Severe COVID-19 Can Reactivate Dormant Viruses and Trigger Long COVID

Key Clinical Takeaways:

• Severe COVID-19 reactivates dormant pathogens, including herpes viruses like Epstein-Barr virus (EBV), cytomegalovirus (CMV), herpes simplex virus (HSV), and typically harmless anelloviruses.
• A study tracking 1,154 hospitalized adults for a year found that nearly half experienced viral reactivation, with anellovirus activity specifically linked to debilitating long COVID symptoms such as severe fatigue.
• Researchers emphasize that these findings establish a correlation rather than definitive causation, driving urgency for future prospective interventional trials testing antiviral therapies.

Tracking Viral Reactivation in Hospitalized Patients

The research team tracked 1,154 adults hospitalized with varying severities of COVID-19, following their recovery trajectories for an entire year. Investigators gathered blood samples, nasal swabs, and lung fluid samples from ventilated patients across six time points during the first month, followed by assessments at three, six, nine, and 12 months. Laboratory tests checked for viral RNA to detect whether lingering, latent viruses were reactivating during and after infection with SARS-CoV-2.

Results showed that many dormant viruses awakened during acute infection, specifically members of the herpes family and anelloviruses. Each pathogen followed a distinct reactivation timeline. Epstein-Barr virus and anelloviruses surfaced early in the infection cycle, while cytomegalovirus and herpes simplex virus emerged later. Each viral awakening correlated with specific immune and metabolic alterations, as well as distinct clinical complications. Nearly half of the cohort—550 out of 1,148 patients—experienced the reactivation of at least one dormant virus despite having competent immune systems.

Following the acute phase, a subset of patients developed debilitating long COVID symptoms, including profound fatigue and a diminished capacity to perform routine daily activities like walking or dressing. In these individuals, anelloviruses frequently remained active long after the initial SARS-CoV-2 infection cleared. 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 to Live Science as “one of the largest and most carefully done studies of its kind.” The team also replicated their primary findings in an independent cohort utilizing blood samples from a Mount Sinai biobank.

Mechanisms Driving Latent Pathogen Awakening

The phenomenon of latent virus reactivation during severe physical stress is documented in other clinical contexts. Anna Cliffe noted that healthy populations, such as astronauts and Antarctic researchers undergoing intense physical and psychological stress, regularly experience viral reactivation and shed multiple herpes viruses. Dr. Esther Melamed, a neuroimmunologist at the University of Texas at Austin and co-author of the study, explained that the immune system typically acts as a guard, keeping hidden past infections suppressed inside cells. When faced with a massive stressor like severe acute infection, sleep deprivation, or surgery, the immune system redirects its resources away from these gatekeeper duties.

“When the guard walks away from the cell, then these viruses have the opportunity to wake up and do whatever they want,” Melamed told Live Science.

While detecting viral RNA signals that viral genes are switching on, experts caution that this metric differs from isolating whole infectious particles. However, the study authors corroborated their genetic findings by detecting viral antibodies alongside elevated quantities of the specific immune cells that these viruses typically inhabit.

Future Interventional Trials and Clinical Implications

The core limitation acknowledged by the researchers is that the observed link between viral reactivation and worse clinical outcomes represents a correlation rather than definitive causation. Dr. Esther Melamed noted that the logical next step involves conducting prospective interventional trials to evaluate whether targeted antiviral medications can improve recovery trajectories for patients battling severe COVID-19 and long COVID.

*Disclaimer: The information provided in this article is for educational and scientific communication purposes only and does not constitute medical advice. Always consult with a qualified healthcare provider regarding any medical condition, diagnosis, or treatment plan.*