Circulating endothelial signatures correlate with worse outcomes in COVID-19, respiratory failure and ARDS.
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Costa Monteiro Ana C, Pickering Harry, Sarma Aartik, Taylor Clove S, Jenkins Meagan M, Hsu Fei-Man, Nadel Brian, Levy Ofer, Baden Lindsey R, Melamed Esther, Ehrlich Lauren I R, McComsey Grace A, Sekaly Rafick P, Cairns Charles B, Haddad Elias K, Shaw Albert C, Hafler David A, Montgomery Ruth R, Corry David B, Kheradmand Farrah, Atkinson Mark A, Brakenridge Scott C, Higuita Nelson I Agudelo, Metcalf Jordan P, Hough Catherine L, Messer William B, Pulendran Bali, Nadeau Kari C, Davis Mark M, Geng Linda N, Fernandez-Sesma Ana, Simon Viviana, Krammer Florian, Kraft Monica, Bime Chris, Calfee Carolyn S, Erle David J, Bosinger Steve, Eckalbar Walter, Maecker Holden, Rahman Adeeb, Guan Leying, Peters Bjoern, Kleinstein Steven H, Augustine Alison D, Diray-Arce Joann, Becker Patrice M, Rouphael Nadine, IMPACC Network, CAFPINT Site investigators of the PALISI Network, Agus Michael, Kulkarni Hrishikesh, Schaenmann Joanna M, Salehi-Rad Ramin, Matthay Michael A, Reed Elaine F, Sapru Anil
Аннотация
METHODS: To test whether elevated endothelial cell signatures (ECS) in circulation plays a role in worse respiratory outcomes, we used unsupervised bulk-transcriptome deconvolution to quantify ECS% in two cohorts. Our pilot analysis included pediatric patients requiring invasive mechanical ventilation (CAF-PINT, NCT01892969). Our validation cohort included adult hospitalized patients with COVID-19 (IMPACC, NCT04378777), testing the association of ECS% to outcomes in patients at risk of acute respiratory failure/ARDS. Primary outcome was 28-day mortality.
RESULTS: In CAF-PINT, day 0 ECS% was higher in non-survivors compared to survivors of respiratory failure (2.8%, IQR 2.4-3.4% versus 2.6%, IQR 2.2-3.0% n = 244, p < 0.05, Wilcoxon rank-sum). In IMPACC, baseline ECS% (< 72 h of hospitalization) was higher in COVID-19 non-survivors versus survivors (2.9%, IQR 2.6-3.4%, versus 2.7%, IQR 2.3-3.1%, n = 932, p < 0.001, Wilcoxon rank-sum). Each 1% increase in baseline ECS% was significantly associated with mortality (adjusted OR 1.36, CI 1.03-1.79) by multivariable logistic regression. Increased baseline ECS% was associated with worse respiratory trajectories (2.5%, IQR 2.2-2.8% for trajectory with no oxygen requirements, 2.9%, IQR 2.6-3.4% for the trajectory with fatal outcome by day 28, n = 932, p < 0.001, one-way ANOVA).
CONCLUSION: Quantifying ECS by deconvolution supports a transcriptomics-driven approach towards the non-invasive evaluation of endothelial damage in respiratory outcomes. This is a first step towards elucidating mechanistic components linking endothelial damage to ARDS utilizing non-invasive, circulating transcriptomic data by leveraging a novel deconvolution approach.