IFIH1 loss-of-function predisposes to inflammatory and SARS-CoV-2-related infectious diseases (preprint)

The IFIH1 gene, encoding melanoma differentiation-associated protein 5 (MDA5), is an indispensable innate immune regulator involved in the early detection of viral infections. Previous studies described MDA5 dysregulation linking it to weakened immunological responses, and increased susceptibility to microbial infections and autoimmune disorders. Monoallelic gain-of-function of the IFIH1 gene has been associated with multisystem disorders, namely Aicardi-Goutieres and Singleton-Merten syndromes, while biallelic loss of this gene causes immunodeficiency. In this study, nine patients suffering from different cases of recurrent infections, inflammatory diseases, severe COVID-19, or multisystem inflammatory syndrome in children (MIS-C) were identified with putative loss-of-function IFIH1 variants by whole exome sequencing. All patients revealed signs of lymphopenia and an increase in inflammatory markers, including CRP, amyloid A, ferritin, and IL-6. One patient with a pathogenic homozygous variant c.2807+1G>A was the most severe case showing immunodeficiency and glomerulonephritis. The c.1641+1G>C variant was identified in the heterozygous state in patients suffering from periodic fever, COVID-19, or MIS-C, while the c.2016delA variant was identified in two patients with inflammatory bowel disease or MIS-C. Expression analysis showed that PBMCs of one patient with a c.2016delA variant had a significant decrease in ISG15, IFNA and IFNG transcript levels, compared to normal PBMCs, upon stimulation with poly(I:C), suggesting that MDA5 receptor truncation disrupts the immune response. Our findings accentuate the implication of rare monogenic IFIH1 loss-of-function variants in altering the immune response, and severely predisposing patients to inflammatory and infectious diseases, including SARS-CoV-2 related disorders.

Clinical and Epidemiological Features and Severity Markers in Children Admitted with Multisystem Inflammatory Syndrome in Children (MISC) in a Tertiary Care Center in UAE (preprint)

Background: Multisystem Inflammatory Syndrome in Children (MISC) is a phenomenon that appeared in children infected with or exposed to SARS-CoV-2. The typical onset of MISC is 4-6 weeks following SARS-CoV-2 infection and is formulated to be due to an immune response. Methods: : Our study retrospectively analyzed data from a tertiary center in UAE of MISC patients who were admitted to either general pediatric wards or pediatric intensive care (PICU) or who came exclusively for follow-up (post PICU admission) from May 2020 to August 2021.   Results: : The total sample size is 50 patients and the study included a comparison of PICU admissions with none PICU admissions. The PICU sample size was 18 patients, 50% females, with mean age of 8.3 years all were previously healthy. PICU patients had deranged blood counts with a lower hemoglobin count, a more pronounced lymphopenia and thrombocytopenia along with hypoalbuminemia. PICU patients presented with relatively higher inflammatory markers: CRP, PCT, ferritin and D-dimer. Immunological studies were significantly higher for IL-6 levels in PICU patients. On echocardiography, higher myocardial dysfunction was more notable in patients admitted to PICU. Children admitted in PICU were provided with more extensive therapy. As part of our study course, we re-evaluated our PICU patients twice, once at 48 hours post PICU admission and again 4-6 weeks after discharge from the hospital. No deaths have been recorded in the cohort. Conclusion: This study evaluated risk factors of MISC and potential severity features. Follow up of patients on discharge showed improvement across all domains.

Genomic and phenotypic characterization of Multisystem Inflammatory Syndrome in Children (MIS-C): a prospective multicenter study from the Middle East (preprint)

Importance: Clinical, genetic and laboratory characteristics of patients with multisystem inflammatory syndrome in children (MISC) in the Middle East have not yet been documented. Objective: To uncover rare genetic variants contributing to MISC in patients of primarily Arab and Asian origin. Design, Setting, and Participants: A prospective multicenter cohort study was conducted between September 2020 and August 2021 in the United Arab Emirates and Jordan. Forty-five patients meeting the case definition of MISC, and a matched control group of twenty-five healthy children with a confirmed severe acute respiratory syndrome coronavirus 2 (SARSCoV2) infection status, were recruited. Whole Exome Sequencing (WES) in all 70 participants was performed to identify rare likely deleterious variants in patients with MISC and to correlate genetic findings with the clinical course of illness. Exposures: SARSCoV2. Main Outcomes and Measures: Fever, organ system complications, laboratory biomarkers, WES findings, treatments, and clinical outcomes. Mann Whitney U test was used to assess the association between genetic variations and MISC attributes. Fishers exact test was used to compute the genetic burden in MISC relative to controls. Results: In 45 MISC patients (23 boys [51.1%]; average age, 7 years [range, 2-14 years]), key inflammatory markers were significantly dysregulated in all patients. Mucocutaneous and gastrointestinal manifestations were reported in 80% (95% CI 66% to 89%) while cardiac and neurological findings were reported in 49% (95% CI 35% to 63%) and 31% (95% CI 19.5% to 45.6%) of patients, respectively. Rare, likely deleterious heterozygous variants in immune related genes including TLR3, TLR6, IFNAR2, IL22RA2, IFNB1, and IFNA6, were identified in 19 patients (42.2%, 95% CI 29% to 56.7%), of whom seven had more than one variant. There was significant enrichment of genetic variants in patients relative to the control group (29 versus 3, P