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
Global healthcare systems are challenged by the COVID-19 pandemic. There is a need to optimize allocation of treatment and resources in intensive care, as clinically established risk assessments such as SOFA and APACHE II scores show only limited performance for predicting the survival of severely ill COVID-19 patients. Comprehensively capturing the host physiology, we speculated that proteomics in combination with new data-driven analysis strategies could produce a new generation of prognostic discriminators. We studied two independent cohorts of patients with severe COVID-19 who required intensive care and invasive mechanical ventilation. SOFA score, Charlson comorbidity index and APACHE II score were poor predictors of survival. Plasma proteomics instead identified 14 proteins that showed concentration trajectories different between survivors and non-survivors. A proteomic predictor trained on single samples obtained at the first time point at maximum treatment level (i.e. WHO grade 7) and weeks before the outcome, achieved accurate classification of survivors in an exploratory (AUROC 0.81) as well as in the independent validation cohort (AUROC of 1.0). The majority of proteins with high relevance in the prediction model belong to the coagulation system and complement cascade. Our study demonstrates that predictors derived from plasma protein levels have the potential to substantially outperform current prognostic markers in intensive care.
Subject(s)
COVID-19 , Blood Coagulation Disorders, InheritedABSTRACT
Heterologous prime-boost vaccination is of increasing interest for COVID-19 vaccines. Evidence of rare thrombotic events associated with ChAdOx1-nCoV19 (Vaxzevria, ChAdOx) has lead several European countries to recommend a heterologous booster with mRNA vaccines for certain age groups (e.g. persons <60years in Germany), who have already received one dose of ChAdOx, although data on reactogenicity and safety of this vaccination regimen are still missing. Here we report reactogenicity data of homologous BNT162b2 (Comirnaty, BNT) or heterologous ChAdOx/BNT prime-boost immunisations in a prospective observational cohort study of 326 healthcare workers. Reactogenicity of heterologous ChAdOx/BNT booster vaccination was largely comparable to homologous BNT/BNT vaccination and overall well-tolerated. No major differences were observed in the frequency or severity of local reactions after either of the vaccinations. In contrast, notable differences between the regimens were observed for systemic reactions, which were most frequent after prime immunisation with ChAdOx (86%, 95CI: 79-91), and less frequent after homologous BNT/BNT (65%, 95CI: 56-72), or heterologous ChAdOx/BNT boosters (48%, 95CI: 36-59). This interim analysis supports the safety of currently recommended heterologous ChAdOx/BNT prime-boost immunisations with 12-week intervals.
Subject(s)
COVID-19 , ThrombosisABSTRACT
BackgroundAdequate patient allocation is pivotal for optimal resource management in strained healthcare systems, and requires detailed knowledge of clinical and virological disease trajectories. MethodsA cohort of 168 hospitalized adult COVID-19 patients enrolled in a prospective observational study at a large European tertiary care center was analyzed. ResultsForty-four percent (71/161) of patients required invasive mechanical ventilation (IMV). Shorter duration of symptoms before admission (aOR 1.22 per day less, 95%CI 1.10-1.37, p<0.01), age 60-69 as compared to 18-59 years (aOR 4.33, 95%CI 1.07-20.10, p=0.04), and history of hypertension (aOR 5.55, 95%CI 2.00-16.82, p<0.01) were associated with need for IMV. Patients on IMV had higher maximal concentrations, slower decline rates, and longer shedding of SARS-CoV-2 than non-IMV patients (33 days, IQR 26-46.75, vs 18 days, IQR 16-46.75, respectively, p<0.01). Median duration of hospitalization was 9 days (IQR 6-15.5) for non-IMV and 49.5 days (IQR 36.8-82.5) for IMV-patients. ConclusionOur results indicate a short duration of symptoms before admission as a risk factor for severe disease and different viral load kinetics in severely affected patients.