Severe cases of COVID-19 can reawaken chronic, dormant viruses that lie hidden in the human body, even in individuals with otherwise healthy immune systems, according to a study published in Nature. Researchers found that nearly half of the hospitalized patients examined in the study experienced a reactivation of at least one latent virus during their illness, pointing to a previously underappreciated consequence of severe SARS-CoV-2 infections.
Severe COVID-19 Triggers Reactivation of Dormant Viruses
The observational analysis tracked 1,154 adult patients who had been hospitalized with COVID-19 across 20 hospitals in the United States between May 2020 and March 2021. All participants in the cohort were unvaccinated and had been infected before newer coronavirus variants became dominant. Investigators gathered biological samples—including blood, nasal swabs, and lung fluid samples from ventilated patients—at multiple time points during hospitalization and followed participants for up to 12 months afterward.
Evidence of at least one reactivated virus was detected in 550 of the 1,148 patients who had sufficient data, translating to 47.9% of the group. The reawakened pathogens included members of the herpesvirus family, such as Epstein-Barr virus, cytomegalovirus, herpes simplex virus, and anelloviruses. Most of those patients had only one additional virus detected during the acute stage of their illness.
Understanding the Pathogens and Temporal Dynamics
Most humans carry multiple generally harmless viruses that remain dormant in the body without causing symptoms because the immune system keeps them under control. However, physiological stress, serious illness, or hormonal imbalances can cause these hidden viruses to revive. In this study led by researchers at Dell Medical School at The University of Texas at Austin, scientists measured the RNA of actively replicating viruses rather than relying solely on antibody responses.
The research team observed that the reactivated viruses did not all wake up simultaneously. Epstein-Barr virus activity, for instance, was most commonly detected near the time patients were admitted to the hospital. RNA from 11 reactivated viruses was found within the first 40 days following hospital admission.
Researchers noted that viral reactivation was correlated with increased disease severity, heightened systemic inflammation, and poorer clinical outcomes. When limiting analysis to the most severely ill patients, those with cytomegalovirus detected in the respiratory tract or Epstein-Barr virus in the nasal cavity were more likely to die within one year. Furthermore, patients showing viral reactivation exhibited higher levels of inflammatory molecules and distinct changes in immune cells, indicating that the body was reacting to more than just the coronavirus.
Links to Long COVID and Physical Disability
After the acute phase of infection passed, a subset of patients developed debilitating symptoms associated with long COVID, including persistent fatigue and a reduced capacity to complete everyday tasks such as walking or dressing. The study revealed that a viral signal belonging to Anelloviridae—a lesser-known family of chronic viruses estimated to remain dormant in roughly 80% to 90% of the general population—appeared more frequently in patients suffering from long COVID and lasting physical disability.
Despite these correlations, study authors and collaborating experts cautioned that the observational work does not definitively prove that reactivated viruses directly cause severe illness or long COVID. Anna Cliffe, an associate professor of microbiology, immunology and cancer biology at the University of Virginia who was not involved in the research, described the project as one of the largest and most carefully conducted studies of its type, noting that the team successfully replicated their primary findings in a separate group of patient blood samples from a Mount Sinai biobank.
Broader Implications for Future Treatment Strategies
The research was conducted in collaboration with a national consortium, including investigators from more than 15 universities across the United States. The work was supported by the Immunophenotyping Assessment in a COVID-19 Cohort consortium, a national study funded by the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health.
Study co-author Dr. Esther Melamed, a neuroimmunologist at the University of Texas at Austin, emphasized the potential urgency of the findings. If our findings on Anelloviridae and long COVID are validated, then it would really create a lot of urgency around better understanding these viruses and developing antivirals for them,
she noted.
Researchers suggested that the molecular signatures of viral reactivation uncovered by the study could eventually support new approaches for predicting, monitoring, and treating both acute COVID-19 and long COVID. While existing antiviral medications might offer treatment options for certain herpesviruses, further clinical trials will be required to establish whether actively treating viral reactivation improves patient outcomes. Additionally, scientists cautioned that the findings may not fully apply to vaccinated populations, individuals infected with more recent viral variants, or people who experience only mild cases of COVID-19.
