Golden jubilee perspective |
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Indian Pediatr 2013;50: 88-92 |
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50 years of Pediatric Immunology: Progress and
Future - A Clinical Perspective
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Surjit Singh, Anju Gupta and Amit Rawat
From the Pediatric Allergy & Immunology Unit,
Advanced Pediatrics Center, PGIMER, Chandigarh, India
Correspondence to: Dr Surjit Singh, Professor of
Pediatrics, Advanced Pediatrics Center, Post Graduate Institute of
Medical Education and Research, Chandigarh 160 012.
Email:
[email protected] m
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Rapidly evolving advances in the field of immunology
over the last few decades have impacted the practice of clinical
medicine in many ways. In fact, understanding the immunological basis of
disease has been pivotal in deciphering the pathogenesis of several
disease processes, infective or otherwise. As of today, there is hardly
any specialty of medicine which is not influenced by immunology.
Pediatric rheumatological disorders, vasculitides, Human
Immunodeficiency Virus (HIV) infection, Primary Immunodeficiency
Diseases (PIDs) and autoimmune disorders fall under the domain of
clinical immunology. This specialty is poised to emerge as a major
clinical specialty in our country. The gulf between bench and bedside is
narrowing down as our understanding of the complex immunological
mechanisms gets better. However, a lot still needs to be done in this
field as the morbidity and mortality of some of these conditions is
unacceptably high in the Indian setup. A number of medical schools and
institutes in the country now have the resources and the wherewithal to
develop into specialized centres of clinical immunology. We need to
concentrate on training more physicians and pediatricians in this field.
The future is bright and the prospects exciting!
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Clinical Immunology has been defined as "a
clinical and laboratory discipline dealing with the study, diagnosis and
management of patients with diseases or disease processes resulting from
disordered immunological mechanisms, and conditions in which
immunological manipulations form an important part of therapy and/or
prevention" [1-3]. It is unfortunate but true, that the recognition of
clinical immunology as a subspecialty in its own right has lagged far
behind that of conventional ‘organ-based’ subspecialties as for instance
cardiology, neurology, gastroenterology and the like.
Rapidly evolving advances in the field of immunology
over the last few decades have impacted the practice of clinical
medicine in ways which were hitherto unimaginable. In fact,
understanding the immunological basis of disease has been pivotal in
deciphering the pathogenesis of several disease processes, infective or
otherwise [1,2]. As a result, there is hardly any specialty of medicine
which can steer clear of immunology. However, for the laity, it is
sometimes difficult to comprehend what exactly clinical immunology is.
This is because unlike other specialties of medicine which are by
definition organ driven, clinical immunology does not have a specific
organ it can claim as its own!
Overlap with Other Disciplines
Clinical immunology has an overlap with several
medical disciplines and this is an important concept to understand.
While specialties like cardiology, neurology and gastroenterology have a
well-defined and ‘loyal’ clientele amongst the patients, the situation
is somewhat different for clinical immunology because diseases related
to the field of immunology cut across specialties as these may affect
several body systems [2,3]. Accordingly, clinical immunologists are in a
unique position to assess diseases in a manner no other specialty
possibly can. This is one of the unique strengths of the specialty [2].
The conundrum of clinical immunology is best exemplified by systemic
lupus erythematosus – the prototype collagen vascular disease [4]. While
lupus can affect any system in the body and management may ordinarily
and logically be considered to be system driven, it is the clinical
immunologist who is in the best position to comprehend and coordinate
the care of this complex multisystem disorder.
Clinical Immunology in the Medical Curriculum in India
At present the undergraduate and postgraduate medical
curricula in India, unfortunately, do little justice to the specialty of
clinical immunology. As a result, students do not get an adequate
exposure to the ‘breadth and the depth’ of the specialty. Their
knowledge skills, therefore, leave a lot to be desired. This needs
urgent remedial action because unlike what is commonly believed,
disorders affecting the immune system are by no means rare conditions.
Components of Pediatric Clinical Immunology
The following five major sets of medical conditions
need the care and expertise of a pediatric clinical immunologist:
1. Pediatric rheumatological disorders
Rheumatological disorders affect nearly 2-5% of the
population depending upon the criteria used to define a rheumatological
disorder [4]. These figures may not look very impressive in isolation,
but when extrapolated on to the country’s population the numbers are
indeed staggering. Rheumatology is, in many ways, the backbone of
clinical immunology and an essential component of any training program
in the subject. It should be noted that approximately 10-20% of patients
with rheumatological disorders have onset of disease in the pediatric
age group [4]. There is a crying need, therefore, to have dedicated
centres of pediatric rheumatology in India. Because of the dearth of
specialists in the field, it is not uncommon to see children with
arthritides in our country being looked after by orthopedic surgeons
even when the child with arthritis rarely needs an orthopedic
intervention. This is a pity considering that the prevalence of juvenile
idiopathic arthritis may be as high as 2-4 per 1000 children below 15
years of age [4].
2. Pediatric vasculitides
Amongst the vasculitides, Kawasaki disease (KD) and
Henoch Schonlein Purpura (HSP) are common pediatric conditions [5-11].
We have recently shown that in the hospital setting at Chandigarh, KD
has now emerged as the commonest vasculitic disorder in children [6].
Studies from Japan suggest that the incidence of KD
can be as high as 239.6/100,000 children below 5 years of age [12]. KD
is now the commonest cause of acquired heart disease amongst children in
Japan and several Western countries [4]. A recent study from Chandigarh
has projected a much lower figure than what has been computed from the
Japanese data, but it is possible that majority of children with KD in
India are perhaps not even being diagnosed at present [5,8,9]. This is a
pity because the complications associated with KD are eminently
preventable. Though the awareness of KD amongst pediatricians and
physicians in India has greatly increased over the last decade, much
still needs to be done in this regard [7]. It is distinctly possible
that in the years to come, KD would supplant rheumatic fever as the
commonest cause of acquired heart disease in India, just as it has in
the West. This has serious implications for health planners in the
country.
It is not often realized that HSP can have
significant long-term morbidity and may not always a benign disorder of
childhood. When HSP occurs in school-age children, the risk of
developing serious nephritis is real and such children need close
follow-up even when they do not have overt features of nephritis at
onset of disease. Early recognition and prompt treatment of HSP
nephritis can result in favorable outcomes [10].
3. Infection with the Human Immunodeficiency Virus
Projections from the National AIDS Control
Organization (NACO) suggest that the prevalence of Human
immunodeficiency virus (HIV) infection in India is showing a downward
trend and is currently in the range of only 0.31% according to the
Annual Report of NACO for the year 2010-11 [13]. Clearly, India has done
remarkably well in the control of this epidemic. However, it is still a
sobering thought that even at this low prevalence the number totals up
to a staggering 2.39 million individuals. Approximately, 3.5% of these
are likely to be children. Whilst patients with HIV infection can also
be undoubtedly looked after by infectious disease specialists, the
clinical immunologist, with his knowledge and expertise in the
intricacies of the immune system, is perhaps better equipped to do so
[14,15]. There are several medical schools in the country which are
running clinics dedicated to the care of children with HIV infection.
However, we need more pediatric clinical immunologists to deal with the
complex medical problems of affected children.
4. Primary immunodeficiency diseases (PIDs)
PIDs are often perceived to be rare disorders by both
physicians and the laity – this is by no means true [16-22]. Recent
community based data from the Jeffrey Modell Foundation (JMF) and the
Immune Deficiency Foundation (IDF), in fact, suggest that 1:1000 to
1:2000 of the population have an underlying PID. Extrapolating these
data on to India’s population suggest that close to a million
individuals in our country may be having an underlying PID [17]. The
vast majority of patients with PID in India, however, remain undiagnosed
and consequently untreated [17]. There is, therefore, a crying need to
create more awareness about PIDs amongst pediatricians and physicians in
our country. Several of the PIDs are now eminently treatable [16].
5. Autoimmune disorders
Another aspect of clinical immunology is the study of
autoimmune disorders, which encompass several major specialties like
neurology, gastroenterology, hepatology, dermatology and ophthalmology.
Clearly, many of these disorders need to be managed jointly by experts
in clinical immunology as well as the conventional organ based
specialists [23-25]. Modern management protocols are increasingly
incorporating immunomodulatory agents and biologicals for many of these
conditions. The expertise and skills of the clinical immunologist are,
therefore, invaluable in designing and fine-tuning of treatment
strategies for a given patient, especially in children [4].
Pediatric Clinical Immunology as a Specialty
Clinical immunology is different from other
conventional medical specialties in many ways. For one, it has its basis
in standardized laboratory tests and reproducible laboratory techniques
[4,23-25]. Any fellowship program in clinical immunology, therefore, has
a strong component of laboratory training. Secondly, training programs
in clinical immunology can vary greatly amongst different countries
[1-3]. For instance, while fellowships in clinical immunology in the
United States of America often have allergy as an integral and a major
component of the training, those in Europe may not give that much
importance to the allergic diathesis. Similarly, some of the pediatric
immunology units in the United Kingdom deal almost exclusively with
PIDs. The component of rheumatology in training programs varies from
center to center and depends understandably upon the profile of referred
patients.
Emergence of Pediatric Clinical Immunology in India
It is heartening to note that, in India, clinical
immunology is rapidly emerging as a specialty in its own right. Several
medical schools/institutes have now started dedicated immunology units
and outpatient clinics. However, a lot still needs to be done in this
field especially as far as pediatric clinical immunology is concerned.
Specialized training facilities for pediatric immunology are, at
present, virtually nonexistent. As a result, there is a dearth of
trained medical professionals. We still do not have a formal
post-doctoral (i.e. DM) course in pediatric immunology anywhere
in the country. This is a major lacuna which needs to be filled.
The Indian Academy of Pediatrics has a dedicated
Rheumatology Chapter which has been instrumental in increasing awareness
about these conditions amongst pediatricians in the country. The chapter
recently held its 10 th
National Conference. The Indian Society for Primary Immune Deficiency
(ISPID) was founded in 2010-2011 with the aim of demystifying the
conundrum of PIDs amongst clinicians and laboratory scientists [17].
NACO has done yeoman service in not only halting the dreaded HIV
epidemic and in facilitating the training of skilled manpower, but in
also increasing the awareness about this condition amongst the medical
professionals as well as in the laity [13].
Advances in Clinical Immunology
Recent advances in clinical immunology have been path
breaking, especially in the field of PIDs [26-30]. The diagnosis of
PIDs, in many situations, is now based on a genetic and molecular basis
rather than on flow cytometry based tests, as was the case in the 1990s.
The list of disorders classified under PIDs has expanded exponentially
and underlying gene defects in many of these disorders have been
unraveled [16]. The International Union of Immunological Societies
Expert Committee on Primary Immunodeficiency Diseases recently reported
on the biennial update of the classification of PIDs in 2011 [16].
The feasibility of a newborn screening program for
severe combined immunodeficiency (SCID) has recently been demonstrated
by the development and implementation of a mass screening programme in
the state of Wisconsin, USA [26]. This is based on assay of T-cell
receptor excision circles (TRECs) using real time quantitative
polymerase chain reaction (PCR). Absent or low levels of TRECs strongly
correlated with a diagnosis of SCID. Several other states in the USA
have now similar program in place. An effort to develop a similar
screening method for B cell immunodeficiencies using
k recombination
excision circles (KRECs) using a similar methodology to TRECs has also
been recently reported [27].
While significant advances have been made in
understanding the pathogenesis of several rheumato-logical disorders, we
are still a long way off from unraveling the etiological basis of these
conditions. We are beginning to realize that the subgroups of juvenile
rheumatoid arthritis may, in fact, be completely different diseases in
themselves. Consequently, the therapeutic strategies for each of these
conditions may need to be worked out separately. Systemic onset juvenile
idiopathic arthritis may be more of an autoinflammatory condition
(involving innate immunity) rather than an autoimmune condition
(involving acquired immunity).
Substantial achievements have also been made in the
treatment of PIDs as well as rheumatological disorders [16, 17].
Hematopoietic stem cell therapy (allogeneic, haploidentical, matched
unrelated) is now well established as a treatment option for many of the
cell mediated immune deficiencies like SCID and the Wiskott Aldrich
syndrome (WAS). Intravenous immunoglobulin therapy has virtually
revolutionized the management of humoral immunodeficiencies like
X-linked agammaglo-bulinemia, common variable immunodeficiency and some
of the IgG subclass deficiencies [16,17]. Gene therapy trials for the
treatment of PIDs have been successfully conducted in the past 2 decades
particularly in Adenosine Deaminase Deficiency (ADA), X-linked SCID and
WAS [28,29]. Novel approaches to gene correction with locus specific
targeting (as for instance with the use of endonucleases, zinc finger
nucleases and transposons) are now being developed and may soon undergo
clinical trials. Generation of induced pluripotent stem cells (iPSCs)
from fibroblasts of patients with PIDs is another exciting field with
tremendous therapeutic potential [25].
Similarly, with the advent of monoclonal antibodies
and other biologicals in the day-to-day management of rheumatological
disorders [30,31], especially juvenile idiopathic arthritis and systemic
lupus erythematosus, the treatment options available to the physician
have undergone a sea change.
The Future of Pediatric Clinical Immunology in India
Pediatric clinical immunology is poised to emerge as
a major clinical specialty in our country. The gulf between the bench
and the bedside is narrowing down as our understanding of the complex
immunological mechanisms gets better [32-35]. However, a lot still needs
to be done in this field as the morbidity and mortality of some of these
conditions is unacceptably high in the Indian setup [36]. A number of
medical schools and institutes in the country now have the resources and
the wherewithal to develop into specialized centres of clinical
immunology. We need to concentrate on training more physicians and
pediatricians in this field. The future is bright and the prospects
exciting!
Contributors: SS drafted the manuscript. He will
act as guarantor of the study. AG and AR helped in manuscript writing
and critical review of literature. The final manuscript was approved by
all authors.
Funding: None; Competing interests: None
stated.
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S, Abel L, Casanova JL. Multifocal tuberculous osteomyelitis: possible
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Sakhuja V. A decade long experience of anti-neutrophil cytoplasmic
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Perspective from a developing country. Indian J Path Microbiol.
2011;54:258-63.
25. Minz RW, Chhabra S, Singh S, Radotra BD, Kumar B.
Direct immunofluorescence of skin biopsy: perspective of an
immunopathologist. Indian J Dermatol Venereol Leprol. 2010;76:150-7.
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Brokopp CD, Kurtycz DF, et al. Development of a routine newborn
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patterns in childhood lupus – 10 years experience in a developing
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