Chronically infecting viruses — such as Epstein Barr, cytomegalovirus (CMV), and herpes virus — are common, and often innocuous and asymptomatic. However, emerging evidence suggests their reactivation may contribute to autoimmune disease and other chronic conditions. In a new Nature study involving 15 biomedical research institutions across the United States, Boston Children's Hospital researchers and their collaborators have discovered that COVID-19 reactivates certain dormant viruses in hospitalized patients. These findings expand understanding of chronically infecting viruses and could inform development of strategies to combat their reactivation.
Physician scientist Ofer Levy, MD, PhD , director of the Precision Vaccines Program (PVP) at Boston Children's, served as a site principal investigator for this National Institutes of Health (NIH)-funded study of 1,154 patients across 20 U.S. biomedical research hospitals that was designed to define biomarkers of COVID severity and outcomes. The research team used genomic sequencing to look for reactivated viruses in the patients since long-cleared viral infections can sometimes reawaken in times of stress.
"This is the largest and most comprehensive biomarker study of COVID-19, in which we followed more than one thousand patients, collected more than 200,000 samples, and generated more than 1 billion data points over the course of a year for this public resource," says Joann Diray Arce, PhD , who leads the PVP-Data Management and Analysis Core and is the lead of the study's Clinical and Data Coordinating Center.
The research team detected 11 reactivated viruses in patients within the first 40 days from admission, with the most detected ones being Epstein-Barr, herpes simplex 1, cytomegalovirus, and Anelloviridae viruses. Notably, reactivation of Anelloviridae, a poorly understood family of viruses typically latent in about 90 percent of the population, was associated prominently with long-term physical disability and long COVID.
"This association with long COVID is an interesting finding as millions around the world suffer from this chronic condition," says Levy. "Having new insight as to the molecular and viral associations with long COVID could point the way to better understanding and ultimately better diagnostics and treatments."
In an analysis of the blood samples from the patients, Epstein-Barr and cytomegalovirus seemed to activate in response to inflammation rather than immune system suppression. The researchers say this is a surprising new mechanism, challenging the prevailing view that chronic viral reactivation is primarily a consequence of immunosuppression. This finding demonstrates that reactivations occur frequently in apparently immunocompetent individuals during severe illness and in association with increased systemic inflammation.
"Although many no longer think of COVID being a problem, up to 50,000 Americans died of COVID in 2025-2026 respiratory season and some estimates suggest over 10 million U.S. adults suffer from long COVID," says Levy. "We need to help these patients recover with the best outcomes." He adds "Moreover, sooner or later, there may be another coronavirus pandemic, which means we need to learn all the lessons we can from COVID-19 to be better prepared."
Next steps for this work will be to uncover how the immune system responds to these viruses over the course COVID-19, with the aim of identifying effective therapeutics and establishing the optimal timing of any interventions.
Other Boston Children's researchers on the study include Jing Chen , PhD, Annmarie Hoch, Al Ozonoff , PhD, Kinga Smolen, PhD, and Hanno Steen, PhD.
