Drug-Induced Hypersensitivity Syndrome and Viral Reactivation

Abstract

Drug-induced hypersensitivity syndrome (DIHS), often referred to as drug reaction with eosinophilia and systemic symptoms (DRESS), is a life-threatening multi-organ system reaction characterized by rash, fever, lymphadenopathy, hepatitis, and leukocytosis with eosinophilia. DIHS has a worldwide distribution but is undoubtedly underdiagnosed in many countries probably due to a lack of awareness. This syndrome has several unique features that cannot be solely explained by drug etiology: they include delayed onset, a paradoxical worsening of clinical symptoms after withdrawal of the causative drugs and unexplained crossreactivity to multiple drugs with different structures. These unique features suggest the additional role of viral infections. Indeed, we demonstrated that not only human herpesvirus 6 (HHV-6) but also other herpesviruses (EpsteinBarr virus, cytomegalovirus and HHV-7) can be reactivated in a sequential manner during the course of DIHS, as demonstrated in graft-versus-host disease. In this review, we will discuss recent work including our own, focusing on the interactions among what we considered the main players of inflammatory responses in DIHS: cross-reactive memory T cells and various herpesviruses.In 1938, Merritt and Putnam [1] reviewed the toxic symptoms caused by therapy with phenytoin and noted that the symptoms could be divided into two cutaneous reactions: the first one being a mild, morbilliform eruption that healed when phenytoin was withdrawn and often did not re-

Drug-induced Liver Injury with HHV-6 Reactivation

“…Although our patient had received treatment with numerous drugs before admission to our hospital, acetaminophen was suspected as the most likely causal agent based on the clinical course, such as repeated doses and receiving the highest score possible on the criteria for DILI (8), although it is possible that other drugs could be the causal agent. Acetaminophen is well-known as a cause of DILI, inducing liver damage through its metabolite N-acetyl-p-benzoquinone imine (10).…”

“…The diagnosis of typical DIHS can be confirmed if the following 7 criteria are fulfilled: 1) maculopapular rash developing after administration of the specific causative drug; 2) prolonged clinical symptoms; 3) fever >38 ; 4) liver dysfunction; 5) leukocytosis, atypical lymphocytosis and eosinophilia; 6) lymphadenopathy; and 7) HHV-6 reactivation. The presence of 5/7 criteria is indicative of atypical DIHS (10).…”

“…Drugs commonly associated with DIHS include antiepileptic drugs, diaphenylsulfone, allopurinol, minocycline and mexiletine (10). One case of suspected DIHS associated with acetaminophen has been previously reported (11).…”

Bronchoscopic Investigation of Atypical Drug-induced Hypersensitivity Syndrome Showing Viral Lung Involvement

“…It has been suggested that a drug-specific immune reaction induces viral reactivation, such as human herpes virus-6 (HHV-6) (2, 3), cytomegalovirus (CMV) (4), or Epstein-Barr virus (EBV) (4), followed by the activation of cytotoxic CD8 + T lymphocytes, which cause tissue damage (5). The diagnosis is confirmed by the presence of seven criteria including HHV-6 reactivation (typical DIHS) or five criteria excluding HHV-6 reactivation (atypical DIHS) during the course of the disease (4,6). Because most DIHS cases have been reported by dermatologists, to the best of our knowledge, there have so far been no reports that examined the reactivation of the virus in lung tissue.…”

Drug rash with eosinophilia and systemic symptoms (DRESS) after an unrelated donor BM transplant

“…4 Furthermore, several authors have suggested a possible interaction between DRESS and reactivation or primary infection with HHV6, 5,6 and other herpesviruses (EBV, CMV and HHV7) can be reactivated during the course of DIHS, as has been demonstrated in GVHD. 7 Our patient suffered a reactivation of HHV causing a viral encephalitis at 4 weeks after the surgery. 8 The differential diagnosis between a severe GVHD and DRESS could be on the basis of gut involvement and jaundice, neither of which is usual in DRESS.…”