Drug-induced Hypersensitivity Syndrome(DIHS): A Reaction Induced by a Complex Interplay among Herpesviruses and Antiviral and Antidrug Immune Responses

Abstract

A relationship between viral infections and the simultaneous or subsequent development of allergic inflammation has often been observed in various clinical situations. Recent studies suggest an intimate relationship between reactivations of herpesviruses including human herpesvirus 6 (HHV-6) and the development of a severe systemic hypersensitivity reaction referred to as drug-induced hypersensitivity syndrome (DIHS). This syndrome has several important clinical features that cannot be solely explained by drug antigen-driven oligoclonal expansion of T cells: they include paradoxical worsening of clinical symptoms after discontinuation of the causative drug. In view of the similarity to GVHD or immune reconstitution syndrome (IRS) in clinical manifestations and emergence of viral infections, the clinical symptoms observed during the course of DIHS and GVHD are likely to be mediated by antiviral T cells that can cross-react with the drug and alloantigens, respectively. In considering common intrinsic properties of the causative drugs to potentially induce immunosuppression, reconstitution of a valid immune response to these viruses, which is typically observed in IRS, may be the most crucial process that takes place after withdrawal of the causative drug in patients with DIHS. Thus, this syndrome should be regarded as a reaction induced by a complex interplay among several herpesviruses (EB virus, HHV-6, HHV-7, and cytomegalovirus), antiviral immune responses, and drug-specific immune responses. This review includes discussion of the pathomechanism, the clinical symptoms, laboratory findings, pathological findings and therapy.

A Case of Drug-Induced Hypersensitivity Syndrome with Recurrent Varicella

“…Drug-induced hypersensitivity syndrome (DIHS) and drug reaction with eosinophilia and systemic symptoms (DRESS) are considered to be closely related to reactivation of various herpes viruses including human herpesvirus 6 (HHV-6) and the development of a severe systemic hypersensitivity reaction [1,2]. We herein report a very rare case with DHIS associated with recurrent varicella secondary to reactivation of the varicella-zoster virus (VZV).…”

“…On the fifth day of illness, histopathological examination of the skin revealed lymphocytic infiltration and vacuolar degeneration at the epidermal-dermal junction, as well as mild lymphocytic infiltration and edema in the superficial dermis. She had symptoms including liver dysfunction, atypical lymphocytes in peripheral blood, high-grade fever, lymphadenopathy along with typical eruption after cessation of carbamazepine as specific medications for DIHS, and was ultimately diagnosed as having atypical DIHS because there was no detection of reactivation of HHV-6 according to the diagnostic criteria [1,3]. Oral administration of prednisolone (PSL) at 50 mg (1 mg/kg)/day was started immediately, resulting in fever reduction within a few days and gradual resolution of the skin eruption.…”

Skin manifestations of drug allergy

“…Published case reports and small series have pointed to oral prednisolone to treat DRESS as probably the most accepted intervention in the treatment of severe drug reactions: 1-1.5 mg kg -1 has been recommended but we have seen efficacious responses to 0.5 mg kg -1 (unpublished) with rapid resolution of rash and fever. The association with human-herpes virus-6 (HHV-6) re-activation characteristically 2 weeks after rash onset, was recognized in the late 1990s [32,54,55] and has been proposed as an explanation for the characteristic flaring seen in this condition [56] although precise explanation of the role of the virus in the disease remains unclear. Careful monitoring for potential viral reactivation is therefore essential, but it should be noted that sporadic reports have identified reactivation of other herpes viruses as well (EBV, CMV, HHV-6, HHV-7, HSV, VZV) [31].…”

“…There may be recurrence of fever, either a leukocytosis or lymphopenia and deterioration of organ function. This is due to reactivation of members of the herpes virus family, HHV6 and HHV7 in particular, but EBV and/or CMV as well [31,32].…”

Allergy to Antibiotics in Children: Who Is to Blame and What to Do?

“…It is usually caused by reactivation of herpesvirus, especially of herpesvirus 6, Epstein-Barr virus or cytomegalovirus [52]. Diagnostic criteria for DRESS diagnosis include the following clinical and paraclinical symptoms [53]: 1) maculopapular rash >3 weeks into the treatment; 2) persistence of clinical symptoms after the causative drug has been withdrawn; 3) fever (>38 o C); 4) hepatic dysfunction (ALT>100 IE/l) or involvement of other organs and systems; 5) peripheral blood disorders that may involve at least 1 of the following symptoms: -leukocytosis (>11x10 9 cells/l); -atypical lymphocytosis (>5%); -eosinophilia (>1.5x10 9 cells/l); 6) lymphadenopathy; 7) herpesvirus 6 reactivations detectable 2-3 weeks after development of symptoms. Presence of all 7 criteria confirms diagnosis "typical drug-induced hypersensitivity syndrome"; presence of 5 criteria is considered to be a symptom of atypical drug-induced hypersensitivity syndrome.…”