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.

Purpose of the studyThe aim of this study was to investigate the relationship of B cell-mediated immunity with disease severity and mortality in patients with COVID-19.Study designIn this retrospective cohort and single-centre study, 208 patients with laboratory-confirmed COVID-19 were recruited. A COVID-19 severity score, ranging from 0 to 10, was used to evaluate associations between various factors. Serum immunoglobulin levels and the number of cells in B lymphocyte subsets were measured and their association with disease severity and mortality in patients with COVID-19 examined.ResultsThe median age of the patients was 50 (35–63) years and 88 (42%) were female. The number of deceased patients was 17. The median COVID-19 severity score was 8 (6–8) in deceased patients and 1 (0–2) in survivors. Deceased patients had significantly lower levels of total B lymphocytes, naive B cells, switched memory B cells, and serum IgA, IgG, IgG1 and IgG2 than recovered patients (all p<0.05). In addition, a significant negative correlation was found between the number of these parameters and COVID-19 severity scores. Decrease in the number of total B cells and switched memory B cells as well as lower serum IgA, IgG and IgG1 levels were independent risk factors for mortality in patients with COVID-19.ConclusionIn the present study, the prognosis of patients with COVID-19 was shown to be associated with the B cell subset and serum immunoglobulin levels.

The prevalence and mortality rates of coronavirus disease 2019 (COVID-19) vary widely among populations. Mucosal immunity is the first barrier to pathogens' entry into the body.Immunoglobulin A (IgA) is the main antibody of mucosal immunity. We explored the relationship between selective immunoglobulin A deficiency (SIgAD) and the severity of COVID-19. We included 424 patients (203 females) with COVID-19. Eleven patients had SIgAD. Laboratory data on patients with SIgAD and normal IgA levels were compared. The relationship between SIgAD and severe COVID-19 infection was explored by logistic regression analysis. In univariate logistic regression analysis, the risk of severe disease in COVID-19 patients with SIgAD was approximately 7.7-fold higher than in the other patients (odds ratio [OR], 7.789; 95% confidence interval [CI], 1.665-36.690, p = 0.008), while it was 4-fold (OR, 4.053; 95% CI, 1.182-13.903, p = 0.026) higher in multivariate logistic regression analysis. Serum IgA levels were positively correlated with total lymphocyte counts, and negatively correlated with C-reactive protein (CRP) levels, which were found as a risk factor for severe COVID-19.In SIgAD patients, the number of SARS-CoV-2 viruses that pass through mucosal membranes may be increased, leading to complications such as cytokine storm syndrome and acute respiratory distress syndrome.

No abstract