SARS-CoV-2 viremia is associated with distinct proteomic pathways and predicts COVID-19 outcomes

Li, Yijia; Schneider, Alexis M; Mehta, Arnav; Sade-Feldman, Moshe; Kays, Kyle R; Gentili, Matteo; Charland, Nicole C; Gonye, Anna Lk; Gushterova, Irena; Khanna, Hargun K; LaSalle, Thomas J; Lavin-Parsons, Kendall M; Lilley, Brendan M; Lodenstein, Carl L; Manakongtreecheep, Kasidet; Margolin, Justin D; McKaig, Brenna N; Parry, Blair A; Rojas-Lopez, Maricarmen; Russo, Brian C; Sharma, Nihaarika; Tantivit, Jessica; Thomas, Molly F; Regan, James; Flynn, James P; Villani, Alexandra-Chloé; Hacohen, Nir; Goldberg, Marcia B; Filbin, Michael R; Li, Jonathan Z

BACKGROUNDSARS-CoV-2 plasma viremia has been associated with severe disease and death in COVID-19 in small-scale cohort studies. The mechanisms behind this association remain elusive.METHODSWe evaluated the relationship between SARS-CoV-2 viremia, disease outcome, and inflammatory and proteomic profiles in a cohort of COVID-19 emergency department participants. SARS-CoV-2 viral load was measured using a quantitative reverse transcription PCR-based platform. Proteomic data were generated with Proximity Extension Assay using the Olink platform.RESULTSThis study included 300 participants with nucleic acid test-confirmed COVID-19. Plasma SARS-CoV-2 viremia levels at the time of presentation predicted adverse disease outcomes, with an adjusted OR of 10.6 (95% CI 4.4-25.5, P < 0.001) for severe disease (mechanical ventilation and/or 28-day mortality) and 3.9 (95% CI 1.5-10.1, P = 0.006) for 28-day mortality. Proteomic analyses revealed prominent proteomic pathways associated with SARS-CoV-2 viremia, including upregulation of SARS-CoV-2 entry factors (ACE2, CTSL, FURIN), heightened markers of tissue damage to the lungs, gastrointestinal tract, and endothelium/vasculature, and alterations in coagulation pathways.CONCLUSIONThese results highlight the cascade of vascular and tissue damage associated with SARS-CoV-2 plasma viremia that underlies its ability to predict COVID-19 disease outcomes.FUNDINGMark and Lisa Schwartz; the National Institutes of Health (U19AI082630); the American Lung Association; the Executive Committee on Research at Massachusetts General Hospital; the Chan Zuckerberg Initiative; Arthur, Sandra, and Sarah Irving for the David P. Ryan, MD, Endowed Chair in Cancer Research; an EMBO Long-Term Fellowship (ALTF 486-2018); a Cancer Research Institute/Bristol Myers Squibb Fellowship (CRI2993); the Harvard Catalyst/Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, NIH awards UL1TR001102 and UL1TR002541-01); and by the Harvard University Center for AIDS Research (National Institute of Allergy and Infectious Diseases, 5P30AI060354).