Most people carry eight to 12 generally harmless viruses at any given time. But now, researchers at the University of Texas at Austin conclude that severe COVID-19 infections can reactivate these viruses, leading to worse clinical outcomes, autoimmune diseases, and other long-term conditions such as long COVID.
Published yesterday in Nature, the observational analysis used longitudinal data from 1,154 hospitalized COVID-19 patients participating in the observational Immunophenotyping Assessment in a COVID-19 Cohort (IMPACC) study.
With the aim of defining biomarkers of COVID severity and outcomes, the researchers generated more than 1 billion data points from 200,000 nasal swabs, blood cells, and endotracheal aspirates from unvaccinated patients at 20 US hospitals from May 2020 to March 2021.
COVID and Epstein-Barr virus, cytomegalovirus
The study is unique in that it was based on the measurement of the RNA of actively replicating viruses rather than on antibody responses, the authors said.
“Viruses use diverse strategies to enhance their persistence and dissemination, including establishing chronic infection,” they wrote. “Chronic viral infections are ubiquitous in humans, with individuals carrying multiple viruses that can reactivate during physiological stress, including severe illness.”
While primary infection with chronic viruses most often causes no symptoms in people with healthy immune systems, some may lead to the development of autoimmune disorders, cancers, and other conditions. The viruses usually stay dormant but can revive in response to stress, hormonal imbalances, sleep deprivation, surgery, or serious illness.
“Notably, SARS-CoV-2 infection has been shown to reactivate chronic viruses such as Epstein–Barr virus and cytomegalovirus (CMV) yet the full extent, temporal dynamics and immunological impact of viral reactivation in COVID-19 remain incompletely understood,” they added.
RNA from 11 reactivated viruses found
RNA from 11 reactivated viruses was detected in patients within the first 40 days after hospital admission, the most common of which were herpes simplex 1 and Anelloviridae viruses, which establish lifelong infections, and to a lesser extent, Epstein-Barr (EBV), CMV, and enteroviruses. Of note, reactivation of Anelloviridae, a poorly understood virus family dormant in roughly 90% of people, was strongly tied to long COVID and long-term physical disability.
When limiting the analysis to severely ill patients, those with CMV in the respiratory tract or EBV in the nasal cavity were more likely to die within one year.
This study provides immune, transcriptomic and metabolomic signatures of viral reactivation that could inform future strategies to prognosticate and treat acute COVID-19 and long COVID.
The authors noted distinct temporal dynamics among the viruses. For instance, EBV was reactivated early in infection, with 24% of patients having detectable RNA near hospital admission, followed by a gradual decline. Anelloviridae RNA often remained steady until 20 days after admission before slowly declining. Viral detection rates by time since symptom onset followed similar patterns.
Another correlation was between virus reactivation and disease severity, host immune effects, and clinical outcomes.
After adjusting for COVID-19 severity, the team found a significant link between Anelloviridae in blood cells and increasing age and between Hispanic ethnicity and EBV and CMV, but no association by sex.
Different viruses were also linked to severe complications. For example, the presence of CMV, part of the Herpesviridae familym in the nasal cavity was linked to pneumothorax (collapsed lung), while in blood cells, CMV was tied to bacteremia, pulmonary vascular disease, kidney complications, stroke, and shock.
Systemic inflammation appeared to reanimate EBV and CMV, which the authors said challenges the prevailing belief that immune suppression is the primary mechanism behind the reactivation of chronic viruses.
If viral reactivations were the result of only a dysregulated immune system, they said, reactivation would be tied not only to severity but also to immune suppression, which the team didn’t find for Herpesviridae. Therefore, viral reactivation may represent a broader phenomenon than previously believed and should be considered in clinical contexts beyond immune suppression.
“Additionally, we demonstrate persistence of viral reactivation in convalescence, and report an association of Anelloviridae with long COVID,” the researchers wrote. “This study provides immune, transcriptomic and metabolomic signatures of viral reactivation that could inform future strategies to prognosticate and treat acute COVID-19 and long COVID.”
Potential role for viral-reactivation monitoring
While the researchers acknowledge that the findings don’t establish causation or an exact mechanism behind viral reactivation and clinical outcomes, it does highlight the prevalence of reactivation during COVID-19 infection and long COVID.
