Nearly half of patients hospitalized with COVID-19 had detectable reactivation of at least one chronic virus during acute illness, according to a longitudinal study published in Nature. The findings describe potential laboratory markers for further investigation but do not establish that viral reactivation causes severe disease or long COVID.
The study included 1,154 patients admitted with COVID-19 to 20 US hospitals between May 2020 and March 2021. All were unvaccinated at enrollment. Researchers collected nasal swabs, peripheral blood mononuclear cells, and, among mechanically ventilated patients, endotracheal aspirates for up to one year.
RNA sequencing was used to identify transcripts from actively replicating viruses. The researchers also assessed immune cell populations, antibody levels, cytokines, proteins, and metabolites. Severe acute respiratory syndrome coronavirus 2 detection by RNA sequencing correlated with reverse transcription quantitative polymerase chain reaction results, supporting the transcript-based approach.
Chronic viral transcripts were detected in 550 of 1,148 evaluable patients during the first 40 days following admission. Most patients with reactivation had one additional virus rather than several.
Epstein-Barr virus reactivated early, with transcripts detected in 24 percent of patients during days one to eight. Human alphaherpesvirus 1 and cytomegalovirus appeared later. Human alphaherpesvirus 1 was detected around days 19 to 23 in 43 percent of patients with endotracheal aspirates and 15 percent of those with nasal samples. Cytomegalovirus was found in 8 percent of peripheral blood mononuclear cell samples during the same period.
Herpesvirus and Anelloviridae transcripts were associated with greater COVID-19 severity. Among critically ill patients, cytomegalovirus in respiratory samples and nasal Epstein-Barr virus or human alphaherpesvirus 1 were also associated with one-year mortality. These relationships remained observational and may reflect, rather than contribute to, severe illness.
During follow-up, Anelloviridae transcripts were more common among patients reporting persistent physical disability or fatigue. Acute viral detection was not associated with the study’s long COVID symptom groups, and Epstein-Barr virus transcripts were not more frequent during acute illness among patients who later developed long COVID.
The study showed that viral transcript detection across blood and respiratory specimens can characterize the timing of reactivation. Quantitative polymerase chain reaction assays are already available for several herpesviruses and Anelloviridae, but the findings do not establish when routine monitoring would improve patient care.
Limitations included the use of RNA sequencing rather than quantitative polymerase chain reaction for viral measurement, sampling of only three specimen types, and participant loss during follow-up. The cohort was limited to unvaccinated, hospitalized patients infected with early severe acute respiratory syndrome coronavirus 2 variants, which may restrict application to current populations.
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