Several herpesviruses can reactivate in a severe drug-induced multiorgan reaction in the same sequential order as in graft-versus-host disease

TLDR

Drug‑induced hypersensitivity syndrome is a severe multiorgan reaction associated with reactivation of human herpesvirus‑6, and evidence suggests other herpesviruses may also contribute, mirroring patterns seen in graft‑versus‑host disease. We aimed to determine whether sequential herpesvirus reactivation occurs in severe DIHS patients, as seen in GVHD, and whether it coincides with post‑drug discontinuation clinical manifestations. We quantified viral DNA of CMV, EBV, HHV‑6, and HHV‑7 in serial blood samples using real‑time TaqMan PCR. In the four patients, a sequential reactivation cascade—starting with HHV‑6 or EBV, followed by EBV or HHV‑7, and culminating in CMV—was observed, and the timing of organ failure after drug withdrawal coincided with these reactivations, indicating that such sequential herpesvirus reactivation drives multiorgan failure in severe drug reactions.

Abstract

Background Drug-induced hypersensitivity syndrome (DIHS) is a severe multiorgan systemic reaction. Numerous studies have linked reactivation of human herpesvirus (HHV)-6 with the development of DIHS. Recent articles have suggested that reactivation of other herpesviruses besides HHV-6 might also be involved in the development of DIHS. On the other hand, recent studies have provided evidence for a role of reactivation of various herpesviruses in the development of graft-versus-host disease (GVHD). Objectives We attempted to determine whether sequential herpesvirus reactivation could be detected in four patients with severe DIHS, as observed in patients with GVHD, and be coincident with various clinical manifestations that developed after discontinuation of the causative drugs. Methods Detection and quantification of viral DNA [cytomegalovirus (CMV), Epstein–Barr virus (EBV), HHV-6 and HHV-7] in sequential blood samples were performed using real-time polymerase chain reaction assays, based on TaqMan technology. Results In these patients, the cascade of virus reactivation initiated by HHV-6 or EBV extended to EBV or HHV-7, and eventually to CMV. Clinical manifestations of this syndrome followed by failure of various organs occurring despite discontinuation of the drug were coincident with these herpesvirus reactivations. Conclusions These results suggest that various herpesviruses can reactivate in the setting of severe drug reactions in a similar sequential order to that described in GVHD. The sequential reactivation of these herpesviruses is responsible for the development of multiorgan failure occurring after discontinuation of the causative drug.