Professional Documents
Culture Documents
2020 Newer Diagnostic Tests For Tuberculosis, Their Utility and Their Limitations PDF
2020 Newer Diagnostic Tests For Tuberculosis, Their Utility and Their Limitations PDF
Newer Diagnostic tests for tuberculosis, their utility and their limitations
PII: S2352-0817(20)30005-2
DOI: https://doi.org/10.1016/j.cmrp.2020.01.004
Reference: CMRP 464
Please cite this article as: Chopra KK, Singh S, Newer Diagnostic tests for tuberculosis, their utility and
their limitations, Current Medicine Research and Practice, https://doi.org/10.1016/j.cmrp.2020.01.004.
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition
of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of
record. This version will undergo additional copyediting, typesetting and review before it is published
in its final form, but we are providing this version to give early visibility of the article. Please note that,
during the production process, errors may be discovered which could affect the content, and all legal
disclaimers that apply to the journal pertain.
© 2020 Sir Ganga Ram Hospital. Published by Elsevier, a division of RELX India, Pvt. Ltd. All rights
reserved.
Title page:
Title: Newer Diagnostic tests for tuberculosis, their utility and their limitations
Authors:
Newer Diagnostic tests for tuberculosis, their utility and their limitations
Abstract:
TB has remained a disease of Public Health Importance since ages affecting more than 10 million
people globally and taking lives of 2 million people worldwide people every year. Despite of the
dramatic improvements made in providing high-quality TB diagnostic services, since the discovery
of the causative bacilli, many people with TB remain undiagnosed or get diagnose only after long
delays. Ten countries account for 77% of this gap and use only smear microscopy for diagnosis,
which forms the backbone of TB diagnosis since 100 years. The challenge becomes onerous when
disease gets associated with drug resistance, HIV, other diseases, etc. in an environment where
transmission is becoming easier by the day. It becomes of paramount importance to address this
biggest public health challenge delivering timely diagnosis using advanced technologies.
Laboratory based diagnostic approach to manage TB relies upon initial microscopic examination
and clinical confirmations, with newer advanced diagnostic tools coming into play such as
genotypic assays (LPA, CBNAAT, LAMP) that are rapid molecular tests, and culture methods
(liquid culture media) with standard drug susceptibility testing assays. Program envisages
correlating the rapid molecular diagnostics, which offers an impressive turnaround time of as low
as around 2 hours, with conventional standard methods to reinforce the diagnostic capacities.
These also provide with august identification of drug resistance patterns for few most important
first line and second line drugs that facilitates the early initiation of correct treatment. The latest
developments have brought these tests to near-patient point of care. Culture tests (liquid culture
media) are highest quality level gold standard technique for the analysis of TB with its increased
sensitivity over all others, but requirement of dedicated facilities & infrastructure pushes it back
the line. Finding a reproducible, efficient, cost effective tool with minimal infrastructure
requirements is an on-going search under TB diagnostics. This review addresses significant
advances made in the diagnosis of infection, clinical disease, and drug resistance over the past
decades.
Keywords: Tuberculosis, diagnostics, genotypic assays, LPA, CBNAAT, Culture, DST
1. Introduction:
Tuberculosis (TB) is a direful onerous disease, causing affliction among human race since
antiquity. According to Global TB Report, 2019, TB affects approximately 10.4 million people
every year, taking a toll on the lives of around 1.8 million people worldwide causing TB deaths.
Despite various furtherance made for early diagnosis of the disease, under Revised National
Tuberculosis Control Program (RNTCP), an unsettling percentage of estimated 4.3 million remains
under reported or undiagnosed every year.1 Fighting the disease is a hornet’s nest, which foists a
grave socioeconomic burden on the diseased and their family members.
Since the discovery of causative organism for TB i.e. the bacilli Mycobacterium
tuberculosis (MTB) in 19th century, humankind has been working arduously to win over the
perilous disease. The Sustainable Development Goals (SDGs) for 2030 and End TB Strategy have
set up a common goal to end the global TB epidemic with targets to reduce TB deaths by 90%,
reduce its incidence by 80% and zero out of pocket expenditure due to TB to be achieved by 2030
as compared to 2015. Following the vision to eliminate the disease, the first challenge begins with
providing early diagnosis for the disease, which has picked up pace expeditiously with fervent
advancements being made under laboratory based diagnostics. Early diagnosis improves survival
by identifying infectious cases to prevent further transmission and various public-health actions.2
The high TB burden countries (around 30) accounted for 87% of the global TB cases,3 where most
cases occur in low and middle income countries. In addition, ten of these countries accounted for
77% of the total estimated gap, where sputum microscopy is the primary method for diagnosing
pulmonary tuberculosis.4 The only WHO-recommended rapid diagnostic test for detection of TB
and rifampicin resistance currently available is the Xpert MTB/ RIF® assay. Globally, the use of
rapid molecular tests is increasing, and many countries are phasing out use of smear microscopy
for diagnostic purposes (although microscopy and culture remains the mainstay for treatment
monitoring).1.
2. Background:
Sputum microscopy was developed as a diagnostic test more than 100 years ago. It became the
backbone of TB control program for diagnosing pulmonary tuberculosis because it could detect the
presence of acid-fast bacilli using Ziehl Neelsen (ZN) staining, in a very short time and was highly
cost efficient. However, it needed a high bacterial load of approx. 5 x 103 –104 bacilli per ml of
sputum sample. Overcoming its shortcomings, florescent dyes came into play, with increased 10%
sensitivity, but required a dark room with conventional microscopes. Then the combination of
Light Emitting Diode with Fluorescent Microscopes (LED-FM) further removed need for dark
room and worked in lesser power. Since then smear microscopy has been sinew to the TB control
program.5
Low sensitivity (25–75% in respect of culture) is the major limitation of the test making it difficult
to diagnose pauci-bacillary cases and resulting in false negatives in most cases. Other limitations
include inability to differentiate between different species of mycobacterium and bacilli viability
are the major limitations of the test. For Extra-pulmonary (EP) cases, histopathology is used,
specificity of which was dependent on the sampling. Limitations of processing EP samples through
histopathology were lack of experts and poor resource settings.
The Gold-standard diagnostic test for TB was Culture using solid media, which had a very high
sensitivity (requiring approximately 10 bacilli per ml of sample). The test had a time consumption
of 6-8 weeks to give the result that lead to delayed diagnoses, making it a major drawback for it.
With the increased pace the program has attained over the past few decades, the requisite for more
sensitive diagnostic tests which produce results in shorter span of time is imperative. The Liquid
media supports growth faster than solid media and since 1980s, semi-automated and automated
liquid culture systems became available.