EBV Reactivation After COVID-19: What We Know (and Don’t)

Epstein-Barr virus (EBV) activation and reactivation have long been cited as a possibility after a COVID-19 infection. EBV has the ability to trigger the development of autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, and myasthenia gravis. While the exact mechanisms behind EBV triggering autoimmunity have not been defined, the most plausible hypothesis is that EBV disrupts B cell regulatory checkpoints, ultimately leading to the development of autoimmune plasma cells. Viruses can reactivate EBV, which is crucial in the pathophysiology of certain autoimmune diseases.

A literature review recently published in the Journal of Microbiology, Immunology and Infection summarized the most recent data on COVID-19 and EBV reactivation. Authors also highlight the role of the SARS-CoV-2-reactivated EBV in the development of autoimmunity, as well as flares and long Covid manifestations.

Documented mechanisms by which a Covid-19 infection may trigger autoimmunity include a “hyper-stimulation of inflammatory responses” with cytokine storm, molecular mimicry, and dysregulation of innate and adaptive immune cells (more here). The activation of T cells and immune cells without a specific target (also known as bystander activation), as well as persistent infection (e.g. long Covid) are also mechanisms for an autoimmune response. While the correlation between SARS-CoV-2 infection and autoimmunity has been observed, the authors point out that direct causality has yet to be proven.

Several mechanisms affecting immune regulation after a COVID-19 infection can reactivate latent viruses, including EBV.

This suggests an additional, indirect effect of the SARS-CoV-2 virus, as “acute infection by different pathogens may provide suitable conditions for EBV to reactivate, increasing the risk for EBV-associated pathologies.” One study included in this review cited EBV as one of the most frequently observed viruses by studies reporting viral reactivation specifically in patients with severe COVID-19. 58% of 895 patients showed EBV reactivation, the highest among viruses studied. In another study with 539 patients infected with Covid-19 and Herpesviridae were reviewed, and EBV was highlighted as one of the top three reactivated viruses concomitant with infection.

Authors also cite several studies that support the relationship between SARS-CoV-2 infection and EBV reactivation, with high incidences of EBV co-infection/ reactivation in COVID-19 patients. EBV reactivation can occur soon after or simultaneously with a COVID-19 infection, even in asymptomatic cases. Additionally, “a direct positive correlation has been reported between EBV reactivation and the severity of SARS-CoV-2 infection and its symptoms.” In one study, EBV reactivation was reported in 92.5% of severe COVID-19 patients hospitalized in the ICU; EBV reactivation has also been associated with longer hospitalization. Patients with long Covid symptoms have shown signs of EBV reactivation, suggesting a contribution of EBV to long-term inflammatory symptoms. In one retrospective study, 66.7% of patients with long Covid symptoms showed EBV reactivation.

Viral reactivation has been noted as a risk factor for in-hospital mortality.

The mortality rate in patients with COVID-19 and the need for more intense immunosuppressive therapies were higher in patients with EBV reactivation. This indicates a strong impact of EBV on the “patho-immunological alterations and outcomes of COVID-19 illness.” In one study evaluating the incidence of EBV reactivation amongst other herpesviruses, EBV was the most and earliest reactivated herpesvirus amongst patients (65%).

The association between EBV and long Covid in patients with asymptomatic or mild infection has not been successfully made. The authors note that the molecular mechanisms underlying EBV’s contribution to COVID-19 infection and symptomatology are also not fully understood.

Studies show that patients experiencing EBV reactivation triggered long Covid fatigue and neurocognitive dysfunction in a statistically significantly higher percentage of Covid-19 patients.

Additionally, authors summarized a proposed model for the pathophysiological link between COVID-19 and EBV to support the susceptibility of autoimmune disease development and reactivation of symptoms. These points include SARS-CoV-2 infection being associated with an increased risk of development or worsening of autoimmune disease, and EBV reactivation being reported in patients with severe COVID-19 and long Covid, including autoimmune diseases. Reactivated EBV promotes the expression of ACE2, the main SARS-CoV-2 surface receptor, which opens the entryway of the virus into epithelial cells, which then has the ability to switch EBV from a latent state to an active state, aka reactivation. It is not clear whether immune system cell exhaustion or hyper-activation is the underlying mechanism for EBV reactivation from SARS-CoV-2 infection.

Overall, the review concludes that EBV reactivation is frequently observed in severe COVID-19 and long Covid and may contribute to autoimmune flares. However, whether this link is causal or coincidental remains unresolved.

Citation

Tarasco, M. C., et al. (2025). COVID-19, Epstein-Barr virus reactivation and autoimmunity: Casual or causal liaisons?. Journal of microbiology, immunology, and infection = Wei mian yu gan ran za zhi, 58(5), 508–516. https://doi.org/10.1016/j.jmii.2025.03.014