Multi-omic Profiling Reveals Early Immunological Indicators for Identifying COVID-19 Progressors

The pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to a rapid response by the scientific community to further understand and combat its associated pathologic etiology. A focal point has been on the immune responses mounted during the acute and post-acute phases of infection, but the immediate post-diagnosis phase remains relatively understudied. We sought to better understand the immediate post-diagnosis phase by collecting blood from study participants soon after a positive test and identifying molecular associations with longitudinal disease outcomes. Multi-omic analyses identified differences in immune cell composition, cytokine levels, and cell subset-specific transcriptomic and epigenomic signatures between individuals on a more serious disease trajectory (Progressors) as compared to those on a milder course (Non-progressors). Higher levels of multiple cytokines were observed in Progressors, with IL-6 showing the largest difference. Blood monocyte cell subsets were also skewed, showing a comparative decrease in non-classical CD14−CD16+ and intermediate CD14+CD16+ monocytes. Additionally, in the lymphocyte compartment, CD8+ T effector memory cells displayed a gene expression signature consistent with stronger T cell activation in Progressors. Importantly, the identification of these cellular and molecular immune changes occurred at the early stages of COVID-19 disease. These observations could serve as the basis for the development of prognostic biomarkers of disease risk and interventional strategies to improve the management of severe COVID-19. One Sentence Summary Immunological changes associated with COVID-19 progression can be detected during the early stages of infection. ### Competing Interest Statement DT, SV, VK, VT, MVL are employed by Janssen Research & Development, LLC. KAD, GT, JTL, SK, JML, BY, MJW, SAS, PK, KMF, CCK, CC maintain equity ownership and employment at Verily Life Sciences LLC, an Alphabet subsidiary. KAD, GT, JTL, SK, JML, BY, CCK are inventors listed on U.S. Application No. 63/496,918. SP receives fees from Jazz Pharmaceuticals, Inc. and UpToDate, Inc., and funding from Philips, Inc., Sommetrics, Inc., Regeneron, Inc., and SaiOx, Inc. CRD serves on advisory boards for Abbott Diagnostics, Ortho/Quidel Diagnostics, and Roche Diagnostics. JAK receives funding from Regeneron and fees from GlaxoSmithKline, AstraZeneca, CereVu Medical, Propeller/ResMed, BData, Inc.