For millions of people living with long COVID, the cause of ongoing symptoms such as breathlessness, brain fog, and fatigue remains unclear. A new review published in eLife by a group of 17 experts, including microbiologists from Rutgers Health, suggests that infections other than SARS-CoV-2 may be involved in these persistent symptoms.
The review argues that co-infections acquired before or during COVID-19 could play a role in prolonging symptoms for many individuals. Maria Laura Gennaro, a microbiologist at Rutgers New Jersey Medical School who chaired the Microbiology Task Force for the National Institutes of Health's Researching COVID to Enhance Recovery initiative, said: "This is an aspect of long COVID that is not talked about a lot."
Long COVID has affected up to 400 million people worldwide and can impact various organs and systems in the body. Despite its prevalence, there are no proven treatments because the causes are still unknown.
The authors highlight evidence linking Epstein-Barr virus (EBV) to long COVID. Most adults carry EBV without symptoms until their immune system is disrupted by an illness like COVID-19. Early research found signs of recent EBV activity in two-thirds of people with long COVID, and those with more severe symptoms had higher antibody levels. Later studies have connected EBV reactivation to common features of long COVID such as fatigue and cognitive issues.
Tuberculosis (TB) is also identified as a possible factor. About one-quarter of the global population carries latent TB. The review notes that COVID-19 can weaken immune cells responsible for keeping TB dormant, which may lead to reactivation. Conversely, having TB might worsen outcomes from COVID-19.
Timing appears important when it comes to co-infections. Infections present before contracting COVID could weaken immunity; those acquired during acute illness could increase tissue damage; while infections after recovery might take advantage of lingering immune dysfunction.
The authors also mention that 44 countries have reported tenfold increases in at least 13 infectious diseases compared to pre-pandemic times—a trend they describe using the term "immunity theft," where vulnerability to other infections rises after acute cases of COVID-19.
If co-infections are indeed part of what drives long COVID symptoms, existing antibiotics and antivirals could potentially be repurposed for treatment pending further clinical trials.
However, the researchers caution against drawing firm conclusions at this stage: "Everyone has heard it a million times, but it bears repeating: Correlation doesn't equal causation," Gennaro said.
She added that proving any causal relationship would require large-scale epidemiological studies and animal experiments—research made more difficult by the lack of suitable animal models for long COVID.
While their findings do not provide immediate solutions for those suffering from lingering post-COVID symptoms, the authors hope this work will prompt new research directions focused on factors beyond just SARS-CoV-2 infection.
