RESUMEN
Inborn errors of immunity (IEI) can present with infections, autoimmunity, lymphoproliferation, granulomas, and malignancy. IEIs are due to genetic abnormalities that disrupt normal host-immune response or immune regulation. The microbiome appears essential for maintaining host immunity, especially in patients with a defective immune system. Altered gut microbiota in patients with IEI can lead to clinical symptoms. Microbial dysbiosis is the consequence of an increase in pro-inflammatory bacteria or a reduction in anti-inflammatory bacteria. However, functional and compositional differences in microbiota are also involved. Dysbiosis and a reduced alpha-diversity are well documented, particularly in conditions like common variable immunodeficiency. Deranged microbiota is also seen in Wiskott-Aldrich syndrome, severe combined immunodeficiency, chronic granulomatous disease, selective immunoglobulin-A deficiency, Hyper IgE syndrome (HIGES), X-linked lymphoproliferative disease-2, immunodysregulation, polyendocrinopathy, enteropathy, x-linked syndrome, and defects of IL10 signalling. Distinct gastrointestinal, respiratory, and cutaneous symptoms linked to dysbiosis are seen in several IEIs, emphasizing the importance of microbiome identification. In this study, we discuss the processes that maintain immunological homeostasis between commensals and the host and the disruptions thereof in patients with IEIs. As the connection between microbiota, host immunity, and infectious illnesses is better understood, microbiota manipulation as a treatment strategy or infection prevention method would be more readily employed. Therefore, optimal prebiotics, probiotics, postbiotics, and fecal microbial transplantation can be promising strategies to restore the microbiota and decrease disease pathology in patients with IEIs.
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Background: Hemophagocytic lymphohistiocytosis (HLH) is characterized by uncontrolled and excessive inflammation leading to high mortality. Aetiology of HLH can be primarily due to genetic causes or secondarily due to infections or rheumatological illness. However, rarely T-cell deficiencies like severe combined immunodeficiency (SCID) can develop HLH. Objective: To describe clinical and laboratory features of SCID cases who developed HLH. Methods: We collected clinical, laboratory, and molecular details of patients with SCID who developed HLH at our center at Chandigarh, North India. Results: Of the 94 cases with SCID, 6 were noted to have developed HLH-like manifestations. Male-female ratio was 5:1. Median (inter-quartile range) age of onset of clinical symptoms was 4.25 months (2-5 months). Median (inter-quartile range) delay in diagnosis was 1 month (1-3.5 months). Family history of deaths was seen in 4 cases. Molecular defects in IL2RG were seen in 5 out of 6 cases. Documented infections include disseminated bacillus calmette-guerin (BCG) infection (n=2), blood stream infections (n=3) with Staphylococcal aureus (n=1), Klebsiella pneumonia (n=1), and Pseudomonas aeruginosa (n=1), pneumonia (influenza H1N1 strain, and K. pneumoniae (n=1). Conclusion: Children with SCID can present with HLH-like manifestations secondary to fulminant infections. A high index of suspicion of SCID is needed in infants who present with HLH who have an associated infection or a suggestive family history. Occurrence of HLH-like manifestations in SCID suggests that T-lymphocytes may not have a significant role in immunopathogenesis of HLH.
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Subtipo H1N1 del Virus de la Influenza A , Gripe Humana , Linfohistiocitosis Hemofagocítica , Inmunodeficiencia Combinada Grave , Niño , Femenino , Humanos , Lactante , Gripe Humana/complicaciones , Linfohistiocitosis Hemofagocítica/complicaciones , Linfohistiocitosis Hemofagocítica/etiología , Masculino , Inmunodeficiencia Combinada Grave/complicaciones , Inmunodeficiencia Combinada Grave/diagnóstico , Linfocitos T/patologíaRESUMEN
Inborn errors of immunity (IEI) are a heterogeneous group of monogenic disorders that include primary immunodeficiency's and other disorders affecting different aspects of the immune system. Next-Generation Sequencing (NGS) is an essential tool to diagnose IEI. We report our 3-year experience in setting up facilities for NGS for diagnosis of IEI in Chandigarh, North India. We used a targeted, customized gene panel of 44 genes known to result in IEI. Variant analysis was done using Ion Reporter software. The in-house NGS has enabled us to offer genetic diagnoses to patients with IEI at minimal costs. Of 121 patients who were included pathogenic variants were identified in 77 patients. These included patients with Chronic Granulomatous Disease, Severe Combined Immune Deficiency, leukocyte adhesion defect, X-linked agammaglobulinemia, Ataxia Telangiectasia, Hyper-IgE syndrome, Wiskott Aldrich syndrome, Mendelian susceptibility to mycobacterial diseases, Hyper-IgM syndrome, autoimmune lymphoproliferative syndrome, and GATA-2 deficiency. This manuscript discusses the challenges encountered while setting up and running targeted NGS for IEI in our unit. Genetic diagnosis has helped our patients with IEI in genetic counselling, prenatal diagnosis, and accessing appropriate therapeutic options.
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Agammaglobulinemia , Ataxia Telangiectasia , Inmunodeficiencia Combinada Grave , Agammaglobulinemia/diagnóstico , Agammaglobulinemia/genética , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Embarazo , Centros de Atención TerciariaRESUMEN
Ghosal hematodiaphyseal dysplasia (GHDD) is a rare, autosomal recessive condition characterised by diaphyseal dysplasia of long bones with defective haematopoiesis. We describe 2 such cases with clinical and radiological evidence of GHDD. Molecular analysis revealed novel variants in TBXAS1 gene in both of them. Suspicion and confirmation of this entity is crucial in cases of refractory anemia with bony deformities, as the clinical manifestations in this entity are usually well responsive to corticosteroids.
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Anemia Refractaria , Osteocondrodisplasias , Anemia Refractaria/diagnóstico por imagen , Anemia Refractaria/genética , Huesos , Niño , Humanos , Osteocondrodisplasias/diagnóstico por imagen , Osteocondrodisplasias/genética , RadiografíaRESUMEN
BACKGROUND: There are limited data on neutrophil function in pediatric-onset systemic lupus erythematosus (pSLE) patients. This study aimed to evaluate phagocytosis and oxidase activity of neutrophils in patients with pSLE. PATIENTS AND METHODS: Eighty-seven patients with pSLE and 44 controls were enrolled. Phagocytic activity was assayed using pHrodoTMRed E. coli BioParticles Phagocytosis Kit by flow cytometry. Determination of NADPH oxidase activity was carried out by Dihyrdrorhodamine-123 (DHR-123) flow cytometry assay. RESULTS: Phagocytic activity of patients' neutrophils (mean 76.59%) was lower than that in controls (91.30%) (p < 0.001). Median delta median fluorescence intensity (ΔMFI) and stimulation index (SI) in patients (ΔMFI: 0.09; SI: 2.79) were also decreased compared to controls (ΔMFI: 0.18; SI: 5.00) (p < 0.002; p < 0.001 respectively). Disease activity showed an inverse correlation with phagocytic activity. Oxidase activity was also significantly low (SI DHR < 40) in 16% of patients. No significant correlation was found between oxidative burst and disease activity. CONCLUSION: Neutrophil function is impaired in patients with pSLE, as evidenced by the markedly reduced phagocytic activity. Phagocytic activity is also inversely correlated with disease activity. The oxidative activity was also reduced but not significantly. IMPACT: Neutrophil phagocytic function is impaired in pediatric-onset systemic lupus erythematosus (pSLE). There is an inverse correlation between disease activity in pSLE and phagocytic activity. NADPH oxidase activity in patients with pSLE did not show significant correlation with disease activity.
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Lupus Eritematoso Sistémico , Neutrófilos , Humanos , Niño , Escherichia coli , Lupus Eritematoso Sistémico/diagnóstico , Fagocitosis , NADPH OxidasasRESUMEN
Germline ATM gene variations result in phenotypic heterogeneity characterized by a variable degree of disease severity. We retrospectively collected clinical, genetic, and immunological data of 26 cases with A-T. Clinical manifestations included oculocutaneous telangiectasia (100%), ataxia (100%), fever, loose stools or infection (67%), cerebellar atrophy (50%), nystagmus (8%), dysarthria (15.38%), and visual impairment (8%). Genetic analysis confirmed ATM gene variations in 16 unrelated cases. The most common type of variation was stopgain variants (56%). Immunoglobulin profile indicated reduced IgA, IgG, and IgM in 94%, 50%, and 20% cases, respectively. T cell lymphopenia was observed in 80% of cases among those investigated. Unusual presentations included an EBV-associated smooth muscle tumour located in the liver in one case and Hyper IgM syndrome-like presentation in two cases. Increased immunosenescence was observed in T-cell subsets (CD4+CD57+ and CD8+CD57+). T-cell receptor excision circles (TRECs) were reduced in 3/8 (37.50%) cases.
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Ataxia Telangiectasia , Síndrome de Inmunodeficiencia con Hiper-IgM , Ataxia Telangiectasia/genética , Proteínas de la Ataxia Telangiectasia Mutada/genética , Humanos , Mutación , Estudios Retrospectivos , Subgrupos de Linfocitos TRESUMEN
OBJECTIVES: To study the incidence, clinical manifestations, and genetic spectrum of primary immunodeficiency diseases (PID)/inborn errors of immunity (IEI) in a tertiary care hospital in Southern India. METHODS: A retrospective analysis of all patients with a clinical suspicion of PID/IEI seen at a tertiary care hospital was performed. All patients had at least one or more warning signs of PID. Serum immunoglobulin levels and other targeted investigations were performed as warranted by the clinical presentation. All families with suspected PID were counseled and offered genetic testing. RESULTS: A total of 225 children were evaluated for PID during the study period of 6 y. Fifty-six of them did not meet the European Society of Immunodeficiencies (ESID) criteria (working definition of clinical diagnosis) and were excluded. An IEI was found in 30/49 (61.2%) patients. The most frequent reason for referral was recurrent/unusual or serious infections (28%), or cytopenia (16%). Group IV diseases of immune dysregulation was the most common category (19%), followed by group III predominant antibody deficiencies in 23/163 (14%), as per the International Union of Immunological Societies (IUIS) classification. CONCLUSIONS: This study highlights the heterogeneity of the present cohort, the underuse of genetic tests, and efforts to provide optimal care for children with possible IEI in this center.
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Síndromes de Inmunodeficiencia , Enfermedades de Inmunodeficiencia Primaria , Niño , Humanos , Síndromes de Inmunodeficiencia/diagnóstico , Síndromes de Inmunodeficiencia/epidemiología , Síndromes de Inmunodeficiencia/genética , India/epidemiología , Enfermedades de Inmunodeficiencia Primaria/genética , Estudios Retrospectivos , Centros de Atención TerciariaRESUMEN
We report a rare case of agranulocytosis and lymphopenia complicated with hemophagocytic lymphohistiocytosis. Diagnosis of reticular dysgenesis was made by detection of a pathogenic stop gain variant in the AK2 gene on targeted next generation sequencing and confirmed by Sanger sequencing. Parents were found to be carriers for this variant. Bone marrow aspirate and biopsy was also performed with a clinical diagnosis of severe combined immunodeficiency with HLH. However, no hemophagocytosis was noted in the bone marrow aspirate or trephine biopsy. Instead, it showed aggregates of large histiocyte-like cells, scattered erythroid precursors and megakaryocytes. These cells were confused to be some form of storage cells, but did not resemble storage cells seen in Gaucher's disease or Niemann Pick disease. Myeloid precursors were very few in number. Reticular dysgenesis was not suspected during admission due to a lack of awareness of this entity. Testing for sensorineural deafness in neonates with severe agranulocytosis and lymphopenia would facilitate an early diagnosis of reticular dysgenesis. To the best of our knowledge, hemophagocytic lymphohistiocytosis has not been previously reported in association with reticular dysgenesis.
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Médula Ósea/patología , Histiocitos/patología , Leucopenia/diagnóstico , Leucopenia/etiología , Linfohistiocitosis Hemofagocítica/complicaciones , Linfohistiocitosis Hemofagocítica/diagnóstico , Inmunodeficiencia Combinada Grave/diagnóstico , Inmunodeficiencia Combinada Grave/etiología , Adenilato Quinasa/genética , Biomarcadores , Biopsia , Células de la Médula Ósea/patología , Análisis Mutacional de ADN , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Pruebas Hematológicas , Humanos , Lactante , Masculino , Mutación , Fenotipo , Índice de Severidad de la EnfermedadRESUMEN
Introduction: Mendelian susceptibility to mycobacterial diseases (MSMD), a group of at least 18 different genetic disorders, encompasses a specific class of inborn errors of immunity that result in predilection to infection with mycobacteria including the weakly virulent strains. Primarily, these consist of defects in the IFN-γ-IL-12/23 circuit that is crucial for immunity against intracellular microorganisms. Although the first genetic etiology of MSMD was discovered in 1996, molecular diagnosis of MSMD in resource-constrained settings may remain far-fetched. Recently, original studies have emerged from developing countries, including India, wherein the genetic diagnosis was confirmed within the country itself. A lag of about 25 years, hence, seems to exist.Areas covered: Herein, we review the clinical, laboratory, and mutational profiles of the genetic defects responsible for causing MSMD. We intend to enhance the recognition of these disorders in settings endemic for tuberculosis and bridge the gap between the developed and developing countries in the field of MSMD research and therapeutics.Expert opinion: Research in the field of MSMD in developing countries, including India, can uncover novel genetic etiologies, as the population exceeds 1.3 billion, a huge burden of tuberculosis exists, and BCG vaccination is given universally at birth.
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Mutación , Infecciones por Mycobacterium , Predisposición Genética a la Enfermedad , Humanos , Recién Nacido , Interleucina-12 , Mutación/genética , Infecciones por Mycobacterium/diagnóstico , Infecciones por Mycobacterium/epidemiología , Infecciones por Mycobacterium/genéticaRESUMEN
BACKGROUND: Chronic granulomatous disease (CGD) presents with a myriad of clinical manifestations pertaining to both immunodeficiency and hyperinflammation. Although Candida infection is a signature organism for patients with CGD, C. lusitaniae pneumonia in CGD has rarely been reported. C. lusitaniae is a ubiquitous ascomycete predominantly infecting immunocompromised hosts and has the potential to rapidly develop multi-drug resistance during therapy. Additionally, C. lusitaniae is recognized for its variable resistance against amphotericin B. To date, C. lusitaniae infections in patients with CGD have not been reviewed in detail. False-positive HIV serology, resulting from polyclonal hypergammaglobulinemia, has been reported in association with several infections, auto-immune diseases, and malignancies. Although CGD is often associated with hypergammaglobulinemia, a false-positive HIV serology in CGD has not been reported previously. PROCEDURE: We report a combination of unique findings in a child with CGD - a false-positive HIV serology, Candida lusitaniae pneumonia, and a novel CYBB mutation. We also provide a detailed review of C. lusitaniae infections in patients with CGD. RESULTS: In patients with CGD, C. lusitaniae has been reported to cause lymphadenitis (cervical, abdominal), fungemia, meningoencephalitis, or abscesses in the liver and spleen. Many CGD patients with C. lusitaniae infection have associated inflammatory complications of the gut (inflammatory bowel disease, colitis). Additionally, almost all C. lusitaniae infections in CGD have been reported in young infants or in patients receiving long-term immunosuppressive therapy. This reflects that further immunocompromise (in addition to the underlying immune deficiency in CGD) may specifically predispose to C. lusitaniae infection (unlike other candidal infections). Most of the CGD patients with documented C. lusitaniae infection have X-linked form of the disease which generally has been postulated to have a more severe clinical phenotype than the autosomal recessive forms of the disease. CONCLUSIONS: HIV serology may be positive in patients with CGD and other inborn errors of immunity as a result of hypergammaglobulinemia. C. lusitaniae, which may have peculiar and evolving antimicrobial sensitivity patterns, needs to be considered in patients with CGD and pneumonia. Lastly, to reiterate, CGD should to be considered in patients with proven C. lusitaniae infection.
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Candidiasis , Enfermedad Granulomatosa Crónica , NADPH Oxidasa 2/genética , Neumonía , Saccharomycetales , Candidiasis/sangre , Candidiasis/genética , ADN Viral/genética , Reacciones Falso Positivas , Enfermedad Granulomatosa Crónica/sangre , Enfermedad Granulomatosa Crónica/genética , VIH/genética , VIH/inmunología , Infecciones por VIH/sangre , Infecciones por VIH/diagnóstico , Humanos , Lactante , Masculino , Mutación , Neumonía/sangre , Neumonía/genética , Proteínas Virales/inmunologíaRESUMEN
Background: Chronic granulomatous disease (CGD) is an inherited defect in phagocytic respiratory burst that results in severe and life-threatening infections in affected children. Single center studies from India have shown that proportion of autosomal recessive (AR) CGD is more than that reported from the West. Further, affected patients have high mortality rates due to late referrals and difficulties in accessing appropriate treatment. However, there is lack of multicentric collaborative data on CGD from India. Objective: To describe infection patterns, immunological, and molecular features of CGD from multiple centers in India. Methods: A detailed proforma that included clinical and laboratory details was prepared and sent to multiple centers in India that are involved in the care and management of patients with inborn errors of immunity. Twelve centers have provided data which were later pooled together and analyzed. Results: Of the 236 patients analyzed in our study, X-linked and AR-CGD was seen in 77 and 97, respectively. Male female ratio was 172:64. Median age at onset of symptoms and diagnosis was 8 and 24 months, respectively. Common infections documented include pneumonia (71.6%), lymphadenitis (31.6%), skin and subcutaneous abscess (23.7%), blood-stream infection (13.6%), osteomyelitis (8.6%), liver abscess (7.2%), lung abscess (2.9%), meningoencephalitis (2.5%), splenic abscess (1.7%), and brain abscess (0.9%). Forty-four patients (18.6%) had evidence of mycobacterial infection. Results of molecular assay were available for 141 patients (59.7%)-CYBB (44.7%) gene defect was most common, followed by NCF1 (31.9%), NCF2 (14.9%), and CYBA (8.5%). While CYBA variants were documented only in Southern and Western parts of India, a common dinucleotide deletion in NCF2 (c.835_836delAC) was noted only in North Indian population. Of the 174 patients with available outcome data, 67 (38.5%) had expired. Hematopoietic stem cell transplantation was carried out in 23 patients, and 12 are doing well on follow-up. Conclusions: In India, proportion of patients with AR-CGD is higher as compared to Western cohorts, though regional differences in types of AR-CGD exist. Clinical profile and mortality rates are similar in both X-linked and AR-CGD. However, this may be a reflection of the fact that milder forms of AR-CGD are probably being missed.
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Enfermedad Granulomatosa Crónica/inmunología , Trasplante de Células Madre Hematopoyéticas , Piel/patología , Preescolar , Femenino , Enfermedad Granulomatosa Crónica/genética , Enfermedad Granulomatosa Crónica/mortalidad , Humanos , India , Lactante , Linfadenitis , Masculino , Mutación/genética , NADPH Oxidasa 2/genética , NADPH Oxidasas/genética , Fagocitosis/genética , Neumonía , Análisis de SupervivenciaAsunto(s)
Aspergilosis/diagnóstico , Aspergilosis/etiología , Aspergillus fumigatus , Enfermedad Granulomatosa Crónica/complicaciones , Osteomielitis/diagnóstico , Osteomielitis/etiología , Cráneo/patología , Antiinfecciosos/uso terapéutico , Aspergilosis/tratamiento farmacológico , Aspergillus fumigatus/inmunología , Biomarcadores , Niño , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Enfermedad Granulomatosa Crónica/diagnóstico , Enfermedad Granulomatosa Crónica/genética , Humanos , Masculino , Miocarditis/diagnóstico , Miocarditis/tratamiento farmacológico , Miocarditis/etiología , Osteomielitis/tratamiento farmacológico , Fenotipo , Radiografía Torácica , Tomografía Computarizada por Rayos X , Resultado del TratamientoAsunto(s)
Exantema , Síndrome Mucocutáneo Linfonodular , Tortícolis , Exantema/diagnóstico , Exantema/etiología , Fiebre/diagnóstico , Fiebre/etiología , Humanos , Masculino , Síndrome Mucocutáneo Linfonodular/complicaciones , Síndrome Mucocutáneo Linfonodular/diagnóstico , Tortícolis/diagnóstico , Tortícolis/etiologíaAsunto(s)
Agammaglobulinemia/complicaciones , Citrobacter freundii , Infecciones por Enterobacteriaceae/diagnóstico , Infecciones por Enterobacteriaceae/etiología , Enfermedades Genéticas Ligadas al Cromosoma X/complicaciones , Síndrome Hemolítico-Urémico/diagnóstico , Síndrome Hemolítico-Urémico/etiología , Agammaglobulinemia/diagnóstico , Agammaglobulinemia/genética , Biopsia , Niño , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Enfermedades Genéticas Ligadas al Cromosoma X/diagnóstico , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Síndrome Hemolítico-Urémico/tratamiento farmacológico , Humanos , Inmunohistoquímica , Inmunosupresores/uso terapéutico , Masculino , Evaluación de Síntomas , Resultado del TratamientoAsunto(s)
Artritis/diagnóstico , Artritis/etiología , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Proteínas de la Membrana/genética , Fenotipo , Antiinflamatorios/uso terapéutico , Artritis/tratamiento farmacológico , Biomarcadores , Niño , Preescolar , Diagnóstico Diferencial , Familia , Femenino , Humanos , Inmunosupresores/uso terapéutico , India , Articulaciones/patología , Masculino , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
Introduction: Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease, characterized by the production of autoantibodies. Numerous mechanisms contribute to the pathogenesis and autoimmunity in SLE. One of the most important mechanisms is the defective function of the early complement components that are involved in clearing the immune-complexes and apoptotic debris. Major evidence supporting this hypothesis is the development of severe lupus in individuals with monogenic defects in any one of the early complement components such as C1q, C1 s, C1 r, C2, or C4.Areas covered: In this review, we discuss hereditary defects in classical complement components and their clinical manifestations, acquired defects of complements in lupus, the role of complements in the pathogenesis of antiphospholipid antibody syndrome and lupus nephritis, and laboratory assessment of complement components and their functions. Articles from the last 20 years were retrieved from PubMed for this purpose.Expert opinion: Complements have a dual role in the pathogenesis of SLE. On one hand, deficiency of complement components predisposes to lupus, while, on the other, excess complement activation plays a role in the organ damage. Understanding the intricacies of the role of complements in SLE can pave way for the development of targeted therapies.
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Proteínas del Sistema Complemento/metabolismo , Riñón/inmunología , Lupus Eritematoso Sistémico/inmunología , Nefritis Lúpica/inmunología , Animales , Anticuerpos Antifosfolípidos/metabolismo , Autoanticuerpos/metabolismo , Activación de Complemento , Humanos , Lupus Eritematoso Sistémico/tratamiento farmacológico , Nefritis Lúpica/tratamiento farmacológico , Terapia Molecular DirigidaRESUMEN
Severe Combined Immunodeficiency (SCID) is an inherited group of rare, life-threatening disorders due to the defect in T cell development and function. Clinical manifestations are characterised by recurrent and severe bacterial, viral, and fungal opportunistic infections that start from early infancy period. Haematopoietic stem cell transplantation (HSCT) is the treatment of choice. The pattern of inheritance of SCID may be X-linked or autosomal recessive. Though the diagnosis of SCID is usually established by flow cytometry-based tests, genetic diagnosis is often needed for genetic counselling, prognostication, and modification of pre-transplant chemotherapeutic agents. This review aims to highlight the genetic aspects of SCID.
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Background: There is paucity of literature on XLA from developing countries. Herein we report the clinical and molecular profile and outcome in a multicenter cohort of patients with XLA from India. Methods: Data on XLA from all regional centers supported by the Foundation for Primary Immunodeficiency Diseases (FPID), USA and other institutions providing care to patients with PIDs were collated. Diagnosis of XLA was based on European Society for Immunodeficiencies (ESID) criteria. Results: We received clinical details of 195 patients with a provisional diagnosis of XLA from 12 centers. At final analysis, 145 patients were included (137 'definite XLA' and eight 'probable/possible XLA'). Median age at onset of symptoms was 12.0 (6.0, 36.0) months and median age at diagnosis was 60.0 (31.5, 108) months. Pneumonia was the commonest clinical manifestation (82.6%) followed by otitis media (50%) and diarrhea (42%). Arthritis was seen in 26% patients while 23% patients developed meningitis. Bronchiectasis was seen in 10% and encephalitis (likely viral) in 4.8% patients. Pseudomonas aeruginosa was the commonest bacterial pathogen identified followed by Streptococcus pneumoniae, Staphylococcus aureus and Klebsiella pneumoniae. Molecular analysis revealed 86 variants in 105 unrelated cases. Missense variants in BTK gene were the most common (36%) followed by frameshift (22%) and nonsense variants (21%). Most pathogenic gene variants (53%) were clustered in the distal part of gene encompassing exons 14-19 encoding for the tyrosine kinase domain. Follow-up details were available for 108 patients. Of these, 12% had died till the time of this analysis. The 5-year and 10-year survival was 89.9% and 86.9% respectively. Median duration of follow-up was 61 months and total duration of follow-up was 6083.2 patient-months. All patients received intravenous immunoglobulin (IVIg) replacement therapy. However, in many patients IVIg could not be given at recommended doses or intervals due to difficulties in accessing this therapy because of financial reasons and lack of universal health insurance in India. Hematopoietic stem cell transplant was carried out in four (2.8%) patients. Conclusion: There was a significant delay in the diagnosis and facilities for molecular diagnosis were not available at many centers. Optimal immunoglobulin replacement is still a challenge.