SARS-CoV-2 infection may be accompanied by reactivation of viruses that persist in the human body in a latent state. A recent analysis of hospitalized COVID-19 patients investigated whether viruses that normally remain dormant can "wake up" during acute illness and whether such reactivations relate to disease severity or prolonged symptoms. The study focused primarily on viruses from the Herpesviridae and Anelloviridae families because of their prevalence in the cohort.
Researchers used data from the Immunophenotyping Assessment in a COVID-19 Cohort (IMPACC) study. All included participants were adults with confirmed SARS-CoV-2 infection who required hospitalization. Samples analyzed included blood and nasal or respiratory specimens, with some data extending up to one year after hospital admission. At enrollment, participants had not received COVID-19 vaccines. The cohort was stratified by clinical severity of COVID-19, and the team used sequencing-based approaches to detect transcripts indicating viral reactivation.
The investigators detected several latent viruses reactivating during acute COVID-19. Reactivations were especially common for viruses in the Herpesviridae and Anelloviridae families. Overall, about 48% of participants with severe COVID-19 experienced viral reactivation. When a reactivation was detected in the acute period, approximately two-thirds of those patients had only one virus identified.
Timing of reactivation varied by virus. For example, human alphaherpesvirus (HSV1) and cytomegalovirus (both in Herpesviridae) tended to reactivate around 20 days after hospital admission in this cohort.
Detection of certain viruses within 40 days of admission was associated with worse clinical outcomes. Among participants classified as critical, detectable nasal levels of Epstein-Barr virus (EBV), HSV1, or cytomegalovirus in the respiratory tract were linked to a higher risk of death within one year.
Separately, identification of Anelloviridae in peripheral blood mononuclear cells was associated with acute complications such as shock and the need for ICU admission. These associations suggest that viral reactivation occurred in a substantial fraction of hospitalized patients and that specific reactivations correlated with defined adverse outcomes in the cohort.
The study reported relationships between viral reactivation and host immune and metabolic responses. Reactivation of Herpesviridae and Anelloviridae correlated with increased levels of certain inflammatory cytokines. Researchers also found associations between viral reactivation and changes in plasma metabolites and in host gene expression profiles. These linked signatures point to a biologic interaction between reactivated latent viruses and the host response during and after acute COVID-19.
Investigators explored links between viral reactivation and persistent post-COVID symptoms commonly termed long COVID. In the recovery phase months after hospitalization, participants reporting ongoing fatigue and physical disability were more likely to have detectable Anelloviridae. The authors highlighted this as the first reported association between Anelloviridae activity and symptoms consistent with long COVID in this study population.
The authors and the article note several important limitations:
The analysis is observational and does not establish causation; it cannot prove that viral reactivation causes worse acute outcomes or long-term symptoms.
Participants were unvaccinated and infected with early SARS-CoV-2 strains, limiting the applicability of findings to vaccinated populations or infections from later variants.
The team inferred viral activity using transcript data, which may have limitations compared with other measures of viral load.
Sampling was restricted to three anatomical sites and endotracheal aspirate data were available only for ventilated patients; this sampling strategy could affect which reactivations were detected.
At the time of data collection, definitions for long COVID were not stable, which may have constrained analyses relating reactivation to persistent symptoms.
Participant dropout over the follow-up period further limited longitudinal completeness.
When details were not reported in the source, such specifics are not available here.
Study co-authors Esther Melamed, MD, PhD, and Cole Maguire, PhD, summarized that nearly half of over 1,150 hospitalized patients had at least one chronic virus reactivate during illness, and that this phenomenon was not confined to people with known immune suppression. They emphasized that many affected patients had been otherwise healthy prior to COVID-19.
External experts quoted in the article cautioned that clinical implications remain uncertain but plausible. Arturo Casadevall, PhD, noted it is conceivable that reactivation of other viruses could contribute to the disease manifestations of COVID-19 and to persistent inflammation associated with long COVID. Jimmy Johannes, MD, observed that if future studies demonstrate a causal role, viral reactivation markers might help identify patients at higher risk for complications or suggest new treatment approaches.
The study authors and commentators also suggested that confirming the association between Anelloviridae and long COVID could open new research directions and raise the possibility—if validated—of developing targeted therapies for reactivated viruses. The article also notes that currently there are no approved treatments for Anelloviridae.
Overall, this analysis of the IMPACC cohort indicates that reactivation of latent viruses during hospitalization for COVID-19 was common in the studied population and correlated with multiple measures of severity, systemic inflammation, and some long-term symptoms. However, further research is required to determine causality, to assess effects in vaccinated or later-variant infections, and to explore whether targeting reactivated viruses could modify outcomes.