Manish Butte

Fetal Pediatr Pathol. 2022 Jun 24:1-10. doi: 10.1080/15513815.2022.2088912. Online ahead of print.

ABSTRACT

BACKGROUND: A small subset of cases of inflammatory bowel disease (IBD) occurs as a result of single gene defects, and typically occurs in young or very young pediatric patients, referred to as “monogenic very-early onset IBD (VEO-IBD)”. The gene variants leading to monogenic VEO-IBD are often associated with primary immunodeficiency syndromes.

CASE REPORT: A six year-old girl presented to our gastroenterology clinic with LRBA deficiency with a heterozygous mutation at c.1399 A > G, p Met467Val, histopathologic chronic active colitis without granulomas and clinical chronic colitis. Her gastrointestinal symptoms began at age 5 with bloody diarrhea, abdominal pain and weight loss. Whole exome sequencing revealed a CARD11 heterozygous de novo mutation (c.220 + 1G > A). She was in clinical remission on only abatacept.

DISCUSSION: We present a case of monogenic VEO-IBD associated with two heterozygous variants in LRBA1 and CARD11, both considered as key players in the newly proposed “immune TOR-opathies”.

PMID:35748740 | DOI:10.1080/15513815.2022.2088912

J Pediatric Infect Dis Soc. 2022 Jun 24:piac057. doi: 10.1093/jpids/piac057. Online ahead of print.

ABSTRACT

Staphylococcus-associated glomerulonephritis (GN) is an uncommon diagnosis in pediatric patients. Empiric therapy with steroids alone could potentially worsen the underlying infectious process in these patients, leading to worse clinical outcomes. An adolescent male diagnosed with GN was subsequently found to have chronic granulomatous disease with a Staphylococcus aureus liver abscess. His GN improved with antibiotics alone. This case illustrates the need to consider chronic infection, and primary immunodeficiency, in the differential diagnosis for new-onset GN.

PMID:35748038 | DOI:10.1093/jpids/piac057

J Clin Immunol. 2022 Jun 23. doi: 10.1007/s10875-022-01299-1. Online ahead of print.

ABSTRACT

As protein-losing enteropathy (PLE) can lead to hypogammaglobulinemia and lymphopenia, and since common variable immunodeficiency (CVID) is associated with digestive complications, we wondered if (1) PLE could occur during CVID and (2) specific features could help determine whether a patient with antibody deficiency has CVID, PLE, or both. Eligible patients were thus classified in 3 groups: CVID + PLE (n = 8), CVID-only (= 19), and PLE-only (n = 13). PLE was diagnosed using fecal clearance of α1-antitrypsin or 111In-labeled albumin. Immunoglobulin (Ig) A, G, and M, naive/memory B and T cell subsets were compared between each group. CVID + PLE patients had multiple causes of PLE: duodenal villous atrophy (5/8), nodular follicular hyperplasia (4/8), inflammatory bowel disease-like (4/8), portal hypertension (4/8), giardiasis (3/8), and pernicious anemia (1/8). Compared to the CVID-only group, CVID + PLE patients had similar serum Ig levels, B cell subset counts, but lower naive T cell proportion and IgG replacement efficiency index. Compared to the CVID-only group, PLE-only patients did not develop infections but had higher serum levels of IgG (p = 0.03), IgA (p < 0.0001), and switched memory B cells (p = 0.001); and decreased naive T cells (CD4⁺: p = 0.005; CD8⁺: p < 0.0001). Compared to the PLE-only group, CVID + PLE patients had higher infection rates (p = 0.0003), and lower serum Ig (especially IgA: p < 0.001) and switched memory B cells levels. In conclusion, PLE can occur during CVID and requires higher IgG replacement therapy dosage. PLE can also mimic CVID and is associated with milder immunological abnormalities, notably mildly decreased to normal serum IgA and switched memory B cell levels.

PMID:35737255 | DOI:10.1007/s10875-022-01299-1

Pediatr Dermatol. 2022 Jun 22. doi: 10.1111/pde.15072. Online ahead of print.

ABSTRACT

Hyper-IgE syndromes (HIES) are a heterogeneous group of rare primary immunodeficiency diseases classically characterized by the triad of atopic dermatitis, and recurrent cutaneous and pulmonary infections. Autosomal dominant, loss-of-function STAT3 pathogenic variants are the most common genetic cause, which lead to deficiency of Th17 lymphocytes, impaired interferon gamma production, and IL-10 signal transduction, and an unbalanced IL-4 state. Dupilumab, a monoclonal antibody to the IL-4a receptor, inhibits both IL-4 and IL-13, and has been shown to improve atopic dermatitis and other manifestations of HIES including asthma and allergic bronchopulmonary aspergillosis. We present a pediatric patient with HIES who presented predominantly with eosinophilic folliculitis, recurrent cutaneous infections, and other non-eczematous findings and achieved sustained clearance with dupilumab.

PMID:35734823 | DOI:10.1111/pde.15072

Sci Rep. 2022 Jun 21;12(1):10416. doi: 10.1038/s41598-022-14522-1.

ABSTRACT

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.

PMID:35729272 | DOI:10.1038/s41598-022-14522-1

Eur Respir J. 2022 Jun 21:2200176. doi: 10.1183/13993003.00176-2022. Online ahead of print.

ABSTRACT

BACKGROUND: Bronchiectasis can result from infectious, genetic, immunological and allergic causes. 60-80% cases are idiopathic, but a well-recognised genetic cause is the motile ciliopathy, primary ciliary dyskinesia (PCD). Diagnosis of PCD has management implications including addressing co-morbidities, implementing genetic and fertility counselling and future access to PCD-specific treatments. Diagnostic testing can be complex, however PCD genetic testing is rapidly moving from research into clinical diagnostics and would confirm the cause of bronchiectasis.

METHODS: This observational study used genetic data from severe bronchiectasis patients recruited to the UK 100,000 Genomes Project and patients referred for gene panel testing within a tertiary respiratory hospital, Patients referred for genetic testing due to clinical suspicion of PCD were excluded from both analyses. Data was accessed from the British Thoracic Society audit, to investigate whether motile ciliopathies are underdiagnosed in people with bronchiectasis in the UK.

RESULTS: Pathogenic or likely pathogenic variants were identified in motile ciliopathy genes in 17/142 (12%) individuals by whole genome sequencing. Similarly in a single centre with access to pathological diagnostic facilities, 5-10% patients received a PCD diagnosis by gene panel, often linked to normal/inconclusive nasal nitric oxide and cilia functional test results. In 4,898 audited patients with bronchiectasis, <2% were tested for PCD and <1% received genetic testing.

CONCLUSIONS: PCD is underdiagnosed as a cause of bronchiectasis. Increased uptake of genetic testing may help to identify bronchiectasis due to motile ciliopathies and ensure appropriate management.

PMID:35728977 | DOI:10.1183/13993003.00176-2022

Clin Chim Acta. 2022 Jun 18:S0009-8981(22)01186-X. doi: 10.1016/j.cca.2022.06.003. Online ahead of print.

ABSTRACT

BACKGROUND: Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disorder (PID) due to genetic defects in the NADPH oxidase of phagocytes. Affected patients become susceptible to infections such as pneumonia, diarrhea, and skin ulcer types. The patients require life-long treatment with prophylactic antibiotics, antifungals, or hematopoietic stem cell transplantation (HSCT) therapy. Early, accurate diagnosis will contribute to the life-prolonging of patients with CGD. This study’s aim is to identify the mutation related to the disease. Case presentation Six patients from different Vietnamese families were collected for genetic analysis at Allergy, Immunology, and Rheumatology Department, Vietnam National Hospital Pediatrics. They were diagnosed with CGD by flow cytometry test with the conversion of dihydrorhodamine (DHR) 123 to rhodamine 123.

METHODS: We performed whole exome sequencing (WES) as a tool for detecting novel mutations. The mutations were confirmed by the Sanger sequencing method in patients and their families. The influence of the mutations was predicted with the in silico analysis tools: PROVEAN, SIFT, PolyPhen 2, Mutation Taster, and MaxEntScan.

RESULTS: In this study, five mutations were found in six unrelated patients with CGD from different Vietnamese families. Three novel pathogenic mutations were detected including one mutation (c.45+2T>G) in the CYBB gene and two mutations (c.187_188insA and c.289G>C) in the NCF2 gene.

CONCLUSIONS: Our results of CGD-related mutations contribute to the general understanding of the etiology of the disease and emphasize that WES sequencing can be used as a tool to help to diagnose carriers as well as assist in genetic counseling and prenatal screening.

PMID:35728702 | DOI:10.1016/j.cca.2022.06.003

Front Immunol. 2022 Jun 2;13:912571. doi: 10.3389/fimmu.2022.912571. eCollection 2022.

ABSTRACT

BACKGROUND: Patients with primary and secondary antibody deficiency are vulnerable to COVID-19 and demonstrate diminished responses following two-dose SARS-CoV-2 vaccine schedules. Third primary vaccinations have been deployed to enhance their humoral and cellular immunity.

OBJECTIVES: To determine the immunogenicity of the third primary SARS-CoV-2 immunisation in a heterogeneous cohort of patients with antibody deficiency.

METHODS: Participants enrolled in the COV-AD study were sampled before and after their third vaccine dose. Serological and cellular responses were determined using ELISA, live-virus neutralisation and ELISPOT assays.

RESULTS: Following a two-dose schedule, 100% of healthy controls mounted a serological response to SARS-CoV-2 vaccination, however, 38.6% of individuals with antibody deficiency remained seronegative. A third primary SARS-CoV-2 vaccine significantly increased anti-spike glycoprotein antibody seroprevalence from 61.4% to 76.0%, the magnitude of the antibody response, its neutralising capacity and induced seroconversion in individuals who were seronegative after two vaccine doses. Vaccine-induced serological responses were broadly cross-reactive against the SARS-CoV-2 B.1.1.529 variant of concern, however, seroprevalence and antibody levels remained significantly lower than healthy controls. No differences in serological responses were observed between individuals who received AstraZeneca ChAdOx1 nCoV-19 and Pfizer BioNTech 162b2 during their initial two-dose vaccine schedule. SARS-CoV-2 infection-naive participants who had received a heterologous vaccine as a third dose were significantly more likely to have a detectable T cell response following their third vaccine dose (61.5% vs 11.1%).

CONCLUSION: These data support the widespread use of third primary immunisations to enhance humoral immunity against SARS-CoV-2 in individuals with antibody deficiency.

PMID:35720400 | PMC:PMC9201027 | DOI:10.3389/fimmu.2022.912571

Front Immunol. 2022 Jun 2;13:886540. doi: 10.3389/fimmu.2022.886540. eCollection 2022.

ABSTRACT

We report two patients with DNA repair disorders (Artemis deficiency, Ataxia telangiectasia) with destructive skin granulomas, presumably triggered by live-attenuated rubella vaccinations. Both patients showed reduced naïve T cells. Rapid resolution of skin lesions was observed following hematopoietic stem cell transplantation. However, the patient with AT died due to complications of severe hepatic veno-occlusive disease 6 month after HSCT. Dried blood spots obtained after birth were available from this patient and showed absent T-cell receptor excision circles (TRECs). Therefore, newborn screening may help to prevent patients with moderate T-cell deficiency from receiving live-attenuated rubella vaccine potentially causing granulomas.

PMID:35720367 | PMC:PMC9201904 | DOI:10.3389/fimmu.2022.886540

Adv Biomed Res. 2022 Apr 29;11:31. doi: 10.4103/abr.abr_169_21. eCollection 2022.

ABSTRACT

Ataxia-telangiectasia (AT) is a type of primary immunodeficiency characterized by an autosomal recessive mode of inheritance and usually presents with progressive cerebellar ataxia in early life. This complex disease is associated with humoral and cellular immune dysfunction and other features including characteristic oculocutaneous telangiectasia and increased predisposition to cancers, particularly lymphoma and leukemia. An 11-year-old Iranian girl presented with primary immunodeficiency and was diagnosed as having AT according to her clinical manifestations and molecular findings. She had a history of two types of non-Hodgkin’s lymphoma and showed spontaneous regression of her diffuse large B-cell lymphoma without any specific treatment. Gene mutations and dysfunction in patients with AT result in different manifestations including abnormal development of the thymus, immunodeficiency, increased susceptibility to malignancies, and increased radiosensitivity. No standard treatment is available for these patients. The use of immunotherapeutic strategies in patients with primary immune deficiency disease-associated tumors is potentially important.

PMID:35720220 | PMC:PMC9201233 | DOI:10.4103/abr.abr_169_21