Plasma proteomics of SARS-CoV-2 infection and severity reveals impact on Alzheimer and coronary disease pathways (preprint)

Identification of the plasma proteomic changes of Coronavirus disease 2019 (COVID-19) is essential to understanding the pathophysiology of the disease and developing predictive models and novel therapeutics. We performed plasma deep proteomic profiling from 332 COVID-19 patients and 150 controls and pursued replication in an independent cohort (297 cases and 76 controls) to find potential biomarkers and causal proteins for three COVID-19 outcomes (infection, ventilation, and death). We identified and replicated 1,449 proteins associated with any of the three outcomes (841 for infection, 833 for ventilation, and 253 for death) that can be query on a web portal (https://covid.proteomics.wustl.edu/). Using those proteins and machine learning approached we created and validated specific prediction models for ventilation (AUC>0.91), death (AUC>0.95) and either outcome (AUC>0.80). These proteins were also enriched in specific biological processes, including immune and cytokine signaling (FDR < 3.72x10-14), Alzheimer's disease (FDR < 5.46x10-10) and coronary artery disease (FDR < 4.64x10-2). Mendelian randomization using pQTL as instrumental variants nominated BCAT2 and GOLM1 as a causal proteins for COVID-19. Causal gene network analyses identified 141 highly connected key proteins, of which 35 have known drug targets with FDA-approved compounds. Our findings provide distinctive prognostic biomarkers for two severe COVID-19 outcomes (ventilation and death), reveal their relationship to Alzheimer's disease and coronary artery disease, and identify potential therapeutic targets for COVID-19 outcomes.

The impact of environmental mycobiomes on geographic variation in COVID-19 mortality (preprint)

Mortality rates during the COVID-19 pandemic have varied by orders of magnitude across communities in the United States. Individual, socioeconomic, and environmental factors have been linked to health outcomes of COVID-19. It is now widely appreciated that the environmental microbiome, composed of microbial communities associated with soil, water, atmosphere, and the built environment, impacts immune system development and susceptibility to immune-mediated disease. The human microbiome has been linked to individual COVID-19 disease outcomes, but there are limited data on the influence of the environmental microbiome on geographic variation in COVID-19 across populations. To fill this knowledge gap, we used taxonomic profiles of fungal communities associated with 1,135 homes in 494 counties from across the United States in a machine learning analysis to predict COVID-19 Infection Fatality Ratios (the number of deaths caused by COVID-19 per 1000 SARS-CoV-2 infections; 'IFR'). Here we show that exposure to increased fungal diversity, and in particular indoor exposure to outdoor fungi, is associated with reduced SARS-CoV-2 IFR. Further, we identify seven fungal genera that are the predominant drivers of this protective signal and may play a role in suppressing COVID-19 mortality. This relationship is strongest in counties where human populations have remained stable over at least the previous decade, consistent with the importance of early-life microbial exposures. We also assessed the explanatory power of 754 other environmental and socioeconomic factors, and found that indoor-outdoor fungal beta-diversity is amongst the strongest predictors of county-level IFR, on par with the most important known COVID-19 risk factors, including age. We anticipate that our study will be a starting point for further integration of environmental mycobiome data with population health information, providing an important missing link in our capacity to identify vulnerable populations. Ultimately, our identification of specific genera predicted to be protective against COVID-19 mortality may point toward novel, proactive therapeutic approaches to infectious disease.

Early initiation of prophylactic anticoagulation for prevention of COVID-19 mortality: a nationwide cohort study of hospitalized patients in the United States (preprint)

ImportanceDeaths among patients with coronavirus disease 2019 (COVID-19) are partially attributed to venous thromboembolism and arterial thromboses. Anticoagulants prevent thrombosis formation, possess anti-inflammatory and anti-viral properties, and may be particularly effective for treating patients with COVID-19. ObjectiveTo evaluate whether initiation of prophylactic anticoagulation within 24 hours of admission is associated with decreased risk of death among patients hospitalized with COVID-19. DesignObservational cohort study. SettingNationwide cohort of patients receiving care in the Department of Veterans Affairs, the largest integrated healthcare system in the United States. ParticipantsAll patients hospitalized with laboratory-confirmed SARS-CoV-2 infection March 1 to July 31, 2020, without a history of therapeutic anticoagulation. ExposuresProphylactic doses of subcutaneous heparin, low-molecular-weight heparin, or direct oral anticoagulants. Main Outcomes and Measures30-day mortality. Secondary outcomes: inpatient mortality and initiating therapeutic anticoagulation. ResultsOf 4,297 patients hospitalized with COVID-19, 3,627 (84.4%) received prophylactic anticoagulation within 24 hours of admission. More than 99% (n=3,600) received subcutaneous heparin or enoxaparin. We observed 622 deaths within 30 days of admission, 513 among those who received prophylactic anticoagulation. Most deaths (510/622, 82%) occurred during hospitalization. In inverse probability of treatment weighted analyses, cumulative adjusted incidence of mortality at 30 days was 14.3% (95% CI 13.1-15.5) among those receiving prophylactic anticoagulation and 18.7% (95% CI 15.1-22.9) among those who did not. Compared to patients who did not receive prophylactic anticoagulation, those who did had a 27% decreased risk for 30-day mortality (HR 0.73, 95% CI 0.66-0.81). Similar associations were found for inpatient mortality and initiating therapeutic anticoagulation. Quantitative bias analysis demonstrated that results were robust to unmeasured confounding (e-value lower 95% CI 1.77). Results persisted in a number of sensitivity analyses. Conclusions and RelevanceEarly initiation of prophylactic anticoagulation among patients hospitalized with COVID-19 was associated with a decreased risk of mortality. These findings provide strong real-world evidence to support guidelines recommending the use of prophylactic anticoagulation as initial therapy for COVID-19 patients upon hospital admission.