Chronic Viral Reactivation and Associated Host Immune Response and Clinical Outcomes in Acute COVID-19 and Post-Acute Sequelae of COVID-19
Authors: Maguire Cole , Chen Jing , Rouphael Nadine , Pickering Harry , Phan Hoang Van , Glascock Abigail , Chu Victoria , Dandekar Ravi , Corry David , Kheradmand Farrah , Baden Lindsey R. , Selaky Rafick , McComsey Grace A. , Haddad Elias K. , Cairns Charles B. , Pulendran Bali , Sesma Ana Fernandez- , Simon Viviana , Metcalf Jordan P. , Agudelo Higuita Nelson I , Messer William B. , David Mark M. , Nadeau Kari C. , Kraft Monica , Bime Chris , Schaenman Joanna , Erle David , Calfee Carolyn S. , Atkinson Mark A. , Brackenridge Scott C. , Ehrlich Lauren I. R. , Montgomery Ruth R. , Shaw Albert C. , Hough Catherine L. , Geng Linda N , Hafler David A. , Augustine Alison D. , Becker Patrice M. , Peters Bjoern , Ozonoff Al , Kim-Schulze Seunghee Hee , Krammer Florian , Bosinger Steve , Eckalbar Walter , Altman Matthew C. , Wilson Michael , Guan Leying , Kleinstein Steven H. ,   IMPACC Network, Smolen Kinga K. , Reed Elaine F. , Levy Ofer , Maecker Holden , Hunt Peter , Steen Hanno , Diray-Arce Joann , Langelier Charles R. , Melamed Esther 
Published: November 2024

Chronic viral infections are ubiquitous in humans, with individuals harboring multiple latent viruses that can reactivate during acute illnesses. Recent studies have suggested that SARS- CoV-2 infection can lead to reactivation of latent viruses such as Epstein-Barr Virus (EBV) and cytomegalovirus (CMV), yet, the extent and impact of viral reactivation in COVID-19 and its effect on the host immune system remain incompletely understood.

Here we present a comprehensive multi-omic analysis of viral reactivation of all known chronically infecting viruses in 1,154 hospitalized COVID-19 patients, from the Immunophenotyping Assessment in a COVID-19 Cohort (IMPACC) study, who were followed prospectively for twelve months. We reveal significant reactivation ofHerpesviridae,Enteroviridae, andAnelloviridaefamilies during acute stage of COVID-19 (0-40 days post- hospitalization), each exhibiting distinct temporal dynamics. We also show that viral reactivation correlated with COVID-19 severity, demographic characteristics, and clinical outcomes, including mortality. Integration of cytokine profiling, cellular immunophenotyping, metabolomics, transcriptomics, and proteomics demonstrated virus-specific host responses, including elevated pro-inflammatory cytokines (e.g. IL-6, CXCL10, and TNF), increased activated CD4+ and CD8+ T-cells, and upregulation of cellular replication genes, independent of COVID-19 severity and SARS-CoV-2 viral load. Notably, persistentAnelloviridaereactivation during convalescence (≥3 months post-hospitalization) was associated with Post-Acute Sequelae of COVID-19 (PASC) symptoms, particularly physical function and fatigue.

Our findings highlight a remarkable prevalence and potential impact of chronic viral reactivation on host responses and clinical outcomes during acute COVID-19 and long term PASC sequelae. Our data provide novel immune, transcriptomic, and metabolomic biomarkers of viral reactivation that may inform novel approaches to prognosticate, prevent, or treat acute COVID- 19 and PASC.