Epstein–Barr Virus and Human Herpesvirus-6 Reactivation in Acute COVID-19 Patients

Abstract

Beyond their pulmonary disease, many COVID-19 patients experience a complex constellation of characteristics, including hyperinflammatory responses, autoimmune disorders, and coagulopathies. However, the pathogenesis of these aspects of COVID-19 is obscure. More than 90% of people are latently infected with the lymphotropic herpesviruses Epstein–Barr Virus (EBV) and/or Human Herpesvirus-6 (HHV-6). Some of the inflammatory features of COVID-19 resemble clinical syndromes seen during EBV and HHV-6 infection, and these latent viruses can be reactivated by inflammatory mediators. We hypothesized that EBV and HHV-6 reactivation might be a common feature of early COVID-19, particularly in patients with more inflammation. We tested for EBV and HHV-6 reactivation in 67 patients acutely hospitalized with COVID-19 using previously validated quantitative PCR assays on the plasma. In our cohort, we found that 15/67 (22.4%) patients had detectable EBV and 3/67 (4.5%) had detectable HHV-6. This frequency of activation is somewhat more than the frequency reported for some healthy cohorts, such as blood donors and other healthy control cohorts. There was no association between EBV or HHV-6 and markers indicative of more inflammatory disease. We conclude that EBV and HHV-6 activation at about day 7 of hospitalization occurred in a modest fraction of our cohort of COVID-19 patients and was not associated with high levels of inflammation. In the modest fraction of patients, EBV and HHV-6 reactivation could contribute to some features of acute disease and pre-disposition to post-acute sequelae in a subset of patients.

Reactivation of herpesviruses during COVID‐19: A systematic review and meta‐analysis

“…The detailed screening process is available in Figure 1. Finally, 32 articles were included in our systematic review 15,18–48 . The characteristics of included studies are shown in Table 1.…”

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Focus on the Pathophysiological and Diagnostic Role of Viruses

“…Therefore, it is possible to speculate that the T-cell hyperactivation and systemic cytokine storm seen in COVID-19 patients may be a predisposing factor for delayed drug hypersensitivity reactions [ 102 ], also given the absence of SARS-CoV-2 RNA in skin biopsies from patients affected by maculopapular skin rashes. Moreover, the reactivation of HHV-6, EBV and CMV has been described in patients with COVID-19 [ 103 , 104 , 105 ], highlighting a possible shared pathophysiological mechanism.…”

COVID-19, SARS-CoV-2 Vaccination, and Human Herpesviruses Infections

“…This group also had higher day-14 and day-28 mortality rates compared to the EBV non-reactivated group. Cases of human herpesvirus-6 reactivation or coinfection have also been reported in association with COVID-19 [ 41 , 42 ]. In both studies [ 41 , 42 ], HHV-6 reactivation was detected, but there was no evidence of an association with COVID-19 disease severity or mortality.…”

“…Cases of human herpesvirus-6 reactivation or coinfection have also been reported in association with COVID-19 [ 41 , 42 ]. In both studies [ 41 , 42 ], HHV-6 reactivation was detected, but there was no evidence of an association with COVID-19 disease severity or mortality.…”