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.

The characterization of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral kinetics in hospitalized patients and its association with mortality is unknown. We analyzed death and nasopharyngeal viral kinetics in 655 hospitalized patients from the prospective French COVID cohort. The model predicted a median peak viral load that coincided with symptom onset. Patients with age ≥65 y had a smaller loss rate of infected cells, leading to a delayed median time to viral clearance occurring 16 d after symptom onset as compared to 13 d in younger patients (P < 10−4). In multivariate analysis, the risk factors associated with mortality were age ≥65 y, male gender, and presence of chronic pulmonary disease (hazard ratio [HR] > 2.0). Using a joint model, viral dynamics after hospital admission was an independent predictor of mortality (HR = 1.31, P < 10−3). Finally, we used our model to simulate the effects of effective pharmacological interventions on time to viral clearance and mortality. A treatment able to reduce viral production by 90% upon hospital admission would shorten the time to viral clearance by 2.0 and 2.9 d in patients of age <65 y and ≥65 y, respectively. Assuming that the association between viral dynamics and mortality would remain similar to that observed in our population, this could translate into a reduction of mortality from 19 to 14% in patients of age ≥65 y with risk factors. Our results show that viral dynamics is associated with mortality in hospitalized patients. Strategies aiming to reduce viral load could have an effect on mortality rate in this population.

Objectives Persistent COVID-19 symptoms have been reported up to 3 months after hospital discharge. Little is known on the frequency and the nature of persistent symptoms beyond 3 months. Here we have assessed, in the longitudinal prospective French COVID-19 cohort, symptoms that persisted 6 months after admission for COVID-19. Methods Hospitalized patients with virologically confirmed COVID-19 were enrolled. Follow-up was planned with a physician's visit at month (M)3 and M6 after admission. Associations between persistence of symptoms at M6 and clinical characteristics at admission were assessed through bivariate and multivariate logistic regression. Results M6 data were available for 1137 participants. Median age was 61 years (IQR 51–71) and 288 (29%, 95% CI 26–32%) were admitted to intensive care unit (ICU) during the acute phase. Six hundred and fifty-five (68%, 95% CI 65–71%) and 639 (60%, 95% CI 57–63%) participants had at least one symptom at M3 and M6 visit, respectively, mostly fatigue, dyspnoea, joint pain and myalgia. At M6, 255 (24%, 95% CI 21–27%) of participants had three or more persistent symptoms. The presence of three or more symptoms at M6 was independently associated with female gender (adjusted odds ratio (aOR) 2.40, 95% CI 1.75–3.30), having three or more symptoms at admission (aOR 2.04, 95% CI 1.45–2.89) and ICU admission/transfer during acute phase (aOR 1.55, 95% CI 1.09–2.18), but not significantly with age or having two or more comorbidities. One hundred and twenty-five (29%, 95% CI 25–34%) of those who initially had a professional occupation were not back to work at M6. Discussion A fourth of individuals admitted to hospital for COVID-19 still had three or more persistent symptoms at M6. Longitudinal follow-up of individuals with severe COVID-19 is warranted to better understand the pathophysiology underlying this long-term persistence.