Researchers have found that COVID-19 may reactivate dormant viruses in a significant portion of hospitalized patients, with potential links to both severe acute illness and lingering long COVID symptoms. A study published in Nature examined over 1,150 patients across 20 U.S. hospitals, tracking viral reactivation patterns for up to a year after admission.
Study design and participants
The research team analyzed blood and nasal swab samples from participants who had not received COVID-19 vaccines and were hospitalized with early SARS-CoV-2 strains. Patients were categorized by illness severity, ranging from mild to critical. The study focused specifically on viruses from the Herpesviridae and Anelloviridae families, which the researchers noted had higher prevalence in this cohort.
According to the authors, the study used advanced sequencing techniques to directly detect when these chronic viruses “wake up” or reactivate. This approach allowed them to identify viral reactivation events that might otherwise go unnoticed in standard clinical testing.
Reactivation rates and timing
About 48% of participants with severe COVID-19 experienced viral reactivation during their illness. Of those who showed reactivation, roughly two-thirds had only one virus detected during the acute period. The timing varied by virus type. Human alphaherpesvirus (HSV1) and cytomegalovirusâboth implicated in various herpes conditionsâtypically reactivated around 20 days after hospital admission.
The study found that detecting certain reactivated viruses within 40 days of hospital admission correlated with worse outcomes. Among critically ill patients, those with detectable levels of Epstein-Barr virus, HSV1, or cytomegalovirus in their respiratory system faced higher mortality risk within a year.
Links to inflammation and long COVID
Researchers identified connections between viral reactivation and inflammatory responses. Certain reactivated viruses were associated with increased inflammatory cytokines, changes in plasma metabolites, and alterations in gene expression. Additionally, detecting Anelloviridae in immune cells correlated with shock and intensive care admission.
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For long COVID patients, the findings proved particularly striking. Participants reporting persistent fatigue and physical disability were more likely to have Anelloviridae present in samples collected months after their hospital stay. This marks the first time this virus family has been linked to prolonged post-COVID symptoms.
The connection between viral reactivation and long COVID symptoms makes biological sense when considering how chronic viruses interact with the immune system. When the body is already fighting one infection, dormant viruses that typically remain suppressed may find an opportunity to reactivate, potentially prolonging the inflammatory state that characterizes long COVID.
Clinical implications and expert perspectives
Experts not involved in the study offered cautious interpretations of the findings. Arturo Casadevall, a microbiology and immunology specialist at Johns Hopkins Medicine, noted that while clinical implications remain uncertain, it is conceivable that viral reactivation contributes to COVID-19 disease and promotes the persistent inflammation seen in long COVID patients.
Jimmy Johannes, a pulmonologist at MemorialCare Long Beach Medical Center, suggested that if future research confirms direct causation, detecting viral reactivation could help identify high-risk patients or point toward new treatment approaches. “Reactivation of viruses such as EBV, cytomegalovirus, and other chronic viruses could contribute to some of the complications associated with COVID-19, particularly by adding to the inflammatory and immune response,” Johannes said.
Study limitations
Researchers acknowledged several constraints. The cohort consisted entirely of unvaccinated patients infected with early SARS-CoV-2 variants, making it unclear how current vaccinated populations or those exposed to newer strains would be affected. The study also relied on transcript analysis to measure viral load, which may have introduced detection limitations. Additionally, because the research was conducted before a standardized long COVID definition existed, researchers faced challenges when examining links between viral reactivation and persistent symptoms.
Participant dropout over the year-long follow-up period also affected data completeness. The authors emphasized that while associations were found, the study cannot prove that viral reactivation directly causes worse COVID-19 outcomes.