Researchers identify viral suspects that could be fueling long COVID

Their view is that, for some individuals, long COVID symptoms could stem from additional infections that occur alongside SARS-CoV-2.

A review published in eLife by 17 experts, including researchers at Rutgers Health, suggests that co-infections acquired before or during a bout of COVID may help drive long-lasting symptoms.

"This is an aspect of long COVID that is not talked about a lot," said Maria Laura Gennaro, a microbiologist at the Rutgers New Jersey Medical School who chaired the Microbiology Task Force for the National Institutes of Health's Researching COVID to Enhance Recovery initiative, a large-scale study of long COVID.

Growing Evidence That Other Pathogens May Play a Role

Long COVID has affected up to 400 million people worldwide and can cause problems ranging from mild disruption to severe disability. It can involve the brain, heart, lungs and digestive system. Despite its widespread impact, no proven treatments exist because the underlying cause remains unclear.

The new review brings together existing scientific findings and expert opinion to highlight an idea that has received relatively little attention: infections other than the coronavirus itself may be important contributors.

EBV Reactivation as a Leading Suspect

One of the strongest lines of evidence centers on Epstein-Barr virus (EBV), the virus that causes mononucleosis. Roughly 95 percent of adults carry EBV in a latent form that usually remains silent until an immune challenge such as COVID triggers its reactivation.

In one early study, researchers reported that two-thirds of people with long COVID showed markers of recent EBV activity, and those with more symptoms had higher antibody levels. Subsequent studies also linked EBV reactivation with well known features of long COVID, including fatigue and cognitive difficulties.

TB and Immune Disruption

Another pathogen receiving attention is tuberculosis (TB). About one-quarter of the global population carries latent TB. Evidence indicates that COVID may reduce the immune cells that normally contain TB, raising the risk that it could reactivate. The connection may also work in the opposite direction, since TB appears capable of worsening COVID outcomes.

The researchers emphasize that timing is important. Infections that occur before COVID may weaken the immune system. Infections during the initial illness may intensify tissue damage. Infections that arise after recovery could take advantage of lingering immune dysfunction caused by COVID.

Rising Rates of Other Diseases and the Idea of Immunity Theft

According to the authors, 44 countries have seen tenfold increases in at least 13 infectious diseases compared with levels observed before the pandemic. One idea they discuss, known as "immunity theft," proposes that an episode of acute COVID may leave people more susceptible to other infections.

If co-infections truly contribute to long COVID, treatments already available could potentially help. Existing antibiotics and antivirals might be repurposed to target specific underlying infections, and clinical trials could examine whether treating these infections improves long COVID symptoms.

A Hypothesis That Still Requires Proof

The researchers caution that their argument remains preliminary. Although the connections they outline are biologically reasonable, they are still unproven. No causal relationship has been confirmed between any co-infection and long COVID.

"Everyone has heard it a million times, but it bears repeating: Correlation doesn't equal causation," Gennaro said.

She added that verifying the hypothesis would require large epidemiological studies and animal research, yet this work is made more difficult by the lack of reliable animal models for long COVID.

Expanding the Search for Answers

The authors hope their findings will encourage more investigation into how co-infections might shape long COVID. While the review does not provide immediate solutions for those currently dealing with long-term symptoms, the researchers suggest that effective treatment may involve looking beyond the coronavirus alone.