Manish Butte

Pediatr Rheumatol Online J. 2023 Jul 20;21(1):73. doi: 10.1186/s12969-023-00846-3.

ABSTRACT

BACKGROUND: Immunization with meningococcal ACWY conjugate vaccine induces protective antibodies against invasive meningococcal disease (IMD) caused by serogroups A, C, W and Y. We studied MenACWY-TT vaccine immunogenicity in adolescents with a heterogenous group of primary and secondary immune deficiency including patients with systemic lupus erythematosus, mixed connective tissue disease, vasculitis, uveitis, 22Q11 syndrome, sickle cell disease, and patients who underwent stem cell transplantation for bone marrow failure.

FINDINGS: We enrolled 69 individuals aged 14-18 years diagnosed with a primary or secondary immune deficiency in a prospective observational cohort study. All patients received a single dose of MenACWY-TT vaccine during the catch-up campaign 2018-19 because of the IMD-W outbreak in the Netherlands. Capsular polysaccharide-specific (PS) IgG concentrations against MenACWY were measured before and 3-6, 12, and 24 months after vaccination. Overall, geometric mean concentrations (GMCs) of MenACWY-PS-specific IgG were lower in patients compared to data from healthy, aged-matched controls (n = 75) reaching significance at 12 months postvaccination for serogroup A and W (adjusted GMC ratios 0.26 [95% CI: 0.15-0.47] and 0.22 [95% CI: 0.10-0.49], respectively). No serious adverse events were reported by study participants.

CONCLUSIONS: The MenACWY conjugate vaccine was less immunogenic in adolescent patients with primary or secondary immunodeficiency compared to healthy controls, urging the need for further surveillance of these patients and supporting considerations for booster MenACWY conjugate vaccinations in these patient groups.

PMID:37475057 | DOI:10.1186/s12969-023-00846-3

Pediatr Rheumatol Online J. 2023 Jul 20;21(1):71. doi: 10.1186/s12969-023-00859-y.

ABSTRACT

BACKGROUND: Primary immunodeficiencies are immunological disorders caused by gene mutations involved in immune system development and activation. Recently, activated phosphoinositide 3-kinase delta syndrome (APDS) due to mutations in the phosphoinositide 3-kinase (PI3K), phosphatidylinositol-4, 5-bisphosphate 3-kinase, catalytic subunit delta gene (PIK3CD), and phosphoinositide 3-kinase regulatory subunit 1 (PIK3R1) genes have been reported to induce a combined immunodeficiency syndrome leading to senescent T cells, lymphadenopathy, and immunodeficiency. The exact diagnosis of these deficiencies is essential for treatment and prognosis. In recent years, targeted treatment with selective PI3Kd inhibitors has had a significant effect on controlling the symptoms of these patients.

CASE PRESENTATION: In this case report, we represent a 27-month-old girl with recurrent fever, an increased level of inflammatory markers, and erythema nodosum, who was referred to the rheumatology clinic. In the course of evaluations, because of the lack of clinical improvement with usual treatments, and a history of frequent respiratory infections, combined immunodeficiency was diagnosed in the immunological investigations. Moreover, whole-exome sequencing was performed for her.

CONCLUSION: The genetic analysis found a novel variant of PIK3CD (c.1429 G > A) in the patient. Following daily antibiotic prophylaxis and monthly IV therapy, the patient’s frequent infections and fevers were controlled.

PMID:37475052 | DOI:10.1186/s12969-023-00859-y

Indian J Pediatr. 2023 Jul 20. doi: 10.1007/s12098-023-04750-2. Online ahead of print.

ABSTRACT

Major Histocompatibility Complex (MHC) Class II deficiency is a rare autosomal recessive primary immunodeficiency caused by mutations in regulatory genes of MHC Class II proteins. Clinical manifestations include respiratory/gastrointestinal infections, failure-to-thrive, septicemia and early death. A 9-mo-old-girl presented with repeated episodes of pneumonia requiring hospitalization and ventilator support since the last 5 mo. Examination revealed absent tonsils, sparse scalp-hair, seborrhea and firm hepato-splenomegaly. Radiograph showed absence of thymic shadow with diffuse pulmonary infiltrates. CT scan showed multiple bilateral ground glass pulmonary opacities with patchy consolidation. Primary immunodeficiency disorder was suspected in view of repeated pulmonary infections, failure to thrive and suggestive family history. Lymphocyte subset assay revealed lymphocytopenia and HLA typing showed absence of HLA-DR expression on B cells suggestive of MHC Class II deficiency. Targeted gene panel detected a homozygous mutation in the RFX-5 gene (RFX5: c.848_849del:p.R283Tfs*6;Homozygous). Though this patient succumbed, parents have been counseled regarding need for prenatal diagnosis.

PMID:37470959 | DOI:10.1007/s12098-023-04750-2

Afr J Paediatr Surg. 2023 Jul-Sep;20(3):218-223. doi: 10.4103/ajps.ajps_15_22.

ABSTRACT

BACKGROUND: Pyogenic liver abscess (LA) is a significant contributor to morbidity and mortality in developing countries like India. The risk factors predisposing to the LA specifically in children are not known. Studies done in the past largely remain inconclusive and have identified only probable causes. The cause of LA in children with no coexisting illness remains unknown.

METHODOLOGY: This prospective observational study was conducted at a tertiary teaching hospital located in New Delhi, India. All children between 2 months and 12 years of age with sonographically confirmed LA presenting to the hospital were included and managed with appropriate intravenous antibiotics and relevant investigations.

RESULTS: A total of 52 children were included. The mean age was 6 years and 4 months, and the male: female ratio was 1.4:1. Around 50% of the patients were malnourished. Fever, abdominal pain and loss of appetite were the most common symptoms. Nine patients (17%) were managed conservatively, 13 (25%) needed percutaneous needle aspiration and 30 (57.69%) required drainage using a pigtail catheter. Poor socioeconomic status and anaemia were found to be the most commonly associated risk factors. Selective immunoglobulin A (IgA) deficiency was the most common primary immunodeficiency disorder followed by T-cell defect. On multivariate analysis, it was seen that in those with clinical icterus, gamma-glutamyl transferases >350 IU/m, and those with impending rupture, the time to defervescence was significantly different (P = 0.05).

CONCLUSION: Poor socioeconomic status causing malnutrition emerged as a significant risk factor for LA in children. Selective IgA deficiency was the most common immunodeficiency seen in a few children. Adopting a conservative approach like aspiration and percutaneous drainage led to lower mortality and good recovery rates.

PMID:37470559 | DOI:10.4103/ajps.ajps_15_22

Pediatr Dermatol. 2023 Jul 19. doi: 10.1111/pde.15397. Online ahead of print.

ABSTRACT

Treatment of severe eczema in patients with primary immunodeficiencies can be particularly challenging as there are no guidelines with regards to these conditions. Dupilumab is an interleukin (IL)-4Rα antagonist that inhibits both IL-4 and IL-13 and is approved for the treatment of atopic dermatitis in pediatric patients. In this report, we describe a patient with a case of severe eczema in the context of Wiskott-Aldrich syndrome-related disorder, who was successfully treated with dupilumab.

PMID:37469225 | DOI:10.1111/pde.15397

J Med Case Rep. 2023 Jul 18;17(1):307. doi: 10.1186/s13256-023-04049-y.

ABSTRACT

BACKGROUND: X-linked severe combined immunodeficiency is caused by IL2RG gene mutation. Several variations have been identified in the IL2RG gene, which potentially can prevent the production of nonfunctional proteins. Herein, a novel X-linked variant in the IL2RG gene is reported in twin brothers, associated with inflammatory bowel symptoms.

CASE PRESENTATION: The patients were 26-month-old monozygotic twin middle-eastern males with failure to thrive and several inpatient admissions due to severe chronic nonbloody diarrhea that started at the age of 12 months. Pancolitis was revealed after performing upper and lower gastrointestinal endoscopies on the twin with more severe gastrointestinal symptoms. Flow cytometric evaluation of the peripheral blood cells showed low levels of CD4+ cells in both patients. Next generation sequencing-based gene panel test results of the two patients proved a novel heterozygous missense X-linked IL2RG mutation (70330011 A > G, p.Trp197Arg) in one of the patients, which was predicted to be deleterious (CADD score of 28), which soon after was confirmed by Sanger segregation in his twin brother. Both parents were wild types and had never experienced similar symptoms. The patients received an human leukocyte antigen (HLA)-matched cord blood transplant. The twin with more severe gastrointestinal symptoms died 1 month after transplantation. In his brother, watery diarrhea eventually subsided after transplantation.

CONCLUSION: Intestinal involvement in X-linked severe combined immunodeficiency is a rare presentation that might be neglected. The increasing availability of genetic screening tests worldwide could be helpful for early detection of such lethal primary immunodeficiency diseases and in implementing effective interventions to handle the severe outcomes.

PMID:37461086 | DOI:10.1186/s13256-023-04049-y

J Allergy Clin Immunol. 2023 Jul 15:S0091-6749(23)00889-8. doi: 10.1016/j.jaci.2023.06.024. Online ahead of print.

ABSTRACT

BACKGROUND: Autoimmune diseases are leading causes of ill health and morbidity and have diverse etiology. Two signaling pathways are key drivers of autoimmune pathology, interferon and NFκB/RelA, defining the two broad labels of interferonopathies and relopathies. Prior work established that genetic loss of function of the NFκB subunit RelB leads to autoimmune and inflammatory pathology in mice and humans.

OBJECTIVE: We sought to characterize RelB-deficient autoimmunity by unbiased profiling of the stimulus-responses of immune sentinel cells, and to determine the functional role of dysregulated gene programs in the RelB-deficient pathology.

METHODS: Transcriptomic profiling was performed on fibroblasts and dendritic cells derived from RelB-deficient patients and knockout mice, and transcriptomic responses and pathology were assessed in mice deficient in both RelB and the type I interferon receptor.

RESULTS: We found that loss of RelB in patient-derived fibroblasts and mouse myeloid cells results in elevated induction of hundreds of interferon-stimulated genes. Removing hyper-expression of the interferon stimulated gene program did not ameliorate the autoimmune pathology of RelB knockout mice. Instead, we found that RelB suppresses a different set of inflammatory response genes in a manner that is independent of interferon signaling but associated with NFκB binding motifs.

CONCLUSION: While transcriptomic profiling would describe RelB-deficient autoimmune disease as an interferonopathy, the genetic evidence indicates that the pathology in mice is interferon-independent.

PMID:37460023 | DOI:10.1016/j.jaci.2023.06.024

PeerJ. 2023 Jul 12;11:e15659. doi: 10.7717/peerj.15659. eCollection 2023.

ABSTRACT

PURPOSE: This research aimed to ascertain the neuroprotective effect of histone deacetylase (HDAC) inhibition on retinal photoreceptors in Pde6b^rd1 mice, a model of retinitis pigmentosa (RP).

METHODS: Single-cell RNA-sequencing (scRNA-seq) explored HDAC and poly (ADP-ribose) polymerase (PARP)-related gene expression in both Pde6b-mutant rd1 and wild-type (WT) mice. The CUT&Tag method was employed to examine the functions of HDAC in rd1 mice. Organotypic retinal explant cultures from WT and rd1 mice were exposed to the HDAC inhibitor SAHA (suberoylanilide hydroxamic acid) postnatally, from day 5 to day 11. The terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL) assay was applied to quantify the percentage of photoreceptor loss in the outer nuclear layer (ONL). HDAC activity was confirmed to be inhibited by SAHA through an HDAC activity assay. Moreover, the study evaluated PARP activity, a key driver of the initial response to DNA damage during photoreceptor degeneration, following HDAC inhibition.

RESULTS: The scRNA-seq revealed that diverse roles of HDAC and PARP isoforms in photoreceptor cell death. HDAC-related genes appeared to regulate cell death and primary immunodeficiency. Alterations in HDAC activity were consistent with the TUNEL-positive cells in the ONL at different time points. Notably, SAHA significantly postponed photoreceptor loss and decreased HDAC and PARP activity, thereby implicating both in the same degenerative pathway.

CONCLUSIONS: This study highlights that the interaction between HDAC inhibition and PARP can delay photoreceptor cell death, proposing a promising therapeutic approach for RP.

PMID:37456870 | PMC:PMC10349563 | DOI:10.7717/peerj.15659

Front Genet. 2023 Jun 29;14:1152768. doi: 10.3389/fgene.2023.1152768. eCollection 2023.

ABSTRACT

Rare variants affecting host defense against pathogens may be involved in COVID-19 severity, but most rare variants are not expected to have a major impact on the course of COVID-19. We hypothesized that the accumulation of weak effects of many rare functional variants throughout the exome may contribute to the overall risk in patients with severe disease. This assumption is consistent with the omnigenic model of the relationship between genetic and phenotypic variation in complex traits, according to which association signals tend to spread across most of the genome through gene regulatory networks from genes outside the major pathways to disease-related genes. We performed whole-exome sequencing and compared the burden of rare variants in 57 patients with severe and 29 patients with mild/moderate COVID-19. At the whole-exome level, we observed an excess of rare, predominantly high-impact (HI) variants in the group with severe COVID-19. Restriction to genes intolerant to HI or damaging missense variants increased enrichment for these classes of variants. Among various sets of genes, an increased signal of rare HI variants was demonstrated predominantly for primary immunodeficiency genes and the entire set of genes associated with immune diseases, as well as for genes associated with respiratory diseases. We advocate taking the ideas of the omnigenic model into account in COVID-19 studies.

PMID:37456666 | PMC:PMC10339319 | DOI:10.3389/fgene.2023.1152768

J Clin Immunol. 2023 Jul 14. doi: 10.1007/s10875-023-01549-w. Online ahead of print.

ABSTRACT

A significant complication of HSCT is graft failure, although few studies focus on this problem in patients with inborn errors of immunity (IE). We explored outcome of second HSCT for IEI by a retrospective, single-centre study between 2002 and 2022. Four hundred ninety-three patients underwent allogeneic HSCT for severe combined immunodeficiency (SCID; n = 113, 22.9%) or non-SCID IEI (n = 380, 77.1%). Thirty patients (6.0%) required second HSCT. Unconditioned infusion or no serotherapy at first HSCT was more common in patients who required second transplant. Median interval between first and second HSCT was 0.97 years (range: 0.19-8.60 years); a different donor was selected for second HSCT in 24/30 (80.0%) patients. Conditioning regimens for second HSCT were predominately treosulfan-based (with thiotepa: n = 18, 60.0%; without, n = 6, 20.0%). Patients received grafts from peripheral blood stem cell (n = 25, 83.3%) or bone marrow (n = 5, 16.7%) with median stem cell dose 9.5 × 10⁶ CD34 + cells/kilogram (range: 1.4-32.3). Median follow-up was 1.92 years (0.22-16.0). Overall survival was 80.8% and event-free survival was 64.7%. Four patients died, two of early-transplant related complications, and two of late sepsis post-second HSCT. Three patients required third HSCT; all are alive with 100% donor chimerism. Cumulative incidence of acute graft-versus-host disease was 28.4%, (all grade I-II). Viral reactivation was seen in 13/30 (43.3%) patients, including HHV6 (n = 6), CMV (n = 4), and adenovirus (n = 2). At latest follow-up, 25/26 surviving patients have donor chimerism ≥ 90% and 16/25 (64.0%) have discontinued immunoglobulin replacement. Second HSCT offers IEI patients with graft failure curative treatment with good overall survival and immunological recovery.

PMID:37452206 | DOI:10.1007/s10875-023-01549-w