Cole Maguire, Jing Chen, Nadine Rouphael, Brinkley Morse, Annmarie Hoch, Harry Pickering, Hoang Van Phan, Abigail Glascock, Victoria Chu, Ravi Dandekar, IMPACC Network, Steven M. Holland, Lindsey B. Rosen, Serena Lee, Tatyana Vaysman, Joann Diray-Arce, Jing Chen, Alvin T. Kho, Carly E. Milliren, Ana C. Chang, Kerry McEnaney, Caitlin Syphurs, Brenda Barton, Claudia Lentucci, Maimouna D. Murphy, Mehmet Saluvan, Tanzia Shaheen, Shanshan Liu, Albert Marisa, Arash Nemati Hayati, Robert Bryant, JAMES ABRAHAM, Mitchell Cooney, Meagan Karoly, Naresh Doni Jayavelu, Scott Presnell, Bernard Kohr, Tomasz Jancsyk, Azlann Arnett, James A. Overton, Randi Vita, Kerstin Westendorf, James A. Overton, Ofer Levy, Hanno Steen, Patrick van Zalm, Benoit Fatou, Kinga K. Smolen, Arthur Viodé, Simon van Haren, Meenakshi Jha, David Stevenson, Athena N. Nguyen, Alec L. Plotkin, Sanya Thomas, Boryana Petrova, Naama Kanarek, Kevin Mendez, Jessica Lasky-Su, Alexandra Tong, Rebecca Rooks, Michael Desjardins, Amy C. Sherman, Stephen R. Walsh, Xhoi Mitre, Jessica Cauley, Xiaofang Li, Bethany Evans, Christina Montesano, Jose Humberto Licona, Jonathan Krauss, Nicholas C Issa, Jun Bai Park Chang, Natalie Izaguirre, Scott R. Hutton, Greg Michelotti, Kari Wong, Scott J. Tebbutt, Casey P. Shannon, Slim Fourati, Paul Harris, Scott Sieg, George Yendewa, Mary Consolo, Heather Tribout, Susan Pereira Ribeiro, Michele A. Kutzler, Mariana Bernui, Gina Cusimano, Jennifer Connors, Kyra Woloszczuk, David Joyner, Carolyn Edwards, Edward Lee, Edward Lin, Nataliya Melnyk, Debra L. Powell, James N. Kim, I. Michael Goonewardene, Brent Simmons
. Here, leveraging multi-omic longitudinal data from 1,154 hospitalized patients with COVID-19 from the Immunophenotyping Assessment in a COVID-19 Cohort (IMPACC) study, we reveal significant reactivation of Herpesviridae and Anelloviridae during acute COVID-19, with distinct temporal dynamics for different viruses, and demonstrate that reactivation correlates with disease severity, host immune effects and clinical outcomes. Although our results do not establish causation between virus reactivation and clinical outcomes, we highlight the prevalence of chronic viral reactivation during acute COVID-19 and long COVID. Our findings challenge the prevailing view that chronic viral reactivation is primarily a consequence of immunosuppression, demonstrating that reactivations occur frequently in immunocompetent individuals during severe illness and in association with increased systemic inflammation. Additionally, we demonstrate persistence of viral reactivation in convalescence, and report an association of Anelloviridae with long COVID. This study provides immune, transcriptomic and metabolomic signatures of viral reactivation that could inform future strategies to prognosticate and treat acute COVID-19 and long COVID.