International Journal of Molecular Sciences Review Current Perspective Regarding the Immunopathogenesis of Drug-Induced Hypersensitivity Syndrome/Drug Reaction with Eosinophilia and Systemic Symptoms (DIHS/DRESS) Fumi Miyagawa * and Hideo Asada Department of Dermatology, Nara Medical University School of Medicine, Nara 634-8522, Japan; [email protected] * Correspondence: [email protected]; Tel.: +81-744-29-8891; Fax: +81-744-25-8511 Abstract: Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS) is a severe type of adverse drug eruption associated with multiorgan involvement and the reactivation of human herpesvirus 6, which arises after prolonged exposure to certain drugs. Typically, two waves of disease activity occur during the course of DIHS/DRESS; however, some patients experience multiple waves of exacerbation and remission of the disease. Severe complications, some of which are related to cytomegalovirus reactivation, can be fatal. DIHS/DRESS is distinct from other drug reactions, as it involves herpes virus reactivation and can lead to the subsequent development of autoimmune diseases. The association between her- pesviruses and DIHS/DRESS is now well established, and DIHS/DRESS is considered to arise as a result of complex interactions between several herpesviruses and comprehensive immune responses, including drug-specific immune responses and antiviral immune responses, each of which may be Citation: Miyagawa, F.; Asada, H. mediated by distinct types of immune cells. It appears that both CD4 and CD8 T cells are involved in Current Perspective Regarding the the pathogenesis of DIHS/DRESS but play distinct roles. CD4 T cells mainly initiate drug allergies Immunopathogenesis of in response to drug antigens, and then herpesvirus-specific CD8 T cells that target virus-infected Drug-Induced Hypersensitivity Syndrome/Drug Reaction with cells emerge, resulting in tissue damage. Regulatory T-cell dynamics are also suggested to contribute Eosinophilia and Systemic Symptoms to the diverse symptoms of DIHS/DRESS. However, the pathomechanisms of this complex dis- (DIHS/DRESS). Int. J. Mol. Sci. 2021, ease remain largely unknown. In particular, how viral infections contribute to the pathogenesis of 22, 2147. https://doi.org/10.3390/ DIHS/DRESS and why autoimmune sequelae arise in DIHS/DRESS are yet to be elucidated. This ijms22042147 review describes the clinical features of DIHS/DRESS, including the associated complications and sequelae, and discusses recent advances in our understanding of the immunopathogenic mechanisms Academic Editor: Uday Kishore of DIHS/DRESS. Received: 1 February 2021 Keywords: severe cutaneous adverse reactions; drug-induced hypersensitivity syndrome; drug reac- Accepted: 19 February 2021 tion with eosinophilia and systemic symptoms; herpesvirus; autoimmune disease; pathomechanism Published: 21 February 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in 1. Introduction published maps and institutional affil- iations. Severe cutaneous adverse reactions (SCARs) encompass a heterogenous group of delayed hypersensitivity reactions, most of which are caused by drugs. These include Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug-induced hypersen- sitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS), and acute generalized exanthematous pustulosis. DIHS/DRESS is a potentially fatal mul- Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. tiorgan hypersensitivity reaction associated with the reactivation of human herpesvirus This article is an open access article 6 (HHV-6) [1,2]. The term DRESS was first proposed in 1996 for a hypersensitivity syn- distributed under the terms and drome that had previously been reported under various names, such as anticonvulsant conditions of the Creative Commons hypersensitivity syndrome, allopurinol hypersensitivity syndrome, sulfone syndrome, and Attribution (CC BY) license (https:// dapsone hypersensitivity, depending on the causative drug [3]. It should be noted that creativecommons.org/licenses/by/ DIHS and DRESS were defined by the Japanese Research Committee on Severe Cutaneous 4.0/). Adverse Reactions (J-SCAR) [1] (Table1) and the RegiSCAR group [ 2] (Table2), respectively, Int. J. Mol. Sci. 2021, 22, 2147. https://doi.org/10.3390/ijms22042147 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, 2147 2 of 13 but both diseases probably belong to the same disease spectrum [4,5]. Specifically, HHV-6 reactivation is included as one of the diagnostic criterion for DIHS, but not for DRESS, and typical DIHS may represent a severe form of DRESS [6]. Table 1. Diagnostic criteria for drug-induced hypersensitivity syndrome (DIHS) established by a Japanese consensus group [1]. 1 Maculopapular rash developing > 3 weeks after starting with a limited number of drugs 2 Prolonged clinical symptoms 2 weeks after discontinuation of the causative drug 3 Fever (>38 ◦C) 4 Liver abnormalities (alanine aminotransferase > 100 U·L−1) a 5 Leukocyte abnormalities (at least one present) a Leukocytosis (>11 × 109 L−1) b Atypical lymphocytosis (>5%) c Eosinophilia (>1.5 × 109 L−1) 6 Lymphadenopathy 7 Human herpesvirus 6 reactivation The diagnosis is confirmed by the presence of the seven criteria above (typical DIHS) or of the five (1~5) (atypical DIHS). a This can be replaced by other organ involvement, such as renal involvement. Table 2. Inclusion criteria for potential case of HSS/DRESS in RegiSCAR [2]. Hospitalization Reaction suspected to be drug related Acute skin rash a Fever above 38 ◦C a Enlarged lymph nodes at at least two sites a Involvement of at least one internal organ a Blood count abnormalities Lymphocytes above or below the laboratory limits a Eosinophils above the laboratory limits (in percentage or absolute count) a Platelets below the laboratory limits a a Three or more required. Our understanding of the pathophysiology of DIHS/DRESS has evolved considerably over the last decade. DIHS/DRESS is distinguished from other drug eruptions by several characteristics, including the fact that it is associated with a limited number of causative drugs, exhibits late onset and a prolonged course, and patients’ clinical symptoms deteri- orate after treatment with the causative drug is discontinued. Herpesvirus reactivation, multiorgan involvement, a relapsing/remitting disease course, and delayed autoimmune diseases are also prominent features of DIHS/DRESS. The current consensus on the patho- genesis of DIHS/DRESS is that it occurs as a result of complex interactions between several herpesviruses and comprehensive immune responses, including drug-specific immune responses and antiviral immune responses, each of which may be mediated by distinct types of immune cells [7] (Figure1). Although the association between herpesviruses and DIHS/DRESS is well established, several aspects of these conditions, including how viral infections contribute to the pathogenesis of DIHS/DRESS and why autoimmune sequelae arise in DIHS/DRESS are yet to be elucidated. In this review, we summarize the clinical features of DIHS/DRESS, including the associated complications and sequelae, and ex- plore current knowledge regarding the immunopathogenic mechanisms of DIHS/DRESS, particularly the roles of T cells and herpesviruses. Int. J. Mol. Sci. 2021, 22, 2147 3 of 13 Int. J. Mol. Sci. 2021, 22, 2147 plications and sequelae, and explore current knowledge regarding the immunopatho-3 of 13 genic mechanisms of DIHS/DRESS, particularly the roles of T cells and herpesviruses. Figure 1. Scheme depicting the clinical course and immunological mechanism involved in Figure 1. Scheme depicting the clinical course and immunological mechanism involved in DIHS/DRESS. DIHS/DRESS are considered to occur as a result of complex interactions between DIHS/DRESS. DIHS/DRESS are considered to occur as a result of complex interactions between several herpesviruses and comprehensive immune responses, including drug-specific immune re- several herpesviruses and comprehensive immune responses, including drug-specific immune responsessponses and antiviral immune responses.responses. AfterAfter thethe resolutionresolution ofof thethe disease,disease, autoimmune autoimmune responses re- sponsesmay appear. may appear. 2. Clinical Features 2. Clinical Features 2.1. Clinical Symptoms 2.1. Clinical Symptoms DIHS/DRESS is characterized by a delayed onset, i.e., it usually occurs 3 weeks to 3 monthsDIHS/DRESSafter the is initiationcharacterized of treatment by a delayed with theonset, causative i.e., it drug,usually and occurs the deterioration 3 weeks to 3 of monthsclinical after symptoms the initiation after the of cessation treatment of with such the treatment causative [1,2 ,drug,7]. These and featuresthe deterioration are peculiar of to clinicalDIHS/DRESS symptoms and after are the not cessation seen in other of such types treatment of drug eruptions. [1,2,7]. These A limited features number are peculiar of drugs, to includingDIHS/DRESS carbamazepine, and are not phenytoin,seen in other phenobarbital, types of drug zonisamide, eruptions. lamotrigine,A limited number mexiletine, of drugs,dapsone, including sulfasalazine, carbamazepine, minocycline, phenytoin, allopurinol, phenobarbital, and vancomycin, zonisamide, are implicated lamotrigine, cause mexiletine,in most cases dapsone, of DIHS/DRESS sulfasalazine, [4,7 ,minocycline,8]. HHV-6 reactivation allopurinol, has and also vancomycin,