Development of long COVID as a consequence of the complex relationship between Epstein-Barr virus and our immune system

Abstract

Introduction: The pathophysiological development of long COVID (LC) is still insufficiently known. However, post infection fatigue syndromes were seen before, among other pathogens including Epstein-Barr virus (EBV). Considering EBV reservoir in COVID-19 patients, this review aims to present current knowledge related to EBV role in development of LC and with the potential diagnostic utility. EBV infection: Following the primary lytic infection of epithelial oropharyngeal and nasopharyngeal cells EBV establishes a very complex mechanism of lifelong survival in B cells. Latent infection with occasional viral reactivations constantly challenges the host's immune response. In individuals with immune imbalance including COVID-19, it could drive long-term consequences. EBV and COVID-19: The activity of EBV has been shown as the most prevalent human herpesvirus infection in COVID-19 population (41%). Correlation between lymphocytopenia-induced disability to remove the EBV, increases in EBV DNA viremia and COVID-19 complications have also been reported. EBV and long COVID: The positivity of EBV DNA during acute SARS-CoV-2 infection predicted the presence of symptoms up to 60 days after COVID-19. Association between EBV infection and symptoms such as brain fog, fatigue, arthralgia and skin rashes have been also described in post infection sequelae ME/CFS. Anti-EBV early antigen-diffuse (EA-D) IgG antibodies were detectable among two-thirds of respondents experiencing LC. Increases in anti-EBNA1 IgG levels analyzed months following COVID-19 onset in convalescent LC population could serve as a potential marker of EBV reactivation at the time of acute SARS-CoV-2 infection. Some authors also managed to show anti-EBV viral capsid antigen (VCA) IgM seropositivity in half of COVID-19 patients indicating of either coinfection or EBV reactivation. Conclusion: As a multisystemic illness, LC is without a defined spectrum of diagnostic and treatment options. Whereas EBV reactivation alone or together with other risk factors drives LC symptoms, further prospective studies involving different cohorts and tissue reservoirs are necessary to understand underlying biological mechanisms.