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  • br Involvement of herpesviruses in drug allergy

    2018-11-12


    Involvement of herpesviruses in drug allergy A relationship between viral infections and the simultaneous or subsequent development of drug eruptions has been observed in a number of clinical situations. One of the well-known examples is ampicillin rash during infectious mononucleosis (IM), an acute illness which is generally the result of delayed primary infection with EBV and is characterized by pharyngitis, cervical lymphadenopathy, fever, and fatigue (Figure 1). Although earlier studies reported that most IM patients, once treated with ampicillin, developed extensive maculopapular rashes in the 2nd week after the administration of the drug, similar rashes have been reported to occur in IM patients who had received other antibiotics, thus indicating that ampicillin is not the sole factor. Because only 10% of patients recovered from IM showed sensitivity to ampicillin and there is a similar prevalence found in the general population, ampicillin rashes during IM are unlikely to be due to a de novo induction of drug antigen-specific T cells uniquely generated by ampicillin alone in the setting of delayed primary infection with EBV. In view of the observation that large expansions of activated EBV-specific CD8+ T cells and increased natural killer (NK) cell numbers are observed during the disease and that EBV-specific T cells have been shown to cross-react with self-human leukocyte antigen (HLA) ldk378 of several common HLA-B alleles, preferential development of drug rashes during the disease may be due to a selective expansion of CD8+ T cells, which are cross-reactive to the drug, from EBV-specific CD8+ T cells already present in large amounts before administration of the drug. Thus, it remains unclear why only a proportion of IM patients develop drug rashes, but it may be related to the attendant release of interleukin (IL) 6, whose level showed correlation with the symptom severity of IM. Interestingly, the acute symptoms of IM resolve in 2–6 weeks, but relapse can occur in the first 6–12 months following infection, a finding that can be also observed in a severe systemic hypersensitivity reaction to drug as described later. Given the similarity in sequences of clinical symptoms and clinical manifestations between IM and such a severe systemic hypersensitivity reaction (Figure 1), knowledge on the immune control of primary and persistent herpesvirus infection could be translated into clinical practice contributing to improved patient care in severe drug eruptions.
    Severe systemic hypersensitivity reaction associated with herpesvirus reactivation Fifteen years ago, we and Dr. Hashimoto\'s group independently published landmark studies that sparked the current advances in our understanding of the role of viral infections in drug allergy. These initial studies detected HHV-6 DNA by polymerase chain reaction (PCR) in blood and skin specimens from patients with the severe systemic hypersensitivity reaction to drug, eventually referred to as drug-induced hypersensitivity syndrome (DiHS). DiHS, also referred to as drug reaction with eosinophilia with systemic symptoms (DRESS), represents the opposite end of a spectrum of severe drug eruptions. The first description of DiHS is credited to Merritt and Putnam, who in 1938 reviewed the toxic symptoms caused by phenytoin and noted that the symptoms could be divided into two cutaneous reactions, a mild, mobilliform eruption and a severe, exfoliative dermatitis with fever and eosinophilia. Since then, substrate feeders has become clear that the latter reaction is also associated with lymphadenopathy and multivisceral involvement. Although the latter reaction was recognized as a distinct syndrome in the early 1960s, there has been much debate about the diagnosis and considerable confusion about the name of this syndrome. Although the term DRESS is still widely used to describe the clinical symptoms, we proposed the alternative term ‘DiHS’ based on a retrospective nationwide survey of patients in Japan: in the survey, HHV-6 reactivations as evidenced by the significant rise in serologic immunoglobulin G (IgG) titers to HHV-6 or the detection of HHV-6 DNA in the blood were detected at a particular time point, 2–3 weeks after the onset of rash in the vast majority of patients regardless of treatment (Figure 2). Based on the survey, a Japanese consensus group named Japanese Research Committee on Severe Cutaneous Adverse Reaction (J-SCAR), established a set of criteria for the diagnosis of DiHS in 2006 (Table 1). The clinical and laboratory features of this syndrome in its florid form are currently well recognized in Japan but there has been debate about the inconsistent and variable terminology in other parts of the world. HHV-6 reactivations can be widely used as a specific and sensitive diagnostic clue in Japan, because they are rarely detected in a milder form of this syndrome. Nevertheless, the validity has not necessarily been confirmed in other parts of the world, largely due to an extraordinarily low prevalence of this test. In this regard, we investigated whether our definite DiHS cases could fall into the category “probable/definite DRESS” defined by the DRESS validation score Kardraun SH et al proposed. Our results showed that all of the definite DiHS cases associated with HHV-6 reactivations fell into the category “probable/definite DRESS”, although no significant correlation was noted between HHV-6 DNA loads detected in the blood and the DRESS validation score. In considering the rare detection of HHV-6 reactivations in a milder form of DiHS, which could be defined as “probable DRESS”, DRESS could represent a condition ranging from a clinically milder form to a florid form of DiHS. Thus, the DRESS validation score is a useful tool for diagnosis of DiHS/DRESS ldk378 when HHV-6 tests are unavailable.