Searching

for light in long tunnel:

PID care in Indonesia
Dina Muktiarti
Department of Child Health
Faculty of Medicine Universitas Indonesia –
Cipto Mangunkusumo Hospital
Allergy Immunology Working Group Indonesia Pediatric Society
Outline
• Background
• How to diagnose PID?
• What can we do in Indonesia?
Background
• Primary immunodeficiency (PID) or human inborn errors of immunity (IEI)
are caused by monogenic germline mutations resulting in loss or gain of
function of the encoded protein.
• Dominant or recessive, autosomal or X-linked, and with complete or
incomplete penetrance.
• Clinical manifestation: increased susceptibility to a broad or narrow
spectrum of infectious diseases, autoimmune, auto-inflammatory,
allergic, and/or malignant phenotypes.
• 406 distinct disorders with 430 different gene defects

Bousfiha A, et al. J Clin Immunol.2020;40:66–81

Prevalence
• PID is under-diagnosed, lead to low reported prevalence.
• Prevalence in general population 1:10.000- 12.000.
è Higher in population with consanguinity
• Male : female = 2-3 : 1

Bonilla FA, et al. J Allergy Clin Immunol. 2015;136:1186-205.

Overview of PID Prevalence
Review

Table 2 Overview of well characterised human primary immunodeficiencies (PIDs)

Representative diseases Estimated prevalence Genetic defect(s)

A. Predominantly antibody deficiencies (,65% of all PIDs)

X-linked agammaglobulinaemia (Bruton’s disease) 1:70000 to 1:400000 BTK
Autosomal recessive agammaglobulinaemia Rare m heavy chain (IGHM), Iga (CD79A), Igb
(CD79B), l5 (IGLL1), BLNK
Common variable immunodeficiency (CVID) 1:25000 to 1:50000 ,15% of patients have variants in ICOS, TACI,
BAFFR or Msh5
Selective IgA deficiency 1:500 (majority are Unknown
asymptomatic)
IgG subclass deficiency Uncertain as most patients Unknown
are asymptomatic
B. Combined T and B cell (,15% of all PIDs)
Severe combined immunodeficiency (SCID) 1:65000 IL2RG, JAK3, IL7RA, ADA, RAG1, RAG2 and
several others
Omenn syndrome Rare RAG1, RAG2, Artemis, IL7RA
C. Phagocytic defects (,10% of all PIDs)
Chronic granulomatous disease 1:200000 CYBB, CYBA, NCF1, NCF2
Severe congenital neutropenia 1:300000 ELA2, GF11, G-CSF3R, HAX1 (Kostmann
syndrome)
Cyclic neutropenia 1:100000 to 1:1000000 ELA2
D. Other cellular immunodeficiencies (,5–10% of all PIDs) Turvey SE, et al. Postgrad
Wiskott–Aldrich syndrome 1:100000 to 1:1000000 WASP Med J. 2009;85:660–6.
DiGeorge syndrome (chromosome 22q11.2 deletion 1:4000 Hemizygous deletions of chromosome 22q11.2
syndrome)
Hyper IgE syndrome 1:100000 STAT3 (in autosomal dominant form)
Ataxia–telangiectasia 1:250000 ATM
The table outlines well characterised human PIDs together with estimates of disease prevalence and associated genetic defects.
Extrapolation of Prevalence Rate of X-linked
Agammaglobulinemia

èHowever, the reported cases on XLA in

Indonesia were less than 10% of estimated
prevalence
èUndiagnosed? Misdiagnosed?
Other source:
Estimated prevalence of XLA is:
- 1/350,000 to 1/700,000 (357-714 cases)
- 3:1,000,000-6:1,000,000 (750-1500 cases)
http://www.cureresearch.com/x/x_linked_agammaglobulinemia/stats-
country_printer.htm
https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=47
Smith CIE, Berglöf A. X-Linked Agammaglobulinemia. 2001 Apr 5 [Updated 2016 Aug 4].
GeneReviews® [Internet]. Available from:
https://www.ncbi.nlm.nih.gov/books/NBK1453/
2019 Update of The International Union of Immunological
Societies (IUIS) Phenotypical Classification

Immunodeficiencies
CID with associated Predominantly
affecting cellular Disease of immune
or syndromic antibody
and humoral dysregulation
features deficiencies
immunity

Congenital defects
Defects in intrinsic
of phagocyte Auto-inflammatory Complement
and innate
number, function, or disorders deficiencies
immunity
both

Bone marrow failure Phenocopies of PID

Bousfiha A, et al. J Clin Immunol.2020;40:66–81

Accurate Diagnosis of Inborn Errors of
Immunity/Primary Immunodeficiency
Clinical presentation/phenotype
Family history

Diagnostic laboratory evaluation Genetic analysis

Immunological (phenotyping, functional) Identification of specific gene/variant

Abraham RS, et al. J Allergy Clin Immunol Pract. 2021;9:613-25

TEN
WARNING
SIGN:
JEFFREY
MODELL
FOUNDATION
Ten warning signs for PID
• > 4 new ear infections within 1 year
• > 2 serious sinus infections within 1 year
• > 2months of oral antibiotic treatment with little effect
• > 2 episodes of pneumonia within 1 year
• Failure of an infant to gain weight or grow normally
• Recurrent, deep skin or organ abscesses
+ Adverse events after
• Persistent thrush in mouth or fungal infection on skin
immunization, especially with live
• Need for intravenous antibiotics to clear infections
vaccines (BCG, OPV, measles)
• > 2 deep-seated infections, including septicemia
• A family history of PID.

Modell V, et al. Immunol Res. 2011;51:61-70.

Subbarayan Aet al. Pediatrics. 2011;127:810-6.
History Clue

S •SEVERE

P •PERSISTENT

U •UNSUAL

R • RECURRENT/RUNS IN FAMILY
Relation to specific cell functions
Clinical Manifestations (Non-Infectious Diseases)

Severe atopic dermatitis Congenital heart disease Ataxia

• Hyper-IgE syndrome (+ • DiGeorge Syndrome • Ataxia telangiectasia

bronchiectasis, (interrupted aortic arch,
pneumotocele, high IgE, pulmonary atresia, aberrant
subclavian, tetralogy of Fallot)
skin abscess)
• Wiskott-Aldrich syndrome
(+thrombocytopenia,
recurrent infections)
• IPEX
(immunodysregulation,
polyendocrinopathy,
enteropathy, X- linked
syndrome)
 + HIV, IgE

4 STAGES OF PID TESTING

http://downloads.info4pi.org/pdfs/4StagesFINAL.pdf.
The ‘Five Fingers’ of the Diagnostic Evaluation for Suspected
Immunodeficiency

Cell number

Cell function

Immunoglobulin level (number)

Antibody function

Complement system studies

Varadhi A, et al. Pediatr Ann. 2013;42:210-5.
Approach to PID

Follow a diagnostic
Pick up the sign Recognize the pattern
protocol

• Gender • Laboratory pattern • Choose diagnostic

• Onset (neutropenia, protocol based on
lymphopenia, low the signs and pattern
• Type of infections immunoglobulin, etc)
• Family history

1. De Vries E. Clin Exp Immunol. 2011;167:108-19.

2. Bousfiha A, et al. J Clin Immunol.2020;40:66–81
 HYPOTHESIS AND THEORY ARTICLE
published: 15 December 2014
doi: 10.3389/fimmu.2014.00627

Primary immune deficiencies – principles of care

Helen Chapel 1 *, Johan Prevot 2 , Hubert Bobby Gaspar 3 ,Teresa Español 4 , Francisco A. Bonilla 5 , Leire Solis 2 ,
Josina Drabwell 2 and The Editorial Board for Working Party on Principles of Care at IPOPI †
1
University of Oxford, Oxford, UK
2
International Patient Organisation for Primary Immunodeficiencies (IPOPI), Downderry, UK
3
University College London Institute of Child Health, London, UK

What can we do in Indonesia?

4
Hospital General Vall d’Hebron, Barcelona, Spain
5
Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA

Edited by:
Guzide Aksu, Ege University School
of Medicine, Turkey
Reviewed by:
Klaus Warnatz, University of Freiburg,
Germany
Laurence E. Cheng, University of
California San Francisco, USA
Primary immune deficiencies (PIDs) are a growing group of over 230 different disorders
caused by ineffective, absent or an increasing number of gain of function mutations in
immune components, mainly cells and proteins. Once recognized, these rare disorders
are treatable and in some cases curable. Otherwise untreated PIDs are often chronic,
serious, or even fatal. The diagnosis of PIDs can be difficult due to lack of awareness or
facilities for diagnosis, and management of PIDs is complex. This document was prepared
by a worldwide multi-disciplinary team of specialists; it aims to set out comprehensive
PID – Principles of Care (1)
THE ROLE FOR SPECIALIZED INDONESIA
CENTERS
• Diagnostic facilities • Limited diagnostic
• Specialist centers and facilities and specialist
networks for patient centers
management • Limited resources for
• Support for PID diagnosis genetic examination
and complications in other
medical specialties • No newborn screening
• Adolescent care
• Role of new genetics
Specialist centers and networks for patient management:
Pediatric Allergy-Immunology Consultants –
Allergy Immunology Working Group IPS
General physicians
General pediatricians
Pediatric Infectious Diseases Consultants
1Pediatric Respirology Consultants
Pediatric Gastroenterology Consultants
3
Internal medicine doctors
1
2
Pulmonologist 2
ENT doctors 13
4
Ophthalmologists 5
4
Dermatologists2 3
Etc

Population: + 280 million

Diagnostic facilities: WHO Essential in Vitro Diagnosis
1. Explanatory notes
1.1 Introduction
WHO presents the second Model List of Essential In Vitro Diagnostics (EDL), which extends the first List,
published in May 2018.1 The List recognizes that in vitro diagnostics (IVDs) are essential for advancing universal
health coverage, addressing health emergencies and promoting healthier populations, which are the three
strategic priorities of the Thirteenth WHO General Programme of Work, 2019–2023.2
II.b Disease-specific IVDs for use in clinical laboratories continued
1.2 Objective Disease Diagnostic test Test purpose Assay format Specimen type WHO prequalifie
The EDL lists IVDs that are recommended by WHO for use in countries. The EDL is not intended to be p
recommended
prescriptive with respect to the IVDs
Primary listed
HIV 1/2 or theForlevels
antibody at which theyRDT
differential can or should
Oralbe used; rather, N/A
fluid countries
should decide which IVDs to select and where to use them, depending on their epidemiology, human resources
Immuno- (anti-HIV Ab) diagnosis of primary Capillary whole blood
and infrastructure. deficiencies immunodeficiencies Venous whole blood
Immunoglobulin To identify patients Radial Serum N/A
The EDL is expected to provide guidance
plasma levelsand
(IgG,serve as aIg levels
with low reference
and for Member States (programme managers,
immuno-
laboratory managers, procurement officers and reimbursement officers) that are developing and/or updating
IgA, IgM) monitor replacement diffusion
(RID)
national EDLs for interventions within universal health coverage and for selecting and using IVDs. It will also be
informative for United Nations agencies and nongovernmental organizations Immunoassay Serum selection, procurement,
that support
Plasma
supply, donation or provision of IVDs and will inform the private medical technology sector about the diagnostic
priorities and the IVDs necessary Lymphocyte
to address globalTohealth
aid in the
issues. Flow Venous whole blood N/A
subtype diagnosis of primary cytometry
enumeration: and secondary
1.3 Scope of the second EDL CD4, CD8, CD20,
CD16/56 cells,
immunodeficiencies

The EDL consists of 122 test categories

B cells, presented
and as follows:
41

NK cells
■ 46 general IVD tests that can be used for routine patient care as well as for the detection and diagnosis
(Refer to HIV
of a wide array of disease conditions;
infection for
enumeration of
■ 69 IVDs intended for the detection, diagnosis and monitoring of specific diseases. The first EDL listed
CD4 cells only)
Diagnostic facilities: Immunology Laboratory Facility
-survey in 14 teaching hospitals-
Test Note
Complete blood count Available in all hospital
Immunoglobulin (IgG, IgA, IgM, IgE) Available in most hospitals.
Lymphocyte subset Available in all hospital for CD4, but not for other lymphocyte
subset.
Complement Available in all hospital
Lymphocyte proliferation test Not available
Granulocyte function-NBT/DHR, etc Not available
Pneumococcal antibody; other antibodies 2 labs* (pneumococcal)
(measles, etc)
Genetic 1 private genetic lab

* Research and private laboratory.

PID – Principles of Care (2)
THE IMPORTANCE OF
REGISTRIES INDONESIA

National registries Under-reported:

International Undiagnosed
experience of Misdiagnosed
registries Small number of
patients registered
 Countries and Continents
PID – Principles of Care (3)
of the World
THE NEED FOR INTERNATIONAL COLLABORATIONS
 PID – Principles of Care (4)

THE ROLE OF PATIENT GROUPS

2 May 2015 24 April 2016 6 May 2017 28 April 2019 2020

Educational Material

https://www.imunodefisiensi-indonesia.org
Educational Material
PID – Principles of Care (5&6)
MANAGING PID
MANAGEMENT AND
TREATMENT OPTIONS FOR PIDs DIAGNOSIS AND CARE IN
ALL COUNTRIES
• Immunoglobulin replacement therapy
(safety, optimal treatment level, access • Access to PID care world-
to a wide choice, PID as priority wide
indications for Ig therapy, site of Ig
treatment) • Access to PID diagnosis
• Hematopoietic stem cell transplantation
• Additional antimicrobial measures
• Access to PID treatments
• Immunological and other treatments
• Gene therapy
• Vaccines
• Comprehensive and holistic approach to
the patient
• Emergency medicine
Access to diagnosis
• Many studies showed that there was a significant delay in PID
diagnosis (3 months –4,7 years).
• In Indonesia:
• Many cases were undiagnosed.
• Many cases had other siblings that died with same problems.
• PID diagnosis was delayed up to 11 years.

Mohammadinejad P, Mirminachi B, Sadeghi B, Movahedi M, Gharagozlou M, Mohammadi J. Iran J Immunol. 2014;11:282-91.

Michos A, Raptaki M, Tantou S, Tzanoudaki M, Spanou K, Liatsis M. J Clin Immunol. 2014;34:836-43.
Gathmann B, Goldacker S, Klima M, Belohradsky BH, Notheis G, Ehl SCEI. Clin Exp Immunol. 2013;173:372-80.
Bahrami A, Sayyahfar S, Soltani Z, Khodadost M, Moazzami B, Rezaei N. Allergol Immunopathol (Madr). 2020;48:711-9.
Access to PID treatment
Access to PID treatment
• Immunoglobulin replacement therapy
• Only IVIG available in Indonesia
• Not supported by national health insurance
• Indication for IVIG in government insurance: GBS, myasthenia
crisis
• Stem cell transplantation
• Not available for PID
 diketahui/tidak lengkap.
b) Manifestasi tetanus secara

National Formularium 1.
klinis.
inj 250 IU (i.m.)
2. inj 500 IU (i.m.)
3 imunoglobulin intravena
a) Hanya digunakan apabila syarat
untuk plasmaferesis tidak
terpenuhi pada terapi:
- Guillain–Barré syndrome (GBS).
- Krisis miastenia.
b) Untuk krisis miastenia, dapat
diberikan di Faskes Tk. 2 dan 3
yang memiliki fasilitas ICU.
1. inj 50 mg/mL
4 serum anti bisa ular :
a) Khusus untuk daerah tertentu.
0
Summary
• To diagnose PID starts with to think PID.
• Ten warning sign from Jeffrey Modell Foundation can be used to
suspect PID in a patient.
• History clue: unusual, severe, opportunistic infection, failure to thrive,
complication of vaccination, and family history of PID
• Indonesia’s challenges for PID care: lack of awareness, limited pediatric
immunology consultants, limited laboratory facility, limited treatment,
limited financial support.
• Next steps: Continue to raise awareness, build networking, identify facility
for improving diagnosis capability, advocacy to policy maker.
 Protecting and improving the lives of the millions of people
living with primary immunodeficiency worldwide by supporting
early diagnosis and access to care
T H A N K YOU