Could Hidden Infections Be Fueling Long COVID

For millions suffering from long COVID, their persistent breathlessness, brain fog and fatigue remain a maddening mystery, but a group of leading microbiologists think they may have cracked the case.

The culprit for some long COVID cases, they suggest, might be other infections that accompany SARS-CoV-2.

A review published in eLife by 17 experts, including those from Rutgers Health, argues that co-infections acquired before or during COVID could cause symptoms to persist indefinitely for many people.

"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.

Long COVID symptoms, which have affected up to 400 million people worldwide, range from mild impairment to severe disability, striking the brain, heart, lungs and digestive system. Yet no proven treatments exist because the underlying causes remain unknown.

The new review synthesizes existing research and expert judgment to make a case that has received little attention: Infections beyond the coronavirus may be critical players.

The most compelling evidence involves Epstein-Barr virus (EBV), the pathogen that causes mononucleosis. About 95% of adults carry latent EBV, typically without symptoms until an immune disruption such as COVID awakens the dormant virus.

Researchers of one early study found that two-thirds of people with long COVID showed signs of recent EBV activity, and those with more symptoms had higher antibody levels. Later research linked EBV reactivation to long COVID hallmarks such as fatigue and cognitive problems.

Tuberculosis (TB) is another potential culprit. About one-quarter of the world's population carries latent TB. Evidence suggests COVID can deplete the immune cells that normally keep TB in check, potentially triggering reactivation. The relationship runs both ways: TB infection also may worsen COVID outcomes.

The timing of co-infections matters, the researchers said. Infections before COVID could leave the immune system compromised. Infections during acute illness could compound tissue damage. Infections afterward could exploit post-COVID immune dysfunction.

The authors noted that 44 nations have experienced tenfold increases in at least 13 infectious diseases compared with pre-pandemic levels. One explanation they cite, called "immunity theft," describes heightened vulnerability to other infections following acute COVID.

If co-infections contribute to long COVID, existing drugs might help. Antibiotics and antivirals could potentially be repurposed to target underlying infections. Clinical trials could test whether treating specific co-infections relieves symptoms.

But the authors acknowledge their argument's limits. The associations they discuss are biologically plausible but remain speculative. No one has established a causal link 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 said proving the hypothesis would require large epidemiological studies and animal experiments, which is complicated by the absence of good animal models for long COVID.

The researchers hope their work will open new lines of investigation. For the millions living with long COVID, the review offers no immediate answers, but its authors suggest that effective treatment may require looking beyond COVID itself.