Long COVID has left millions grappling with relentless symptoms like breathlessness, brain fog, and fatigue, leaving both patients and doctors searching for answers. But what if the root of this mystery lies not solely in the coronavirus itself, but in hidden infections lurking in the shadows? A groundbreaking review published in eLife by 17 leading experts, including researchers from Rutgers Health, suggests that co-infections—those occurring before, during, or after COVID—may be the missing piece of this complex puzzle. And this is the part most people miss: these infections could be silently prolonging symptoms, even when COVID itself seems to have faded.
"This is a side of long COVID that doesn’t get nearly enough attention," explains Maria Laura Gennaro, a microbiologist at Rutgers New Jersey Medical School and chair of the Microbiology Task Force for the National Institutes of Health's long COVID research initiative. Her team argues that infections beyond SARS-CoV-2 could be critical players in the persistent symptoms affecting up to 400 million people worldwide. From mild impairments to severe disabilities, long COVID strikes the brain, heart, lungs, and digestive system—yet no proven treatments exist because its underlying causes remain shrouded in mystery.
But here's where it gets controversial: The review highlights compelling evidence pointing to the Epstein-Barr virus (EBV), the culprit behind mononucleosis. Roughly 95% of adults carry latent EBV, often without symptoms—until something like COVID disrupts the immune system and reactivates it. Early studies found that two-thirds of long COVID patients showed signs of recent EBV activity, with higher antibody levels correlating to more severe symptoms. Later research linked EBV reactivation to hallmark long COVID issues like fatigue and cognitive problems. Could this be more than a coincidence? The jury’s still out, but it’s a question worth asking.
Another potential culprit? Tuberculosis (TB). About one-quarter of the global population carries latent TB, and evidence suggests COVID can weaken the immune cells that keep it in check, potentially triggering reactivation. What’s more, this relationship might go both ways—TB infection could also worsen COVID outcomes. It’s a complex interplay that challenges our understanding of both diseases.
The timing of these co-infections matters too. Infections before COVID could leave the immune system vulnerable, while those during acute illness might compound tissue damage. Post-COVID infections could exploit lingering immune dysfunction. The authors point to a startling trend: 44 nations have seen tenfold increases in at least 13 infectious diseases since the pandemic began. One theory, dubbed "immunity theft," suggests that acute COVID leaves us more susceptible to other infections. But is this a cause or merely a correlation? That’s the million-dollar question.
If co-infections are indeed driving long COVID, existing treatments like antibiotics and antivirals could be repurposed to target these underlying infections. Clinical trials could test whether treating specific co-infections alleviates symptoms. Yet, the authors caution that their argument remains speculative. No causal link has been established between any co-infection and long COVID. As Gennaro aptly puts it, "Correlation doesn’t equal causation—no matter how many times we hear it."
Proving this hypothesis would require large-scale epidemiological studies and animal experiments, complicated by the lack of reliable animal models for long COVID. For now, the review offers no quick fixes for the millions suffering, but it opens new avenues for research. Perhaps effective treatment lies not in focusing solely on COVID, but in looking beyond it.
What do you think? Could hidden infections be the key to unlocking the long COVID mystery? Or is this just another piece of a much larger puzzle? Share your thoughts in the comments—let’s spark a conversation that could shape the future of long COVID research.
