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
Background: Information is lacking regarding long-term survival and predictive factors for mortality in patients with acute hypoxemic respiratory failure due to coronavirus disease 2019 (COVID-19) and undergoing invasive mechanical ventilation. We aimed to estimate 90-day and 180-day survival of patients with COVID-19 requiring invasive ventilation and to develop a predictive model for intensive care unit mortality.Methods: Retrospective, multicentre, national cohort study between March 8 and April 30, 2020 in 16 intensive care units (ICU) in Spain. Participants were consecutive adults who received invasive mechanical ventilation for COVID–19. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection detected in positive testing of a nasopharyngeal sample and confirmed by real time reverse-transcriptase polymerase chain reaction (rt-PCR). The primary outcomes were 90-day and 180-day survival after hospital admission. Secondary outcomes were length of ICU and hospital stay, and ICU and in-hospital mortality. A predictive model and a nomogram were developed to estimate the probability of ICU mortality. Results: 868 patients were included (median age, 64 years [interquartile range [IQR], 56-71 years]; 72% male). Severity at ICU admission, estimated by SAPS3, was 56 points [IQR 50-63]. Prior to intubation, 26% received some type of noninvasive respiratory support. The 90-day and 180-day survival rates were 69% (95% confidence interval [CI] 66%-72%) and 59% (95% CI 56%-62%) respectively. The predictive factors associated with ICU mortality were: age (odds ratio [OR] 1.049 [95% CI 1.032-1.066] per 1-year increase), SAPS3 (OR 1.025 [95% CI 1.008-1.041] per 1-point increase), neutrophil to lymphocyte ratio (OR 1.009 [95% CI 1.002-1.016]), a failed attempt of noninvasive positive pressure ventilation previous to orotracheal intubation(OR 2.131 [95% CI 1.279-3.550]), and use of selective digestive decontamination (OR 0.587 [95% CI 0.358-0.963]).Conclusion: The long-term survival of mechanically ventilated patients with severe COVID-19 reaches more than 50% and may help to provide individualized risk stratification and potential treatments.Trial registration: ClinicalTrials.gov Identifier: NCT04379258. Registered 10 April 2020 (retrospectively registered).
Subject(s)
COVID-19ABSTRACT
Background: Bacterial and fungal co-infection has been reported in patients with COVID-19, but there is limited experience on these infections in critically ill patients.Aim: To assess the characteristics and outcome of ICU-acquired infections in COVID-19 patients.Methods: In this retrospective single-centre, case-control study, we included 140 patients with severe COVID-19 admitted to the ICU between March and May 2020. We evaluated the epidemiological, clinical and microbiological features, and outcome of ICU-acquired infections.Results: Fifty seven patients (40.7%), developed a bacterial or fungal nosocomial infection during ICU stay. Infection occurred after a median of 9 days (IQR 5-11) of admission, and was significantly associated with the APACHE II score (p=0.02). There were 91 episodes of infection: primary (31%) and catheter-related (25%) bloodstream infections were the most frequent, followed by pneumonia (23%), tracheobronchitis (10%) and urinary tract infection (8%), that were produced by a wide spectrum of Gram positive (55%) and Gram negative bacteria (30%) as well as fungi (15%). In 60% of cases, infection was associated with septic shock, and a significant increase in SOFA score. Overall ICU mortality was 36% (51/140). Infection was significantly associated with death (OR 2.7, 95% CI 1.2-5.9, p=0.015), and a longer ICU stay (p<0.001).Conclusions: Bacterial and fungal nosocomial infection is a common complication of ICU admission in patients with COVID-19. It usually presents as a severe form of infection and it is associated with a high mortality and longer course of ICU stay.
Subject(s)
Shock, Septic , Urinary Tract Infections , Mycoses , Pneumonia , Critical Illness , Death , COVID-19 , Community-Acquired InfectionsABSTRACT
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.