Three years into the COVID-19 pandemic, we still don`t fully understand the causes of Long COVID. One theory suggests that during acute SARS-CoV-2 infection, the immune system weakens and cannot keep under control viruses that are normally present in people. One such virus is the Epstein-Barr virus, or EBV, which is present in more than 95% of healthy adults in an inactive state. When stress occurs, for example during infection with another virus, EBV can become active again.
This EBV reactivation can cause various clinical manifestations, including fatigue, memory loss, sleep disturbance, joint stiffness, sore throat, muscle pain, headaches, fever, gastrointestinal complications and different skin rashes. Many of these symptoms are very similar to, or even the same as, those reported in patients with Long COVID. The following summarizes important clinical studies on EBV reactivation in patients with Long COVID.
Many Long COVID symptoms may be the result of COVID-19 inflammation-induced EBV reactivation.
Most patients with reactivated EBV infection
Already in 2021, results from two small studies indicated that EBV reactivation may be one cause of more severe acute COVID-19 and Long COVID symptoms. In the first study of 67 participants with COVID-19, the researchers found that those with reactivated EBV infection (~55% of all participants) were more likely to experience fever and inflammation than participants who were negative for EBV reactivation. No other symptoms were significantly different between the two groups, although the recovery time was slightly longer in participants with reactivated EBV infection who also needed more oxygen inhalations.
In the second study, two-thirds of participants (20/30) with Long COVID and only 10% of those (2/20) who did not develop Long COVID had a reactivated EBV infection. The most frequent symptoms among participants with EBV reactivation were fatigue, insomnia, headaches, muscle pain and confusion. A more detailed analysis of this study also demonstrated that EBV reactivation occurred at the time of, or soon after, the contraction of the SARS-CoV-2 infection.
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Association between EBV reactivation and fatigue
According to a new Austrian study, EBV reactivation may also explain the development of fatigue, which is one of the most common symptoms of Long COVID. In this analysis, 30 participants with Long COVID fatigue and 20 participants who have fully recovered after COVID-19, were tested for EBV after 7–9 months (median) after the beginning of acute SARS-CoV-2 infection. EBV reactivation was detected in 50% of participants with fatigue and 20% of participants without symptoms.
These findings suggest that EBV reactivation may cause Long COVID fatigue in some patients, but the authors highlighted that further and larger studies are needed to clarify this association.
Further and larger studies are needed to clarify findings.
EBV is among the factors that can predict Long COVID
Findings from these smaller reports were corroborated in larger studies. A recent major study investigated symptoms of Long COVID and the presence of EBV in 280 participants with SARS-CoV-2 infections, including 208 with Long COVID. Four months after the COVID-19 diagnosis, fatigue and neurocognitive symptoms were considerably more common among participants with evidence of recent EBV reactivation. No strong association was observed with other typical symptoms of Long COVID, such as heart and lung problems or gastrointestinal complications. Interestingly, the study authors pointed out that these findings do not directly prove that EBV reactivation caused Long COVID symptoms because also some participants without signs of EBV reactivation developed symptoms.
They suggested that there are probably many other causes of Long COVID symptoms, for example, SARS-CoV-2 that remains in the body and continues to harm the immune system
There is currently no therapy specifically approved for the treatment of patients with EBV reactivation.
Another extensive Long COVID study is among the first to experimentally prove the causes of this condition and the results were published in one of the most cited and prestigious medical journals, Cell. This complex analysis investigated 309 COVID-19 patients from the initial diagnosis to 2–3 months later and identified EBV viremia (virus present in the blood) at the time of initial infection as a risk factor for the development of Long COVID. Other risk factors confirmed in this study were type 2 diabetes, SARS-CoV-2 viremia and the presence of particular autoantibodies.
As EBV reactivation can be detected at the beginning of COVID-19, the researchers concluded that the treatment with antiviral therapy early in the disease course may be beneficial for treating acute COVID-19 and relieving Long COVID symptoms. However, well-controlled studies are needed to verify whether antivirals can improve the symptoms of Long COVID.
