Background Primary immunodeficiency diseases (PIDDs) are clinically and genetically heterogeneous disorders thus far associated with mutations in more than 300 genes. The clinical phenotypes derived from distinct genotypes may overlap. Genetic etiology can be a prognostic indicator of disease severity and can influence treatment decisions. Objective To investigate the ability of whole-exome screening methods to detect disease-causing variants in individuals with PIDDs. Methods Individuals with PIDDs from 278 families from 22 countries were investigated using whole-exome sequencing (WES). Computational CNV prediction pipelines and an exome-tiling chromosomal microarray were also applied to identify intragenic copy number variants (CNVs). Analytic approaches initially focused on 475 known or candidate PIDD genes, but were non-exclusive and were further tailored based upon clinical data, family history and immunophenotyping. Results A likely molecular diagnosis was achieved in 110 (40%) unrelated probands. Clinical diagnosis was revised in about half (60/110) and management was directly altered in nearly a quarter (26/110) of families based on the molecular findings. Twelve PIDD-causing CNVs were detected, including seven smaller than 30 Kb that would not have been detected with conventional diagnostic CNV arrays. Conclusion This high-throughput genomic approach enabled detection of disease-related variants in unexpected genes, permitted detection of low-grade constitutional, somatic and revertant mosaicism, and provided evidence of a mutational burden in mixed PIDD immunophenotypes.

Based on the known and emerging biology of autoimmune diseases and COVID‐19, it was hypothesised that whilst B‐cell depletion should not necessarily expose people to severe SARS‐CoV‐2‐related issues, it may inhibit or blunt the protective immunity following infection and vaccination. This is supported clinically, as the majority of SARS‐CoV‐2 infected, CD20‐depleted people with autoimmunity, have recovered. However, in CD‐20 treated people until naïve B‐cells repopulate, based on B‐cell repopulation‐kinetics and vaccination responses, from published rituximab, and unpublished ocrelizumab (NCT00676715, NCT02545868) trial data shown here suggests that it may be possible to undertake dose‐interruption to maintain inflammatory disease control, whilst allowing effective vaccination against SARS‐CoV‐29, if and when an effective vaccine is available.

Highlights1. What is already known about this topic? SARS-CoV-2 causes asymptomatic or mild infection in about 80% of humans, while an excessive immune response has killed millions. Differential susceptibility and risk factors became a concern early in the pandemic. Several monogenic defects that involve innate viral sensors or affect interferon response pathways, as well as autoantibodies against type 1 interferons, have been identified in 14% of patients with life-threatening COVID-19. The impact of the novel betacoronavirus infection in patients with known inborn errors of immunity is less clear. Case series and reports from different countries have suggested a minor impact or even a potential protective effect of the IEI for some patients.2. What does this article add to our knowledge? We describe findings and outcomes of COVID-19 in 31 pediatric and adult patients with known IEI from Mexico, 84% of whom survived. Pediatric patients had a higher hospitalization rate. Inpatient mortality was 40%, and ICU mortality was 63%. Six patients died of secondary bacterial infection or uncontrolled systemic inflammation, but not from overwhelming viral infection. One patient with an autoinflammatory disorder under treatment with anakinra had a catastrophic clinical course. Eighty percent of patients received IVIG as part of their treatment for acute SARS-CoV-2 infection.3. How does this study impact current management guidelines? We recommend continued and/or high-dose IVIG in patients with known IEI seeking care for COVID-19. Patients with autoinflammatory disorders, especially those with inflammasome dysregulation, should probably take extreme measures to prevent exposure, while doctors taking care of SARS-CoV-2 infected patients with immune deficiencies must do everything they can to prevent secondary bacterial infections. The high survival of patients with COVID-19 in the context of inborn errors of immunity worldwide (over 80%) might be the result of patientphysician awareness and special care.