Viral and Host Factors Are Associated With Mortality in Hospitalized Patients With COVID-19
Neil R. Aggarwal, Jacquie Nordwall, Dominique L. Braun, Lucy Chung, Jordan Coslet, Tatyana Der, Nnakelu Eriobu, Adit A. Ginde, Awori J. Hayanga, Helene Highbarger, Mark Holodniy, Juan Pablo Horcajada, Mamta K. Jain, Kami Kim, Sylvain Laverdure, Jens Lundgren, Ven Natarajan, Hien Nguyen, Sarah Pett, Andrew Phillips, Garyphallia Poulakou, David Price, Philip A. Robinson, Angela J Rogers, Uriel Sandkovsky, Katy Shaw-Saliba, Jeffrey M. Sturek, Barbara W. Trautner, Michael R. Waters, Cavan Reilly, for the ACTIV-3/TICO Study Group, David Sahner, John Tierney, Susan Vogel, Betsey Herpin, Mary Smolskis, Laura A McKay, Kelly Cahill, Page Crew, Ratna Sardana, Sharon Segal Raim, Lisa Hensely, J. Ponce Lorenzo, Rebecca Mock, Judith Zuckerman, Negin Atri, Mark D. Miller, David Vallée, Lucy Chung, Nayon Kang, Kevin Barrett, Stacey J. Adam, Sarah Read, Ruxandra Draghia‐Akli, Judy Currier, Eric Hughes, Rachel H. Harrigan, Laura Amos, Amy Carlsen, Anita Carter, Gary Collins, Bionca Davis, Eileen Denning, Alain DuChêne, Kate Eckroth, Nicole Engen, Alex Frase, Greg Gandits, Birgit Grund, Merrie Harrison, Nancy Hurlbut, Payton Kaiser, Joseph S. Koopmeiners, Gregg Larson, Sue Meger, Shweta Sharma Mistry, Thomas A. Murray, Ray Nelson, Kien Quan, Siu Fun Quan, Cavan Reilly, Lianne Siegel, Greg Thompson, David M. Vock, Jamie Walski, Annetine C. Gelijns, Alan J. Moskowitz, Emilia Bagiella, Ellen Moquete, Karen O'Sullivan, Mary E. Marks, Evan Accardi, Emily Kinzel, Sarah Burris, Gabriela Bedoya, Lola Gupta, Jessica Overbey, Milerva Santos, Marc A. Gillinov, Marissa A. Miller
Abstract
BACKGROUND: Persistent mortality in adults hospitalized due to acute COVID-19 justifies pursuit of disease mechanisms and potential therapies. The aim was to evaluate which virus and host response factors were associated with mortality risk among participants in Therapeutics for Inpatients with COVID-19 (TICO/ACTIV-3) trials. METHODS: A secondary analysis of 2625 adults hospitalized for acute SARS-CoV-2 infection randomized to 1 of 5 antiviral products or matched placebo in 114 centers on 4 continents. Uniform, site-level collection of participant baseline clinical variables was performed. Research laboratories assayed baseline upper respiratory swabs for SARS-CoV-2 viral RNA and plasma for anti-SARS-CoV-2 antibodies, SARS-CoV-2 nucleocapsid antigen (viral Ag), and interleukin-6 (IL-6). Associations between factors and time to mortality by 90 days were assessed using univariate and multivariable Cox proportional hazards models. RESULTS: Viral Ag ≥4500 ng/L (vs <200 ng/L; adjusted hazard ratio [aHR], 2.07; 1.29-3.34), viral RNA (<35 000 copies/mL [aHR, 2.42; 1.09-5.34], ≥35 000 copies/mL [aHR, 2.84; 1.29-6.28], vs below detection), respiratory support (<4 L O2 [aHR, 1.84; 1.06-3.22]; ≥4 L O2 [aHR, 4.41; 2.63-7.39], or noninvasive ventilation/high-flow nasal cannula [aHR, 11.30; 6.46-19.75] vs no oxygen), renal impairment (aHR, 1.77; 1.29-2.42), and IL-6 >5.8 ng/L (aHR, 2.54 [1.74-3.70] vs ≤5.8 ng/L) were significantly associated with mortality risk in final adjusted analyses. Viral Ag, viral RNA, and IL-6 were not measured in real-time. CONCLUSIONS: Baseline virus-specific, clinical, and biological variables are strongly associated with mortality risk within 90 days, revealing potential pathogen and host-response therapeutic targets for acute COVID-19 disease.