Abstract:
Chronic viral infections are ubiquitous in humans, with individuals carrying multiple viruses that can reactivate during physiological stress, including severe illness1. Notably, SARS-CoV-2 infection has been shown to reactivate chronic viruses such as Epstein-Barr virus and cytomegalovirus, yet the full extent, temporal dynamics and immunological impact of viral reactivation in COVID-19 remain incompletely understood2-7.
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.
Source: Maguire C, Chen J, Rouphael N, Morse BA, Hoch A, Pickering H, Phan HV, Glascock A, Chu V, Dandekar R; IMPACC Network; Corry D, Kheradmand F, Baden LR, Sekaly RP, McComsey GA, Haddad EK, Cairns CB, Pulendran B, Fernandez-Sesma A, Simon V, Metcalf JP, Agudelo Higuita NI, Messer WB, Davis MM, Nadeau KC, Kraft M, Bime C, Schaenman J, Erle D, Calfee CS, Atkinson MA, Brakenridge SC, Ehrlich LIR, Montgomery RR, Shaw A, Hough CL, Hafler D, Augustine AD, Becker PM, Peters B, Ozonoff A, Kim-Schulze S, Krammer F, Bosinger SE, Eckalbar W, Altman MC, Wilson M, Guan L, Kleinstein SH, Smolen KK, Reed EF, Levy O, Maecker H, Hunt P, Steen H, Diray-Arce J, Langelier CR, Melamed E. Virus reactivation in acute and long COVID-19. Nature. 2026 Aug;656(8128):700-711. doi: 10.1038/s41586-026-10740-z. Epub 2026 Aug 5. PMID: 42557313; PMCID: PMC13489964. https://pmc.ncbi.nlm.nih.gov/articles/PMC13489964/ (Full text)