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.

Introduction Human herpesvirus-6 (HHV-6) is a ubiquitous lymphotropic betaherpesvirus that can reactivate in drug rash with eosinophilia and systemic symptoms (DRESS). Despite recent publications advancing our understanding of HHV-6 in DRESS, the exact role of HHV-6 in disease pathogenesis remains unclear. Methods A scoping review with the PubMed query “(HHV 6 AND (drug OR DRESS OR DIHS)) OR (HHV6 AND (drug OR DRESS OR DIHS))” was conducted in accordance with PRISMA guidelines. Articles containing original data on at least one DRESS patient with HHV-6 testing were included. Results Our search returned a total of 373 publications, of which 89 met eligibility criteria. HHV-6 reactivation occurred in 63% of DRESS patients (n = 748), which was significantly more often than other herpesviruses. HHV-6 reactivation was associated with worse outcomes and greater severity in controlled studies. Case reports have demonstrated sometimes fatal HHV-6-related multi-organ involvement. Temporally, HHV-6 reactivation typically occurs 2 to 4 weeks after DRESS onset and has been linked to markers of immunologic signaling, such as OX40 (CD134), an HHV-6 entry receptor. Efficacy of antiviral or immunoglobulin treatment has only been demonstrated anecdotally, and steroid use may affect HHV-6 reactivation. Conclusion HHV-6 is implicated in DRESS more than in any other dermatologic condition. It is still unclear whether HHV-6 reactivation is cause or consequence of DRESS dysregulation. Similar pathogenic mechanisms precipitated by HHV-6 in other contexts may be relevant in DRESS. Future randomized controlled studies to assess effects of viral suppression on clinical outcomes is needed.

A patient with an ultimate diagnosis of human herpesvirus-6 (HHV-6) encephalitis developed central nervous system (CNS) symptoms 13 days after undergoing myeloablative haploidentical allogeneic hematopoietic stem cell transplant (HSCT). Due to the patient’s body habitus, magnetic resonance (MR) imaging was not obtained until the onset of retrograde amnesia on day +24. MR imaging and other clinical findings eliminated all skepticism of HHV-6 encephalitis and HHV-6 antivirals were initiated on day +28, leading to gradual recovery. This case demonstrates some of the factors that may complicate the diagnosis of post-alloHSCT HHV-6 encephalitis. Because HHV-6 encephalitis and viremia can occur without warning, a single negative study should not exclude future development, especially if CNS symptoms are present. Acute graft-versus-host disease and cord blood transplantation are both significant risk factors for HHV-6 encephalitis. Human leukocyte antigen (HLA) mismatch, engraftment complications, or certain HLA alleles have also been associated with HHV-6 encephalitis. Chromosomally integrated HHV-6 must also be ruled out to prevent inappropriate and potentially harmful administration of antivirals. Due to the severe short- and long-term sequelae of HHV-6 encephalitis, appropriate treatment should be administered as soon as possible.