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.

Background Coronavirus disease 2019 (COVID-19) is a respiratory disease associated with endotheliitis and microthrombosis. Objectives To correlate endothelial dysfunction to in-hospital mortality in a bi-centric cohort of COVID-19 adult patients. Methods Consecutive ambulatory and hospitalized patients with laboratory-confirmed COVID-19 were enrolled. A panel of endothelial biomarkers and von Willebrand factor (VWF) multimers were measured in each patient ≤ 48 h following admission.Results Study enrolled 208 COVID-19 patients of whom 23 were mild outpatients and 189 patients hospitalized after admission. Most of endothelial biomarkers tested were found increased in the 89 critical patients transferred to intensive care unit. However, only von Willebrand factor antigen (VWF:Ag) scaled according to clinical severity, with levels significantly higher in critical patients (median 507%, IQR 428-596) compared to non-critical patients (288%, 230-350, p < 0.0001) or COVID-19 outpatients (144%, 133-198, p = 0.007). Moreover, VWF high molecular weight multimers (HMWM) were significantly higher in critical patients (median ratio 1.18, IQR 0.86-1.09) compared to non-critical patients (0.96, 1.04-1.39, p < 0.001). Among all endothelial biomarkers measured, ROC curve analysis identified a VWF:Ag cut-off of 423% as the best predictor for in-hospital mortality. The accuracy of VWF:Ag was further confirmed in a Kaplan-Meier estimator analysis and a Cox proportional Hazard model adjusted on age, BMI, C-reactive protein and d-dimer levels. Conclusion VWF:Ag is a relevant predictive factor for in-hospital mortality in COVID-19 patients. More than a biomarker, we hypothesize that VWF, including excess of HMWM forms, drives microthrombosis in COVID-19.

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 Coronavirus disease 2019 (COVID‐19) is a respiratory disease associated with vascular inflammation and endothelial injury. Objectives To correlate circulating angiogenic markers vascular endothelial growth factor A (VEGF‐A), placental growth factor (PlGF), and fibroblast growth factor 2 (FGF‐2) to in‐hospital mortality in COVID‐19 adult patients. Methods Consecutive ambulatory and hospitalized patients with COVID‐19 infection were enrolled. VEGF‐A, PlGF, and FGF‐2 were measured in each patient ≤48 h following admission. Results The study enrolled 237 patients with suspected COVID‐19: 208 patients had a positive diagnostic for COVID‐19, of whom 23 were mild outpatients and 185 patients hospitalized after admission. Levels of VEGF‐A, PlGF, and FGF‐2 significantly increase with the severity of the disease (P < .001). Using a logistic regression model, we found a significant association between the increase of FGF‐2 or PlGF and mortality (odds ratio [OR] 1.11, 95% confidence interval [CI; 1.07–1.16], P < .001 for FGF‐2 and OR 1.07 95% CI [1.04–1.10], P < .001 for PlGF) while no association were found for VEGF‐A levels. Receiver operating characteristic curve analysis was performed and we identified PlGF above 30 pg/ml as the best predictor of in‐hospital mortality in COVID‐19 patients. Survival analysis for PlGF confirmed its interest for in‐hospital mortality prediction, by using a Kaplan‐Meier survival curve (P = .001) and a Cox proportional hazard model adjusted to age, body mass index, D‐dimer, and C‐reactive protein (3.23 95% CI [1.29–8.11], P = .001). Conclusion Angiogenic factor PlGF is a relevant predictive factor for in‐hospital mortality in COVID‐19 patients. More than a biomarker, we hypothesize that PlGF blocking strategies could be a new interesting therapeutic approach in COVID‐19.

Background: Coronavirus disease 2019 (COVID-19) has been associated with coagulation disorders, in particular high concentrations of D-dimers, and increased frequency of venous thromboembolism. Aim: To explore the association between D-dimers at admission and in-hospital mortality in patients hospitalized for COVID-19, with or without symptomatic venous thromboembolism. Methods: From 26 February to 20 April 2020, D-dimer concentration at admission and outcomes (in-hospital mortality or venous thromboembolism) of patients hospitalized for COVID-19 in medical wards were analysed retrospectively in a multicentre study in 24 French hospitals. Results: Among 2878 patients enrolled in the study, 1154 (40.1%) patients had D-dimer measurement at admission. Receiver operating characteristic curve analysis identified a D-dimer concentration > 1128 ng/mL as the optimum cut-off value for in-hospital mortality (area under the curve 64.9%, 95% confidence interval [CI] 0.60–0.69), with a sensitivity of 71.1% (95% CI 0.62–0.78) and a specificity of 55.6% (95% CI 0.52–0.58), which did not differ in the subgroup of patients with venous thromboembolism during hospitalization. Among 545 (47.2%) patients with D-dimer concentration > 1128 ng/mL at admission, 86 (15.8%) deaths occurred during hospitalization. After adjustment, in Cox proportional hazards and logistic regression models, D-dimer concentration > 1128 ng/mL at admission was also associated with a worse prognosis, with an odds ratio of 3.07 (95% CI 2.05–4.69; P < 0.001) and an adjusted hazard ratio of 2.11 (95% CI 1.31–3.4; P < 0.01). Conclusions: D-dimer concentration > 1128 ng/mL is a relevant predictive factor for in-hospital mortality in patients hospitalized for COVID-19 in a medical ward, regardless of the occurrence of venous thromboembolism during hospitalization.

Background: Coronavirus disease 2019 (COVID-19) has been associated with cardiovascular complications and coagulation disorders.Objectives: To explore clinical and biological parameters of COVID-19 patients with hospitalization criteria that could predict referral to intensive care unit (ICU).Methods: Analyzing the clinical and biological profiles of COVID-19 patients at admission.Results: Among 99 consecutive patients that fulfilled criteria for hospitalization, 48 were hospitalized in the medicine department, 21 were first admitted to the medicine ward department and referred later to ICU, and 30 were directly admitted to ICU from the emergency department. At admission, patients requiring ICU were more likely to have lymphopenia, decreased SpO2, a D-dimer level above 1,000 ng/mL, and a higher high-sensitivity cardiac troponin (Hs-cTnI) level. A receiver operating characteristic curve analysis identified Hs-cTnI above 9.75 pg/mL as the best predictive criteria for ICU referral [area under the curve (AUC), 86.4; 95% CI, 76.6–96.2]. This cutoff for Hs-cTnI was confirmed in univariate [odds ratio (OR), 22.8; 95% CI, 6.0–116.2] and multivariate analysis after adjustment for D-dimer level (adjusted OR, 20.85; 95% CI, 4.76–128.4). Transthoracic echocardiography parameters subsequently measured in 72 patients showed an increased right ventricular (RV) afterload correlated with Hs-cTnI (r = 0.42, p = 0.010) and D-dimer (r = 0.18, p = 0.047).Conclusion: Hs-cTnI appears to be the best relevant predictive factor for referring COVID-19 patients to ICU. This result associated with the correlation of D-dimer with RV dilatation probably reflects a myocardial injury due to an increased RV wall tension. This reinforces the hypothesis of a COVID-19-associated microvascular thrombosis inducing a higher RV afterload.

Objective The clinical relevance of antiphospholipid antibodies (aPLs) in COVID‐19 is controversial. This study was undertaken to investigate the prevalence and prognostic value of conventional and nonconventional aPLs in patients with COVID‐19. Methods This was a multicenter, prospective observational study in a French cohort of patients hospitalized with suspected COVID‐19. Results Two hundred forty‐nine patients were hospitalized with suspected COVID‐19, in whom COVID‐19 was confirmed in 154 and not confirmed in 95. We found a significant increase in lupus anticoagulant (LAC) positivity among patients with COVID‐19 compared to patients without COVID‐19 (60.9% versus 23.7%; P < 0.001), while prevalence of conventional aPLs (IgG and IgM anti–β2‐glycoprotein I and IgG and IgM anticardiolipin isotypes) and nonconventional aPLs (IgA isotype of anticardiolipin, IgA isotype of anti‐β2‐glycoprotein I, IgG and IgM isotypes of anti–phosphatidylserine/prothrombin, and IgG and IgM isotypes of antiprothrombin) was low in both groups. Patients with COVID‐19 who were positive for LAC, as compared to patients with COVID‐19 who were negative for LAC, had higher levels of fibrinogen (median 6.0 gm/liter [interquartile range 5.0–7.0] versus 5.3 gm/liter [interquartile range 4.3–6.4]; P = 0.028) and C‐reactive protein (CRP) (median 115.5 mg/liter [interquartile range 66.0–204.8] versus 91.8 mg/liter [interquartile range 27.0–155.1]; P = 0.019). Univariate analysis did not show any association between LAC positivity and higher risks of venous thromboembolism (VTE) (odds ratio 1.02 [95% confidence interval 0.44–2.43], P = 0.95) or in‐hospital mortality (odds ratio 1.80 [95% confidence interval 0.70–5.05], P = 0.24). With and without adjustment for CRP level, age, and sex, Kaplan‐Meier survival curves according to LAC positivity confirmed the absence of an association with VTE or in‐hospital mortality (unadjusted P = 0.64 and P = 0.26, respectively; adjusted hazard ratio 1.13 [95% confidence interval 0.48–2.60] and 1.80 [95% confidence interval 0.67–5.01], respectively). Conclusion Patients with COVID‐19 have an increased prevalence of LAC positivity associated with biologic markers of inflammation. However, LAC positivity at the time of hospital admission is not associated with VTE risk and/or in‐hospital mortality.