In patients with severe COVID-19, reactivation of viruses, such as herpes simplex, cytomegalovirus, and EBV occurs, and functional exhaustion of cytotoxic lymphocytes has been suggested as the cause [6, 7]. Since COVID-19 can cause cellular immune dysfunction , it can induce reactivation of latent viruses. Several studies have reported a high incidence of reactivated EBV in patients with COVID-19 [5, 9]. In addition, these studies reported that COVID-19 was more severe in patients with EBV viremia. However, these studies were cross-sectional studies; therefore, it is not known whether EBV viremia affects the progression of COVID-19. Because severely ill patients were the main test targets, and no time span over which the test was conducted was provided, the effect of EBV viremia on progression to severe COVID-19 might have been overestimated. However, we performed the PCR test within 2.3 days on average and conducted a cohort study only in patients with mild COVID-19; therefore, there is less possibility of bias for critical illness.
EBV viremia is common, even in severely ill patients with diseases other than COVID-19. Reactivation of EBV is significantly related to the dysfunction of cellular immunity . EBV is latent in nearly 90% of people, which is the highest rate among herpes viruses . SARS-CoV-2 viral infection can cause functional exhaustion of antiviral lymphocytes and their cytopathic effect . Therefore, we expected EBV viremia to be an indicator of immune burnout. However, in this study, there was no difference in lymphocyte subset or severe expression incidence between the EBV-positive and -negative groups.
The possibility that EBV can cause reduced immunity, rather than simply being an indicator, cannot be ruled out. During EBV reactivation, EBV interferes with the activity of NK cells and helper T cells. EBV causes B-cell transformation  and produces proteins that primarily impair interferon production during the lytic phase . With this mechanism, EBV infection or reactivation can reduce the defense against infection by other pathogens. Moreover, the pathogenicity of reactivated EBV is still being discussed. One study reported that EBV DNA was detected in the lower respiratory tract of patients with severe respiratory tract infections in which no other pathogen has been detected . However, it is difficult to conclude that EBV has a cytopathic effect in all cases where other pathogens have not been identified, because it is not easy to identify the causative pathogen of pneumonia in many cases. However, some researchers claim that the pathogenicity of reactivated EBV might be the result of a compromised immune system, whereas others claim that it is just an indicator of severe illness .
To observe the effects of EBV viremia, we conducted a cohort study to compare the ARDS progression of COVID-19 in the EBV viremia and non-viremia groups at the time of hospital admission. Although the incidence of EBV viremia differed according to COVID-19 severity at admission, there was no higher probability of disease progression in the group with EBV viremia. Further, although the total number of ARDS cases was small, all ARDS cases occurred in the EBV-negative group. The rate of progression to pneumonia requiring oxygen therapy was not different between the EBV viremia group and the other group. Early EBV viremia does not seem to affect COVID-19 prognosis. However, for severe COVID-19, the setting may differ from that in the present study. In severe COVID-19 cases, steroid use is often prolonged. In addition, the immunity of the host may decrease because of critical illness. In these cases, EBV viremia can persist at high levels. This persistent viremia can reduce immunity for the reasons mentioned above, and this immunocompromised status can become part of a vicious cycle that worsens EBV viremia. Therefore, in severely ill patients, including those undergoing long-term steroid treatment, further studies on EBV viremia may be needed.
This study has several limitations. First, there was no follow-up test for EBV viremia; therefore, it could not be confirmed whether EBV viremia persisted in severely ill patients. Second, the study was conducted with a relatively small number of patients. Additional studies with more patients are needed, and the mechanism of EBV viremia must be determined. Third, a comparison with the non-COVID-19 control group was challenging. In particular, patients with COVID-19 pneumonia are admitted to university hospitals earlier than those with other diseases in South Korea. However, even after accounting for this, there is no evidence that EBV viremia occurs more frequently in patients with COVID-19 than in those with other infectious diseases of similar severity, or that early EBV viremia causes severe COVID-19.