Yoko Kano

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

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, re-constitution 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.

Defective Regulatory T Cells In Patients with Severe Drug Eruptions: Timing of the Dysfunction Is Associated with the Pathological Phenotype and Outcome

Toxic epidermal necrolysis (TEN) and drug-induced hypersensitivity syndrome (DIHS) represent two ends of a spectrum of severe drug eruptions: DIHS is unique in that severe epidermal damage seen in TEN is absent, sequential reactivations of herpesviruses occur, and autoimmunity often ensues. To investigate whether changes in regulatory T (Treg) cell function would contribute to variability in the clinical manifestations, we examined the frequency, phenotype, and function of Treg cells both during the acute stage and again long after clinical resolution of both diseases. Dramatic expansions of functional Treg cells were found in the acute stage of DIHS. In contrast, Treg function was profoundly impaired in TEN, although present in normal frequency. Skin homing addressins were more preferentially expressed on Treg cells in DIHS than in TEN. Indeed, Treg cells were more abundantly present in the skin lesions of DIHS. Surprisingly, Treg cells contracted upon resolution of DIHS became functionally deficient, whereas their functional defects in TEN were restored upon recovery. These findings indicate that a transitory impairment in their function during the acute stage of TEN may be related to severe epidermal damage, while a gradual loss of their function after resolution of DIHS may increase the risk of subsequently developing autoimmune disease.

Utility of the lymphocyte transformation test in the diagnosis of drug sensitivity : dependence on its timing and the type of drug eruption

Background:  Lymphocyte transformation test (LTT) is a safety and reproducible test to assess activation of drug‐specific T cells in vitro; however, there are several practical concerns such as the time of testing and the influence of treatment. Our aim was to define the right timing to perform LTT for determining the causative agent in various types of drug reactions.

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

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).

The Variable Clinical Picture of Drug-Induced Hypersensitivity Syndrome/Drug Rash with Eosinophilia and Systemic Symptoms in Relation to the Eliciting Drug

Drug-induced hypersensitivity syndrome (DIHS)/drug rash with eosinophilia and systemic symptoms (DRESS) is a life-threatening adverse reaction characterized by skin rashes, fever, leukocytosis with eosinophilia or atypical lymphocytosis, lymph node enlargement, and liver or renal dysfunction. The syndrome develops 2 to 6 weeks after initiation of administration of a specific drug. It has been demonstrated that various herpesvirus reactivations, in addition to human herpesvirus 6, contribute to internal organ involvement and the relapse of symptoms observed long after discontinuation of the causative drugs. A better understanding of the interplay in the development of DIHS/DRESS has implications for safer and more efficient treatment of this syndrome.

Current understanding of cytomegalovirus infection in immunocompetent individuals

Human cytomegalovirus (CMV) is a member of the herpes family of viruses. After primary infection, it undergoes latency/persistence. Significant progress has been made in the last few years in detecting CMV. The most available approach to the diagnosis of CMV infection is the direct detection of CMV antigen in nuclei of peripheral blood leukocytes, an assay known as pp65 direct antigenemia test. CMV infection is well controlled in the immunocompetent hosts; however, there are various immunological changes in immune function during and after recovery from CMV infections. Characteristic changes in lymphocyte subsets occur during CMV infection, mainly involving expansion and activation of CD8+ T lymphocytes and NK cells. On the other hand, CMV has an array of immune escape strategies for establishing a life long latent state: CMV inhibits major histocompatibility complex (MHC) class I expression within infected cells and impairs IFN-gamma-induced MHC class II-dependent antigen presentation by macrophages; it can also encode proteins that can interfere with the presentation of viral peptide antigens to T cells. While cutaneous manifestations of CMV seen in immunocompromised patients have been extensively reported, those in adult immunocompetent individuals have received relatively little attention: in this setting the primary CMV infection appears as CMV mononucleosis. At the time of occurrence of the mononucleosis syndrome, a variety of extracutaneous and cutaneous manifestations occur. These clinical symptoms are not the direct consequence of proliferation of CMV in given tissues but indicative of the immunological response toward CMV. The incidence of the appearance of eruptions in CMV mononucleosis is variable. Certain drugs given in the early stage of this disease play an important role in the development of eruption, just as with the ampicillin rashes in the Epstein-Barr virus mononucleosis. Although the mechanism by which drugs trigger the development of rashes in patients with CMV mononucleosis is unknown, it is assumed that CMV is likely to be a potential amplifier of drug rashes induced by activation of drug-specific T cells. By improving methods for detection of CMV, we can recognize that many types of eruptions other than CMV mononucleosis could be induced by primary infection or reactivation of CMV.

Visceral Involvements and Long-term Sequelae in Drug-induced Hypersensitivity Syndrome

Drug-induced hypersensitivity syndrome (DIHS) is a severe systemic reaction with several herpesvirus reactivations. Multiple organ failures appear during the course of the disease. The severity of DIHS is determined by the degree of visceral involvement. Autoimmune diseases also develop several months to years after the apparent clinical resolution of DIHS.

Short- and long-term outcomes of 34 patients with drug-induced hypersensitivity syndrome in a single institution.

BACKGROUND Drug-induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe systemic hypersensitivity reaction caused by specific drugs, in which herpesvirus reactivations and organ dysfunction occur during the course of the disease. Although recent reports have documented the development of autoimmune disease after complete resolution of DIHS/DRESS, relatively little is known about long-term outcomes after complete resolution of the disease. OBJECTIVE The aim of this study was to retrospectively analyze complications and sequelae in the early and late phases of DIHS/DRESS according to treatment. METHODS In all, 34 patients were classified into 2 groups: 14 patients with oral corticosteroid treatment; and 20 with noncorticosteroid treatment. The disease time course was divided into 2 periods: the first 6 months after onset of the drug reaction (early phase); and the period thereafter (late phase). Investigations to detect the presence of viral/bacterial infectious diseases, organ dysfunction, and autoantibodies were performed in both early and late phases. RESULTS Herpesvirus infections and pneumonia were detected in 6 and 2 patients, respectively, in the corticosteroid treatment group in the early phase. In the noncorticosteroid treatment group, 2 patients developed autoimmune diseases, namely lupus erythematosus and autoimmune thyroiditis. Autoantibodies were detected in 44.4% of patients examined in the late phase of the disease. LIMITATIONS This study only evaluated a small number of autoantibodies. CONCLUSION The need for anti-inflammatory effects from systemic corticosteroids should be balanced with the risk of infectious diseases and the benefits of preventing the appearance of later autoimmune conditions in patients with DIHS/DRESS.

The dynamics of herpesvirus reactivations during and after severe drug eruptions: their relation to the clinical phenotype and therapeutic outcome

Drug‐induced hypersensitivity syndrome/drug rash with eosinophilia and systemic symptoms (DIHS/DRESS) and Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) represent contrasting poles of severe drug eruptions, and sequential reactivations of several herpesviruses have exclusively been demonstrated in the former. No previous studies, however, were extended beyond the acute stage. We sought to investigate whether herpesvirus reactivations could also be observed in SJS/TEN and beyond the acute stage of both diseases.

Drug-Induced Hypersensitivity Syndrome: Recent Advances in the Diagnosis, Pathogenesis and Management

Drug-induced hypersensitivity syndrome (DIHS), also referred to as drug reaction with eosinophilia with systemic symptoms, is a life-threatening multiorgan system reaction caused by a limited number of drugs such as anticonvulsants. This syndrome is characterized by fever, rash, lymphadenopathy, hepatitis, and leukocytosis with eosinophilia. DIHS has several unique features that include the delayed onset, paradoxical deterioration of clinical symptoms after withdrawal of the causative drug and unexplained cross-reactivity to multiple drugs with different structures. Because of these features and a lack of awareness of this syndrome, DIHS is undoubtedly underdiagnosed in many countries despite its worldwide distribution. The clinical variability in the presentation and course of clinical symptoms of DIHS could now be interpreted as an indication that several herpesviruses reactivate in a sequential manner independently in the different organs. Dramatic expansions of functional regulatory T (Treg) cells observed in the acute stage would serve to induce such sequential reactivations of herpesviruses while a gradual loss of Treg function occurring after resolution of DIHS could increase the risk of subsequently developing autoimmune disease. Although systemic corticosteroids are the mainstay of treatment, it remains to be determined whether this treatment is beneficial from a viewpoint of disease outcome and sequelae.