Interindividual clinical variability in the course of SARS-CoV-2 infection is immense. We report that at least 101 of 987 patients with life-threatening COVID-19 pneumonia had neutralizing IgG auto-Abs against IFN-ω (13 patients), the 13 types of IFN-α (36), or both (52), at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1,227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 were men. A B cell auto-immune phenocopy of inborn errors of type I IFN immunity underlies life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men.

Clinical outcome upon infection with SARS-CoV-2 ranges from silent infection to lethal COVID-19. We have found an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern TLR3- and IRF7-dependent type I interferon (IFN) immunity to influenza virus, in 659 patients with life-threatening COVID-19 pneumonia, relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally define LOF variants in 23 patients (3.5%), aged 17 to 77 years, underlying autosomal recessive or dominant deficiencies. We show that human fibroblasts with mutations affecting this pathway are vulnerable to SARS-CoV-2. Inborn errors of TLR3- and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection.

Significance There is growing evidence that preexisting autoantibodies neutralizing type I interferons (IFNs) are strong determinants of life-threatening COVID-19 pneumonia. It is important to estimate their quantitative impact on COVID-19 mortality upon SARS-CoV-2 infection, by age and sex, as both the prevalence of these autoantibodies and the risk of COVID-19 death increase with age and are higher in men. Using an unvaccinated sample of 1,261 deceased patients and 34,159 individuals from the general population, we found that autoantibodies against type I IFNs strongly increased the SARS-CoV-2 infection fatality rate at all ages, in both men and women. Autoantibodies against type I IFNs are strong and common predictors of life-threatening COVID-19. Testing for these autoantibodies should be considered in the general population.

Background Susceptibility of children and adults to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and persistence of antibody response to the virus after infection resolution remain poorly understood, despite their significant public health implications. Methods A cross-sectional seroprevalence study with prospective recruitment of volunteer families that included at least one first-reported adult case positive by SARS-CoV-2 PCR and at least one child aged less than 15 years living in the same household under strict home confinement was conducted in the Health Region of metropolitan Barcelona (Spain) during the pandemic period April 28-June 3, 2020. All household members were tested at home by a rapid SARS-CoV-2 antibody assay in finger-prick obtained capillary blood. Results A total of 381 family households including 381 first-reported PCR-positive adult cases and 1,084 contacts (672 children, 412 adults) were enrolled. SARS-CoV-2 infection seroprevalence rates were 17.6% (118/672) in children and 18.7% (77/335) in adult contacts (p=0.64). Among first-reported cases, seropositivity rates varied from 84.0% in adults previously hospitalized and tested within 6 weeks since the first positive PCR result to 31.5% in those not hospitalized and tested after that lag time (p<0.001). Nearly all (99.9%) positive pediatric contacts were asymptomatic or had mild symptoms. Conclusion Children appear to have similar probability as adults to become infected by SARS-CoV-2 in quarantined family households but remain largely asymptomatic once infected. Adult antibody protection against SARS-CoV-2 seems to be weak at early convalescence and beyond 6 weeks post-infection confirmation, especially in cases that have experienced mild disease.

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