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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 11  |  Issue : 6  |  Page : 262-268

Clinical and laboratory profile of children with primary immunodeficiency - Perspective from a developing country


1 Department of Pediatrics, St. Johns Medical College Hospital, Bengaluru, Karnataka, India
2 Division of Pediatric Hematology and Oncology, St. Johns Medical College Hospital, Bengaluru, Karnataka, India
3 Department of Pediatrics, Aster CMI Hospital, Bengaluru, Karnataka, India

Date of Submission26-Jul-2021
Date of Decision14-Nov-2021
Date of Acceptance26-Nov-2021
Date of Web Publication31-Dec-2021

Correspondence Address:
Dr. Ranjini Srinivasan
Department of Pediatrics, St. Johns Medical College Hospital, Bengaluru - 560 034, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/cmrp.cmrp_74_21

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  Abstract 


Aim: The aim of the study was to describe the clinical and laboratory features of children diagnosed with primary immunodeficiency from India.
Background: Primary immunodeficiency disorders (PIDs) are a diverse group of conditions with heterogeneous presentation.
Materials and Methods: A retrospective chart review of clinical and laboratory data of 40 children with primary immunodeficiency between 1 month and 18 years of age was carried out. A diagnosis of primary immunodeficiency was made based on the standard criteria.
Results: Among the 40 children reviewed, males were more affected than females (1.8:1). Seventy per cent of the patients had onset of symptoms before 1 year of age. Recurrent fever (50%) was the most common presentation. Various infections included pneumonia (45%), gastrointestinal infections (18%), oral thrush (15%), recurrent otitis media (7.5%) and recurrent skin infections (5%). Non-infective complications included neurological manifestations such as developmental delay and seizures (10%), growth failure (38%) and cytopenia. Patients were categorised into combined humoral and cellular immunodeficiency (30%), predominant antibody deficiencies (12%), diseases of immune dysregulation (32%), congenital deficiencies in phagocytes (10%) and deficiencies in innate and intrinsic immunity (15%). A genetic confirmation of the immunodeficiency could be obtained only in half of all patients (49%).
Conclusions: Children with PIDs can present with typical manifestations such as recurrent life-threatening infections or may have more unusual presentations such as cytopenia or unexplained growth failure.

Keywords: Genotype, immune system, infections, malnutrition


How to cite this article:
Krishna S, Srinivasan R, Prakash A, Bhattad S, Indumathi C K. Clinical and laboratory profile of children with primary immunodeficiency - Perspective from a developing country. Curr Med Res Pract 2021;11:262-8

How to cite this URL:
Krishna S, Srinivasan R, Prakash A, Bhattad S, Indumathi C K. Clinical and laboratory profile of children with primary immunodeficiency - Perspective from a developing country. Curr Med Res Pract [serial online] 2021 [cited 2022 Jan 16];11:262-8. Available from: http://www.cmrpjournal.org/text.asp?2021/11/6/262/334582




  Introduction Top


Primary immunodeficiency disorders (PIDs) are a heterogeneous group of disorders caused by genetic defects in the immune system. These disorders are not as rare as they were previously thought to be. To date, there are more than 400 identifiable PIDs that have been classified into nine categories by the International Union of Immunological Societies (IUIS) based on the clinical and immunological phenotypes. The prevalence of these disorders is on the rise and is known to affect 1 in 1200–2000 individuals.[1] Newer modalities such as flow cytometry and genetic analysis have aided in confirming the diagnosis of these conditions.

Based on the incidence of PID in other countries being 1 in 1000, it is estimated that the possible number of patients with PID in India is roughly around 1 million.[2] South India with its higher rates of consanguinity potentially has a higher rate of PID diagnosis. However, in resource-limited countries, the prevalence of PID continues to be low as they are underdiagnosed. Limited awareness of the magnitude of the problem and lack of availability of technical assistance including newer available diagnostic aids to establish a diagnosis are some of the possible explanations for the low prevalence. Second, the endemic nature of infections and coexisting nutritional deficiencies may confound the diagnosis even further. As a result, the majority of patients in India continue to remain undiagnosed and untreated.[3]

In general, there is a paucity of data from the developing world on the spectrum of PIDs seen and also the outcomes. This is a retrospective study where we have reviewed the clinical manifestations, investigations and the treatment options including transplant in a cohort of children diagnosed with PID. We compare our experience with other case series from both developed and developing countries to describe differences in clinical presentation, challenges to diagnosis and barriers to treatment in the developing country context.


  Materials and Methods Top


The study was carried out at a tertiary level teaching hospital in South India with a 90-bedded paediatric department. Clinical and laboratory data of children from new-borns to 18 years of age between January 2012 and May 2020 were retrospectively reviewed. All those who were diagnosed with primary immunodeficiency as per the IUIS were included in the study.[4] Institutional ethics committee approval was obtained. Demographic data, clinical and radiological features and laboratory investigations including complete blood counts, peripheral smear, flow cytometry reports, immunoglobulin levels, complement levels, nitro blue tetrazolium and dihydrorhodamine tests, workup for infections including tuberculosis and genetic tests were obtained from medical records and analysed. Bone marrow aspiration was done in cases of prolonged fever, cytopenia or when haemophagocytic lymphohistiocytosis was suspected. Descriptive statistics was applied to obtain the results in our study.


  Results Top


Data of 40 children with suspect/confirmed primary immunodeficiency were collected. Of these, 26 (65%) were male with a sex ratio of 1.8:1 (M:F). Almost two-third of patients (70%) had onset of symptoms before 1 year of age. The mean age of onset of symptoms was 17 months (±22.5 months). The youngest age at diagnosis was in the neonatal period where a new-born with severe combined immunodeficiency was diagnosed at birth. Average time lag between onset of symptoms and age of diagnosis was 31.5 months (±48.33 months). Almost half of affected children (53%) were born out of non-consanguineous parentage. Twenty-seven per cent children had history suggestive of PID among the first-degree relative/family members. Recurrent fever (50%), pneumonia (45%) and failure to thrive (37%) were the most common clinical features at presentation. Other manifestations included oral thrush, chronic diarrhoea, recurrent ear infections, development delay and seizures. Infections that the patients presented with included pneumonia (45%), gastrointestinal infections (18%), oral thrush (15%), recurrent otitis media (7.5%) and recurrent skin infections (5%). Few children also presented with bleeding problems in the form of skin and oral bleeds (10%). Findings on examination included rash, generalised lymphadenopathy, Bacille Calmette Guérin (BCG) adenitis, pallor, clubbing and facial dysmorphism [Figure 1]. Organomegaly was seen in 42% of the children. 65% of patients with PID had anaemia out of which 35% had severe anaemia that required transfusions. Almost half the patients (55%) had a normocytic blood picture and 32% had microcytic hypochromic anaemia. Direct Coombs test was positive only in one patient. The anaemia was due to one or more factors including micronutrient deficiencies, anaemia of chronic disease and bone marrow infiltration/suppression. Other abnormalities seen in blood counts were Leukopenia (17%), leucocytosis (40%), neutropenia (22%) and thrombocytopaenia (30%). Mycobacterium bovis was isolated from all the patients diagnosed with Mendelian susceptibility to mycobacterial diseases (MSMD). The organisms isolated from patients with other types of PIDs were Staphylococcus aureus, Nocardia, and Aspergillosis. Some unusual sites of infection were temporal bone osteomyelitis (congenital neutropaenia) and testicular abscess (hyper-immunoglobulin E syndrome).
Figure 1: The clinical features of the various classes of primary immunodeficiency disorders

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[Table 1] depicts the demographic characteristics, clinical and laboratory features of children with PID and the various classes of PIDs.
Table 1: Demographic characteristics of different classes of primary immunodeficiency disorders

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Using the IUIS classification (4), the PIDs were classified into those affecting cellular and humoral immunity and combined immune deficiencies (30%), predominant antibody deficiencies (12.5%), diseases of immune dysregulation (32.5%), congenital deficiencies in phagocytes (10%) and deficiencies in innate and intrinsic immunity which included patients with MSMD (15%). Genetic confirmation was obtained in 17 patients (42.5%) as represented in [Table 2] which depicts the results of next-generation sequencing in our patients. However, there were differences between the clinical phenotype and the genetic diagnosis in 5 (29%) of our patients who had genetic testing done as depicted in [Table 3]. Among those with genetic confirmation, the baseline workup for immunodeficiency including flow cytometry and immunoglobulin levels was normal in 3 patients (17.6%) and the condition was diagnosed only by molecular analysis. More than half of all the patients (57%) were lost to follow-up, and only one patient underwent stem cell transplant. Among those who had genetically confirmed PIDs, 8 patients died (47%) and 3 patients were lost to follow-up.
Table 2: Primary immunodeficiencies diagnosed based on genetic analysis

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Table 3: Depicting the phenotypic and genomic differences

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  Discussion Top


Clinical presentation of PIDs can vary from relatively benign forms such as IgA deficiency to life-threatening ones such as severe combined immunodeficiency (SCID).[5] The complex nature of the illness, limited diagnostic facilities and need for resource-consuming treatment in developing countries are the common obstacles in the effective management of these patients. The above deficiencies may also explain the possible reasons for lack of published data in resource-limited countries.

In the present study, it was noted that males were affected predominantly which could be partly due to gender bias in seeking medical care, an unfortunate reality in some parts of the world. However, this pattern of male predominance has been reported in other PID registries as well.[6],[7] This male preponderance holds good even if the immunodeficiency diseases with X-linked forms of inheritance are excluded. Overall, the reason for this difference is not clear but may be partly explained by genetic susceptibility.[6]

Age of onset of symptoms varied based on the type of PID. Seventy per cent of the patients had onset of symptoms before the age of 1 year. Most of these patients had combined cellular and humoral immunodeficiencies, phagocytic defects or disorders of immune dysregulation. In a study by Gupta et al. on a cohort of 120 children with PID, 86% had varied age of presentation ranging between 3 months and 17 years of age.[8] In a retrospective study on 112 Chinese children, it was observed that those children with SCID and Wiskott-Aldrich syndrome presented earlier with the median age of onset of symptoms being 1 month and 4 months respectively, while primary antibody-related deficiencies had a later presentation at a median age of 26.5 months.[9] In our cohort, the diagnosis of SCID in one patient was obtained even before the onset of symptoms in view of a significant family history of multiple sibling deaths as a result of which flow cytometry done at birth clinched the diagnosis.

Almost half the patients were born of consanguineous parentage and nearly one-third had an affected family member. In a study done in North India by Gupta et al.,[8] consanguinity was seen in 80% of patients and 23% of patients had a history of previous sibling death. In another similar retrospective study conducted in Iran on 59 patients with PID, consanguinity was observed in 61% of patients and family history was positive in 34% of the affected patients.[10] On the other hand, data obtained from a United Kingdom PID registry reported consanguinity in 2.9% of 4097 cases and 24% were identified as familial cases.[11] This is probably because consanguinity rates, in general, vary between populations due to differences in religion, culture and geography, with higher levels being reported in Middle East and Western Asia, Arab and African Countries and South India.[12]

The most common symptom in our patients was that of recurrent fever which was most likely due to an infectious process. The various infections that the patients presented with included pneumonia (43%), diarrhoea (16%), thrush (16%), ear infections (11%) and skin infections (2%). BCG adenitis was reported in 21% of the patients. This was predominantly seen in patients diagnosed with MSMD. In a similar study done by Mirzaee et al. in Iran, out of 80 patients with immunodeficiency, pneumonia (30%), diarrhoea (18.8%) and otitis media (15%) were the most common infections encountered in these patients.[13] Neurological manifestations in the form of developmental delay and seizures were seen in around 10% of our patients. In our study, growth failure was seen in 38% of children at the time of diagnosis and was noted predominantly in those children with combined immunodeficiencies and disorders of immune dysregulation. Khalilzedah et al. reported growth failure in 69% of patients in their cohort of 59 PID patients.[14] Causes for growth failure in PIDs are usually multifactorial due to recurrent infections, chronic inflammation increasing the resting energy expenditure and a hyper-catabolic state, anorexia or malabsorption. In the developing world, growth failure due to under-nutrition and recurrent infections may be overlooked as malnutrition itself is not an uncommon feature in many children admitted for infections. Hence, a high index of suspicion to consider PID as a possibility rather than only nutrition-related growth failure may help identify more children with PIDs. In addition to the above, the association of genetic syndromes with PIDs or the presence of secondary endocrinopathies as a result of autoimmunity in children with PID may also contribute to short stature in these patients.[15]

Haematological features such as anaemia were present in nearly two third of our patients. Out of these, almost half the patients presented with severe anaemia requiring transfusion. Almost 40% of the anaemic patients had pancytopenia. Thrombocytopaenia was seen in one-third of our patients. In our study, anaemia and thrombocytopaenia were predominantly seen in patients with combined immunodeficiencies. Majority of patients had normocytic normochromic anaemia on the peripheral blood smear. Bleeding manifestations were noted in 8% of children. Data obtained from 80 patients with PID from a registry in Iran revealed that anaemia was predominantly seen in patients with phagocytic disorders and thrombocytopenia was mainly seen in those patients with humoral immunodeficiencies.[13] The most common autoimmune manifestations in PIDs are immune thrombocytopenic purpura followed by autoimmune haemolytic anaemia. However, autoimmune haemolytic anaemia was not as commonly seen in our study as reported in literature. This may be because one-third of the patients in our study had disorders of immune dysregulation who predominantly presented with pancytopenia. Leucocytosis was observed to occur more commonly than leukopenia in our study. This could be due to the presence of a concomitant infectious process as majority of our patients presented with recurrent fever.

Among the various immunodeficiency syndromes, nearly one-third of our patients presented with diseases of immune dysregulation. Further, India has been witnessing among physicians, an increasing awareness regarding haemophagocytic lymphohistiocytosis and its association with various infectious and autoimmune processes as evidenced by a rising trend in published literature regarding the same. Thirty per cent of children presented with features of combined immunodeficiencies. Predominant antibody deficiencies, phagocytic defects and defects in innate and intrinsic immunity were each seen in 12%, 11% and 15% of the patients, respectively. This finding was similar to what was seen in a study conducted by Chinnabhandra et al. who presented the data of 47 patients from a hospital-based registry.[6] In this study, 29% of the patients presented with immune dysregulation, 28% with B and T cell abnormalities, 23% with antibody deficiencies, 15% with other well-defined immunodeficiency syndromes and 4% with phagocytic defects. Data available in the literature from other studies in India and elsewhere show wide variation in the prevalence of various subclasses of immunodeficiency syndromes.[6],[13],[16]

The diagnosis was confirmed by genetic testing in half the patients in our study. In the study by Chinnabhandra et al., molecular testing was possible only in 25% of their patients.[6] In a study carried out in Kuwait by Al-Herz et al. that looked into the genetic causes of primary immunodeficiencies, the diagnostic yield of genetic analysis was around 70%.[17] In resource-limited countries like India, the main obstacles to molecular diagnosis are the availability of only few testing centres and the high cost. Benefits of genetic analysis include early reliable diagnosis, prognostication of the disease and early initiation of treatment such as antibody replacement and haematopoietic stem cell transplantation. Genetic testing not only helps in discovering novel disease-causing genes but may also uncover new inheritance patterns of known genes which may be associated with new or unexpected clinical phenotypes.

In our study as well, we noticed genotypic and phenotypic discrepancies in a few patients whose clinical presentation and genetic diagnosis did not go hand in hand. Targeted therapies such as immunosuppression, usage of monoclonal antibodies or specific molecule inhibitors are facilitated once molecular diagnosis is established. Furthermore, genetic counselling and prenatal diagnosis can be offered only after the genetic confirmation of the disease.[10]

About 43% of patients are on follow-up. All children on follow-up are on symptomatic treatment including intravenous immunoglobulin and prophylaxis based on the underlying diagnosis. However, as only less than half the patients are on our follow-up, it was not possible to obtain the overall mortality data. The expenses incurred both from diagnosis and treatment of a child with PID including haematopoietic stem cell transplant contribute to morbidity and mortality as it prevents timely care and medical treatment from being administered.

There were few interesting observations in our study. Although consanguinity is very common in South India, we would have expected a larger number of patients to have presented with problems of immunodeficiency. This may be due to lack of awareness and timely referrals. Almost one-third of our patients presented with failure to thrive. The endemic nature of many infectious diseases such as tuberculosis and high prevalence of malnutrition in the country may be some of the reasons why immunodeficiency as a possibility might have been overlooked. Although autoimmunity is the main cause for cytopenia in children with immunodeficiency, it was not a predominant manifestation observed in our cohort of patients. It may therefore be reasonable to suspect immunodeficiency as one of the possibilities in a child presenting with unexplained anaemia or pancytopenia against a background of recurrent infections or growth failure when other causes have been ruled out. Although less than half the patients in our study had a genetically confirmed diagnosis, it was interesting to note that in a subset of patients, there were discrepancies between the clinical phenotype described and the immunodeficiency syndrome confirmed subsequently by molecular technique. It is therefore important to attempt to get a genetic confirmation for every patient with a clinical diagnosis of primary immunodeficiency so that therapy is more targeted.

The findings from the present study are compared with other studies done in developing and developed countries as depicted in [Table 4].[11],[18],[19],[20],[21],[22] The mean lag time to diagnosis in our study is comparable with that of developing countries. However, the genetic diagnosis, follow-up and long-term prognosis remain still challenging in most countries.
Table 4: Comparative studies: Primary immunodeficiency disorders studies from India and other countries

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There are certain limitations in our study. Given the retrospective nature, data capture was limited to case notes and no prospective data analysis was done. Similarly, a sizeable proportion of patients were lost to follow-up, so outcomes could not be studied. The costs incurred in the treatment of these children subsequently as well as the prognosis of many of these conditions without transplant could be a deterrent for sustained follow-up. Another drawback is that only 50% of patients could have genetic confirmation of PID.


  Conclusions Top


The suspicion and detection of PID are on the rise. Clinical manifestations are heterogeneous, and apart from recurrent infections, PID should be suspected in a child with unexplained growth failure and cytopenia. Increasing awareness, early diagnosis, prompt referral and initiation of timely treatment are the cornerstones in effectively managing patients with these disorders. Lack of diagnostic facilities and overbearing costs incurred in the treatment of these patients are some of the challenges faced in resource-limited countries. Efforts should be made to facilitate access to genetic diagnosis in as many centres as possible for genotype confirmation and to plan therapeutic interventions. This warrants a collective contribution from healthcare personnel, parents and government to provide more affordable and easily available therapeutic options to improve the quality of life of children with PID.

Acknowledgements

Medgenome Laboratory Ltd, Bangalore, Dr. Casanova, Dr. Jacinta & team from Laboratory of Human Genetics of Infectious Diseases, France were acknowledged.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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