ABSTRACT
Due to the highly variable clinical phenotype of Coronavirus disease 2019 (COVID-19), deepening the host genetic contribution to severe COVID-19 may further improve our understanding about underlying disease mechanisms. Here, we describe an extended GWAS meta-analysis of 3,260 COVID-19 patients with respiratory failure and 12,483 population controls from Italy, Spain, Norway and Germany, as well as hypothesis-driven targeted analysis of the human leukocyte antigen (HLA) region and chromosome Y haplotypes. We include detailed stratified analyses based on age, sex and disease severity. In addition to already established risk loci, our data identify and replicate two genome-wide significant loci at 17q21.31 and 19q13.33 associated with severe COVID-19 with respiratory failure. These associations implicate a highly pleiotropic ~0.9-Mb 17q21.31 inversion polymorphism, which affects lung function and immune and blood cell counts, and the NAPSA gene, involved in lung surfactant protein production, in COVID-19 pathogenesis.
Subject(s)
COVID-19 , Respiratory InsufficiencyABSTRACT
Health care workers (HCW) are at an increased risk since they are directly exposed to SARS-CoV-2 infected patients, nevertheless, some remained without the development of anti-SARS-CoV-2 antibodies, suggesting lesser susceptibility to infection1-5. This study aimed to ascertain a potential specific cellular immune response to SARS-CoV-2 in these largely exposed HCWs.In this cross-sectional, case-control study, we analyzed 39 exposed uninfected HCWs and 17 convalescent HCWs. Cellular immune response was evaluated after SARS-CoV-2 stimulation with peptide pools (proteins S, M, and N), using bead-based multiplex assay (12 cytokines).Overall, 94.8% of uninfected HCWs had some degree of specific cellular response to SARS-CoV-2 structural proteins that could be classified, according to the number of cytokine production, as strong (61.5%), partial (33.3%), and weak/no response (5.1%). Strong responders showed a higher anti-inflammatory cytokine production (IL5 and IL10, p<0.001 and 0.002, respectively), and similar (IFN-γ and TNF-α, p=0.435 and 0.532, respectively) or higher (IL12, p=0.021) pro-inflammatory production compared to convalescents, resulted in a predominantly Th2 response. This study demonstrated a consistent and polyfunctional immune cellular response after stimulation with SARS-CoV-2 peptides in extensively exposed individuals that should be considered to establish the infection susceptibility, the impact in herd immunity, and the risk of relapses.
Subject(s)
Severe Acute Respiratory Syndrome , COVID-19ABSTRACT
Background. Respiratory failure is a key feature of severe Covid-19 and a critical driver of mortality, but for reasons poorly defined affects less than 10% of SARS-CoV-2 infected patients. Methods. We included 1,980 patients with Covid-19 respiratory failure at seven centers in the Italian and Spanish epicenters of the SARS-CoV-2 pandemic in Europe (Milan, Monza, Madrid, San Sebastian and Barcelona) for a genome-wide association analysis. After quality control and exclusion of population outliers, 835 patients and 1,255 population-derived controls from Italy, and 775 patients and 950 controls from Spain were included in the final analysis. In total we analyzed 8,582,968 single-nucleotide polymorphisms (SNPs) and conducted a meta-analysis of both case-control panels. Results. We detected cross-replicating associations with rs11385942 at chromosome 3p21.31 and rs657152 at 9q34, which were genome-wide significant (P<5x10-8) in the meta-analysis of both study panels, odds ratio [OR], 1.77; 95% confidence interval [CI], 1.48 to 2.11; P=1.14x10-10 and OR 1.32 (95% CI, 1.20 to 1.47; P=4.95x10-8), respectively. Among six genes at 3p21.31, SLC6A20 encodes a known interaction partner with angiotensin converting enzyme 2 (ACE2). The association signal at 9q34 was located at the ABO blood group locus and a blood-group-specific analysis showed higher risk for A-positive individuals (OR=1.45, 95% CI, 1.20 to 1.75, P=1.48x10-4) and a protective effect for blood group O (OR=0.65, 95% CI, 0.53 to 0.79, P=1.06x10-5). Conclusions. We herein report the first robust genetic susceptibility loci for the development of respiratory failure in Covid-19. Identified variants may help guide targeted exploration of severe Covid-19 pathophysiology.
Subject(s)
Severe Acute Respiratory Syndrome , COVID-19 , Respiratory InsufficiencyABSTRACT
Background: Information about incidence, clinical characteristics and outcomes of HIV-infected individuals with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is scarce. We characterized individuals with coronavirus disease 2019 (COVID-19) among a cohort of HIV-infected adults regularly followed-up at an HIV clinic in Madrid, Spain, one of the most affected cities worldwide.Methods: In this observational study, we included all consecutive HIV-infected individuals who were diagnosed of suspected or confirmed COVID-19 as of April 14, 2020. Demographic, clinical, treatment, and laboratory data, including HIV-specific information, were extracted from the electronic health records. We compared the characteristics of HIV-infected individuals with COVID-19 with a representative sample of HIV-infected individuals evaluated before the COVID-19 pandemic (n=1,302), and described the evolution and outcomes of individuals with COVID-19 according to baseline characteristics.Findings: Thirty-seven HIV-infected individuals (mean, 53·5 years; females, 16%) were diagnosed with COVID-19 (incidence, 1·3%, 95% confidence interval: 0·9-1·8%). Of them, 29 (78%) were laboratory confirmed cases, and 26 (70%) required hospitalization. Overall, 29 (78%) individuals had comorbidities, predominantly hypertension and diabetes, higher than that observed among HIV-infected individuals without COVID-19 ( P =0·006). Additionally, a significantly higher percentage of individuals with COVID-19 were receiving tenofovir prior to COVID-19 diagnosis compared to HIV-infected individuals without COVID-19 (70% versus 52%, P =0·030), and the rate of prior protease inhibitor use was similar in both groups (mostly darunavir, 19% versus 18%, P =0·830). Clinical, analytical and radiological presentation of COVID-19 in HIV-infected individuals was similar to that described in the general population: five (14%) were critically-ill, and two (5%) died. Two out of five critically ill individuals had CD4+ counts <200 cells/mm3.Interpretation: Our findings indicate that COVID-19 predominantly affects HIV-infected individuals with comorbidities. These data do not suggest a protective effect of CD4+ count or previous antiretroviral therapy on the rate of infection or outcomes.Funding Statement: None.Declaration of Interests: MJPE has received research grants or honoraria for lectures or for participation in advisory boards from Abbott, Bristol-Myers Squibb, Boehringer Ingelheim, Gilead Sciences, ViiV-Healthcare previously GlaxoSmithKline, Roche, and Janssen; and unrestricted grants from Abbott, ViiVHealthcare previously GlaxoSmithKline, Gilead Sciences and Janssen. For the remaining authors, none was declared.Ethics Approval Statement: The study protocol was approved by our Institutional Review Board (EC 110/20), and patients provided oral informed consent in order to minimize staff exposure.