient was given gonadotropin releasing hormone
of the fragments also show a few cystic nests and congested agonist 3.75 mg intramuscularevery 4 weeks for 3 doses.
vessels. Immunohistochemical staining was done After the third dose, a repeat transvaginal ultrasound
revealing that the epithelial lining of these tubular spaces was done and the previously seen bladder mass is still
showed positive for CK7, vimentin, estrogen receptor and evident, anterior and separated from the uterine body,
progesterone receptor and negative for CK20. The stroma measuring 3.47 x 2.71 x 2.32 cm (Figure 2).
surrounding some of these glands shows CD 10 positivity.
Final histochemical findings of the biopsy are compatible
with mullerianosis of the bladder.
The patient was advised resection of the bladder
mass, however, patient opted to go home to the
Philippines, hence her subsequent consultation.
On the day of consultation, the patient initially
consulted with a private urologist, an ultrasound of the
kidney, urinary bladder, and pelvis was requested which
revealed an isoechoic mass measuring 3.3 x 3.1 x 3.4 cm
seen arising from the superior wall of the urinary bladder.
Initial impression was endometriosis of the bladder.
The plan of the urologist was to do surgical excision
of the bladder mass. The patient was then referred
to an obstetrician-gynecologist for evaluation and co-
management.
Her past medical history is non-contributory, she Figure 1. Bladder mass (yellow arrows) as described pre-
had asthma since childhood; her last attack was in 2013. treatment with gonadotropin releasing hormone agonist.
Asterisk (*) posterior wall of the urinary bladder
She had breast cyst incision in 2005. For her menstrual
history, she had her menarche at twelve years old, with
regular menstrual periods occurring every twenty-eight
to thirty-five days, lasting for about five days, using two
moderately soaked pads per day. She started experiencing
non-progressive dysmenorrhea two years ago only on her
second day of menses, with no any other symptoms.
On physical examination, the external genitalia are
normal looking with normal distribution of pubic hair,
no masses, no lesion. Speculum exam revealed a smooth
vagina, with no masses, no lesion, with prominent rugae,
the cervix looks parous, pinkish, smooth, no masses, no
lesions, and with no discharge coming out of the cervical
os. Upon internal examination the cervix is midline
closed, non-parous, corpus slightly enlarged. Bimanual
examination revealed a 4 cm tender mass palpated anterior
to the cervix and posterior to the bladder. There is no Figure 2. Bladder mass (yellow arrows) as described post-
adnexal mass or tenderness, and no blood per examining treatment with gonadotropin releasing hormone agonist.
finger. All other systemic exams were unremarkable. Asterisk (*) posterior wall of the urinary bladder

Volume 41, Number 2, PJOG March-April 2017 27

 The patient at this time was asymptomatic and
physical exam revealed that the cervix is closed, non-
parous, and posterior, there is a 2 cm movable firm, non-
tender mass anterior to the cervix.
The gonadotropin releasing hormone agonist was
given for three more doses in Kuwait and at present the
patient remains to be asymptomatic.
CASE DISCUSSION
Mullerianosis is a rare benign new growth that
may present as a growing mass anywhere in the pelvic
area, it consists of three histologic tissues, comprised by
endometriosis, endocervicosis, and endosalpingiosis.1-2 It
was first described by Young and Clement in 1996, and is
defined as the presence of at least two of the three tissues
previously mentioned. They reported three cases where
the patients had masses up to 4 cm in maximal size, which
involved the posterior wall of the urinary bladder, treated
by transurethral resection. Microscopic examination
showed prominent involvement of the lamina propria and
muscularis propria by tubules and cysts lined by müllerian-
type epithelium.1
Up to present, this entity is very rare with fewer than
20 cases reported in English literature and in journals1-15.
Currently there is no published case report of this rare
condition here in the Philippines.
Most of the published literatures reports presence
of mullerianosis in the urinary bladder, its most common
location1-8, likewise the index patient had the lesion on
the dome of the urinary bladder, although the lesion was
also reported to occur rarely in the following locations
like the ureter10-11, mesosalpinx12, inguinal lymph nodes13,
and conus medularis of the spinal cord14. It occurs in
nulliparous and multiparous women under the age
group, ranging from 23-53 years old in most literature.
However, one case of mullerianosis was reported in a
70 year-old woman presenting with persistent vaginal
bleeding after polypectomy, magnetic resonance imaging
done for further studies revealed bladder lesions despite
absence of any urinary symptoms. Cystoscopy done
revealed three polypoid masses on the bladder trigone.
The polypoid lesions were biopsied and histopathology
and histochemical studies revealed mullerianosis5. It may
also be associated with previous history of pelvic surgery
or cesarean delivery3-5. The index patient did not have any
history of pelvic surgery, and hence the etiology may be
that of a different theory.
The pathogenesis of this rare entity is still unclear,
with few cases reported there were only two theories
formulated. Since mullerianosis is somehow related with
endometrisos, implantation theory was formulated, and
is applicably limited to patients who had previous pelvic
28 Volume 41, Number 2, PJOG March-April 2017
surgery or cesarean delivery. Also the presence of two or
more mullerian tissues like that of the fallopian tubes and
cervix seems arguable against implantation theory, and
the presence of the lesion on distant sites could not be
explained by this theory2,4-8. Hence implantative theory
may only be valid for cases of mullerianosis, occurring
in women with previous pelvic surgery or cesarean
delivery, those with single mullerian tissue, and invalid for
those presenting with lesions in distant parts. The more
appropriate theory for these cases would be that of the
theory of metaplastic origin, first proposed by Donne et al.
In this report, the theory of metaplastic origin was based
on the following observations, mostly the opposite of that
of the implantative theory, in that the presence of two
or more mullerian tissues rather than an isolated one is
better explained by metaplasia, secondly this multiplicity
reflects the lesion’s capacity of differentiation; and lastly
the invariable location of the lesion at the posterior wall
and dome of the bladder, an area that topographically
corresponds to its peritoneal covering16. There is also
a report by Koren and colleagues where they describe
the continuity between the mullerian glands and the
urothelium, and that it is hormonally receptive17, all of
these observations leads to metaplastic origin theory.
Clinical features from case reports presented
differently, but the most frequent clinical presentations
are non-specific lower urinary tract symptoms including
hematuria4, dysuria, painful and increased frequency of
micturition6, bladder mass, right iliac fossa pain7, pelvic
cyclical pain, and other symptoms related to the extent
of involvement8. Occasionally, it is an incidental finding
during investigation for other disorders4. The index patient
presented with hematuria, dysuria, and lumbar pain.
As with endometriosis and endocervicosis,
mullerianosis has the potential to be misdiagnosed
as invasive adenocarcinoma in the bladder wall15.
Close resemblance to malignancy lies to the histologic
appearance of the glandular structures and cell and
nuclear stratification, however, mullerianosis lacks
invasion of the adjacent structure compared to
adenocarcinoma. Adenocarcinomas also show cellular
features of malignancy, and high index of proliferation or
mitoses9. Malignant transformation of mullerianosis in a
urinary bladder is extremely rare. Only one endometriod
carcinoma complicating mullerianosis was reported in the
literature8.
The differential diagnoses of mullerianosis include
both benign and malignant lesions. Benign lesions like
cystitis glandularis, urachal remnants, and nephrogenic
adenoma, malignant lesions ranging from primary
adenocarcinoma of the bladder and secondary spread
from adenocarcinoma of the cervix. Thus it is important
to diagnose mullerianosis correctly, since management
of these lesions differ immensely. Cystitis glandularis
are polypoid focus of bladder mucosal thickenings and
irregularities due to metaplasia of the urothelium. To
differentiate it from mullerianosis, cystitis glandularis are
superficially located on the bladder wall, with preservation
of the muscularis propria, histochemically it does not
have staining for estrogen and progesterone receptors.
Treatment also differs, cystitits glandularis should be
removed by surgical excision because of its association
with adenocarcinoma and patients should be monitored.
Urachal remnant is any congenital anomaly associated
with the urachus. The urachus is related to the dome of
the urinary bladder, failure to obliterate will cause urachus
to persist in a number of configurations. To differentiate,
demonstration of endometrial gland in mullerianosis,
through CD10 immunostaining is significant. Management
for urachal remnant is also excision. Nephrogenic
adenoma is a benign mass that may involve the bladder
and may appear histologically, as that of mullerianosis
with the presence of small tubules lined by cuboidal
and hobnail cells, the difference is that nephrogenic
adenoma does not feature mucinous cells, have no
immunoreactivity for hormone receptors, and is situated
deep in the muscularis propria. Mullerianosis may also
simulate an infiltrating primary adenocarcinoma of the
urinary bladder, those of primary adenocarcinoma arising
from the bladder and those that are primary malignant
lesion of the urachal remnants. Both malignancies arise
in older women as compared to mullerianosis which
arise in fertile age. Differentiation of these malignant
lesions compared to that of mullerianosis is complicated
by their preferential location at the dome of the bladder,
as well as the lesions’ demarcation from normal bladder
tissue. Diagnosis can be confirmed by histologic evidence
of endometrial glands with periglandular endometriod
stroma, lack of cytonuclear atypia, and absence of mitoses
and desmoplasia in mullerianosis. Lastly, secondary spread
from adenocarcinoma of the cervix can be easily ruled out
by clinical history and physical examination, as well as
other diagnostic modalities as deemed appropriate2-9.
Initial imaging may be in the form of pelvic
ultrasonographylike transvaginal ultrasound and KUB
ultrasound and may reveal nodular, polypoid, mass-like
lesions ranging from 2-4 cm involving the dome of the
bladder.5
KUB ultrasound in the index patient revealed an
isoechoic mass measuring 3.3 x 3.1 x 3.4 cm seen arising
from the superior wall of the urinary bladder which exhibits
no uptake on color flow study.
The transvaginal ultrasound of the index patient
revealed a mass anterior and separated to the uterine
body measuring 3.51 x 3.07 x 2.81 cm. It is seen within the
posterior wall of the urinary bladder.
A case report described the lesion in magnetic
resonance imaging as a 2 x 3 cm mass in the posterior wall
of the bladder, extending through the full wall thickness,
and there was a thin plane between it and the serosal
surface of the uterus7.
Gross description is best noted during cystoscopy,
in literature reviews of gross description of mullerianosis,
it is described as polypoid, mass like lesions ranging
from 1.0-4.5 cm in size, predominantly involving the
dome or the posterior wall of the bladder2. A case report
of mullerianosis by Guan and colleagues described
mullerianosis excised from the dome of the left lateral wall
of the bladder; grossly it had internal cystic structures and
an inverted growth pattern. Some of the cysts were dark
blue to black in color. Some reveals a submucosal nodule
or a darkly colored cyst covered by hyperemic mucosa,
and there may be associated scarring and fibrosis with
distortion of the bladder wall.5 Cystoscopy in the index
patient revealed that the mass forms a bridge in the middle
of the urinary bladder at the base separating bladder into
two halves. The growth at the dome of the urinary bladder
extends to the right lateral wall. There were multiple blue
domed cysts with different sizes.
This leads us to the importance of biopsy, subsequent
histologic findings, and histochemical evaluation. The
definitive diagnosis for cases of mullerianosis is confirmed
by histology4. In histologic examination by hematoxylin-
eosin stain, mullerianosis of the urinary bladder appears
as a lesion consisting of an admixture of variable sized,
band-appearing glands that are deeply situated within the
lamina propria and the muscularis propria of the urinary
bladder wall, and which resemble the tubal, endocervical,
and endometrial epithelia (Figure 3)2.
In a case reported by Maeda et.al, histopathologic
study of the case revealed the presence of variably-sized
dilated tubular glans in the lamina propria and muscularis
propria of the bladder. The surface urothelium was without
atypia, and no connection between the surface urothelial
mucosa and dilated tubular glands noted. The dilated
glands were covered by ciliated cuboidal cells containing
small round nuclei without nucleolus which corresponds
to tubal-type epithelium. Some of the tubular glands were
covered by columnar cells with intracytoplasmic mucin
and small round nuclei, resembling endocervical mucosa.
Tiny focus of endometrial tissue and stroma was observed
adjacent to the dilated tubal-type gland (Figure 3).6
Histologic report of the index patient revealed the
following results; the lamina propria and the muscularis
shows multiple tubular and glandular spaces lined by
ciliated tubal like and nonciliated columnar epithelium
and a focal area lined by mucinous epithelium similar
to that of the endocervix. A focus of hemosiderin laden
macrophages surrounding a strip of surface endometrial
Volume 41, Number 2, PJOG March-April 2017 29
Figure 3. A, Glands lined by endocervical epithelium in the lamina propria of endoscopically resected fragments of urinary bladder
wall. B, Endocervical and endometrial glands surrounded by endometrial stroma deeply located in bladder wall. C, Endometrial
gland with surrounding stroma within muscularis propria of bladder fragments. D, Gland lined by ciliated tubal-type epithelium in
the bladder wall (hematoxylin-eosin, original magnifications 3100 [A and B], 3200 [C], and 3400 [D]).2

like epithelium, some of the fragments is lined by an
admixture of urothelium and mullerian epithelium. Some
of the fragments also show a few cystic nests and congested
vessels, consistent with the diagnosis of mullerianosis.
In line with the derivation of this tissue,
immunohistochemical staining can be done to reveal
the presence of estrogen receptors and progesterone
receptors (Figure 4).2 Also, similar to the orthotopic
endometrium, the stroma surrounding the endometrial
glands of mullerianosis is diffusely stained by anti-CD10
antibody, and the glandular epithelia stain positively for
Ca-125.2
In the index patient, immunohistochemical staining
was done revealing that the epithelial lining of these
tubular spaces showed positive immunoreactivity for CK7,
vimentin, estrogen receptor and progesterone receptor
and negative for CK20. The stroma surrounding some of
these glands shows CD 10 positivity. Immunoreactivity to
CK7 with negative CK20 is immunophenotyic for tubal-type
mullerian tissue, and is consistent with endosalpingiosis.
Endocervicosis and endometriosis on the other hand
comprise co-expression of vimentin and keratin and the
presence of estrogen and progesterone receptors while
CD10 is a reliable and sensitive immunohistochemical
marker of normal endometrial stroma.
Diagnosis of mullerianosis imposes grave importance
for its management, since correct diagnosis may benefit
patients who do not want to undergo surgery since this
lesion is responsive to hormone therapy2.
Among the literatures reviewed, there was no
consensus with regards to the treatment of mullerianosis,
although several of the documented cases were
managed primarily by resection of the bladder mass.
Hormonal treatment may be started immediately
with gonadotrophin releasing hormone agonist, oral
contraceptives, progestogens, or danazol18. Many surgical

30 Volume 41, Number 2, PJOG March-April 2017

Figure 4. A, Nuclear staining for estrogen receptors in the endometrial epithelial and stromal cells found within the fragments of
urinary bladder wall. B, CD10 stain in the stroma surrounding endometrial glands (estrogen receptor stain, original magnification3200
[A]; CD10 stain, original magnification3200 [B]).
modalities have been used for the treatment of these
lesions: transurethral resection and both open and
laparoscopic partial cystectomy19. Endoscopic resection
of the bladder lesions is diagnostic as well as therapeutic,
but the preferred treatment will depend on the age of the
patient, the size, number and depthof infiltration of the
bladder lesions, and their location within the bladder5.
Hormonal therapy alone have not been widely
discussed for the management of mullerianosis, this is
probably primarily because a surgical approach to obtain
a tissue diagnosis has usually been undertaken20. In the
index patient, an initial biopsy of the tumor already gave
the diagnosis of mullerianosis. The option to undergo
medical therapy was the appropriate management for the
index patient considering her age and fertility status (G0).
It is certain that the müllerian tissues are hormone
responsive; thereby efforts have been made to treat
symptoms with hormone therapies, reducing hormonal
stimulation and assuch, reducing associated symptoms.
Some available case reports have demonstrated both a
reduction in symptoms and lesion size after a 3-6 month
period of hormonal augmentation20.
The index patient was given gonadotropin releasing
hormone agonist 3.75 mg intramusclar every 4 weeks for
3 doses in the Philippines and was continued for 3 more
doses in Kuwait.
The efficacy of gonadotropin-releasing hormone
agonists in the treatment of this lesion is controversial.
Indeed, though disappearance of the symptoms is observed
following therapy, the lesion may remain unchanged in
size and appearance. Pharmacologic treatment might be
the most appropriate in the case of mullerianosis arisen
in sites, such as the spinal compartment, where surgical
intervention may lead to life-threatening complications20.
Nonetheless this case report addresses a rare lesion
in the index patient and it highlights the importance of
identifying appropriate and effective long-term treatment.
The choice of management should be pointed to the
improvement of the symptoms with much less morbidity
and complications.
CASE SUMMARY
We are presented with a rare case of a benign
gynecologic lesion which initially presented with urologic
signs and symptoms mimicking a neoplastic process
probably malignant involving in most cases the urinary
bladder. High index of suspicion with proper imaging
modalities and extensive histologic evaluation with
immunohistochemical staining will lead to the diagnosis of
mullerianosis, an extremely rare, certainly benign tumor
like neoplasia with histologic findings of at least two out of
three lesions including endometriosis, endosalpingiosis,
and endocervicosis. Correct diagnosis is of great value to
patients who do not want to undergo surgical removal of
this lesion primarily because this condition is responsive
to hormonal therapy, as seen in this case report.
Volume 41, Number 2, PJOG March-April 2017 31
REFERENCES
1. Young RH, Clement PB. M ullerianosis of the urinary bladder. Mod
Pathol. 1996; 9(7):731-737.
2. Valeria Barresi, MD, Dipartimento di Patologia Umana, Policlinico
G. Martino, Pad D, Via Consolare Valeria. Mullerianosis of the
Bladder, A rare Tumor like Lesion. 98125 Messina, Italy.
3. Ranjini Kudva and Padmaraj Hegde. Mullerianosis of the
Urinary Bladder. Indian J Urol. 2012 Apr-Jun; 28(2):206-207.doi:
10.4103/0970-1591.98469.
4. Kenneth Ogah & Rachael Hartis & Paul Hilton. Mullerianosis
involving the urinary bladder. Int Urogynecol J. 2012; 23:123-125.
5. Vella, Josefa et.al. Müllerianosis of the Urinary Bladder.
International Journal of Surgical Pathology. 19(4):548-551.
6. Koki Maeda1,2*, Fumiyoshi Kojima1*, Mitsuaki Ishida1*,
Muneo Iwai1, Akiko Kagotani1, Akihiro Kawauchi2. Case Report
Müllerianosis and endosalpingiosis of the urinary bladder: report
of two cases with review of the literature. Int J Clin Exp Pathol.
2014; 7(7):4408-4414.ISSN:1936-625/IJCEP0000637.
7. S. islam, j.j.w. tumman, r.f.t. mcmahon and s.r. payne. Müllerianosis
of the urinary bladder. Department of Urological Surgery,
Manchester Royal Infirmary, UK. 2003.
8. Hui Guan, M.D., Ph.D.,* Dorothy L. Rosenthal, M.D., and Yener
S. Erozan, M.D..Mullerianosis of the Urinary Bladder: Report of
a Case with Diagnosis Suggested in Urine Cytology and Review of
Literature. Diagnostic Cytopathology, Vol 40, No 11 DOI 10.1002/
dc.
9. Pattomthadathil Sankaran Jayalakshmy, Shasi Velusamy, Joy
Augustine. Multiloculated cystic Mullerianosis of uterus: A case
report. J Turk Ger Gynecol Assoc. 2014; 15:197-200.
10. Nogales FF, Zuluaga A, Arrabal M, Dhakal HP, Aguilar D. M¨
ullerianosis of the ureter: a metaplastic lesion. J Urol. 1999;
162(6):2090-2091.
32 Volume 41, Number 2, PJOG March-April 2017
11. Li WM, Yang SF, Lin HC et al. M¨ ullerianosis of ureter: a rare cause
of hydronephrosis. Urology. 2007; 69(6):1208.e9-e11.
12. Lim S, Kim JY, Park K, Kim BR, Ahn G. Mullerianosis of the
mesosalpinx: a case report. Int J Gynecol Pathol. 2003; 22(2):209-
212.
13. Sinkre P, Hoang MP, Albores-Saavedra J. Mullerianosis of inguinal
lymph nodes: report of a case. Int J Gynecol Pathol. 2002; 21(1):60-
64.
14. Barresi V, Cerasoli S, Vitarelli E, Donati R. Spinal intradural m¨
ullerianosis: a case report. Histol Histopathol. 2006; 21(10):1111-
1114.
15. Peter A. Humphrey Department of Pathology Yale University
School of Medicine New Haven, Connecticut. Endometriosis,
Endocervicosis, Mullerianosis. juro.2014.08.012 Vol. 192, 1523-
1524, November 2014 Printed in U.S.A.
16. Donne C, Vidal M, Buttin X, et al. Mullerianosis of the
urinary bladder: Clinical and immunohistochemical findings.
Histopathology. 1998; 33:290-292.
17. Koren J, Mensikova J, Mukensnabl P, Zamecnik M. Mullerianosis of
the urinary bladder: report of a case with suggested metaplastic
origin. Virchows Arch. 2006; 449(2):268-271.
18. A. Antonelli, C. Simeone, D. Zani, et al., “Clinical aspects and
surgical treatment of urinary tract endometriosis: our experience
with 31 cases,” European Urology, vol. 49, no. 6, pp. 1093-1097,
2006.
19. C. Maccagnano, F. Pellucchi, L. Rocchini et al., “Diagnosis and
treatment of bladder endometriosis: state of the art,” Urologia
Internationalis, vol. 89, no. 3, pp. 249-258, 2012.
20. Rufaro Ndokera,1 Simon Brewster, 2 Sunanda Dhar3Müllerianosis:
a rare cause of acute renal colic.
 The effectiveness of evening primrose oil gel capsule as a
cervical ripening agent during labor induction as measured
by bishop score on term singleton pregnant patients*
By Nina Nonette Diansuy, MD and Angela S. Aguilar, MD, FPOGS
Department of Obstetrics and Gynecology, Philippine General Hospital, University of the Philippines-Manila

ABSTRACT

Background: Pre-induction of labor cervical ripening increases success of labor induction when there is unfavorable cervix. Evening
primrose oil soft gel capsule contains linoleic and gamma-linolenic acid, which are precursors of prostaglandins E1 andE2.

Objective: To measure the effectiveness of evening primrose oil capsule as a cervical ripening agent by measuring the Bishop score
before and 4 hours after intravaginal insertion of six capsules.

Methods: A quasi-experimental cross-sectional study was conducted from the period of May to July 2016 involving labor induction
patients with a Bishop score ≤4, an intact amniotic sac and a Biophysical profile score of 10/10 or 8/8.

Results: Thirteen patients had an average age of 27±6 years, and a mean age of gestation of 40±1 weeks. Seven patients (54%)
were nulliparous, 2 (15%) were primiparous and 4 (31%) were multiparous. Seven patients (54%) had hypertension, 1 (8%) had
diabetes mellitus, 5 (38%) had post-term pregnancies. A paired t-test was done to check for statistically significant changes in the
Bishop score. Change in the Bishop score from baseline to 4 hours after insertion of evening primrose oil capsules was statistically
significant (p=0.001). Eleven patients (85%) had improvement in the Bishop score after 4 hours, 4 (31%) of which had a clinically
significant change in the Bishop score (≥4). Specifically, there were statistically significant changes in the dilatation (p=0.027),
effacement (p=0.006) and consistency (p=0.002). The mean birth weight of deliveries was 3192±351 grams. Nine patients (69%)
underwent primary low segment cesarean section, six (46%) of which for nonreassuring fetal status, 2 (15%) for arrest in cervical
dilatation, and 1 (8%) for intraamnionic infection. Four patients (31%) successfully delivered vaginally.

Conclusion: Results showed a positive effect on the Bishop score during cervical ripening although further studies are needed to
establish direct correlation.

Keywords: Bishop score, cervical ripening, evening primrose oil capsule, labor induction

INTRODUCTION recruits leukocytes and inflammatory cytokines such as

L
abor induction is the stimulation of contractions
before onset of labor. Its success depends primarily
in the readiness of the cervix to dilate during uterine
contractions.1 Cervical ripening is the process that helps
soften the cervix in preparation for labor. Preinduction
cervical ripening may either be done using mechanical or
pharmacological methods.
Prostaglandins are physiologically active lipid
compounds with diverse hormone-like effects. They are
derived enzymatically from fatty acids and are found
in almost every tissue in the human body. Among its
many function, prostaglandins play a key role in cervical
ripening by acting as a pro-inflammatory agent that
*Finalist, 2016 Philippine Obstetrical and Gynecological Society (POGS)
Research Paper Contest, October 27, 2016, 3rd Floor POGS Building,
Quezon City
interleukin-8. Specifically, prostaglandin E2 increases the
concentration of glycosaminoglycans and the activity of
elastin, which contributes to the extracellular remodeling
of the cervix2. Prostaglandin E2 (Dinoprostone) is currently
the drug of choice in well-resourced countries. However,
due to its cost and instability, there is a need for an
alternative cervical ripening agent. To date, there is still
no gold standard preinduction cervical ripening agent that
has proven to improve outcomes during the latent phase.
Evening primrose oil is a natural product extracted
from Oenotherabiennis L. seeds. It is used as a dietary
supplement because of its high content of polyunsaturated
fatty acids, particularly linoleic and gamma-linolenic acid
(18:3n-6). Its effects have been reported in rheumatic and
arthritic conditions, atopic dermatitis, premenstrual and
menopausal syndrome, and diabetic neuropathy3.
Studies on the use of evening primrose oil for
cervical ripening has been controversial. Although it has
already been proven safe and effective to use in cervical
Volume 41, Number 2, PJOG March-April 2017 1
priming prior to hysteroscopy4, there are limited data in
pregnant patients. The reason for this is that there have
really been a few studies to support its use, primarily
because of the fear of adverse effects to the fetus. One
local study in pregnant patients using evening primrose
oil for preinduction cervical ripening demonstrated
significant effect in the Bishop score and cervical length
by transvaginal ultrasound and no documented adverse
effect monitored using the modified Biophysical profile5.
Because of the scarcity of evidence, its use is still not
recommended.
OBJECTIVES
The general objective of the study is to determine
the effectiveness of evening primrose oil gel capsule as a
cervical ripening during labor induction on term singleton
pregnant patients. The specific objective is to determine
the change in Bishop score after administration of evening
primrose oil gel capsules.
MATERIALS AND METHODS
A quasi-experimental cross-sectional design from the
period of May to July 2016 was done to assess the efficacy
of evening primrose oil in the induction of labor. Women
who presented to the outpatient clinics and emergency
department in a tertiary hospital for induction of labor
was included.
Criteria for inclusion:
1) age>18 years old
2) accurate dating of gestation by last menstrual period
or sonologic aging including crown rump length (CRL)
measurements in the first trimester of pregnancy or
two sonographic estimations of fetal age
3) singleton term pregnancy
4) cephalic presentation
5) unfavorable cervical status defined as a Bishop score
(BS) of ≤4
6) intact amniotic membranes
7) Biophysical profile of 10/10 or 8/8
8) patients with stable maternal conditions, with any of
the following conditions:
a. at least 37 weeks age of gestation; chronic
hypertension with superimposed preeclampsia;
b. at least 38 weeks age of gestation; gestational
or overt diabetes mellitus;
c. 41 weeks age of gestation for induction of labor
with unfavorable cervix
Criteria for exclusion:
1) any contraindications to vaginal delivery:
2 Volume 41, Number 2, PJOG March-April 2017
a. placentaprevia
b. previous uterine scar
c. estimated fetal weight more than or equal to
4000 grams
Demographics were encoded and categorized
using descriptive statistics. Bishop score before and 4
hours after intravaginal insertion of evening primrose oil
capsules were determined by the same examiner. A paired
t-test was done to determine statistical significance on
the Bishop score and each of its component: dilatation,
effacement, consistency, position and station.
RESULTS
There were 13 patients admitted for labor induction
from May to July 2016. The mean age of patients was 27±6
years, with mean age of gestation of 40±1 weeks. Seven
patients (54%) were nulliparous, 2 (15%) were primiparous
and 4 (31%) were multiparous. Seven patients (46%) had
hypertension, 1 (8%) had diabetes mellitus, 5 (38%) had
post-term pregnancies (Table 1).
The change in the Bishop score from baseline to 4
hours after insertion of evening primrose oil capsules
was statistically significant (p=0.001). Eleven patients
(85%) had improvement in the Bishop score after 4 hours
from insertion of evening primrose oil capsule. Among
those with improvement, four patients (31%) had an
improvement in Bishop score ≥4. Analysis of the specific
components of the Bishop score showed statistically
significant change in the dilatation (p=0.027), effacement
(p=0.006) and consistency (p=0.002), while no significant
change was noted in the position (p=0.08) and station
(0.17). Changes in the cervical status were further analyzed
based on the clinical changes in terms of cervical dilatation
and effacement. Eleven patients (85%) had significant
improvement in both cervical dilatation and effacement
(p=0.0007 for dilatation, and p=0.0002 for effacement)
but of these, only 5 (38%) had pertinent increase to effect
a change in the Bishop score in terms of dilatation and 5
Table 1. Baseline Characteristics of the Study Population (n=13).
Mean age 27±6 years
Mean age of gestation 40±1 weeks
Parity Frequency
Nulliparous 7 (54%)
Primipara 2 (15%)
Multiparous 4 (31%)
Hypertension 7 (54%)
Diabetes mellitus 1 (8%)
Post term 5 (38%)
 Figure 1. Changes in the Bishop Score.
Table 2. Secondary Outcomes.
Mode of delivery Cesarean section
Nonreassuring fetal status 6 (46%)
Arrest in cervical dilatation 2 (15%)
Intraamnionic infection 1 (8%)
Vaginal delivery 4 (31%)
(38%) in terms of effacement (Figure 1).
Nine patients (69%) underwent primary low segment
cesarean section, six (46%) of which for nonreassuring
fetal status, 2 (15%) for arrest in cervical dilatation, and
1 (8%) for intraamnionic infection. Four patients (31%)
successfully delivered vaginally (Table 2). The mean birth
weight of the babies was 3192±351 grams.
DISCUSSION
The mean age of patients was 27±6 years, with
mean age of gestation of 40±1 weeks. Seven (54%)
patients were nulliparous, 5 (38%) of which delivered
by cesarean section (2 for cephalopelvic disproportion,
2 for nonreassuring fetal status and 1 for intraamnionic
infection). Seven patients (54%) had hypertension,
1 (8%) had diabetes mellitus, 5 (38%) had post-term
pregnancies. The effectiveness of evening primrose oil
capsule was measured using the Bishop score before and
4 hours after intravaginal insertion of six capsules. Eleven
(85%) patients had a statistically significant increase in
Bishop score, 4 (31%) patients of which had a clinically
significant increase to a Bishop score of ≥4. Further
analysis on the components of the Bishop score revealed
statistically significant changes in the dilatation (p=0.027),
effacement (p=0.006) and consistency (p=0.002), This may
be explained by extracellular matrix remodeling during
cervical ripening through the actions of prostaglandins1,2.
Evening primrose oil capsule contains precursors of
prostaglandins E1 and E2, which may facilitate faster
and more productions of the said prostaglandins. Both
prostaglandins also have relaxation effects on smooth
muscles that alterthe cervical vascular tone2,6, which could
probably explain the significant change in consistency.
Furthermore, prostaglandins act as uterotonins1 thereby
effecting cervical dilatation and effacement, which is more
effective in a ripened cervix. Change in station and position
were not significant in this study. Station is determined by
the descent of the presenting part, which occurs later in
the labor process. The posterior angle of the cervix, which
is clinically determined by its position, may be the last
to change after descent of the presenting part. Descent
redirects the cervical angle towards the vaginal canal for
delivery. This sequence of changes was also supported
by other studies where Bishop score, cervical aperture,
consistency and length had a positive predictive value
in vaginal delivery7,8. The significant change in cervical
ripening as measured by the Bishop score can suggest but
not conclude to be a direct effect of evening primrose oil
capsule.
The study population was limited to term pregnancies
with a medical complication, such as hypertension or
diabetes mellitus, that warrants delivery or pregnancies
reaching 41 weeks age of gestation with no complications.
The biophysical profile of the fetus included was either
an 8/8 or 10/10 to exclude pregnancies already with
Volume 41, Number 2, PJOG March-April 2017 3
fetal compromise. Although it is already proven that the
use of Biophysical profile over intrapartal fetal heart rate
monitoring does not reduce perinatal death or frequency of
low Apgar scores, it is still prudent to assess the biophysical
profile to document fetal acidemia or oligohydramnios,
which significantly increases risk of an intrapartal fetal
demise, especially if there is a planned intervention. A
normal score may be predictive of the absence of fetal
compromise at that time but not of the delivery outcome
especially in high-risk pregnancies because deterioration
in the maternal clinical status can also affect the fetal
status9.
In this preliminary result, there seems to be a higher
rate of cesarean section deliveries (69%), six (46%) of which
for nonreassuring fetal status, 2 (15%) for arrest in cervical
dilatation, and 1 (8%) for intraamnionic infection. However,
no immediate correlation between those that delivered by
cesarean section for nonreassuring fetal status and evening
primrose oil capsule can be made because the interval
from intervention to delivery ranges from 9 to 70 hours.
Furthermore, patients included were at baseline, high-
risk for cesarean section even prior to the intervention.
In fact, patients who delivered for nonreassuring fetal
status had an average age of gestation of 40.5 weeks and
2 had concomitant severe preeclampsia. The patient that
developed intraamnionic infection was already 41 weeks,
had amniotomy 36 hours prior to delivery at 3cm cervical
dilatation for labor augmentation, from which the amniotic
fluid was noted to be thickly meconium stained.
The preliminary results show promise regarding the
use of evening primrose oil gel capsule for cervical ripening.
It is however limited by the small number of participants
REFERENCES
1. Cunningham, FG. KJ Leveno, SL Bloom, CY Spong, JS Dashe, BL
Hoffman, BM Casey, JS Sheffield. Williams Obstetrics. 24th edition.
McGraw Hill Education. 2014.
2. Blesson, CS. N Roos, O Stephansson, B Masironi, S Reinert,
YV Stjernholm, G Ekman-Ordeberg, L Sahlin. Expression and
Localization of Prostaglandin Receptors and Stromal Factors in
Human Cervix—Variations in Pregnant and Non-pregnant States.
Open Journal of Molecular and Integrative Physiology. 2013; 3:
147-157.
3. Mahady, GB. HH Fong, NR Farnsworth. Botanical Dietary
Supplements: Quality, Safety and Efficacy. Sweets and Zeitlinger,
Lissie, The Netherlands. Pp. 75-85. 2001.
4. Carreon, GA. GG Tanangonan. Cervical Priming Prior to Operative
Hysteroscopy: A Randomized Clinical Trial Comparing Evening
Primrose Oil Versus Dinoprostone Gel. Philippine Journal of
Reproductive Endocrinology and Infertitility. 2012; 9(2):74-81.
5. Vahdat, M, K Tahermanesh, AM Kashi, M Ashouri, MS Dodaran, M
Kashanian, P Alizadeh, SM Abed, AF Yazdi, N Hashemi, SA Esfahani,
4 Volume 41, Number 2, PJOG March-April 2017
as well as the quasi-experimental design, which restricts
the association not only of the adverse events/outcomes
but also the favorable results. Continuation of the study is
recommended to further strengthen the above findings.
CONCLUSION
There is a statistically and clinically significant change
in the Bishop score before and 4 hours after insertion of
six Evening primrose oil capsules. Particularly, there were
statistically significant changes in dilatation, consistency
and effacement.
LIMITATION
Since this is a preliminary study, the internal validity
of evening primrose oil capsule was tested using a quasi-
experimental cross-sectional study design. No comparison
to current drugs in use was done. Time to active phase of
labor or time to delivery was not included as outcomes.
The sample size was also small, thus, may have a lower
statistical power.
RECOMMENDATIONS
A case-control study is recommended to test the
effects of evening primrose oil capsule compared to other
pharmacologic agents in use. A larger sample size is also
suggested to better see the true effect of evening primrose
oil capsule. Other parameters should also be tested to
determine the specific effects of evening primrose oil
capsule in labor induction.
BF Nasiri. Evening Primrose Oil Effect on the Ease of Cervical
Ripening and Dilatation Before Operative Hysteroscopy. Thrita.
2015; 4(3):e29876.
6. Schmitz, T. BA Levine, PW Nathanielsz. Localization and Steroid
Regulation of Prostaglandin E2 receptor Protein Expression in
Ovine Cervix. Society for Reproduction and Fertility. 2006; 131:
743-750.
7. Akyol, Alpaslan, O. Karadamir, A. Gedikbasi, H. Cemal Ark, A.
Gulkilik. The Role of Bishop Score For Successful Labor Induction.
Perinatal Journal. Vol: 15, Issue:1. April 2007.
8. Bahadori, F., H. Ayatollahi, M. Naghavi-Behzad, H. Khalkhali, Z.
Naseri. Predicting Factors on Cervical Ripening and Response
to Induction in Women Pregnant Over 37 Weeks. Med Ultrason
2013, Vol. 15, No. 3, 191-198.
9. Lalor, JG, B. Fawole, Z. Alfirevic, D. Devane. Biophysical Profile for
Fetal Assessment in Hgh Risk Pregnancies. Cochrane Database
Systematic Review 2008.
 N
ow
in
de
xe
d
in
Journal of the
ASEAN
Journal of Federation
the of
Endocrine
ASEAN Societies
Federation of
Endocrine Societies
Vol. 32 No. 2 November 2017 | ISSN 0857-1074 | eISSN 2308-118x

REVIEW ARTICLE
Bone Metabolism and Fracture Risk in Diabetes Mellitus
Melisa Puspitasari, Dyah Purnamsari, Bambang Setyohadi, Harry Isbagio

ORIGINAL ARTICLES
Health-Related Quality of Life (HR