Clinical, immunological and molecular profiles of DOCK8 deficiency in six patients from a tertiary care centre in North India.

BACKGROUND: Dedicator of cytokinesis protein 8 (DOCK8) deficiency is an autosomal recessive form of combined immunodeficiency. This rare disorder is characterized by an increased predisposition to allergy, autoimmunity and malignancies. OBJECTIVES: To analyse clinical, immunological and molecular profiles of patients with DOCK8 deficiency. METHODS: Clinic records of all patients attending the primary immunodeficiency clinic from 2018 to 2021 were reviewed. Six patients from five families were found to have DOCK8 deficiency. RESULTS: Median age at diagnosis was 7.5 years (range 2-13), with a male/female ratio of 5 : 1. Among the six patients, recurrent eczematous skin lesions were the predominant cutaneous manifestation, present in five patients (83%). Warts and molluscum contagiosum were evident in two patients (33%) and one patient (16%), respectively. Two patients had recalcitrant prurigo nodularis lesions and two had epidermodysplasia verruciformis-like lesions. Food allergies and asthma were reported by one patient each. Of the six patients, recurrent sinopulmonary infections were detected in five (83%). Epstein-Barr virus-driven non-Hodgkin lymphoma with liver metastases was the only case of malignancy, in a 4-year-old boy. IgE was elevated in all patients. Lymphopenia and eosinophilia were observed in three patients (50%) and five patients (83.3%), respectively. Genetic analysis showed DOCK8 pathogenic variants in all patients: homozygous deletion mutations in two patients, compound heterozygous deletion mutations in one, and homozygous nonsense mutations in two. A novel pathogenic homozygous missense variant in the DOCK8 gene was identified in one patient. CONCLUSIONS: DOCK8 deficiency should be considered as a possibility in any patient with early onset eczema, cutaneous viral infections and increased predisposition to allergy, autoimmunity and malignancy.

Juvenile localized scleroderma: A single-centre experience from India.

BACKGROUND: Juvenile localized scleroderma (JLS) or morphoea, a rare chronic autoimmune disease predominantly affects skin, subcutaneous tissue and occasionally the adjacent muscle, fascia and bone. We report the largest single-centre cohort of patients with JLS from India. METHODS: Patients who were diagnosed to have JLS were enrolled from the Paediatric Dermatology Clinic and the Paediatric Rheumatology Clinic of a tertiary care referral hospital in India. Collected data included details of the clinical profile, laboratory investigations and management. RESULTS: We analysed 84 patients with Juvenile localized scleroderma. Median age of disease onset was 5 years, and median age at diagnosis was 8 years. Commonest subtype was linear scleroderma (57 patients, 67.7%) followed by plaque morphoea and generalized morphoea. Fourteen patients (16.6%) were noted to have extracutaneous manifestations (ECMs). These included arthritis in eight (33.3%), brain parenchymal abnormalities in four (4.7%) and pulmonary involvement in two (8.3%) patients. Antinuclear antibody (ANA) was positive in eight/25 patients (32%; diffuse and speckled pattern in four patients each). One amongst these also had elevated anti-dsDNA titres. Positive ANA was found to have no association with ECMs (p 1.000). Patients were treated using methotrexate (61 patients; 72.6%), dexamethasone oral mini-pulse (OMP; 35 patients; 41.6%), calcipotriol (39 patients; 46.4%), topical corticosteroids (32 patients; 38%) and topical tacrolimus (three patients; 3.7%). Using linear regression analysis, administration of dexamethasone OMP and calcipotriol was found to be a predictor of good treatment response (p 0.034 and 0.019, respectively). CONCLUSION: Early use of systemic corticosteroids along with methotrexate may be more beneficial than methotrexate therapy alone.

Case report: Chronic granulomatous disease presenting with early-onset inflammatory bowel disease and normal oxidative burst testing.

Background: Due to the lack of widespread availability of flow cytometry services for immunodeficiency, nitroblue tetrazolium test (NBT) is the commonly used screening modality to identify patients with chronic granulomatous disease (CGD) in developing countries. Procedure: We report a child with X-linked CGD with residual NADPH oxidase activity who had an indeterminate NBT result even in the presence of classical manifestations of CGD. Results: A 7-year-old boy presented with recurrent episodes of inflammatory colitis and Burkholderia cepacia septicaemia at the age of 3 years. He also had cervical adenitis due to Mycobacterium tuberculosis. NBT performed on multiple occasions was not suggestive of CGD. Dihydrorhodamine (DHR) test using phorbol myristate acetate (PMA) as a stimulant revealed a small blunt peak suggestive of AR-CGD; however, significant reduction in NADPH oxidase activity was noted with milder stimulants such as Escherichia coli and Staphylococcus aureus. Genetic analysis revealed a hemizygous pathogenic variant in CYBB. Flow cytometry showed diminished gp91phox expression in the patient's neutrophils suggestive of X-linked CGD. Conclusion: Our case highlights that early-onset inflammatory bowel disease can be a presenting manifestation of CGD and diagnosis of CGD can be missed if NBT alone is used for screening, especially in the presence of NADPH oxidase activity. Diagnosis of "CGD with residual NADPH oxidase activity" requires a high degree of clinical suspicion, and performing DHR with different stimulants can unravel the diagnosis.

Mechanisms of Immune Dysregulation in COVID-19 Are Different From SARS and MERS: A Perspective in Context of Kawasaki Disease and MIS-C.

Coronaviruses have led to three major outbreaks to date-Severe Acute Respiratory Syndrome (SARS; 2002), Middle East Respiratory Syndrome (MERS; 2012) and the ongoing pandemic, Coronavirus Disease (COVID-19; 2019). Coronavirus infections are usually mild in children. However, a few children with MERS had presented with a severe phenotype in the acute phase resulting in progressive pneumonic changes with increasing oxygen dependency and acute respiratory distress requiring ventilatory support. A subset of children with a history of SARS-CoV-2 infection develops a multisystem hyper-inflammatory phenotype known as Multisystem Inflammatory Syndrome in Children (MIS-C). This syndrome occurs 4-6 weeks after infection with SARS-CoV-2 and has been reported more often from areas with high community transmission. Children with MIS-C present with high fever and often have involvement of cardiovascular, gastrointestinal and hematologic systems leading to multiorgan failure. This is accompanied by elevation of pro-inflammatory cytokines such as IL-6 and IL-10. MIS-C has several similarities with Kawasaki disease (KD) considering children with both conditions present with fever, rash, conjunctival injection, mucosal symptoms and swelling of hands and feet. For reasons that are still not clear, both KD and MIS-C were not reported during the SARS-CoV and MERS-CoV outbreaks. As SARS-CoV-2 differs from SARS-CoV by 19.5% and MERS by 50% in terms of sequence identity, differences in genomic and proteomic profiles may explain the varied disease immunopathology and host responses. Left untreated, MIS-C may lead to severe abdominal pain, ventricular dysfunction and shock. Immunological investigations reveal reduced numbers of follicular B cells, increased numbers of terminally differentiated CD4+T lymphocytes, and decreased IL-17A. There is still ambiguity about the clinical and immunologic risk factors that predispose some children to development of MIS-C while sparing others. Host-pathogen interactions in SARS, MERS and COVID-19 are likely to play a crucial role in the clinical phenotypes that manifest. This narrative review focuses on the immunological basis for development of MIS-C syndrome in the ongoing SARS-CoV-2 pandemic. To the best of our knowledge, these aspects have not been reviewed before.

Autoimmunity in Wiskott-Aldrich Syndrome: Updated Perspectives.

Wiskott-Aldrich syndrome (WAS) is an uncommon X-linked combined-immunodeficiency disorder characterized by a triad of thrombocytopenia, eczema, and immunodeficiency. Patients with WAS are also predisposed to autoimmunity and malignancy. Autoimmune manifestations have been reported in 26%-72% of patients with WAS. Autoimmunity is an independent predictor of poor prognosis and predisposes to malignancy. Development of autoimmunity is also an early pointer of the need for hematopoietic stem-cell transplantation. In this manuscript, we have collated the published data and present a narrative review on autoimmune manifestations in WAS. A summary of currently proposed immunopathogenic mechanisms and genetic variants associated with development of autoimmunity in WAS is also included.

Reticular dysgenesis exacerbated by hemophagocytic lymphohistiocytosis and the presence of unusual histiocyte-like cells in bone marrow.

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.

Hemophagocytic Lymphohistiocytosis in Children with Chronic Granulomatous Disease-Single-Center Experience from North India.

BACKGROUND: Chronic granulomatous disease (CGD) is an inherited defect in components of the nicotinamide adenine dinucleotide phosphate oxidase complex that results in potential life-threatening infective and noninfective complications. Hemophagocytic lymphohistiocytosis (HLH) is an unusual but important inflammatory complication of CGD. Optimal management strategies have not yet been identified in children with CGD who develop HLH. OBJECTIVE: To analyze clinical and laboratory features of HLH in CGD from a tertiary-care center in North India. METHODS: A retrospective review of medical records of children with CGD diagnosed in the last 20 years was performed. Clinical and laboratory features of children with CGD who developed HLH were analyzed. RESULTS: Of 80 patients diagnosed with CGD, 5 (6.25%) had evidence of HLH. All 5 were males; 4 had X-linked CGD and 1 had autosomal recessive CGD (NCF2 defect). Two children with CGD had HLH as the predominant presenting manifestation mimicking the clinical presentation of congenital HLH. Infectious triggers identified were bloodstream infections (n = 3) (Candida albicans, Burkholderia cenocepacia, Francisella noatuensis), pneumonia (n = 4), and splenic abscess (n = 1). We document the first human infection with a fish pathogen, F. noatuensis, in a child with X-linked CGD. Although mortality was seen in 3 children who received only intravenous (IV) immunoglobulin therapy, the other 2 who received IV methylprednisolone pulse therapy survived. CONCLUSION: HLH can be a presenting manifestation of CGD, and workup for CGD must be considered in children with HLH. Early recognition with optimal management of both infectious trigger and HLH is very important to prevent mortality.

Clinical, Immunological, and Molecular Profile of Chronic Granulomatous Disease: A Multi-Centric Study of 236 Patients From India.

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.

Case Reports: Survival from Rabies: Case Series from India.

Rabies, a zoonotic viral encephalitis, continues to be a serious public health problem in India and several other countries in Asia and Africa. Survival is rarely reported in rabies, which is considered to be almost universally fatal. We report the clinical and radiological findings of eight patients with laboratory-confirmed rabies who survived the illness. With the exception of one patient who recovered with mild sequelae, all survivors had poor functional outcomes. The reported survival from rabies in recent years may reflect an increased awareness of the disease and greater access to better critical care facilities in rabies-endemic countries. Nonetheless, there is an urgent need to focus on preventive strategies to reduce the burden of this dreadful disease in rabies-endemic countries.