Immunopathogenic Insights on Preferential Human Herpesvirus-6 Reactivation in Drug Rash With Eosinophilia and Systemic Symptoms: A Scoping Review

Abstract

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.

From Viral Infection to Autoimmune Reaction: Exploring the Link between Human Herpesvirus 6 and Autoimmune Diseases

“…A hallmark of this condition is herpesvirus reactivation, especially HHV-6. A recent review revealed that among the analyzed articles, HHV-6 reactivation was significantly more common than other herpesviruses and affected 63% of DRESS patients [ 148 ]. The reactivation of HHV-6 has been strongly associated with DiHS/DRESS severity and relapsing episodes following the initial acute phase, even after the interruption of the culprit drug [ 148 , 149 ].…”

Relevance of Human Herpesvirus 6 Reactivation in Drug Rash With Eosinophilia and Systemic Symptoms

“…We suggest some additional considerations that are associated with viral reactivation. First, in DRESS, reactivation of HHV-6B occurs more frequently (in about 60% of cases) than does reactivation of CMV, Epstein-Barr virus, and HHV-7 . Reactivation of HHV-6B in blood is typically detected weeks after the onset of DRESS .…”

“…First, in DRESS, reactivation of HHV-6B occurs more frequently (in about 60% of cases) than does reactivation of CMV, Epstein-Barr virus, and HHV-7 . Reactivation of HHV-6B in blood is typically detected weeks after the onset of DRESS . For that reason, it has been assumed that reactivation of the virus is not likely a cause of DRESS and that drugs that trigger DRESS also encourage reactivation of the virus.…”

“…This could indicate that viral reactivation in the skin is associated with the onset of DRESS. Whether it has a causal role, it is plausible that viral reactivation may exacerbate and prolong the pathology of DRESS, and there are several possible immunopathologic mechanisms for how HHV-6 reactivation might do this …”

“…Second, the possible benefit of antiviral therapy in patients with DRESS and evidence of HHV-6 reactivation (even if CMV reactivation is not present) deserves study. To our knowledge, no randomized trials or large prospective studies have assessed antiviral therapy in DRESS, although many positive outcomes have been associated with antiviral administration . The treatment of HHV-6 encephalitis, a potentially fatal HHV-6 sequelae, with ganciclovir or valganciclovir following hematopoietic cell transplant is currently validated and recommended .…”