Changing outcomes of stem cell transplantation in primary immunodeficiencies: Results from a tertiary-care charitable trust hospital in Mumbai.

Background: Hematopoietic stem cell transplantation in primary immunodeficiency disorders has come a long way since the first transplant in 1968. In India, pediatric stem cell transplantation long-term survival outcomes range from 62.5% to 75%, compared to 90% in high-income countries. Objective: We present single-center data of primary immunodeficiency transplants with immune-reconstitution evaluation after transplantation from a charitable trust hospital. Methods: Retrospective data of children transplanted for primary immunodeficiency disorders from March 2019 to March 2022 in a newly established transplant unit were collected. Data of pretransplant infections and comorbidities, surveillance for carbapenem-resistant Enterobacteriaceae, transplant characteristics, donor source, graft-versus-host disease, posttransplant infections, immune reconstitution, overall survival at 1 year, and immunodeficiency-free survival were collated. Results: Twenty-one patients underwent transplantation for primary immunodeficiency disorders. The median age at transplantation was 3 years and 5 months (range, 7 months to 17 years). Seventy-five percent of the cohort had organ involvement, with lung being the most common organ involved, followed by central nervous system. Fifty-two percent of children had peritransplant infections, with most of them recognized at the pretransplant assessment. Among 20 of 21 children with engraftment, 94% had complete chimerism initially, with 33% developing mixed chimerism over time. The median duration of immunosuppression was 3 months after transplantation, and only 1 child required systemic graft-versus-host disease treatment for more than a year. Immune-reconstitution showed good T-cell recovery at 3 months and naive T-cell production at 6 months. There was no regimen-related or sepsis-related mortality. Overall survival of the cohort was 95% at 1-year follow-up. Immunodeficiency-free survival was 86% after a median follow-up of 20 months. Conclusions: Immunodeficiency-free and graft-versus-host disease-free survival can be achieved in the majority of children with primary immunodeficiencies using enhanced supportive care and the latest transplantation algorithms.

Monogenic inborn errors of immunity in autoimmune disorders.

To estimate the prevalence of monogenic inborn errors of immunity in patients with autoimmune diseases (AID), the study included 56 subjects (male:female ratio: 1.07) with mean age of onset of autoimmunity 7 years (4 months-46 years). 21/56 had polyautoimmunity. 5/56 patients met the JMF criteria for PID. The different AID referred were hematological (42%) > gastrointestinal (GI) (16%) > skin (14%) > endocrine (10%) > rheumatological (8%) > renal (6%) > neurological (2%). 36/56 reported recurrent infections. 27/56 were on polyimmunotherapy. 18/52 (35%) had CD19 lymphopenia, 24/52 (46%) had CD4 lymphopenia, 11/52 (21%) had CD8 lymphopenia, and 14/48 (29%) had NK lymphopenia. 21/50 (42%) had hypogammaglobinemia; 3 of whom were given rituximab. 28/56 were found to have pathogenic variants among PIRD genes. These 28 patients had 42 AID among which hematological was most common (50%) > GI (14%) = skin (14%)> endocrine (9%) > rheumatological (7%) > renal and neurological (2%). Hematological AID was the most common AID (75%) in children with PIRD. Positive predictive value (PPV) of abnormal immunological tests was 50% and sensitivity of 70%. JMF criteria had specificity of 100% in identifying PIRD and sensitivity of 17%. Polyautoimmunity had a PPV of 35% and sensitivity of 40%. 11/28 of these children were offered transplant. 8/28 were started on sirolimus, 2/28 on abatacept, and 3/28 on baricitinib/ruxolitinib after diagnosis. In conclusion, 50% of children with AID have underlying PIRD. LRBA deficiency and STAT1 GOF were the most common PIRD. Age at presentation, number of autoimmunity, routine immunological tests, and JMF criteria are not predictive of underlying PIRD. Early diagnosis with exome sequencing alters the prognosis and opens new therapeutic avenue.

Clinical, immunological and molecular findings of patients with DOCK-8 deficiency from India.

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.

The Effect of Multi-source Feedback on Core Competencies of Pediatric Residents.

OBJECTIVE: The study was conducted to evaluate impact of multisource feedback in pediatric residency training. METHODS: A crossover study of pediatric residents at Wadia Children's Hospital was conducted with assessment of core competencies like knowledge, practice-based learning, system-based practice, professionalism, communication skills and interpersonal interaction. After randomization both groups (A and B) were given MSF and traditional feedback, respectively and later the groups were crossed over to other method of feedback. Control faculty assessed both groups at three points - Pre-intervention, after first and after second intervention. RESULTS: There were 16 residents in each group (13,7,7 in first, second and third year of residency, respectively). Both groups had comparable scores in all six competencies at entry point. Group A after MSF showed significant improvement in all six competencies (all P<0.01). No significant improvement was observed in group B after traditional feedback. After cross-over to MSF, group B showed statistically significant improvement in all core competencies. Traditional feedback to group A after crossover showed statistically significant improvement only in knowledge, professionalism and system based practice. OUTCOME: MSF was beneficial in improving competency based performance scores in pediatric residents.

Clinical and Molecular Findings in Mendelian Susceptibility to Mycobacterial Diseases: Experience From India.

Mendelian Susceptibility to Mycobacterial diseases (MSMD) are a group of innate immune defects with more than 17 genes and 32 clinical phenotypes identified. Defects in the IFN-γ mediated immunity lead to an increased susceptibility to intracellular pathogens like mycobacteria including attenuated Mycobacterium bovis-Bacillus Calmette-Guérin (BCG) vaccine strains and non-tuberculous environmental mycobacteria (NTM), Salmonella, fungi, parasites like Leishmania and some viruses, in otherwise healthy individuals. Mutations in the IL12RB1 gene are the commonest genetic defects identified. This retrospective study reports the clinical, immunological, and molecular characteristics of a cohort of 55 MSMD patients from 10 centers across India. Mycobacterial infection was confirmed by GeneXpert, Histopathology, and acid fast bacilli staining. Immunological workup included lymphocyte subset analysis, Nitro blue tetrazolium (NBT) test, immunoglobulin levels, and flow-cytometric evaluation of the IFN-γ mediated immunity. Genetic analysis was done by next generation sequencing (NGS). Disseminated BCG-osis was the commonest presenting manifestation (82%) with a median age of presentation of 6 months due to the practice of BCG vaccination at birth. This was followed by infection with Salmonella and non-typhi Salmonella (13%), Cytomegalovirus (CMV) (11%), Candida (7%), NTM (4%), and Histoplasma (2%). Thirty-six percent of patients in cohort were infected by more than one organism. This study is the largest cohort of MSMD patients reported from India to the best of our knowledge and we highlight the importance of work up for IL-12/IL-23/ISG15/IFN-γ circuit in all patients with BCG-osis and suspected MSMD irrespective of age.

Outcome of Children Admitted With SARS-CoV-2 Infection: Experiences From a Pediatric Public Hospital.

OBJECTIVE: To study clinical characteristics and outcome of children with admitted to a paediatric hospital in Mumbai, India. METHODS: Review of medical records of 969 children admitted between 19 March and 7 August, 2020, to assess the clinico-demographic characteristics, disease severity and factors predicting outcome in COVID-19 children. Variables were compared between children who were previously healthy (Group I) and those with co-morbidity (Group II). RESULTS: 123 (71 boys) children with median (IQR) age of 3 (0.7- 6) years were admitted, of which 47 (38%) had co-morbidities. 39 (32 %) children required intensive care and 14 (11.4%) died. Male sex, respiratory manifestation, oxygen saturation <94%; at admission, mechanical ventilation, inotrope, hospital stay of <10 days were independent predictors of mortality. Oxygen saturation <94% at admission (OR 35.9, 95% CI 1.5-856) and hospital stay <10 days (OR 9.1, 95% CI 1.04-99.1) were significant. CONCLUSION: COVID-19 in children with co-morbidities causes severe disease. Association of mortality with oxygen saturation by pulse oximeter <94% on admission, and hospital stay <10 days, needs further evaluation.

Multisystem Inflammatory Syndrome in Children: Clinical Features and Management-Intensive Care Experience from a Pediatric Public Hospital in Western India.

BACKGROUND: Multisystem inflammatory syndrome (MIS) associated with severe acute respiratory syndrome coronavirus (SARS-CoV-2) (MIS-C) in children is being increasingly reported across the world. MATERIALS AND METHODS: Children fulfilling the World Health Organization criteria of MIS-C needing pediatric intensive care unit between April 15 and July 26, 2020 were studied. RESULTS: There were 21 patients with median age of 7 years [interquartile range (IQR) 1.9-12.1], of which 11 were females. SARS-CoV-2 real-time polymerase chain reaction positive in 8/21 and/or antibody positive 16/21. Fever was present in all patients, and gastrointestinal symptoms being second most frequent (16/21). One child had aplastic anemia, while the rest had no comorbidities. Nearly all presented with shock (n = 20/21) and 90% needed vasoactive drugs with a median Vasoactive Inotropic Score of 40 (IQR 20-95). Thirteen children needed ventilatory support and one needed peritoneal dialysis. Nine children had left ventricular dysfunction and five had dilatation of coronaries on echocardiography. Inflammatory markers C-reactive protein [98 mg/dL (IQR 89-119)], serum ferritin [710 mg/dL (IQR 422-1,609)], and serum interleukin-6 levels [215 ng/L (IQR 43-527)] were uniformly elevated. Eighteen children received pulse methyl-prednisolone, eleven intravenous immunoglobulins, and four tocilizumab. Eighteen children (86%) were discharged home while three died. CONCLUSION: In our cohort, MIS-C was seen in previously healthy children with fever, gastrointestinal symptoms, and shock. Early and aggressive management of shock and immune modulation with methyl-prednisolone and intravenous immunoglobulin were used. HOW TO CITE THIS ARTICLE: Shobhavat L, Solomon R, Rao S, Bhagat I, Prabhu S, Prabhu S, et al. Multisystem Inflammatory Syndrome in Children: Clinical Features and Management-Intensive Care Experience from a Pediatric Public Hospital in Western India. Indian J Crit Care Med 2020;24(11):1089-1094.

Evolution of ventricular outpouching through the fetal and postnatal periods: Unabating dilemma of serial observation or surgical correction.

Ventricular outpouching is a rare finding in prenatal sonography and the main differential diagnoses are diverticulum, aneurysm, and pseudoaneurysm in addition to congenital cysts and clefts. The various modes of fetal presentation of congenital ventricular outpouching include an abnormal four-chamber view on fetal two-dimensional echocardiogram, fetal arrhythmia, fetal hydrops, and pericardial effusion. Left ventricular aneurysm (LVA)/nonapical diverticula are usually isolated defects. Apical diverticula are always associated with midline thoracoabdominal defects (epigastric pulsating diverticulum or large omphalocele) and other structural malformations of the heart. Most patients with LVA/congenital ventricular diverticulum remain clinically asymptomatic but they can potentially give rise to complications such as ventricular tachyarrhythmias, systemic embolism, sudden death, spontaneous rupture, and severe valvular regurgitation. The treatment of asymptomatic LVA and isolated congenital ventricular diverticulum is still undefined. In this review, our aim is to outline a systematic approach to a fetus detected with ventricular outpouching. Starting with prevalence and its types, issues in fetal management, natural course and evolution postbirth, and finally the perpetual dilemma of serial observation or surgical correction is discussed.

Cardiovascular aspect of Beta-thalassaemia.

Beta-thalassaemia major is a genetic blood disorder caused by the reduced synthesis of beta globin chain. The consequences of the resulting chronic anaemia are also common and include growth retardation, bone marrow expansion, extramedular hematopoiesis, splenomegaly, increased intestinal iron absorption, susceptibility to infections, and hypercoagulability. Transfusional iron overload can affect heart function by directly damaging tissue through iron deposition or via iron-mediated effects at other sites. Cardiac dysfunction is common in patients with thalassaemia and is the leading cause of mortality. The main cardiac abnormalities reported in patients with thalassaemia major (TM) and iron overload are left ventricular systolic and diastolic dysfunction, pulmonary hypertension, valvulopathies, arrhythmias and pericarditis. These cardiac abnormalities are a consequence of the general co-morbid conditions in thalassaemia but are closely related to concomitant endocrine deficiencies, hypercoagulability state and inflammatory milieu. Iron's toxicity within cells arises from its capacity to catalyse the production of reactive oxygen species that cause lipid peroxidation and organelle damage, which lead ultimately to cell death and fibrosis. With the introduction of new technologies such as cardiac magnetic resonance T2* , the early detection of cardiac iron overload and associated cardiac dysfunction is now possible, allowing time for reversal through iron chelation therapy.