Herpesvirus Traits and Long-COVID

Herpesviruses are unique in that, once contracted, they remain in the body for life, often lying dormant until circumstances such as stress or a weakened immune system trigger their reactivation. This raises the question: Could long-COVID be a manifestation of such reactivation?

Recent research indicates that EBV, also known as human herpesvirus 4, may indeed be implicated in some long-COVID cases. A study from Yale School of Medicine employed advanced blood immune profiling and machine learning to identify biomarkers that differentiate long-COVID patients from those who do not experience prolonged symptoms.

Klein et al. analyzed a cohort of 178 individuals, comprising 99 long-COVID patients, 40 uninfected healthy participants, and 39 convalescent individuals (those who had recovered from a prior SARS-CoV-2 infection). Most of those who had contracted COVID-19 previously were not hospitalized during their initial infection over a year prior.

The immune profiling revealed several significant differences:

• The long-COVID group exhibited abnormal immune responses involving monocytes, dendritic cells, and exhausted T-cells.
• Cortisol levels were notably lower in the long-COVID cohort, marking it as a key predictor of this condition.
• There were no significant differences in levels of over 6,000 autoantibodies among the groups.
• Antibody responses were heightened against several viral proteins, particularly those related to EBV.

Understanding EBV's Role in Long-COVID

The study's findings align with previous research linking EBV reactivation to long-COVID. For instance, Peluso et al. (2022) found that heightened antibody responses to EBV proteins were associated with inflammatory markers and the development of long-COVID. Similarly, Su et al. (2022) noted that increased levels of EBV gene fragments in COVID-19 patients correlated with signs of T-cell activation and exhaustion.

Other studies have also reported a higher incidence of EBV DNA in throat samples from long-COVID patients compared to non-long-COVID counterparts. The cumulative evidence suggests that EBV reactivation might contribute to long-COVID in approximately 30-50% of cases, although not every long-COVID patient shows these markers.

Klein et al. emphasized that long-COVID is likely a complex syndrome influenced by multiple biological factors, including EBV reactivation. Notably, the presence of EBV-related immune markers seems to correlate with specific symptoms such as fatigue and neurological issues but not necessarily with cardiopulmonary or gastrointestinal symptoms.

The Broader Implications of EBV

EBV is a widespread virus, with over 90% of individuals worldwide infected at some point, often in childhood. While many experience mild symptoms, others may develop chronic conditions like chronic fatigue syndrome, which is also a potential diagnosis for long-COVID. The persistent cycles of EBV latency and reactivation place the immune system under continuous pressure, leading to chronic inflammation and T-cell exhaustion, which are common in various chronic diseases.

The potential for EBV to contribute to other serious conditions, such as B-cell-related cancers and multiple sclerosis, raises concerns. Klein et al. highlighted the need for further research to determine whether EBV reactivation may predispose long-COVID patients to autoimmune diseases.

Future Directions in EBV Treatment

Currently, no specific vaccines or antiviral therapies exist for EBV, with only general symptomatic treatments recommended. However, recognizing the role of EBV in chronic diseases could pave the way for new therapeutic approaches. Promising antiviral candidates, currently in pre-clinical and clinical testing, might soon offer hope for effective EBV treatments.

As the prevalence of long-COVID continues to rise, it is critical to address the threat posed by EBV and explore potential treatments not only for long-COVID but for other EBV-associated chronic conditions.