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To assess the incidence of anti-HLA donor-specific antibodies and the effectiveness of desensitization strategy in children who underwent haploidentical HSCT at our hospital. A retrospective review, management and outcomes of children with positive anti-HLA DSA who underwent haploidentical HSCT at our hospital from 2020 to 2022. Three patients with Thalassemia major were treated with 2 cycles of pretransplant immune suppression (PTIS) comprising Fludarabine and Dexamethasone in addition to desensitization. Five out of the 26 children who underwent haploidentical HSCT had positive anti-HLA DSA. Post desensitization, three out of the 5 children engrafted with sustained full donor chimerism, 1 patient developed primary graft rejection, while 1 patient died. It is feasible to desensitize children with high anti-HLA donor specific antibodies undergoing haploidentical HSCT to improve outcomes.
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Anemia Aplástica , Hepatite A , Hepatite , Criança , Humanos , Anemia Aplástica/complicaçõesRESUMO
DOCK8 deficiency affects various cell subsets belonging to both the innate and adaptive immune systems. Clinical diagnosis is challenging, as many cases present with severe atopic dermatitis as the only initial manifestation. Though flow cytometry helps in the presumptive diagnosis of DOCK8-deficient patients by evaluating their DOCK8 protein expression, it requires subsequent confirmation by molecular genetic analysis. Currently, haematopoietic stem cell transplantation (HSCT) is the only curative treatment option available for these patients. There is a paucity of data from India on the clinical diversity and molecular spectrum of DOCK8 deficiency. In the present study, we report the clinical, immunological and molecular findings of 17 DOCK8-deficient patients from India diagnosed over the last 5 years.
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Síndrome de Job , Humanos , Índia , Fatores de Troca do Nucleotídeo Guanina/genéticaRESUMO
BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare but important cause of end-stage liver disease in children. Conventional chemotherapeutic agents that are otherwise the standard-of-care in LCH may be counterproductive in patients with hepatic decompensation. Furthermore, the precise role of liver transplantation (LT) in the management of LCH remains unclear. METHODS: Review of a prospectively collected database (January 2014 to December 2020) of children with liver disease was performed. All clinical details of patients with LCH managed at our center were collected and data analyzed. Based on the outcomes, a management algorithm was proposed. RESULTS: Of the eight (five male) patients referred to our unit, six (75%) underwent LT (four and two for compensated and decompensated cirrhosis, respectively). Median age at diagnosis of LCH was 25 (range: 9-48) months. Two patients, who had previously completed LCH-specific chemotherapy, underwent upfront LT for compensated cirrhosis. Other two patients with compensated cirrhosis showed evidence of active disease. They underwent LT following completion of chemotherapy. Two children with decompensated cirrhosis also had evidence of active disease and were started on modified chemotherapy Both of them had progression of liver disease while on chemotherapy. Hence, an urgent LT was performed which was followed by completion of chemotherapy in these patients. On a median follow-up of 30.5 (10.5-50) months, all post-LT patients were alive with stable graft function and showed no disease recurrence. CONCLUSION: We demonstrate that an algorithmic approach, along with newer chemotherapeutic agents, results in excellent outcomes in LCH patients with liver involvement. Larger multicentric studies on this rare disease are, however, needed to validate our findings.
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Histiocitose de Células de Langerhans , Transplante de Fígado , Criança , Humanos , Masculino , Lactente , Pré-Escolar , Transplante de Fígado/efeitos adversos , Histiocitose de Células de Langerhans/tratamento farmacológico , Cirrose Hepática/cirurgia , Cirrose Hepática/etiologia , Recidiva , Estudos RetrospectivosRESUMO
Gastrointestinal (GI) manifestations are the second most common complications of primary immune deficiencies (PIDs) after pulmonary disease, affecting up to one-half of children with PIDs. Non-infectious GI manifestations such as allergic, autoimmune, and inflammatory disorders can be the predominant manifestations of PIDs. We present a series of five children who presented predominantly with these GI manifestations of PID, not attributable to infections. Very early age of onset (infancy), parental consanguinity, and failure to respond to hypoallergenic formula led to strong suspicion for underlying PIDs. Next-generation sequencing led to the underlying genetic diagnosis. Early diagnosis and hematopoietic stem cell transplantation could be life-saving in these children.
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Hipersensibilidade , Síndromes de Imunodeficiência , Doenças da Imunodeficiência Primária , Criança , Humanos , Síndromes de Imunodeficiência/complicações , Síndromes de Imunodeficiência/diagnóstico , Trato Gastrointestinal , PesquisaRESUMO
Acute graft-versus-host disease is an extremely rare complication after pediatric liver transplant. Despite a better prognosis in pediatric than in adult recipients, graft-versus-host disease is associated with high mortality. We report 2 cases of pediatric recipients with acute graft-versus-host disease; both had identical clinical presentation. Remission was achieved in both patients, but the first patient developed Epstein-Barr virus-induced posttransplant lymphoproliferative disease and recurrence of graft-versus-host disease after the immunosuppression regimen was altered. The treatment options and clinical considerations for care of such patients are discussed. It is important to maintain a high degree of suspicion for graft-versus-host disease in every posttransplant patient with persistent skin rash, with or without fever and diarrhea, and confirm the diagnosis.
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Infecções por Vírus Epstein-Barr , Doença Enxerto-Hospedeiro , Transplante de Fígado , Transtornos Linfoproliferativos , Adulto , Humanos , Criança , Transplante de Fígado/efeitos adversos , Infecções por Vírus Epstein-Barr/diagnóstico , Herpesvirus Humano 4 , Doadores Vivos , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/etiologia , Transtornos Linfoproliferativos/diagnósticoRESUMO
Background: Primary immunodeficiency (PID) having defects related to lymphocyte cytotoxic pathway or T-cell dysfunction are well known for developing opportunistic infections and Epstein-Barr virus (EBV)-associated diseases. CARMIL2 deficiency is a recently described combined immunodeficiency (CID) disorder characterized by defective CD28-mediated T cell co-stimulation, altered cytoskeletal dynamics, susceptibility to various infections and Epstein Barr Virus smooth muscle tumor (EBV-SMT). Case report: We report a homozygous CARMIL2 pathogenic variant presenting with recurrent infections and EBV associated smooth muscle tumor (SMT) in a child. Conclusion: The present study reports that EBV SMT may occur in a child with CARMIL2 deficiency.
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Infecções por Vírus Epstein-Barr , Tumor de Músculo Liso , Criança , Humanos , Herpesvirus Humano 4/genética , Tumor de Músculo Liso/genética , Tumor de Músculo Liso/complicações , Tumor de Músculo Liso/patologia , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/patologiaAssuntos
Anemia Hemolítica Congênita não Esferocítica , Anemia Hemolítica , Icterícia Obstrutiva , Esferocitose Hereditária , Anemia Hemolítica/diagnóstico , Anemia Hemolítica/genética , Anemia Hemolítica Congênita não Esferocítica/diagnóstico , Anemia Hemolítica Congênita não Esferocítica/genética , Anquirinas , Criança , Eritrócitos , HumanosRESUMO
Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of immune dysregulation characterized by hyperactivation of the immune system, excessive cytokine secretion and severe systemic inflammation. HLH is classified as familial (FHL) when associated with mutations in PRF1, UNC13D, STX11, and STXBP2 genes. There is limited information available about the clinical and mutational spectrum of FHL patients in Indian population. This study is a retrospective analysis of 101 molecularly characterized FHL patients over the last 10 years from 20 different referral centers in India. FHL2 and FHL3 together accounted for 84% of cases of FHL in our cohort. Patients belonging to different FHL subtypes were indistinguishable based on clinical and biochemical parameters. However, flow cytometry-based assays viz. perforin expression and degranulation assay were found to be specific and sensitive in diagnosis and classification of FHL patients. Molecular characterization of respective genes revealed 76 different disease-causing mutations including 39 (51%) novel mutations in PRF1, UNC13D, STX11, and STXBP2 genes. Overall, survival was poor (28%) irrespective of the age of onset or the type of mutation in our cohort. Altogether, this article sheds light on the current scenario of FHL in India. Our data reveal a wide genetic heterogeneity of FHL in the Indian population and confirms the poor prognosis of FHL. This study also emphasizes that though mutational analysis is important for diagnostic confirmation of FHL, flow cytometry based assays help significantly in rapid diagnosis and functional validation of novel variants identified.
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Biomarcadores , Suscetibilidade a Doenças , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/etiologia , Fenótipo , Alelos , Criança , Pré-Escolar , Terapia Combinada , Biologia Computacional/métodos , Bases de Dados Genéticas , Gerenciamento Clínico , Suscetibilidade a Doenças/imunologia , Feminino , Predisposição Genética para Doença , Humanos , Índia , Lactente , Linfo-Histiocitose Hemofagocítica/metabolismo , Linfo-Histiocitose Hemofagocítica/terapia , Masculino , Mutação , Perforina/genética , Perforina/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Resultado do TratamentoRESUMO
BACKGROUND: Primary immunodeficiency disorders are genetically heterogeneous immune disorders with a wide range of infectious and non-infectious manifestations. OBJECTIVE: To describe a single-center experience of primary immunodeficiency disorders. DESIGN: Retrospective analysis from January 2015 to January 2020. SETTING: Tertiary care children's hospital. PARTICIPANTS: One hundred and twelve children (<18 years) diagnosed with primary immunodeficiency disorders. OUTCOME MEASURE: Diagnostic spectrum, clinical features, and outcome. RESULTS: The median (IQR) age of the first clinical manifestation and lag time in diagnosis was 10 (27) and 11 (18) months, respectively. Twenty-seven children (24%) were diagnosed during their first presentation. Thirty-six (32%) children had phagocytic disorders, 20 (17.8%) had combined/cellular defects, 18 (16%) had predominant antibody deficiencies and 17 (15%) had disorders of immune dysregulation. Non-infectious manifestations were seen in 54 (48%). Eight children underwent hematopoietic stem cell transplantation, 44 (39%) children were on antimicrobial prophylaxis and supportive therapy, 36 (32%) were lost to follow-up and 24 (21%) children died. CONCLUSION: Congenital defects of phagocyte function, followed by combined/cellular defects are the commonest primary immune deficiencies (PIDs) identified in southern India. Long lag time in diagnosis and high mortality in our cohort emphasizes the need for early diagnosis and early referral.
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Síndromes de Imunodeficiência , Doenças da Imunodeficiência Primária , Criança , Hospitais , Humanos , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/epidemiologia , Índia/epidemiologia , Lactente , Estudos Retrospectivos , Atenção Terciária à SaúdeRESUMO
Lymphoproliferative disorders occurs due to uncontrolled proliferation of lymphocytes that causes lymphocytosis, lymphadenopathy, and involvement of extra nodal sites (bone marrow, liver and spleen) and occur primarily due to immune dysfunction. We describe series of cases with non malignant LPD encountered in our practice and their varied clinical presentation, difficulties in diagnosis, underlying etiology, treatment and outcome. Many of these disorders are self limiting, however some are associated with significant morbidity, hence treatment must be tailored based on the underlying immune dysfunction and aggressiveness of the clone.
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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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Doença Granulomatosa Crônica/imunologia , Transplante de Células-Tronco Hematopoéticas , Pele/patologia , Pré-Escolar , Feminino , Doença Granulomatosa Crônica/genética , Doença Granulomatosa Crônica/mortalidade , Humanos , Índia , Lactente , Linfadenite , Masculino , Mutação/genética , NADPH Oxidase 2/genética , NADPH Oxidases/genética , Fagocitose/genética , Pneumonia , Análise de SobrevidaAssuntos
Infecções por Vírus Epstein-Barr , Linfo-Histiocitose Hemofagocítica , Transtornos Linfoproliferativos , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/diagnóstico , Herpesvirus Humano 4 , Humanos , Linfo-Histiocitose Hemofagocítica/diagnóstico , Transtornos Linfoproliferativos/diagnósticoRESUMO
Hereditary hemolytic anemias present a unique diagnostic challenge due to their wide phenotypic and genotypic spectrum. Accurate diagnosis is essential to ensure appropriate treatment. We report two cases, which presented as hemolytic anemias, but initial workup was inconclusive and they were finally diagnosed with the help of Next Generation Sequencing (Dehydrated Hereditary Stomatocytosis and KÓ§ln Hemoglobinopathy). The introduction of gene sequencing to aid diagnosis of these disorders is a revolutionary step forward and should be incorporated earlier in the workup of such patients.
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OBJECTIVE: To study the profile of children with Hemophagocytic Lymphohistiocytosis (HLH) in a tertiary care hospital for children. METHODS: A retrospective analysis of case records of 52 children diagnossed with HLH was performed. RESULTS: Of the 52 children 13% (n = 7) had Familial HLH and 87% (n = 45) had secondary HLH (sHLH). Common manifestations were fever (100%), organomegaly (87%), respiratory distress (54%), neurological symptoms (31%) and skin rashes (26.2%). Anemia and thrombocytopenia were present in 51% and 73% respectively. Hyperferritinemia was present in 96% and hypofibrinogenemia in 42% and high lactate dehydrogenase (LDH) in 91%. Bone marrow examination showed hemophagocytosis in 80%. Most common etiology among infections was viral infections (67%), of which Dengue was the most common (52%). Among children with sHLH 51% received supportive care only. Thirty-seven percent (n = 17) received intravenous (IV) immunoglobulin and steroids. Of these 77% (n = 35) recovered completely. Children with familial HLH were initiated on HLH 2004 protocol but all of them expired due to disease progression. CONCLUSIONS: Identifying HLH early and managing it, poses a significant challenge. Prompt recognition and initiation of immunosuppressive therapy is extremely important for the better outcome; hence high clinical suspicion and structured work up including immunological, and genetic studies is required. It may be difficult to differentiate primary and secondary HLH in many instances unless genetic analysis is done. Identification of familial HLH is necessary for early referral to Hematopoietic Stem Cell Transplantation (HSCT). Hence screening for primary HLH needs to be considered in all children with HLH.
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Transplante de Células-Tronco Hematopoéticas , Linfo-Histiocitose Hemofagocítica , Viroses , Criança , Febre , Humanos , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/terapia , Estudos RetrospectivosRESUMO
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.