Publications by authors named "Pandiarajan Vignesh"

127 Publications

Targeted Gene Sanger Sequencing Should Remain the First-Tier Genetic Test for Children Suspected to Have the Five Common X-Linked Inborn Errors of Immunity.

Front Immunol 2022 8;13:883446. Epub 2022 Jul 8.

Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, National Taiwan University Children's Hospital, Taipei, Taiwan.

To address inborn errors of immunity (IEI) which were underdiagnosed in resource-limited regions, our centre developed and offered free genetic testing for the most common IEI by Sanger sequencing (SS) since 2001. With the establishment of The Asian Primary Immunodeficiency (APID) Network in 2009, the awareness and definitive diagnosis of IEI were further improved with collaboration among centres caring for IEI patients from East and Southeast Asia. We also started to use whole exome sequencing (WES) for undiagnosed cases and further extended our collaboration with centres from South Asia and Africa. With the increased use of Next Generation Sequencing (NGS), we have shifted our diagnostic practice from SS to WES. However, SS was still one of the key diagnostic tools for IEI for the past two decades. Our centre has performed 2,024 IEI SS genetic tests, with in-house protocol designed specifically for 84 genes, in 1,376 patients with 744 identified to have disease-causing mutations (54.1%). The high diagnostic rate after just one round of targeted gene SS for each of the 5 common IEI (X-linked agammaglobulinemia (XLA) 77.4%, Wiskott-Aldrich syndrome (WAS) 69.2%, X-linked chronic granulomatous disease (XCGD) 59.5%, X-linked severe combined immunodeficiency (XSCID) 51.1%, and X-linked hyper-IgM syndrome (HIGM1) 58.1%) demonstrated targeted gene SS should remain the first-tier genetic test for the 5 common X-linked IEI.
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http://dx.doi.org/10.3389/fimmu.2022.883446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9304939PMC
July 2022

Healing With Complication: An Unusual Case of Nasal Tip Ulceration in Leukocyte Adhesion Deficiency Type 1.

J Allergy Clin Immunol Pract 2022 Jul 15. Epub 2022 Jul 15.

Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, India.

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http://dx.doi.org/10.1016/j.jaip.2022.06.019DOI Listing
July 2022

Cardiovascular Abnormalities in Juvenile Dermatomyositis: A Scoping Review for the Clinical Rheumatologists.

Front Med (Lausanne) 2022 24;9:827539. Epub 2022 Jun 24.

Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, India.

Juvenile dermatomyositis (JDM) is a common form of inflammatory myositis in children. Vasculopathy and endothelial dysfunction play significant roles in the pathogenesis of JDM. Cardiac involvement in JDM is often underestimated, and it may be a potential indicator of poor prognosis. Cardiac dysfunction in JDM can occur both in the acute and chronic stages of the disease. Amongst the acute complications, acute congestive heart failure (CHF), myocarditis, arrhythmia, and complete heart block are common. However, these remain unrecognized due to a lack of overt clinical manifestations. Increased rates of cardiovascular abnormalities have been noted with anti-SRP and anti-Jo 1 auto-antibody positivity. Long-term follow-up studies in JDM have shown an increased prevalence of hypertension, atherosclerosis, coronary artery disease, and metabolic syndrome in adolescence and adulthood. Monitoring of body-mass index, blood pressure, and laboratory evaluation of fasting glucose and lipid profile may help in identifying metabolic syndrome in children with JDM. Steroid-sparing agents, daily exercise, and a healthy diet may reduce such long-term cardiac morbidities. Current use of multimodality imaging such as stress-echocardiography, contrast-enhanced echocardiography, cardiac magnetic resonance imaging, and positron emission tomography has increased the diagnostic yield of subclinical heart disease during acute and chronic stages of JDM. This review elaborates on different aspects of cardiac dysfunction in JDM. It also emphasizes the importance of cardiac screening in long-term follow-up of children with JDM.
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http://dx.doi.org/10.3389/fmed.2022.827539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9263083PMC
June 2022

Features of Hemophagocytic Lymphohistiocytosis in Infants With Severe Combined Immunodeficiency: Our Experience From Chandigarh, North India.

Front Immunol 2022 23;13:867753. Epub 2022 Jun 23.

Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India.

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 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 (n=1), (n=1), and (n=1), pneumonia (influenza H1N1 strain, and K. (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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http://dx.doi.org/10.3389/fimmu.2022.867753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9260510PMC
June 2022

Utility of targeted next generation sequencing for inborn errors of immunity at a tertiary care centre in North India.

Sci Rep 2022 Jun 21;12(1):10416. Epub 2022 Jun 21.

Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, 160012, India.

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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http://dx.doi.org/10.1038/s41598-022-14522-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9213413PMC
June 2022

A Novel CEBPE Variant Causes Severe Infections and Profound Neutropenia.

J Clin Immunol 2022 Jun 20. Epub 2022 Jun 20.

Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Center (APC), Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, 160012, India.

Purpose: Specific granule deficiency (SGD) is a rare inborn error of immunity resulting from loss-of-function variants in CEBPE gene (encoding for transcription factor C/EBPε). Although this genetic etiology has been known for over two decades, only a few patients with CEBPE variant-proven SGD (type I) have been reported. Herein, we describe two siblings with a novel homozygous CEBPE deletion who were noted to have profound neutropenia on initial evaluation. We aimed to evaluate the immunohematological consequences of this novel variant, including profound neutropenia.

Methods: Light scatter characteristics of granulocytes were examined on various automated hematology analyzers. Phagocyte immunophenotype, reactive oxygen species generation, and Toll-like receptor (TLR) signaling were assessed using flow cytometry. Relative expression of genes encoding various granule proteins was studied using RT-PCR. Western blot analysis and luciferase reporter assay were performed to explore variant C/EBPε expression and function.

Results: Severe infections occurred in both siblings. Analysis of granulocyte light scatter plots revealed automated hematology analyzers can provide anomalously low neutrophil counts due to abnormal neutrophil morphology. Neutrophils displayed absence/marked reduction of CD15/CD16 expression and overexpression (in a subset) of CD14/CD64. Three distinct populations of phagocytes with different oxidase activities were observed. Impaired shedding of CD62-ligand was noted on stimulation with TLR-4, TLR-2/6, and TLR-7/8 agonists. We demonstrated the variant C/EBPε to be functionally deficient.

Conclusion: Homozygous c.655_665del variant in CEBPE causes SGD. Anomalous automated neutrophil counts may be reported in patients with SGD type I. Aberrant TLR signaling might be an additional pathogenetic mechanism underlying immunodeficiency in SGD type I.
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http://dx.doi.org/10.1007/s10875-022-01304-7DOI Listing
June 2022

Lymphoproliferation in Inborn Errors of Immunity: The Eye Does Not See What the Mind Does Not Know.

Front Immunol 2022 4;13:856601. Epub 2022 May 4.

Department of Pediatrics (Clinical Immunology and Rheumatology), Postgraduate Institute of Medical Education and Research, Chandigarh, India.

Inborn errors of immunity (IEIs) are a group of heterogeneous disorders characterized by a broad clinical spectrum of recurrent infections and immune dysregulation including autoimmunity and lymphoproliferation (LP). LP in the context of IEI may be the presenting feature of underlying immune disorder or may develop during the disease course. However, the correct diagnosis of LP in IEI as benign or malignant often poses a diagnostic dilemma due to the non-specific clinical features and overlapping morphological and immunophenotypic features which make it difficult to treat. There are morphological clues to LP associated with certain IEIs. A combination of ancillary techniques including EBV-associated markers, flow cytometry, and molecular assays may prove useful in establishing a correct diagnosis in an appropriate clinical setting. The present review attempts to provide comprehensive insight into benign and malignant LP, especially the pathogenesis, histological clues, diagnostic strategies, and treatment options in patients with IEIs.
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http://dx.doi.org/10.3389/fimmu.2022.856601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9114776PMC
May 2022

Deficiency of Human Adenosine Deaminase Type 2 - A Diagnostic Conundrum for the Hematologist.

Front Immunol 2022 3;13:869570. Epub 2022 May 3.

Pediatric Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.

Deficiency of adenosine deaminase type 2 (DADA2) was first described in 2014 as a monogenic cause of polyartertitis nodosa (PAN), early onset lacunar stroke and livedo reticularis. The clinical phenotype of DADA2 is, however, very broad and may involve several organ systems. Apart from vasculitis, children may present with i) Hematological manifestations (ii) Lymphoproliferation and iii) Immunodeficiencies. Patients with DADA2 can have variable patterns of cytopenias and bone marrow failure syndromes. Patients with DADA2 who have predominant haematological manifestations are associated with ADA2 gene variants that result in minimal or no residual ADA2 activity. Lymphoproliferation in patients with DADA2 may range from benign lymphoid hyperplasia to lymphoreticular malignancies. Patients may present with generalized lymphadenopathy, splenomegaly, autoimmune lymphoproliferative syndrome (ALPS) like phenotype, Hodgkin lymphoma, T-cell large granular lymphocytic infiltration of bone marrow and multicentric Castleman disease. Immunodeficiencies associated with DADA are usually mild. Affected patients have variable hypogammaglobulinemia, decrease in B cells, low natural killer cells, common variable immunodeficiency and rarely T cell immunodeficiency. To conclude, DADA2 has an extremely variable phenotype and needs to be considered as a differential diagnosis in diverse clinical conditions. In this review, we describe the evolving clinical phenotypes of DADA2 with a special focus on haematological and immunological manifestations.
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http://dx.doi.org/10.3389/fimmu.2022.869570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9110783PMC
May 2022

Novel TBXAS1 variants in two Indian children with Ghosal hematodiaphyseal dysplasia: A concise report.

Eur J Med Genet 2022 May 6;65(5):104498. Epub 2022 Apr 6.

Allergy Immunology Unit, Department of Pediatrics, Advances Pediatrics Centre, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India. Electronic address:

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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http://dx.doi.org/10.1016/j.ejmg.2022.104498DOI Listing
May 2022

Distal Coronary Artery Abnormalities in Kawasaki disease: experience on CT Coronary Angiography in 176 children.

Rheumatology (Oxford) 2022 Apr 8. Epub 2022 Apr 8.

Paediatric Allergy Immunology Unit, Department of Pediatrics, Advanced Paediatrics Centre, Post Graduate Institute of Medical education and Research, Chandigarh, India -160012.

Objective: Precise evaluation of coronary artery abnormalities (CAAs) in Kawasaki disease (KD) is essential. The aim of this study is to determine role of CT coronary angiography (CTCA) for detection of CAAs in distal segments of coronary arteries in patients with KD.

Methods: CTCA findings of KD patients with distal coronary artery involvement were compared with those on transthoracic echocardiography (TTE) during the period 2013-2021.

Results: Amongst 176 patients with KD who underwent CTCA (128-Slice Dual Source scanner), 23 (13.06%) had distal CAAs (right coronary - 15/23; left anterior descending - 14/23; left circumflex - 4/23 patients). CTCA identified 60 aneurysms - 37 proximal (36 fusiform; 1 saccular) and 23 distal (17 fusiform; 6 saccular); 11 patients with proximal aneurysms had distal contiguous extension; 9 patients showed non-contiguous aneurysms in both proximal and distal segments; 4 patients showed distal segment aneurysms in absence of proximal involvement of same coronary artery; 4 patients had isolated distal CAAs. On TTE, only 40 aneurysms could be identified. Further, distal CAAs could not be identified on TTE. CTCA also identified complications (thrombosis, mural calcification and stenosis) that were missed on TTE.

Conclusions: CAAs can, at times, occur in distal segments in isolation and also in association with, or extension of, proximal CAAs. CTCA demonstrates CAAs in distal segments of coronary arteries, including branches, in a significant number of children with KD - these cannot be detected on TTE. CTCA, therefore, may be considered as a complimentary imaging modality in children with KD who have CAAs on TTE.
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http://dx.doi.org/10.1093/rheumatology/keac217DOI Listing
April 2022

Unusual clinical manifestations and predominant stopgain ATM gene variants in a single centre cohort of ataxia telangiectasia from North India.

Sci Rep 2022 03 8;12(1):4036. Epub 2022 Mar 8.

Allergy and Immunology Laboratory, Department of Pediatrics, Advanced Pediatric Centre, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, 160012, India.

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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http://dx.doi.org/10.1038/s41598-022-08019-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8904522PMC
March 2022

Kawasaki disease does not affect coronaries alone: large vessels can be involved as well.

Clin Rheumatol 2022 06 8;41(6):1927-1928. Epub 2022 Mar 8.

Allergy Immunology Unit, Department of Pediatrics, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.

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http://dx.doi.org/10.1007/s10067-022-06118-xDOI Listing
June 2022

Phenomic Analysis of Chronic Granulomatous Disease Reveals More Severe Integumentary Infections in X-Linked Compared With Autosomal Recessive Chronic Granulomatous Disease.

Front Immunol 2021 24;12:803763. Epub 2022 Jan 24.

Allergy & Immunology Unit, Department of Paediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India.

Background: Chronic granulomatous disease (CGD) is an inborn error of immunity (IEI), characterised by recurrent bacterial and fungal infections. It is inherited either in an X-linked (XL) or autosomal recessive (AR) mode. Phenome refers to the entire set of phenotypes expressed, and its study allows us to generate new knowledge of the disease. The objective of the study is to reveal the phenomic differences between XL and AR-CGD by using Human Phenotype Ontology (HPO) terms.

Methods: We collected data on 117 patients with genetically diagnosed CGD from Asia and Africa referred to the Asian Primary Immunodeficiency Network (APID network). Only 90 patients with sufficient clinical information were included for phenomic analysis. We used HPO terms to describe all phenotypes manifested in the patients.

Results: XL-CGD patients had a lower age of onset, referral, clinical diagnosis, and genetic diagnosis compared with AR-CGD patients. The integument and central nervous system were more frequently affected in XL-CGD patients. Regarding HPO terms, perianal abscess, cutaneous abscess, and elevated hepatic transaminase were correlated with XL-CGD. A higher percentage of XL-CGD patients presented with BCGitis/BCGosis as their first manifestation. Among our CGD patients, lung was the most frequently infected organ, with gastrointestinal system and skin ranking second and third, respectively. species, , and were the most frequent pathogens to be found.

Conclusion: Phenomic analysis confirmed that XL-CGD patients have more recurrent and aggressive infections compared with AR-CGD patients. Various phenotypic differences listed out can be used as clinical handles to distinguish XL or AR-CGD based on clinical features.
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http://dx.doi.org/10.3389/fimmu.2021.803763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8818666PMC
February 2022

Features of nephrotic syndrome in infants with severe combined immunodeficiency.

J Allergy Clin Immunol Pract 2022 01;10(1):356-357

Department of Pediatrics, Advanced Pediatrics Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, India; Allergy Immunology Unit, Advanced Pediatrics Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, India.

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http://dx.doi.org/10.1016/j.jaip.2021.09.052DOI Listing
January 2022

Utility of Immunohistochemistry and Immunofluorescence in Determining the Pathogenic Variants of Chronic Granulomatous Disease.

J Clin Immunol 2022 01 14;42(1):85-93. Epub 2021 Oct 14.

Department of Pediatrics (Allergy and Immunology Unit), Postgraduate Institute of Medical Education and Research, Chandigarh, India.

Background: Chronic granulomatous disease (CGD) is a primary immunodeficiency disorder of phagocytes due to defects in any of the five subunits of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. An initial diagnosis of CGD is made by flow cytometry-based dihydrorhodamine assay or nitro blue tetrazolium test, which is further confirmed by molecular assays. Expression of five subunits of NADPH oxidase components by either flow cytometric or western blot analysis provides clues toward the potential gene targets which are subsequently confirmed by various genetic assays. Immunohistochemistry (IHC) and immunofluorescence (IF) have never been earlier used to determine the expression of different subunits of NADPH oxidase system. We evaluated the utility of IHC and IF in determining the underlying pathogenic variants of CGD.

Materials And Methods: Twelve genetically confirmed cases of CGD, comprising of biopsy specimens (n = 6), tissue blocks from autopsy cases (n = 3), and cellblocks of cell pellet prepared from peripheral blood (n = 4) were included. IHC for p67phox and p47phox subunits and IF for cytochrome b558 were performed.

Results: All 4 cases with pathogenic variation of NCF2 gene showed loss of expression for p67phox subunit. Two cases with pathogenic variation of NCF1 gene showed loss of expression for p47phox subunit. Five cases, except a single case with CYBB gene pathogenic variation, showed loss of expression for cytochrome b558 on IF. Thus, loss of expression consistently matched with the underlying genetic defects assessed by sequencing.

Conclusions: Our results confirm our hypothesis that IHC and IF are two rapid, economical, pathologist-friendly techniques providing pertinent information regarding the underlying pathogenic variants and such immuno-analysis can be easily performed on the tissue.
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http://dx.doi.org/10.1007/s10875-021-01148-7DOI Listing
January 2022

Hematologically important mutations: The autosomal forms of chronic granulomatous disease (third update).

Blood Cells Mol Dis 2021 12 28;92:102596. Epub 2021 Jul 28.

Dept of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.

Chronic granulomatous disease (CGD) is an immunodeficiency disorder affecting about 1 in 250,000 individuals. CGD patients suffer from severe, recurrent bacterial and fungal infections. The disease is caused by mutations in the genes encoding the components of the leukocyte NADPH oxidase. This enzyme produces superoxide, which is subsequently metabolized to hydrogen peroxide and other reactive oxygen species (ROS). These products are essential for intracellular killing of pathogens by phagocytic leukocytes (neutrophils, eosinophils, monocytes and macrophages). The leukocyte NADPH oxidase is composed of five subunits, four of which are encoded by autosomal genes. These are CYBA, encoding p22, NCF1, encoding p47, NCF2, encoding p67 and NCF4, encoding p40. This article lists all mutations identified in these genes in CGD patients. In addition, cytochrome b chaperone-1 (CYBC1), recently recognized as an essential chaperone protein for the expression of the X-linked NADPH oxidase component gp91 (also called Nox2), is encoded by the autosomal gene CYBC1. Mutations in this gene also lead to CGD. Finally, RAC2, a small GTPase of the Rho family, is needed for activation of the NADPH oxidase, and mutations in the RAC2 gene therefore also induce CGD-like symptoms. Mutations in these last two genes are also listed in this article.
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http://dx.doi.org/10.1016/j.bcmd.2021.102596DOI Listing
December 2021

Mania associated with overdose of nevirapine in an adolescent: A case report.

Indian J Psychiatry 2021 Jul-Aug;63(4):401-403. Epub 2021 Aug 7.

Department of Paediatrics, Post Graduate Institute of Medical Education and Research, Chandigarh, India. E-mail:

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http://dx.doi.org/10.4103/0019-5545.323389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8363900PMC
August 2021

Achromobacter xylosoxidans Pneumonia in a Young Child with Chronic Granulomatous Disease-a Case-Based Review.

J Clin Immunol 2021 10 14;41(7):1686-1692. Epub 2021 Jul 14.

Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, 160012, India.

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http://dx.doi.org/10.1007/s10875-021-01079-3DOI Listing
October 2021

An updated review on Mendelian susceptibility to mycobacterial diseases- a silver jubilee celebration of its first genetic diagnosis.

Expert Rev Clin Immunol 2021 10;17(10):1103-1120

Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, India.

: 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.: 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.: 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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http://dx.doi.org/10.1080/1744666X.2021.1956314DOI Listing
October 2021

Clinical profile, long-term follow-up and outcome of juvenile systemic scleroderma: 25 years of clinical experience from North-West India.

Clin Exp Rheumatol 2021 Jul-Aug;39 Suppl 131(4):149-156. Epub 2021 Jul 6.

Allergy Immunology Unit, Department of Paediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, India.

Objectives: To describe the clinical profile, long-term follow-up and outcome of juvenile systemic scleroderma (JSSc) from a tertiary care referral hospital in North-West India.

Methods: A review of case records was performed and children with JSSc (disease onset <14 years of age) were analysed. Diagnosis was based on the Paediatric Rheumatology European Society/American College of Rheumatology/European League against Rheumatism provisional classification criteria for JSSc.

Results: Forty patients (28 girls and 12 boys; F:M ratio= 2.3:1) were diagnosed with JSSc (including 22 children with overlap) in the last 25 years. Mean age at symptom onset was 7.75±3.19 years with a mean delay in diagnosis of 2.275±2.09 years. Raynaud's phenomenon was seen in 26/40 (65%) patients at presentation. Lung involvement was noted in 40% patients. Methotrexate was the most commonly used therapy, followed by oral prednisolone. Patients without overlap had higher incidence of cutaneous ulcers as compared to patients with overlap (55% vs. 18%; p-value: 0.01). Patients with overlap required significantly higher oral prednisolone (81% vs. 22%), methotrexate (72% vs. 38%) and hydroxychloroquine (54% vs. 5%) while cyclophosphamide (13% vs. 44%) and azathioprine (9% vs. 44%) were used relatively less in this group. Mortality was 15% at a mean follow-up of 51.75 months. Infections were noted to be the most common cause of death. There was no significant difference in the mortality between patients with and without lung disease or patients with or without overlap.

Conclusions: We describe the largest single-centre cohort with longest follow-up of juvenile systemic scleroderma from India.
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http://dx.doi.org/10.55563/clinexprheumatol/7ubxxiDOI Listing
August 2021

What Lies Ahead for Young Hearts in the 21 Century - Is It Double Trouble of Acute Rheumatic Fever and Kawasaki Disease in Developing Countries?

Front Cardiovasc Med 2021 24;8:694393. Epub 2021 Jun 24.

Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, India.

Rheumatic heart disease (RHD), the principal long-term sequel of acute rheumatic fever (ARF), has been a major contributor to cardiac-related mortality in general population, especially in developing countries. With improvement in health and sanitation facilities across the globe, there has been almost a 50% reduction in mortality rate due to RHD over the last 25 years. However, recent estimates suggest that RHD still results in more than 300,000 deaths annually. In India alone, more than 100,000 deaths occur due to RHD every year (Watkins DA et al., N Engl J Med, 2017). Children and adolescents (aged below 15 years) constitute at least one-fourth of the total population in India. Besides, ARF is, for the most part, a pediatric disorder. The pediatric population, therefore, requires special consideration in developing countries to reduce the burden of RHD. In the developed world, Kawasaki disease (KD) has emerged as the most important cause of acquired heart disease in children. Mirroring global trends over the past two decades, India also has witnessed a surge in the number of cases of KD. Similarly, many regions across the globe classified as "high-risk" for ARF have witnessed an increasing trend in the incidence of KD. This translates to a double challenge faced by pediatric health care providers in improving cardiac outcomes of children affected with ARF or KD. We highlight this predicament by reviewing the incidence trends of ARF and KD over the last 50 years in ARF "high-risk" regions.
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http://dx.doi.org/10.3389/fcvm.2021.694393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263915PMC
June 2021

Epigenetics in Kawasaki Disease.

Front Pediatr 2021 25;9:673294. Epub 2021 Jun 25.

Department of Pediatrics, Advanced Pediatrics Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, India.

Kawasaki disease (KD) is a common febrile multisystemic inflammatory illness in children that preferentially affects coronary arteries. Children with KD who develop coronary artery aneurysms have a life-long risk of premature coronary artery disease. Hypothesis of inherent predisposition to KD is supported by epidemiological evidence that suggests increased risk of development of disease in certain ethnicities and in children with a previous history of KD in siblings or parents. However, occurrence of cases in clusters, seasonal variation, and very low risk of recurrence suggests an acquired trigger (such as infections) for the development of illness. Epigenetic mechanisms that modulate gene expression can plausibly explain the link between genetic and acquired predisposing factors in KD. Analysis of epigenetic factors can also be used to derive biomarkers for diagnosis and prognostication in KD. Moreover, epigenetic mechanisms can also help in pharmacogenomics with the development of targeted therapies. In this review, we analysed the available literature on epigenetic factors such as methylation, micro-RNAs, and long non-coding RNAs in KD and discuss how these mechanisms can help us better understand the disease pathogenesis and advance the development of new biomarkers in KD.
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http://dx.doi.org/10.3389/fped.2021.673294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266996PMC
June 2021

False-positive HIV serology, Candida lusitaniae pneumonia, and a novel mutation in the CYBB gene.

Immunobiology 2021 07 2;226(4):152110. Epub 2021 Jul 2.

Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India. Electronic address:

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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http://dx.doi.org/10.1016/j.imbio.2021.152110DOI Listing
July 2021

Hematologically important mutations: X-linked chronic granulomatous disease (fourth update).

Blood Cells Mol Dis 2021 09 2;90:102587. Epub 2021 Jun 2.

Dept of Pediatrics and Laboratory for Leukocyte Function, Meir Medical Centre, Kfar Saba, Israel.

Chronic granulomatous disease (CGD) is an immunodeficiency disorder affecting about 1 in 250,000 individuals. CGD patients suffer from severe bacterial and fungal infections. The disease is caused by a lack of superoxide production by the leukocyte enzyme NADPH oxidase. Superoxide and subsequently formed other reactive oxygen species (ROS) are instrumental in killing phagocytosed micro-organisms in neutrophils, eosinophils, monocytes and macrophages. The leukocyte NADPH oxidase is composed of five subunits, of which the enzymatic component is gp91, also called Nox2. This protein is encoded by the CYBB gene on the X chromosome. Mutations in this gene are found in about 70% of all CGD patients in Europe and in about 20% in countries with a high ratio of parental consanguinity. This article lists all mutations identified in CYBB and should therefore help in genetic counseling of X-CGD patients' families. Moreover, apparently benign polymorphisms in CYBB are also given, which should facilitate the recognition of disease-causing mutations. In addition, we also include some mutations in G6PD, the gene on the X chromosome that encodes glucose-6-phosphate dehydrogenase, because inactivity of this enzyme may lead to shortage of NADPH and thus to insufficient activity of NADPH oxidase. Severe G6PD deficiency can induce CGD-like symptoms.
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http://dx.doi.org/10.1016/j.bcmd.2021.102587DOI Listing
September 2021

SARS-CoV-2 Infection in a Child with Severe Congenital Neutropenia.

J Clin Immunol 2021 08 3;41(6):1165-1168. Epub 2021 May 3.

Department of Hematology, Post Graduate Institute of Medical Education and Research, Chandigarh, 160012, India.

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http://dx.doi.org/10.1007/s10875-021-01054-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092716PMC
August 2021

Wiskott Aldrich Syndrome: A Multi-Institutional Experience From India.

Front Immunol 2021 16;12:627651. Epub 2021 Apr 16.

Department of Pediatrics, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.

Background: Wiskott Aldrich syndrome (WAS) is characterized by bleeding manifestations, recurrent infections, eczema, autoimmunity, and malignancy. Over the last decade, improved awareness and better in-house diagnostic facilities at several centers in India has resulted in increased recognition of WAS. This study reports collated data across major primary immunodeficiency diseases (PID) centers in India that are involved in care of children with WAS and highlights the varied clinical presentations, genetic profile, and outcomes of patients in India.

Methods: Request to share data was sent to multiple centers in India that are involved in care and management of patients with PID. Six centers provided requisite data that were compiled and analyzed.

Results: In this multi-institutional cohort, clinical details of 108 patients who had a provisional diagnosis of WAS were received. Of these, 95 patients with 'definite WAS' were included Fourteen patients were classified as XLT and 81 patients as WAS. Median age at onset of symptoms of patients was 3 months (IQR 1.6, 6.0 months) and median age at diagnosis was 12 months (IQR 6,48 months). Clinical profile included bleeding episodes (92.6%), infections (84.2%), eczema (78.9%), various autoimmune manifestations (40%), and malignancy (2.1%). DNA analysis revealed 47 variants in 67 cases. Nonsense and missense variants were the most common (28.4% each), followed by small deletions (19.4%), and splice site defects (16.4%). We also report 24 novel variants, most of these being frameshift and nonsense mutations resulting in premature termination of protein synthesis. Prophylactic intravenous immunoglobulin (IVIg) was initiated in 52 patients (54.7%). Hematopoietic stem cell transplantation (HSCT) was carried out in 25 patients (26.3%). Of those transplanted, disease-free survival was seen in 15 patients (60%). Transplant related mortality was 36%. Outcome details were available for 89 patients. Of these, 37% had died till the time of this analysis. Median duration of follow-up was 36 months (range 2 weeks- 12 years; IQR 16.2 months- 70 months).

Conclusions: We report the first nationwide cohort of patients with WAS from India. Bleeding episodes and infections are common manifestations. Mortality continues to be high as curative therapy is not accessible to most of our patients.
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http://dx.doi.org/10.3389/fimmu.2021.627651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086834PMC
September 2021

Skewed TCR Alpha, but not Beta, Gene Rearrangements and Lymphoma Associated with a Pathogenic TRAC Variant.

J Clin Immunol 2021 08 28;41(6):1395-1399. Epub 2021 Apr 28.

Paediatric Allergy Immunology Unit, Department of Paediatrics, Advanced Paediatrics Centre, Postgraduate Institute of Medical Education & Research, Sector 12, Chandigarh, 160012, India.

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http://dx.doi.org/10.1007/s10875-021-01047-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8316983PMC
August 2021

Renal Biopsy in Children-Effect on Treatment Decisions: A Single-Center Experience.

Indian J Pediatr 2021 Oct 13;88(10):1036-1039. Epub 2021 Apr 13.

Pediatric Nephrology Unit, Department of Pediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India.

Renal biopsy is an important diagnostic tool, though invasive and carries risks involved with sedation. The authors wanted to compare suspect histopathological diagnosis with final diagnosis and find out impact of biopsy findings on treatment. They retrospectively analyzed 108 patients. Details of patients, diagnosis, treatment and complications due to kidney biopsy were documented. Statistical analysis was done using SPSS version 20.0 (IBM, NY). Indications of 108 children (69 boys, 39 girls) undergoing renal biopsy were steroid-resistant nephrotic syndrome (35.1%), steroid-dependent nephrotic syndrome requiring calcineurin inhibitors (CNI) (12%), nephrotic range proteinuria with atypical features (16.7%), lupus nephritis (13%), and acute kidney injury (AKI) stage 3 (17.6%). Suspect and histopathological diagnoses were similar in 53% cases with agreement factor of 0.462. Treatment changed in 28.7%. Renal biopsy made substantial impact in patients with nephrotic range proteinuria with atypical features (55.6%) and AKI stage 3 (52.6%). One (0.9%) had developed gross hematuria, which resolved spontaneously.
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http://dx.doi.org/10.1007/s12098-021-03721-9DOI Listing
October 2021

Spectrum of Systemic Auto-Inflammatory Diseases in India: A Multi-Centric Experience.

Front Immunol 2021 19;12:630691. Epub 2021 Mar 19.

Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.

Systemic autoinflammatory diseases (SAID) are rare inherited disorders involving genes regulating innate immune signaling and are characterized by periodic or chronic multi-systemic inflammation. To describe spectrum of clinical, immunological, molecular features, and outcomes of patients with SAID in India. Request to share data was sent to multiple centers in India that are involved in care and management of patients with Inborn Errors of Immunity. Six centers provided requisite data that were compiled and analyzed. Data on 107 patients with SAID were collated-of these, 29 patients were excluded due to unavailability of complete information. Twelve patients (15%) had type 1 interferonopathies, 21 (26%) had diseases affecting inflammasomes, 30 patients (41%) had non-inflammasome related conditions and 1five patients (19%) had Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA). Type1 interferonopathies identified in the cohort included patients with Deficiency of Adenosine Deaminase 2 ( (six patients; five families); STING-associated vasculopathy infantile-onset (SAVI) (three patients, one family); Spondyloenchondro-dysplasia with Immune Dysregulation (SPENCD) (two patients). Diseases affecting inflammasomes include Mevalonate Kinase Deficiency (eight patients); Cryopyrin-Associated Periodic Syndromes (CAPS) (seven patients); NLR Family, Pyrin domain-containing 12 NLRP12) (two patients); Familial Mediterranean fever (FMF) (two patients); Autoinflammation and PLCG-associated antibody deficiency and immune dysregulation (APLAID) (two patients). TNF receptor-associated periodic syndrome (TRAPS) (three patients); A20 haploinsufficiency (four patients); Deficiency of Interleukin 1 Receptor Antagonist (DIRA) (two patients) were categorized as non-inflammasome related conditions. There were significant delays in diagnosis Corticosteroids and other immunosuppressive agents were used for treatment as anti-IL-1 drugs and other biological agents were and still are not available in India. Eight (16.3%) patients had so far succumbed to their illness. This is the first nationwide cohort of patients with SAID from India. Clinical manifestations were diverse. Overlapping of clinical features with other relatively common rheumatological disorders often resulted in delays in diagnosis. More nationwide efforts are needed to enhance awareness of SAID among health care professionals and there is an urgent need to make targeted immunotherapies universally available.
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http://dx.doi.org/10.3389/fimmu.2021.630691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017183PMC
September 2021

The Spectrum of Clinical, Immunological, and Molecular Findings in Familial Hemophagocytic Lymphohistiocytosis: Experience From India.

Front Immunol 2021 5;12:612583. Epub 2021 Mar 5.

Department of Pediatrics, Post Graduate Institute of Medical Education and Research, Chandigarh, India.

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 , and 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 , and 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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http://dx.doi.org/10.3389/fimmu.2021.612583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973116PMC
June 2021
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