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New aspects of drug-induced hypersensitivity syndrome

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Abstract

Drug-induced hypersensitivity syndrome (DIHS) is caused by a limited number of specific drugs and is characterized by late onset, infectious mononucleosis-like symptoms, and herpesvirus 6 (HHV-6) reactivation. Recently, the involvement of herpes viruses other than HHV-6, such as Epstein-Barr virus and cytomegalovirus, has been reported. Many approaches have been used to analyze the pathological mechanism, and have revealed new aspects of DIHS. Here, we focused on three key recent findings regarding DIHS: (i) overlap between DIHS and Stevens-Johnson syndrome/toxic epidermal necrolysis; (ii) the relevance of Epstein-Barr virus in the development of infectious mononucleosis-like symptoms of DIHS; and (iii) roles of monomyeloid precursors increased in the blood and plasmacytoid dendritic cells increased in the lesion skin in HHV-6 reactivation.

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... It has been reported that the prognosis of DIHS may be influenced by age, genetic factors, presence of underlying disease, viral reactivation, and type of treatment. Hepatitis and renal dysfunction are observed during the early phase of DIHS [5]. In this case, liver and renal dysfunction were observed on admission day, August 20. ...
... After carbamazepine dosage is stopped, a symptom may still progress and require about one month before it is relieved. This case showed two peaks characteristics clinically, and it was revealed from the reports about the course that reactivation of HHV-6 was involved [5]. The rise of the anti-HHV-6 IgG antibody titer was not seen 7 days after symptom onset, but a significant rise in the anti-HHV-6 IgG antibody titer was observed at 25 days after onset. ...
... In future, a genetic risk factor for carbamazepine-induced DIHS may provide useful information for decisions regarding individualized medication of anticonvulsants [7]. Oral administration of corticosteroids remains the general cure for the treatment of DIHS [5]. ...
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An 88-year-old man was diagnosed with trigeminal neuralgia, and treatment of carbamazepine 200 mg/day was initiated. About 6 weeks later, the patient developed a skin rash accompanied by fever. He was admitted to hospital and diagnosed with drug-induced hypersensitivity syndrome (DIHS) caused by carbamazepine. Oral carbamazepine treatment was stopped, but blood tests showed acute liver and acute renal failure. Drug-induced lymphocyte stimulation test (DLST) for carbamazepine, human herpes virus-6 (HHV-6) IgG, and CMV-HRP were negative. Oral prednisolone therapy was begun 18 days later. The titer of HHV-6 IgG antibodies was then detected (640 times). Following treatment, liver and renal function improved and the erythema disappeared.
... Drug-induced hypersensitivity syndrome (DIHS) is characterized by a limited number of causal drugs, delayed onset, worsening of clinical symptoms after discontinuation of the causal drugs, sequential reactivations of several herpesviruses, and development of several organ system failures long after clinical resolution. 1,2 The causal drugs of DIHS include carmabazepine, phenytoin, phenobarbital, zonisamide, mexiletine, diaphenylsulfone (dapson), salazosulfapyridine and allopurinol. 2,3 The data of DIHS have been collected to date mostly by referring to published article or meeting abstracts. ...
... 1,2 The causal drugs of DIHS include carmabazepine, phenytoin, phenobarbital, zonisamide, mexiletine, diaphenylsulfone (dapson), salazosulfapyridine and allopurinol. 2,3 The data of DIHS have been collected to date mostly by referring to published article or meeting abstracts. Japan has a relief system for sufferers from adverse drug reactions (ADRs) managed by the Pharmaceuticals and Medical Devices Agency (PMDA) which provides relief benefits for patients with severe ADRs in the appropriate use of the drugs concerned. ...
... 9 Diaphenylsulfone is classified as an antileprosy drug, but it is usually used for skin diseases such as erythema elevatum diutinum, linear IgA bullous dermatosis and prurigo pigmentosa in Japan. Although minocycline-induced DIHS has been reported frequently in other countries, it is not common in Japan, 2 and there were only 4 cases (0.4%) in this study. It is true that PMDA data include the reports by non-dermatologists. ...
... 3 In addition to Epstein-Barr virus (EBV), cytomegalovirus (CMV), and human herpesvirus 7 (HHV7), human herpesvirus 6 (HHV6) infection has also been associated with DHS. [3][4][5][6] Patients with DHS have been reported to have elevated antibody titers to HHV6 or detection of HHV6 on polymerase chain reaction (PCR) studies, although not all patients with DHS manifest an association with HHV6. Some authors have raised concern that HHV6-positivity in context of DHS may influence disease severity in affected patients. ...
... Some authors have raised concern that HHV6-positivity in context of DHS may influence disease severity in affected patients. [6][7][8] In addition, it has been speculated that systemic corticosteroid treatment of those with DHS and concomitant expression of HHV6 may prolong the drug reaction, although it remains unclear whether the presence of HHV6 is pathogenic or a non-pathogenic marker for disease severity. 5,6,9 Although systemic corticosteroids have been the mainstay of treatment, their efficacy remains controversial. ...
... [6][7][8] In addition, it has been speculated that systemic corticosteroid treatment of those with DHS and concomitant expression of HHV6 may prolong the drug reaction, although it remains unclear whether the presence of HHV6 is pathogenic or a non-pathogenic marker for disease severity. 5,6,9 Although systemic corticosteroids have been the mainstay of treatment, their efficacy remains controversial. 3,5,[10][11][12][13][14] This study evaluated pediatric patients with DHS who have concomitant expression of HHV6 on the basis of increased viral copy number on PCR studies to determine if they present with a different disease course when compared to those with DHS who do not have evidence of HHV6 infection or reactivation. ...
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Background: Human herpesvirus (HHV)6 positivity in the context of drug hypersensitivity syndrome (DHS) may influence disease severity. Systemic corticosteroid treatment of those with DHS testing positive for HHV6 has been speculated to prolong the duration of disease. Objectives: To evaluate whether paediatric HHV6-positive patients with DHS develop a more severe illness than those without presumed reactivation, and to evaluate the response to systemic corticosteroid treatment. Methods: A retrospective case series of 29 paediatric inpatients treated for DHS and tested for HHV6 was undertaken. HHV6-positive and -negative patients were identified and stratified into groups treated or not treated with systemic corticosteroids to examine their disease severity on the basis of hospital length of stay (LOS), total number of febrile days (Tfeb) and days until cessation of progression (CTP). Results: Human herpesvirus6-positive patients had similar demographic characteristics to those of HHV6-negative patients, but had significantly longer hospital LOS (11·5 days vs. 5 days, P = 0·039), Tfeb (12·5 days vs. 3 days, P = 0·032) and CTP (4 days vs. 2 days, P = 0·014). All HHV6-positive patients and most (80%) of the HHV6-negative patients received systemic corticosteroids. Among the HHV6-negative patients, those who received corticosteroids showed significantly shorter CTP than those who did not (3 days vs. 2 days, P = 0·043). Additionally, there was a trend towards shorter hospital LOS and Tfeb among HHV6-negative patients who received corticosteroids vs. those who did not, although these differences were not statistically significant. The most common inciting drugs included trimethoprim-sulfamethoxazole (34%), phenytoin (10%) and amoxicillin (10%). Conclusions: Human herpesvirus6 positivity with DHS is associated with a more severe disease course. Treatment with systemic corticosteroids was associated with a trend towards reduced hospital LOS and Tfeb, and a significantly reduced number of days until cessation of progression.
... Although the pathophysiology of DRESS remains unclear, T cell-mediated hypersensitivity reactions to drugs may be involved in its pathogenesis [4][5][6] . T effector lymphocytes have been classified into several subsets, including T helper 1 (Th1) cells, Th2 cells, and Th17 cells, based on cytokine production profiles [7,8] . ...
... HHV-6 reactivation typically occurs 2-3 weeks after the onset of DRESS [1][2][3][4] . Although the mechanisms underlying HHV-6 reactivation in DRESS remain unclear, HHV-6 reactivation may be secondary to an initial immunological reaction directed against the causative drug. ...
Article
Background: Drug rash with eosinophilia and systemic symptoms (DRESS), also known as drug-induced hypersensitivity syndrome, is characterized by severe drug-induced reactions with extensive cutaneous lesions and visceral involvement. Although T cell-mediated hypersensitivity reactions to drugs may be involved in the pathogenesis of DRESS, there is limited data regarding the T-cell phenotypes responsible for the pathogenesis of DRESS. Objective and methods: Using flow cytometry, we investigated the cytokine profiles and cutaneous lymphocyte antigen (CLA) expression in circulating T cells in patients with DRESS. Results: The proportions of circulating IL-4- and IL-13-producing CD4+ T cells, but not CD8+ T cells, were significantly higher in patients with DRESS during the active stage of the disease than in healthy subjects, and these proportions declined during the recovery stage. No differences in the proportions of circulating IFN-γ-, IL-17-, and IL-22-producing CD4+ and CD8+ T cells were observed between patients with DRESS and healthy subjects. A strong correlation between the proportion of IL-13-producing CD4+ T cells and serum levels of thymus and activation-regulated chemokine was observed. The proportion of CLA-expressing CD4+ T cells was significantly higher during the active stage of the disease. Moreover, the proportion of IL-13-producing CD4+ T cells was higher in the CLA+ subset than in the CLA- subset. Conclusions: Skin-homing IL-13-producing CD4+ T cells may be involved in the pathogenesis of DRESS.
... 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. ...
... The diagnosis is confirmed by the presence of the seven criteria above (typical DIHS) or of the five (1-5) (atypical DIHS). This can be replaced by other organ involvement, such as renal involvement [3]. ...
Article
Drug-induced hypersensitivity syndrome (DIHS) is attributed to immunodeficiency caused by certain drugs. Herein, we report a patient with DIHS due to recurrent varicella caused by reactivation of the varicella-zoster virus (VZV). The patient was a 39-year-old woman, who had started oral carbamazepine treatment for trigeminal neuralgia eight weeks before developing a high-grade fever and dark red plaques appearing over the entire body. She was diagnosed as having DIHS with liver dysfunction, atypical lymphocytes in peripheral blood, and lymphadenopathy. Oral administration of prednisolone at 50 mg/day was started and then tapered to 40 mg/day 13 days after the onset. Vesicles and blisters with bleeding in part subsequently appeared sporadically on the trunk and limbs. At that time, anti-VZV-IgM and VZV IgG antibody titers exceeded the normal ranges, and the patient was thus considered to have recurrent varicella. Mild symptoms including scattered blisters disappeared without treatment. This case suggested that VZV is one of the earliest viruses to reactivate in the development of DIHS.
... Therefore, a case diagnosed as SJS or TEN from its mucocutaneous symptoms, can also be diagnosed as DIHS from its clinical course and positive viral reactivation (Table 4). 10,51 Time of onset after the initiation of the causative drug does differ between DIHS and SJS/TEN. DIHS has a later onset of 2e6 weeks in 80% of the cases, most commonly at 4e5 weeks, while SJS/TEN has an early onset of within 3 weeks for 67% of cases. ...
... The overlapping cases were all caused by anticonvulsants. 51 In another study by Teraki et al., 8 patients diagnosed with SJS/ TEN due to anticonvulsants were examined, and a similarity with DIHS was seen. Seven of the 8 patients developed symptoms >3 weeks after starting anticonvulsants. ...
Article
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Toxic epidermal necrolysis (TEN) is a severe adverse drug reaction characterized by necrosis of the epidermis. Its incidence is approximately 1 per million a year and average mortality rate is high at 25–35%. TEN has a flu-like prodrome, followed by atypical, targetoid erythematous or purpuric macules on the skin. These macules coalesce to form flaccid blisters that slough off as areas of epidermal necrosis. Drugs such as allopurinol, sulfonamides, and carbamazepine are the most common causes. The human leukocyte antigen (HLA)-B*15:02 in Asians being administered carbamazepine and the HLA-B*58:01 antigen in patients of all ethnicities being administered allopurinol are known to be high-risk factors. Rapid diagnosis, discontinuation of the causative drug, and supportive treatment are essential for better prognosis and improvement of sequelae. Till now, systemic corticosteroids and intravenous immunoglobulins have been used as the most common active interventions; however, no gold standard has been established. In Japan, physicians follow a unique diagnostic criteria and treatment guideline to improve the diagnosis rate and streamline treatments. This may be a contributing factor for the lower mortality rate (14.3%). The efficacy of systemic corticosteroids, immunoglobulins, and plasmapheresis may have been beneficial as well. In Japan, TEN is defined as an epidermal detachment of over 10% of the body surface area (BSA), while the globally accepted definition established by Bastuji-Garin describes it as an epidermal detachment of over 30% of the BSA. In Japanese individuals, HLA-A*02:06, HLA-A*02:07, HLA-A*31:01 and HLA-B*51:01 may be linked to higher risks of TEN.
... İHSS, hayatı tehdit eden ciddi bir ilaç reaksiyonudur (1). Sınırlı sayıda ilaçla ortaya çıkması, geç başlangıçlı olması, uzamış seyri ve mononükleozisi andıran bulguları nedeniyle DRESS adı verilen ilaç reaksiyonlarından ayrılır (6). İHSS, DRESS'den daha ciddi olguları içeren formdur. ...
... İHSS'de mortalite %20'lere ulaşabilmektedir ve özellikle ileri yaş, renal yetmezlik, CMV reaktivasyonuna bağlı gelişen sarılık, hepatit görülen olgularda artmaktadır (5)(6)(7). Bunun aksine EBV reaktivasyonu gelişmiş olgularda akut dönemde daha hafif klinik seyir görülmekte; ancak yıllar sonra gelişen tip 1 diyabet ve hipotiroidi gibi geç dönemde ortaya çıkan otoimmün hastalıklardan sorumlu olmaktadır (7). HHV-6 reaktivasyonu, İHSS'li olguların çoğunda görülürken DRESS olarak tanımlanan olguların bir kısmında saptanabilmektedir (5). ...
Article
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The etiology of fever and rash is a challenging condition for clinicians in the diagnosis. Viral and bacterial agents are the most etiological factors, but drugs, chemicals, foods, and rheumatic diseases can also cause fever and rash. Drug-induced hypersensitivity syndrome is one of the life-threatening reactions in which systemic multiple organ involvement can be seen. The mortality rate in drug-induced hypersensitivity syndrome (DIHS) is about 20%. Therefore, it is important to clarify the etiology without delay. In our study, we aimed to present a rare case of salazopyrin hypersensitivity mimicking a viral illness with skin rash.
... 18 Other recent investigations using PCR of viral DNA identified early reactivation of HHV-6 and EBV, with later involvement of HHV-7 and CMV. 19 Among HHV, the most convincing data regarding the association of viral infection and DRESS concern HHV-6. 14-16 HHV-6 reactivation has been recently proposed as one of the criteria for confirmation of DRESS. ...
... Current management of DRESS generally includes discontinuation of the culprit drug and treatment with systemic corticosteroids. 19 However, no antiviral treatments have been suggested despite the evidence for a role of HHV. In the present case, sulfasalazine was immediately withdrawn and the patient was treated with intravenous corticosteroids. ...
Article
Full-text available
Drug rash with eosinophilia and systemic symptoms (DRESS) is a life-threatening systemic drug reaction characterized by fever, rash, hematological abnormalities, lymphadenopathy, and multiple internal organ involvement. Unfortunately, a long latency period as well as clinicians' unawareness of the disease entity often results in a delay of prompt diagnosis and treatment in clinical practice. A search of the literature revealed only few reports on DRESS in patients with inflammatory bowel diseases. The pathogenesis of the disease is not clearly understood, although several possible mechanisms, such as drug detoxification, slow acetylation, and reactivation of human herpes viruses, have been proposed in its development. Here, we present a rare case of DRESS associated with viral reactivation and defects in drug metabolism in a 22-year-old man who had been on sulfasalazine for 6 weeks to treat ulcerative colitis.
... В норме обеспечивают защиту при туберкулёзе, лепре, сифилисе [54]. По этому механизму развивается макулопапулёзная сыпь на лекарственные препараты [101]. Реакции IVa типа лежат в основе ревматоидного артрита (суставные поражения) [91], болезни Крона [27] и саркоидоза [65]. ...
Article
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THE PREPARATION OF PEDIATRICS IN DIFFERENT COUNTRIES OF THE WORLD V. G. Maidannyk, V. V. Zagorodnii (Kiev) Department of Pedіatrіcs N 4 A. Bohomolets National Medical University The authors carried out the analysis of training system of doctors-pediatrists in the different countries of Europe and USA. It is shown, that exists three models of the organization of rendering of medical care of children: pediatric model (the doctor-pediatrist as a primary part of rendering of medical care of children), system of the general practice (the doctor-pediatrist carries out functions of the adviser) and the combined system which is based on the listed above models. Pointed that the system of the general practice is inherent in the countries with a high level of incomes on one inhabitant of the country.
... 4 Changes in regulatory T cells and B cells have been found in DRESS syndrome. 14 Intravenous immunoglobulins contain antibodies that regulate immune responses by inhibiting cytotoxic T cells. IVIG interferes with the generation and activation of cytotoxic T cells and decreases their activity by blocking important cell surface molecules like antigen-specific T cell receptor. ...
... The results of the skin patch test for diagnosis can vary from one medicine to the next, and its negative predictive value is less than 100. 9,10 The strategy to diagnose when DRESS syndrome is suspected to happen due to any anti-TB drug as follows: Discontinue anti-TB treatment for at least one month after DRESS recovery, then perform skin patch tests to guide drug re-introduction.When stopping anti-TB medicines is not an option, second-line TB therapy should be started temporarily.If immediate reintroduction of first-line TB drugs is needed, Rifampicin should be avoided, and a dermatology specialist should be consulted. 4 Systemic corticosteroids must be given when there is cardiac, respiratory, or severe hepatic involvement. ...
Article
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A severe adverse reaction called Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS syndrome), is usually described by eosinophilia, fever, swollen lymph nodes, severe skin rash and extensive systemic association. It is distinguished by a lengthy latency period, which is characteristic drug reaction with eosinophilia and systemic symptoms (DRESS). Formerly known as drug-induced delayed multi-organ hypersensitivity syndrome (DIDMOHS) or drug-induced hypersensitivity (DIHS). There are a variety of clinical symptoms associated with the syndrome yet it is still poorly understood. Drugs most commonly implicate in Anticonvulsants are the most common cause of DRESS syndrome, followed by sulfonamides and a variety of anti-inflammatory medications.Anti-tubercular therapy (ATT) is rarely associated with DRESS syndromeWe present the case of a 60-year-old female patient who had previously been treated with Anti-tubercular Therapy for Tubercular Meningitis (ATT).She was admitted to the hospital with presenting complaints of vomiting, burning micturition, fever associated with chills, generalized swelling and reddish skin all over the body including facial puffiness. The problem was successfully resolved by refraining from the offending medication and administering supportive care. Thus, the case illustrates the necessity of considering anti-tubercular drug reactions even when symptoms are delayed. Keywords: Anti-tubercular Therapy (ATT), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), Adverse drug reaction (ADR), Drug-induced, Systemic symptoms syndrome
... Additionally, his HLA type (HLA-DRB1* 09:01-HLA-DQB1* 03:03) was previously reported to be associated with acute-onset T1DM (4). After ruling out other causes, such as viral infection or drug-induced hypersensitivity syndrome, the cause of FT1DM was deemed to be nivolumab treatment (5). Given the patient's CPR level of 5.92 ng/mL, his ability to secrete insulin appeared to be preserved at the time of his first visit, which might have caused us to overlook the onset of FT1DM. ...
Article
A 77-year-old-man with renal cell carcinoma who was undergoing nivolumab treatment visited our department due to hyperglycemia; his plasma glucose level was 379 mg/dL. Although his serum C-peptide immunoreactivity (CPR) level was preserved (5.92 ng/mL), we suspected an onset of fulminant type 1 diabetes mellitus (FT1DM) and immediately started insulin therapy. His CPR levels gradually decreased and were depleted within 1 week. We later discovered that the patient's casual CPR level had been abnormally high (11.78 ng/mL) 2 weeks before his admission. Hence, the possibility of FT1DM in hyperglycemic patients undergoing nivolumab treatment should not be excluded, even with a preserved CPR level.
... Les équipes japonaises (27,52,68,69) ...
Thesis
Ce travail relate un cas de DRESS induit par la sulfasalazine ; sa description clinique etbiologique ; les explorations cliniques, biologiques et iconographiques réalisées ; le traitement administré à la patiente et l'évolution constatée, tant clinique que biologique.Ce travail fait un état des lieux sur les multiples évolutions concernant le « Drug Reaction with Eosinophilia and Systemic Symptoms » durant ces 15 dernières années. Un consensus est obtenu sur son intitulé. Les critères cliniques et biologiques sont recensés afin d'établir, a posteriori, des critères diagnostiques permettant de confirmer ou non les diagnostics de DRESS. Les connaissances sur la physiopathologie du DRESS ont considérablement évolué durant cette période, donnant aux réactivations virales un rôle central dans son développement. Les virus de la famille des herpès virus humain (HHV 6, HHV 7, CMV et EBV) doivent être impérativement recherchés lors d'un cas de DRESS. Les traitements sont aussi mieux codifiés. Les tests allergologiques sont devenus de réalisation fréquente. Un suivi spécialisé en Centre de référence est requis afin d'assurer une rapidité de prise en charge symptomatique et de diagnostic biologique (notamment par PCR virales) ; d'assurer un suivi à distance de la phase aigüe en raison des possibles complications tardives, notamment immunologiques ; d'assurer un conseil dans l?utilisation de molécules apparentées à la molécule inductrice, après réalisation de tests allergologiques
... The reactivation of several viruses, such as human herpesvirus-(HHV-) 6, HHV-7, cytomegalovirus (CMV), and Epstein-Barr virus, sometimes occurs over the prolonged clinical course [35]. Cutaneous lesions emerging as late systemic manifestations of CMV tend to be rare, presenting as ulcerated erythematous papules that histopathologically exhibit intranuclear inclusion [36]. ...
Article
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Diagnosis of severe cutaneous adverse drug reactions should involve immunohistopathological examination, which gives insight into the pathomechanisms of these disorders. The characteristic histological findings of erythema multiforme (EM), Stevens–Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) provide conclusive evidence demonstrating that SJS/TEN can be distinguished from EM. Established SJS/TEN shows full-thickness, extensive keratinocyte necrosis that develops into subepidermal bullae. Drug-induced hypersensitivity syndrome (DIHS) and exanthema in drug reaction with eosinophilia and systemic symptoms (DRESS) each display a variety of histopathological findings, which may partly correlate with the clinical manifestations. Although the histopathology of DRESS is nonspecific, the association of two or more of the four patterns—eczematous changes, interface dermatitis, acute generalized exanthematous pustulosis- (AGEP-) like patterns, and EM-like patterns—might appear in a single biopsy specimen, suggesting the diagnosis and severe cutaneous manifestations of DRESS. Cutaneous dendritic cells may be involved in the clinical course. AGEP typically shows spongiform superficial epidermal pustules accompanied with edema of the papillary dermis and abundant mixed perivascular infiltrates. Mutations in IL36RN may have a definite effect on pathological similarities between AGEP and generalized pustular psoriasis.
... Drug-induced hypersensitivity syndrome (DIHS) is a severe adverse drug reaction caused by carbamazepine, allopurinol, or mexiletine; it is characterized by visceral organ involvement and the reactivation of various human herpesviruses, such as HHV-6, human cytomegalovirus (HCMV), and EBV (11). Although the frequency of fulminant T1DM in DIHS is only 0.54%, this is much higher than the frequency in the general Japanese population (0.010%) (12), indicating that virus reactivation might be associated with the onset of fulminant T1DM. ...
Article
Context Fulminant type 1 diabetes mellitus (T1DM) is thought to be partly caused by virus infection. Objective This study investigated the mechanism of β cell destruction in fulminant T1DM after drug-induced hypersensitivity syndrome (DIHS). Methods We determined the localization of viruses of human cytomegalovirus (HCMV), human herpesvirus 6 (HHV-6) and Epstein-Barr virus (EBV), and the expression of interferon regulatory factor 3 (IRF3) and viral receptors of Z DNA binding protein 1 (ZBP1) and retinoic acid-inducible gene I (RIG-I), together with inflammatory cells by immunohistochemistry of pancreas from an autopsy fulminant T1DM patient with DIHS or seven subjects with normal glucose tolerance who underwent pancreatectomy. Results HCMV-positive cells were detected in islets and exocrine areas in the fulminant T1DM patient. Greater numbers of macrophages, and CD4+ and CD8+ T lymphocytes had infiltrated into HCMV-positive islets than negative islets and 52.6% of HCMV-positive cells were also positive for IRF3. α cells expressed IRF3, ZBP1 or RIG-I. No HCMV-positive cells were detected in the control subjects. HHV-6-positive, but not EBV-positive, cells were present in the patient and the control subjects. Conclusions These findings indicate that the immunoresponse caused by HCMV infection was associated with β cell injury.
... One hypothesis states the possible reactivation of viruses including HHV6 and other herpes virus (including CMV, EBV, HHV-7) that may act as an amplifier of an inadequate immune reaction. 3,13 HHV6 in particular has been incriminated as a cofactor for the development of DRESS and is one of the diagnostic criteria in the J-SCAR scoring system. 1 In our patient there was no viral PCR evidence of reactivation of HHV6 and the other tested human herpes viruses. ...
Article
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Background: Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare and potentially life-threatening acute drug-induced hypersensitivity reaction. Antiepileptic drugs (AEDs) predominantly aromatic AEDs are commonly reported in DRESS. To date there are no reports of sulthiame AED causing DRESS syndrome. Method: We report a 10-year-old girl of Indian descent with AED resistant epilepsy on maintenance sodium valproate and clonazepam. Sulthiame AED was initiated to try to improve her seizure control. Five weeks after commencing sulthiame, she developed fever with a diffuse erythematous morbilliform maculopapular rash, elevated transaminases and atypical lymphocytes. At day 3 of illness, she deteriorated with worsening elevation of liver transaminases, thrombocytopenia, progression of rash, hepatosplenomegaly, pneumonitis and markedly elevated inflammatory markers. Immunomodulatory treatment of pulse methylprednisolone was given from day 7 which was associated with improvement inflammatory markers and complete resolution of rash from day 30 of illness. Results: The diagnosis of sulthiame-induced DRESS syndrome was made based on clinical, laboratory and skin histology findings. She was HLA-B heterozygous for HLA-B(∗)15:123 and 15:240 and HLA-A homozygous for HLA-A(∗)11:01:09. Both these HLA-A and HLA-B typing has not been reported before in cutaneous drug reactions. Conclusion: This is the first reported case of sulthiame-induced DRESS syndrome. Our case expands the list of possible susceptible HLA alleles associated with cutaneous drug reactions. It also raises the awareness of possible DRESS syndrome among patients commenced on sulthiame who will require immediate discontinuation of sulthiame and consideration of prompt treatment of corticosteroids.
... 32 Nevertheless, overlapping cases between CADR have been described between DRESS and SJS/TEN, DRESS and AGEP, and AGEP and SJS/TEN. [29][30][31][33][34][35] Our study reinforces the possibility that overlap of MPE and DRESS also exists. This possibility was recently raised also by Ortonne et al. 27 when discussing histological features of the exanthema in DRESS and MPE, which showed more frequent erythema multiforme-like or interface dermatitis and a denser infiltrate of T cells in DRESS but no clear-cut difference from MPE. ...
Article
Background: Inpatients with cutaneous adverse drug reactions (CADR) with overlapping features between maculopapular exanthema (MPE) and drug reaction with eosinophilia and systemic symptoms (DRESS) were examined. Objectives: To characterize patients with exanthema and few systemic symptoms not meeting the criteria for DRESS [overlapping MPE-DRESS (MP/DR)]. Methods: We undertook a comparative analysis of clinical and laboratory features of patients with MPE, MP/DR and DRESS (2008-12). Results: We identified 132 inpatients (85 women/47 men, mean age 64·0 ± 17·7 years) with CADR, 37 with DRESS, 28 with MPE, 34 with MP/DR and 33 with other patterns. There were no significant differences in sex, age or concomitant diseases. Allopurinol was the main cause of DRESS (40·5%) and MP/DR (29·4%); antimicrobials were the main cause in MPE (35·7%). In MP/DR the latency period (18·06 ± 13·17 days) was significantly longer than in MPE but shorter than in DRESS. Although hospitalization time was similar to DRESS (13·26 ± 7·41 days), duration of therapy and follow-up in MP/DR was shorter. Exanthema/erythroderma were frequently associated with facial oedema in MP/DR (73·5%) and DRESS (89·2%) but only in 42·0% of patients with MPE. MP/DR histopathology showed keratinocyte vacuolization and perivascular and interstitial infiltrate of lymphocytes, eosinophils and neutrophils, similar but milder than in DRESS, with less interface dermatitis, exocytosis and spongiosis. DRESS was associated with liver involvement (78·4%) and eosinophilia (78·4%), but only in 64·7% and 11·8%, respectively, of patients with MP/DR. Conclusions: An overlapping pattern between MPE and DRESS was identified and characterized. There may be a continuum spectrum between MPE and DRESS.
... Different mechanisms have been implicated in its development that include slow acetylation and detoxification defects leading to reactive metabolite formation and subsequent immunological reactions. [16] Reactivation of human herpes, including Epstein-Barr virus and human herpes virus (HHV)-6 and 7 has also been implicated. ...
Article
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Drug reaction with eosinophilia and systemic symptom syndrome (DRESS) is a hypersensitivity drug reaction, most frequently associated with antiepileptic drugs, characterized by skin rash, fever, pharyngitis, lymphadenopathy, and visceral organ involvement, typically presenting within 8 weeks of initiation of therapy. Management involves prompt withdrawal of the offending drug and use of systemic corticosteroids. We here present a rare case of DRESS secondary to levetiracetam. Only few case reports of DRESS secondary to levetiracetam have been published so far.
... The present case fulfilled the Japanese consensus group diagnostic criteria for DIHS, except for the rash induced by a limited number of drugs. 1 ...
... Furthermore, glutamic acid decarboxylase antibodies were detected (2 U/mL, negative level <0.5 U/mL), indicating an autoimmune pathogenesis (specificity 99%). 4 Islet cell antibody was negative. She developed hyperglycemia within 1 month while on a weaning dose of prednisone that was likely partly responsible for her hyperglycemia. ...
... This occurs due to an immunological phenomenon that acts as a stimulator of virus reactivation. 20,21,23 Patient 4 was admitted with clinical DRESS/DIHS and presented dengue after 20 d. Thus, we believe that the patient contracted dengue in the presence of DRESS/DIHS, as it is an acute infectious disease without chronicity or latency and is endemic in the study area. ...
... 5 The reactivation of CMV is also experienced by severe DIHS patients, and it has been previously reported in approximately 30% of DIHS patients. 6 A patient with CMV reactivation clinically has recurring transient fever, cutaneous eruptions, or various severe complications. In particular, gastrointestinal bleeding, myocarditis, and pneumonia may occasionally be fatal in DIHS patients. ...
Article
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Drug-induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe adverse systemic reaction.1 DIHS is characterized by its limited number of causative drugs, late onset, clinical similarity to infectious mononucleosislike syndrome, and prolonged clinical course owing to relapse.2 Subjects with DIHS are known to show reactivation of human herpesvirus (HHV)-6, cytomegalovirus (CMV), Epstein-Barr virus, and HHV-7.3 This report describes the case of DIHS with a dramatic reactivation of CMV and a development of gastric ulcers, in which CMV was immunohistochemically detected.
... Viral reactivation of different herpesviruses, particularly HHV-6 but also EBV, cytomegalovirus, and HHV-7, has been noted. 48,49 Polymerase chain reaction analysis of peripheral blood mononuclear cells (PBMC) and serum from 40 patients with DRESS syndrome detected EBV DNA in the PBMC from all patients, while EBV reactivation occurred in 16 of 38 cases (42%). 50 The study showed that expanded CD8+ T cells responded to EBV antigen, regardless of whether EBV reactivation was detectable, and suggested that culprit drugs trigger EBV reactivation in latent cases. ...
Article
Epstein-Barr virus (EBV) is a human B-lymphotropic herpes virus and one of the most common viruses in humans. Specific skin signs related to EBV infection are the exanthem of mononucleosis, which is observed more frequently after ingestion of amoxicillin, and oral hairy leukoplakia, a disease occurring mostly in immunocompromised subjects with HIV infection. Other more uncommon cutaneous disorders that have been associated with EBV infection include virus-related exanthems or diseases such as Gianotti-Crosti syndrome, erythema multiforme, and acute genital ulcers. Other skin manifestations, not correlated to virus infection, such as hydroa vacciniforme and drug-induced hypersensitivity syndrome have also been linked to EBV. The putative involvement of EBV in skin diseases is growing similarly to other areas of medicine, where the role of EBV infection is being investigated in potentially debilitating inflammatory diseases. The prognosis of EBV infection in healthy, immunocompetent individuals is excellent. However, lifelong infection, which is kept in check by the host immune system, determines an unpredictable risk of pathologic unpredictable scenarios. In this review, we describe the spectrum of non-tumoral dermatological manifestations that can follow EBV primary infection or reactivation of EBV in childhood.
Article
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Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare, potentially life‐threatening, delayed, drug‐induced hypersensitivity reaction. Immediate withdrawal of the culprit drug and administration of systemic corticosteroids is the most widely accepted treatment. However, it is difficult to manage patients with DRESS syndrome who are not responsive to systemic steroids. We studied the efficacy of intravenous immunoglobulins (IVIGs) in patients with DRESS syndrome unresponsive to systemic steroids. We retrospectively reviewed patients with DRESS syndrome who received IVIG in addition to systemic steroids during 2012–2017 and compared the clinical features and course of DRESS syndrome, before and after IVIG treatment. Eighteen DRESS patients (9 men) were included. The most frequent offending drugs were dapsone in five patients, followed by vancomycin in three patients and carbamazepine in three patients. Rash, fever, lymphadenopathy, atypical lymphocytes, and hepatic involvement were common clinical findings. IVIG treatment was added within a median time of 7 days from the commencement of systemic steroid therapy. After IVIG treatment (total dosage: 1–2 g/kg), the fever resolved within a median time of 1 day (range, 0–3) and liver enzymes improved substantially within a median time of 13 days (range, 0–27). No severe adverse reactions related to IVIG therapy were observed in this study; however, there was one case of mortality. The addition of IVIG in DRESS syndrome in cases refractory to systemic steroid treatment may be helpful in hastening recovery. However, comparative studies using a placebo group are needed.
Article
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In the general population, up to 10% of children treated by antibiotics have cutaneous adverse drug reaction, but allergy is confirmed in less than 20% of patients. Most of the non-allergic reactions are probably due to virus, such as enterovirus acute infection or Ebstein-Barr Virus (EBV) acute infection or reactivation. Especially in children, viruses have the propensity to induce skin lesions (maculopapular rash, urticaria) due to their skin infiltration or immunologic response. In drug-related skin eruptions, a virus can participate by activating an immune predisposition. The culprit antibiotic is then the trigger for reacting. Even in severe drug-induced reactions, such as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome, viruses take part in immune phenomena, especially herpes viruses. Understanding the mechanisms of both virus-and drug-induced skin reaction is important to develop our clinical reflection and give an adaptive care to the patient. Our aim is to review current knowledge on the different aspects and potential roles of viruses in the different type of drug hypersensitivity reactions (DHR). Although major advances have been made those past year, further studies are needed for a better understanding of the link between viruses and DHR, to improve management of those patients.
Article
Objectives Trichloroethylene (TCE) -induced hypersensitivity syndrome (TIHS) is a potentially life-threatening disease. Several genetic susceptibility biomarkers have been found to be associated with TIHS, and this systematic prospective study has been conducted to evaluate the utility of these genetic susceptibility biomarkers in preventing the disease. Methods The newly hired TCE-exposed workers were recruited from March 2009 to October 2010. HLA-B*13:01 genotyping and 3-month follow-up procedure were conducted. All workers were monitored for adverse reaction by telephone interview every week. The workers with early symptoms of TIHS were asked to go to the hospital immediately for further examination, diagnosis and treatment. The medical expense record data of patients with TIHS were collected for cost-effectiveness analysis in 2018. Results Among 1651 workers, 158 (9.57%) were found to carry the HLA-B*13:01 allele and 16 (0.97%) were diagnosed with TIHS. HLA-B*13:01 allele was significantly associated with an increased TIHS risk (relative risk=28.4, 95% CI 9.2 to 86.8). As a risk predictor of TIHS, HLA-B*13:01 testing had a sensitivity of 75%, a specificity of 91.1% and an area under curve of 0.83 (95% CI 0.705 to 0.955), the positive and negative predictive values were 7.6% and 99.7%, respectively. The incidence of TIHS was significantly decreased in HLA-B*13:01 non-carriers (0.27%) compared with all workers (0.97%, p=0.014). Cost-effectiveness analysis showed that HLA-B*13:01 screening could produce an economic saving of $4604 per TIHS avoided. Conclusions Prospective HLA-B*13:01 screening may significantly reduce the incidence of TIHS and could be a cost effective option for preventing the disease in TCE-exposed workers.
Article
There are countless skin lesions that can bring the small patient to the consultation. Sometimes the appearance of the lesions is highly suggestive of a disease, sometimes the anamnesis is the one that helps us significantly in establishing the diagnosis. For maximum accuracy in establishing the diagnosis and therapy, the consultation is mandatory to be complete. We will take into account the appearance and localization of the rash, the clinical evolution and associated symptoms, such as pruritus or fever, localization with endemic diseases such as chicken pox, for example, residing in unhealthy conditions (increases the possibility of having scabies, pediculosis, bacterial, fungal or viral infections). The morphology and distribution of the lesions are the key features that help to establish the diagnosis. Sometimes lab tests or even skin biopsies may be needed. Any skin lesion is accompanied by the concern of the parents, but also of the children, and in the case of adolescents the worries of being excluded from the social group may arise. The term dysmorphophobia describes the irrational, persistent, pathological fear of becoming deformed, centered on the illusion of total or partial modification of the body pattern(1) and this condition is increasingly encountered in medical practice.
Article
Cutaneous drug reactions are a common reason for calls and visits. This term chiefly refers to hypersensitivity reactions ranging from benign rash without contraindication of treatment to severe life-threatening clinical pictures, such as anaphylactic shock and epidermal necrolysis. They should be carefully managed from the outset. Indeed, history taking and precise semiological description of the lesions are crucial to the formulation of recommendations for the patient. Allergological investigation of such reactions has developed greatly in recent decades and must now be carried out much more extensively. The arrival of new drug families such as biotherapies and the development of drug habituation protocols constitute the challenges of tomorrow for cutaneous drug reactions. Copyright © 2019. Published by Elsevier Masson SAS.
Chapter
In diagnosing cutaneous adverse drug reactions, the histopathological findings must be examined, and those findings provide insight into the pathomechanisms of these disorders. The characteristic histological findings of Stevens–Johnson syndrome and toxic epidermal necrolysis are crucial for diagnosing and discriminating from erythema multiforme. Drug-induced hypersensitivity syndrome and exanthema in drug reaction with eosinophilia and systemic symptoms each shows variable histopathological findings, which may have a partial relationship with the clinical features. Acute generalized exanthematous pustulosis presents spongiform superficial epidermal pustules associated with edema of the papillary dermis and abundant mixed perivascular infiltrates.
Chapter
Drug reaction with eosinophilia and systemic symptoms (DRESS) is a delayed, potentially life-threatening, hypersensitivity reaction characterized by a widespread, long-lasting skin eruption, fever, lymphadenopathy, hematological abnormalities, and organ involvement. Time to onset and course are relatively long; relapses may occur. Clinical and biological variability make DRESS a challenging diagnosis. Pathogenesis is not exactly known, but probably reflects a complex interplay of drug and viral-related factors in which genetics and abnormal metabolic pathways of drugs play an important role. Although associated with many drugs, DRESS is mainly observed after a limited number of “high risk” drugs. Early recognition, prompt withdrawal of the culprit, and treatment with corticosteroids are the mainstay of management.
Article
Las toxicodermias constituyen un motivo frecuente de alarma o de consulta. Bajo este término, están reunidas principalmente las toxicodermias por hipersensibilidad, que abarcan desde una erupción benigna, que no contraindica el tratamiento, hasta cuadros clínicos graves que comprometen el pronóstico vital, como el choque anafiláctico y las necrólisis epidérmicas. No se puede descuidar el tratamiento de estas reacciones, y además desde su fase inicial. En efecto, los datos procedentes de la anamnesis y una descripción semiológica detallada de las lesiones son capitales para establecer una serie de recomendaciones que después podrán ser remitidas al paciente. Durante estas últimas décadas, la exploración alergológica de las toxicodermias ha experimentado un gran desarrollo, y en la actualidad debe ser mucho más exhaustiva. La llegada de nuevas familias de medicamentos, a la cabeza de las cuales están las bioterapias, y el desarrollo de los protocolos de habituación medicamentosa constituyen para las toxicodermias los desafíos del futuro.
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Vemurafenib improves survival of melanoma patients. However, cutaneous side-effects commonly occur in them. Nivolumab and ipilimumab are monoclonal antibodies against programmed death 1 and cytotoxic T-lymphocyte-associated antigen 4, both of which regulate excessive T-cell activation. Although these agents induce antitumor immunity against melanoma, the modified immune condition may result in an unexpected adverse reaction which has not been observed previously. Herein, we report a case who manifested severe erythema multiforme-like eruption with mucosal involvement associated with vemurafenib following nivolumab. The patient also subsequently suffered from ipilimumab-induced interstitial pneumonia with refractory course. Such a case has never been reported. This case suggested that dermatologists should pay special attention to unexpected adverse events of these drugs, and carefully observe cutaneous and respiratory status of patients during the treatment of melanoma.
Chapter
Am häufigsten manifestiert sich eine Arzneimittelallergie an der Haut. Milde unkomplizierte makulöse und papulöse Exantheme ohne schwere systemische Symptome repräsentieren wiederum die häufigsten kutanen unerwünschten Arzneimittelwirkungen (UAW). An zweiter Stelle stehen die urtikariellen Exantheme mit oder ohne Angioödemen. Das entzündliche Reaktionsmuster der Haut resultiert in unterschiedlichen Manifestationen, die andere Hautkrankheiten imitieren können. Auch initial milde Hautveränderungen können Prodromalzeichen für schwere bullöse Exantheme oder im Fall der Urtikaria einer Anaphylaxie darstellen (Bircher 1996, 2008).
Chapter
Viral infections are frequently associated with the development of exanthems, especially in the pediatric population. Exanthems can include erythematous, vesicular, and petechial types, although most viral exanthems are erythematous papules and macules. Many of the viral exanthems are associated with low-grade fever, myalgias, headache, rhinorrhea, or gastrointestinal symptoms. Owing to the large number of viral exanthems, this chapter focuses on measles, rubella, hand-foot-and-mouth disease, erythema infectiosum, and roseola infantum. It talks about the pathogenesis for drug-induced exanthems, and describes features of a drug rash with eosinophilia and systemic symptoms. In addition, the chapter focuses on role of viruses play in the development of drug eruptions. Finally, it describes the treatment regimens have been used in patients infected with viral exanthems. Most viral exanthems are self-limiting conditions that only require symptomatic treatment. For patients with pruritus, relief can be obtained with antihistamines, topical antipruritic lotions, or topical corticosteroids.
Article
Primary human herpesvirus (HHV)-6B and HHV-7 infections can cause exanthem subitum, which is a common febrile exanthematous disease in childhood. Additionally, reactivation of the viruses has been implicated in skin manifestations. There are different incidence rates of exanthem subitum among patients with primary HHV-6B or HHV-7 infection in Japan and the United States. This disease is generally a benign, self-limiting disease, and it rarely causes complications such as febrile seizures and encephalitis. HHV-6B and HHV-7 reactivate in patients with drug-induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptom (DRES), which has the clinical triad of fever, rash, and internal organ involvement due to drug exposure. Additionally, HHV-6B reactivation was associated with fever and skin rash or acute graft-versus-host disease in hematopoietic stem cell transplantation.
Article
Drug-induced hypersensitivity syndrome (DIHS) and drug reaction with eosinophilia and systemic symptoms (DRESS) are life-threatening multiorgan system reactions caused by a limited number of drugs and characterized by fever, skin rashes, lymphadenopathies, hematological abnormalities, and hepatitis. Unique features of these syndromes are delayed onset, a paradoxical deterioration of clinical symptoms after withdrawal of the causative drug, and a long duration of the syndrome with some flare-ups. The clinical features of these syndromes could be caused by several herpesvirus reactivations, including human herpesvirus 6 (HHV-6), Epstein-Barr virus, and cytomegalovirus. The severity of DIHS/DRESS is commonly determined by the degree of visceral involvement. Although its pathophysiology remains to be determined, genetic, pharmacologic, and immunologic mechanisms have partly been clarified. Systemic corticosteroids are the first-line treatment for DIHS/DRESS. Autoimmune sequelae may occur after a disease-free interval of several months to years after resolution of the acute illness; therefore, long-term follow-up is necessary.
Chapter
Human herpesvirus-6 (HHV-6) is the collective name for HHV-6A and HHV-6B, two closely related betaherpesviruses that have a combined seroprevalence of over 90% in adults worldwide. An increased awareness of diseases associated with HHV-6 acute infection (AI) and reactivation in both immunocompetent and immunocompromised patients has resulted in growing interest in the evaluation of the best treatment options available for the clinical management of HHV-6 disease; however, no compound has yet been approved for the specific treatment of HHV-6 infection. Thus, clinicians most often utilize the anti-cytomegalovirus (CMV) agents ganciclovir, cidofovir, and foscarnet for the treatment of HHV-6 AI and reactivation. This chapter reviews the reported in vitro efficacies of several anti-HHV-6 compounds and discusses current and future approaches to the clinical management of HHV-6 AI.
Article
Severe delayed drug-induced skin reactions in children are not common but potentially serious. This article describes aspects concerning the etiology, pathogenesis and clinical manifestations of these processes; it presents three paediatric cases, namely STS (Steven Johnson Syndrome), TEN (toxic epidermal necrolysis), probably related to amoxicillin/clavulanate and ibuprofen and DRESS (a drug reaction with eosinophilia and systemic symptoms) secondary to phenytoin; and in relation to them, the diagnosis and the treatment of these processes are discussed and reviewed. The AGEP (acute generalised exanthematous pustulosis) is also reviewed. The aetiological diagnosis of severe non-immediate reactions is difficult, and the value of current allergological testing is not well defined in these cases. Diagnosis is based on clinical history, the empirical risk of drugs to trigger SJS/TEN or DRESS, and the in vivo and in vitro testing of the suspect drug. Skin biopsy confirms that the clinical diagnosis and delayed hypersensitivity tests, especially the patch test and the lymphoblastic transformation test (LTT), may be important to confirm the aetiological diagnosis, in our cases emphasising the latter. These diseases can be life threatening (especially DRESS and TEN) and/or have a high rate of major complications or sequelae (SJS/TEN). The three cases described progressed well without sequelae. All were treated with corticosteroids, which is the most currently accepted treatment although the effect has not been clearly demonstrated. Copyright © 2015 SEICAP. Published by Elsevier Espana. All rights reserved.
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Drug-induced hypersensitivity syndrome (DIHS; also known as drug reaction with eosinophilia and systemic symptoms [DRESS]) is a life-threatening condition first described by Chaikenetal. in 1950. It is characterized by extensive mucocutaneous rash; fever; lymphadenopathy; hepatitis; hematological abnormalities; damage to several organs such as kidney, heart, lungs, and pancreas; and possible reactivation of human herpesvirus-6 (HHV-6) or other herpes virus. Rare and severe cases may present hepatic necrosis, and about 15% of them result in death or liver transplantation. A hallmark of this syndrome is the late onset of symptoms after the drug exposure. The most common culprit drugs are the aromatic anticonvulsants (in almost 30% of the cases) and the antibiotics (which in some series represent 20% of the cases). The authors report a case of a 41-year-old female who presented to the emergency department with erythroderma, acute hepatitis, acute pancreatitis and acute renal failure, and was then treated with corticosteroid after the diagnosis of DIHS/DRESS. A specific culprit drug could not confidently be determined due to the presence of multiple drugs used by the patient. The clinical and laboratory outcome was apparently satisfactory, but unexpectedly, on the sixth day of hospitalization, the patient complained of nonspecific malaise, drowsiness, which progressed in a few hours with signs and symptoms of hepatic failure, refractory shock, and death. The autopsy findings showed submassive hepatic necrosis, and the immediate cause of death was attributed to hepatic failure.
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Over the past decades, it has become abundantly clear that enzymes evolved to detoxify and eliminate foreign chemicals from the body, occasionally generate highly reactive metabolites which have toxicological implications. To decrease the probability of late clinical failure or market withdrawal, there has been an increased prioritization on understanding key metabolic processes that might cause drug interactions or toxicities. Significant advances have been made in the detection of reactive metabolites and in understanding the structure activity relationship. It is now widely accepted that compounds with certain functional groups such as anilines, quinones, hydrazines, thiophenes, furans, acylpropionic acids, and alkynes have a much greater associated risk towards formation of reactive metabolites than compounds that do not contain such "structural alerts". Detection of reactive metabolites is usually done with in vitro assays, which have become more sensitive with advances in mass spectrometry. As an increasingly large number of compounds that form reactive metabolites have been identified, much of the focus has shifted from detection to evaluation of toxicological implication. While there is a disproportionate number of compounds metabolized to reactive metabolites that are associated with drug-induced hepatotoxicity and serious skin toxicities such as toxic endothelial necrolysis and Steven's Johnson syndrome, attempts to predict toxicity based on in vitro testing have been discouraging. In this review we attempt to summarize the experimental options available to evaluate reactive metabolites.
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Nonablative laser are one of the categories of devices in the field of nonablative methods. Sparing the epidermis is the common mechanism of action of nonablative methods. The high complication rate of side effects and the prolonged recovery time, encouraged the researchers to produce devices more safe than the ancient ablative lasers.
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Introduction: Discoid lupus erythematosus (DLE) is an inflammatory skin disease seen in patients with or without systemic LE. There are several clinical features, such as localized DLE, generalized/widespread DLE, hypertrophic/verrucous DLE and mucosal DLE. There are topical and systemic therapy options. Topical therapies include corticosteroids and calcineurin inhibitors. As systemic therapies, antimalarials are acknowledged as the first-line option throughout the world. Dapsone and/or retinoids are also useful with careful evaluation of their positive and adverse effects. In order to develop better treatments, it is important to know and investigate the mechanisms of skin eruption development using several methods such as mouse models. Areas covered: This manuscript summarizes the disease features, pathogenesis, diagnosis and current and new targeted treatments for DLE. A literature search on PubMed and the Cochrane Database of Systematic Reviews has been undertaken and the most relevant references have been considered. Expert opinion: Treatment for DLE includes topical and systemic options. The professional use of topical corticosteroids and topical calcineurin inhibitors is considered to be first-line. Next, antimalarials are accepted as a first-line systemic therapy when topical therapies are ineffective. If the antimalarial treatment programme is insufficient, an immunosuppressive or immunomodulator may be added. Some new, promising agents are considered in patients who are refractory to various combinations of antimalarials and immunosuppressives/immunomodulators.
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Cutaneous adverse drug reactions (ADRs) constitute a major pediatric health problem frequently encountered in clinical practice, and represent a diagnostic challenge. Children are more susceptible than adults to errors in drug dosage because of their smaller body size; moreover, ADRs can mimic other skin diseases of children, especially viral exanthems. Most ADRs with cutaneous involvement are mild and resolve on withdrawal of the causative drug. The most common forms of cutaneous ADRs, maculopapular exanthems and urticarial reactions, have excellent outcomes. Less frequent but more severe reactions may incur a risk of mortality.
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Drug hypersensitivity syndromes such as abacavir hypersensitivity and the severe cutaneous adverse drug reactions have been associated with significant short- and long-term morbidity and mortality. More recently, these immunologically mediated and previously unpredictable diseases have been shown to be associated with primarily class I but also class II HLA alleles. The case of the association of HLA-B*57:01 and abacavir hypersensitivity has created a translational roadmap for how this knowledge can be used in the clinic to prevent severe reactions. Although many hurdles exist to the widespread translation of such HLA screening approaches, our understanding of how drugs interact with the major histocompatibility complex has contributed to the discovery of new models that have provided considerable insights into the immunopathogenesis of severe cutaneous adverse drug reactions and other T-cell–mediated drug hypersensitivity syndromes. Future translation of this knowledge will facilitate the development of preclinical toxicity screening to significantly improve efficacy and safety of drug development and design.
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The Drug Reaction with Eosinophilia and Systemic Symptoms syndrome, also known as Drug Induced Hypersensitivity Syndrome presents clinically as an extensive mucocutaneous rash, accompanied by fever, lymphadenopathy, hepatitis, hematologic abnormalities with eosinophilia and atypical lymphocytes, and may involve other organs with eosinophilic infiltration, causing damage to several systems, especially to the kidneys, heart, lungs, and pancreas. Recognition of this syndrome is of paramount importance, since the mortality rate is about 10% to 20%, and a specific therapy may be necessary. The pathogenesis is related to specific drugs, especially the aromatic anticonvulsants, altered immune response, sequential reactivation of herpes virus and association with HLA alleles. Early recognition of the syndrome and withdrawal of the offending drug are the most important and essential steps in the treatment of affected patients. Corticosteroids are the basis of the treatment of the syndrome, which may be associated with intravenous immunoglobulin and, in selected cases, Ganciclovir. The article reviews the current concepts involving this important manifestation of adverse drug reaction.
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Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe, drug-induced reaction that involves both the skin and the viscera. Evidence for reactivation of herpes family viruses has been seen in some DRESS patients. To understand the immunological components of DRESS and their relationship to viral reactivation, we prospectively assessed 40 patients exhibiting DRESS in response to carbamazepine, allopurinol, or sulfamethoxazole. Peripheral blood T lymphocytes from the patients were evaluated for phenotype, cytokine secretion, and repertoire of CD4+ and CD8+ and for viral reactivation. We found Epstein-Barr virus (EBV), human herpes virus 6 (HHV-6), or HHV-7 reactivation in 76% of the patients. In all patients, circulating CD8+ T lymphocytes were activated, exhibited increased cutaneous homing markers, and secreted large amounts of tumor necrosis factor-alpha and interferon-gamma. The production of these cytokines was particularly high in patients with the most severe visceral involvement. In addition, expanded populations of CD8+ T lymphocytes sharing the same T cell receptor repertoire were detected in the blood, skin, liver, and lungs of patients. Nearly half of these expanded blood CD8+ T lymphocytes specifically recognized one of several EBV epitopes. Finally, we found that the culprit drugs triggered the production of EBV in patients' EBV-transformed B lymphocytes. Thus, cutaneous and visceral symptoms of DRESS are mediated by activated CD8+ T lymphocytes, which are largely directed against herpes viruses such as EBV.
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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.
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To measure the virus load in patients with symptomatic Epstein-Barr virus (EBV) infections, we used a real-time PCR assay to quantify the amount of EBV DNA in blood. The real-time PCR assay could detect from 2 to over 10(7) copies of EBV DNA with a wide linear range. We estimated the virus load in peripheral blood mononuclear cells (PBMNC) from patients with symptomatic EBV infections. The mean EBV-DNA copy number in the PBMNC was 10(3.7) copies/microg of DNA in patients with EBV-related lymphoproliferative disorders, 10(4.1) copies/microg of DNA in patients with chronic active EBV infections, and 10(2.2) copies/microg of DNA in patients with infectious mononucleosis. These numbers were significantly larger than those in either posttransplant patients or immunocompetent control patients without EBV-related diseases. In a patient with infectious mononucleosis, the virus load decreased as the symptoms resolved. The copy number of EBV DNA in PBMNC from symptomatic EBV infections was correlated with the EBV-positive cell number determined by the in situ hybridization assay (r = 0.842; P < 0.0001). These results indicate that the real-time PCR assay is useful for diagnosing symptomatic EBV infection and for monitoring the virus load.
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Interferons (IFNs) are the most important cytokines in antiviral immune responses. “Natural IFN-producing cells” (IPCs) in human blood express CD4 and major histocompatibility complex class II proteins, but have not been isolated and further characterized because of their rarity, rapid apoptosis, and lack of lineage markers. Purified IPCs are here shown to be the CD4+CD11c− type 2 dendritic cell precursors (pDC2s), which produce 200 to 1000 times more IFN than other blood cells after microbial challenge. pDC2s are thus an effector cell type of the immune system, critical for antiviral and antitumor immune responses.
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We investigated whether a causal relationship exists between human herpesvirus 6 (HHV-6) and skin rash resembling acute graft-versus-host disease (GVHD) following bone marrow transplantation (BMT). Isolation of HHV-6 was used to monitor active HHV-6 infection in this study. We analyzed 25 episodes of skin rash in 22 recipients. All recipients were seropositive for HHV-6 before BMT. The onset of skin rash started prior to 30 days post transplantation (group A) in 15 of 25 cases, but after that (group B) in the remaining 10 cases. Twenty-five skin tissue samples were obtained from 22 recipients. The HHV-6 genome was detected in four of 15 skin samples from group A, but not detected in those from group B. HHV-6 was isolated from 11 of 22 recipients around 2 to 3 weeks after BMT (range 14 to 28 days after BMT). HHV-6 was isolated at a time between 10 days before and after the onset of skin rash (skin rash-related viremia) in nine cases in group A. Meanwhile, no skin rash-related viremia was observed in group B. Of the four recipients with positive detection of HHV-6 genome in their skin tissue (group A), two had HHV-6 viremia at the same time. The association between the timing of HHV-6 infection and the onset of skin rash was analyzed statistically. HHV-6 viremia (skin rash-related viremia) was found in nine of 15 (60%) cases in group A, compared with none of 10 (0%) cases in group B. This difference was statistically significant (P = 0.008). Moreover, HHV-6 infection (skin rash-related viremia and/or positive detection of HHV-6 DNA in skin tissue) was demonstrated in 11 of 15 (73.3%) cases in group A, compared with none of 10 (0%) cases in group B (P = 0.001). Thus, this study suggests that HHV-6 may be involved in the development of skin rash in the first month after allogeneic BMT.
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Anticonvulsant hypersensitivity syndrome (AHS) is a life-threatening, drug-induced, multiorgan system reaction. The identification of predisposing factors is clearly needed to predict the incidence and outcome of AHS; attention has recently been focused on reactivation of human herpesvirus 6 (HHV-6). To determine whether immunosuppressive conditions that can allow HHV-6 reactivation could be specifically detected in association with the onset of AHS. We analyzed patients with AHS who were treated during 1997-2002. Two groups of patients receiving anticonvulsants served as controls. Department of Dermatology, Kyorin University School of Medicine, Tokyo, Japan. Patients Ten patients with AHS. The results of serologic tests for antibody titers for various viruses, including HHV-6, HHV-6 DNA detection by real-time polymerase chain reaction, immunoglobulin levels by turbidimetric immunoassay, IgG subclass levels by nephelometry, and CD19(+) B-cell counts by flow cytometric analysis, were sequentially assessed. Serum IgG levels (mean, 745 mg/dL) and circulating B-cell counts (mean, 88/ micro L) in patients with AHS were significantly decreased at onset compared with control groups (P<.001 and P =.007, respectively). These alterations returned to normal on full recovery. Reactivation of HHV-6 as judged by a greater than 4-fold increase in HHV-6 IgG titers was exclusively detected in most patients with AHS associated with decreased IgG levels and B-cell counts. A decrease in immunoglobulin levels and B-cell counts can be associated with HHV-6 reactivation and the subsequent onset of AHS. These immunological alterations might be a useful predictor of the development of AHS.
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Human and mouse plasmacytoid dendritic cells have been shown to correspond to a specialized cell population that produces large amounts of type I interferons in response to viruses, the so-called natural interferon-producing cells. As a result, intensive investigation is now focused on the potential functions of plasmacytoid dendritic cells in both innate and adaptive immunity. Here we review recent progress on the characterization of plasmacytoid dendritic cell origin, development, migration and function in immunity and tolerance, as well as their effect on human diseases.
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We report a case of tribenoside-induced hypersensitivity syndrome associated with cytomegalovirus reactivation and investigation of the immunological characteristics of the circulating and skin-infiltrating lymphocytes. Activated CD8+ T cells outnumbered CD4+ cells in both the circulation and the skin lesions. Upon in vitro stimulation with the drug, CD4+ cells proliferated and produced interferon-gamma. The circulating CD8+ cells used limited T-cell receptor Vbetas, some of which are restricted to cytomegalovirus-derived peptide in the context of the HLA-A2 haplotype. CD8+ cells and cytomegalovirus-containing cells closely co-localized in the skin lesions. These results suggested that CD4+ cells were drug-reactive, whereas cytomegalovirus activated CD8+ cells in the present case. These two cell types seemed to play a distinct role in drug-induced hypersensitivity syndrome.
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Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe adverse drug reactions with high mortality. To present the current clinical characteristics and treatment of SJS and TEN in Japan, we retrospectively analyzed reports of SJS and TEN published in medical journals from 2000 to 2006. Fifty-two cases of SJS (19 males and 33 females; mean age, 45.2 years) and 65 cases of TEN (31 males and 34 females; mean age, 45.7 years) were reported. Thirty-six cases of SJS (69.2%) and all cases of TEN were caused by drugs, such as nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics, and anticonvulsant drugs. Hepatitis was the most common organ involvement in both SJS and TEN. Renal dysfunction and respiratory disorders were also involved in some cases. The major complication was sepsis, but in only 1.9% of SJS and 10.8% of TEN. Most cases were treated systemically with corticosteroids, and 42 cases (80.8%) of SJS and 39 cases (60.0%) of TEN were treated with corticosteroids alone. Plasmapheresis and/or immunoglobulin therapy was combined with corticosteroid therapy in some cases. The mortality rates for patients with SJS and TEN were 1.9% and 6.2%, respectively. The mortality in TEN decreased remarkably from 21.6% (58/269) during the previous 17 years (1981 to 1997). Improvement of treatment may be one of the reasons for the decrease in mortalities of both SJS and TEN.
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Drug-induced hypersensitivity syndrome (DIHS/DRESS) is an adverse drug-induced reaction of severity similar to that of Stevens–Johnson syndrome. DIHS is distinguished from other drug reactions by certain characteristics: late onset, clinical similarity to mononucleosis-like syndrome, and prolonged course. Human herpesvirus 6 (HHV-6) can be reactivated 2–3 weeks after the onset of rash in the vast majority of DIHS patients. Patients with HHV-6 reactivation show more severe symptoms, including long-lasting fever, lymphadenopathy, leukocytosis, appearance of atypical lymphocytes, and hepatitis. DIHS may involve encephalitis, non-autoimmune (idiopathic) fulminant type 1 diabetes mellitus and myocarditis. The mortality rate for DIHS is 8%, which is higher than the mortality rate for Stevens– Johnson syndrome.
Article
Since the first description by Saltzstein in 1959, the denomination of drug-induced pseudolymphoma was used to describe two cutaneous adverse drug reactions with a histological picture mimicking malignant lymphoma. On the basis of clinical 1resentation, this term includes two different patterms: (1) hypersensitivity syndrome which begins acutely in the first 2 months after the initiation of the drug and associates fever, a severe skin disease with characteristic infiltrated papules and facial edema or an exfoliative dermatitis, lymphadenopathy, hematologic abnormalities (hypereosinophilia, and atypical lymphocytes) and organ involvement such as hepatitis, carditis, interstitial nephritis, or interstial pneumonitis. The cutaneous histological pattern shows a lymphocytic infiltrate, sometimes mimicking a cutaneous lymphoma, and the mortality rate is about 10%. When organ involvement exists, corticosteroids are often prescribed with dramatic improvement. Relapses may occur. (2) drug-induced pseudolymphoma which has a more insidious beginning with nodules and infiltrated piaques appearing several weeks after the beginning of the drug without constitutional symptoms. A pseudolymphoma pattern is seen on cutaneous histological slides. Complete improvement is usual after drug withdrawal, but a delayed lymphoma is possible. To decrease the ambiguity of the denomination of hypersensitivity syndrome, we propose the term of DRESS (Drug Rash with Eosinophilla and Systemic Symptoms).
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The management of drug-induced hypersensitivity syndrome or drug reaction with eosinophilia and systemic symptoms (DRESS) is not codified. Demonstration of the reactivation of Herpesviruses illustrates the specific pathophysiology of this syndrome. Proposals for the management of DRESS were elaborated by the cutaneous adverse drug reaction working group of the French Society of Dermatology to help with its management. From a review of literature and the experience of the members of this group, consensual proposals were written about diagnostic criteria, tests, treatment options, and follow-up. These proposals will need to be validated in prospective studies. A decisional tree of treatment options is proposed, based on the severity of visceral manifestations. The importance of a rapid withdrawal of the culprit drug and of a long-term follow-up is underlined. Treatment will be adapted to the clinicobiological status (topical corticosteroid, systemic corticosteroid, intravenous gammaglobulins, antivirals).
Article
Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome, toxic epidermal necrolysis (TEN), and Stevens-Johnson syndrome (SJS) are rare and life-threatening conditions that may be precipitated by anticonvulsive agents. We describe a patient with overlapping features of these hypersensitivity syndromes.
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Overt cytomegalovirus (CMV) disease is a serious viral infection that usually occurs in immunocompromised patients but rarely in immunocompetent patients. Cutaneous lesions, albeit rare, occur as late systemic manifestations of CMV infections and are usually fatal. We describe 2 patients with drug-induced hypersensitivity syndrome (one end of a spectrum of severe drug eruptions) who subsequently developed cutaneous CMV ulcers at unusual sites, such as the trunk; this occurrence was immediately followed by gastrointestinal manifestations, which were fatal in 1 patient. To identify factors predictive of CMV disease, we retrospectively investigated the prevalence of CMV reactivation during drug-induced hypersensitivity syndrome in 18 patients. In this analysis, patients were divided into 2 groups depending on the positivity of CMV DNA in the blood. Older and male patients with antecedent high human herpesvirus 6 DNA loads are at risk for CMV disease irrespective of corticosteroid administration. A rapid reduction in white blood cell numbers is also predictive of the onset of CMV disease.
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Virological and serological studies were carried out prospectively to evaluate the possible activation of human herpesvirus-6 (HHV-6) in 50 infants and children with acute measles by isolation of HHV-6 from peripheral blood and by determining neutralizing antibodies to the virus. All but 5 patients (90%) were seropositive to HHV-6 in the acute stage of measles and 18 (40%) had a significant increase in HHV-6 antibody titers thereafter, whereas only 2 of 27 patients who were initially seropositive to Epstein-Barr virus (EBV) viral capsid antigen (VCA) had a significant rise in antibody titers to EBV VCA. Among 18 patients with a significant increase in HHV-6 titers, the virus was isolated from the peripheral blood mononuclear cells of three patients in the early convalescent stage of measles. These results indicate that activation of HHV-6 may occur frequently a few weeks after primary infection with the measles virus.
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Human herpesvirus-6 (HHV-6) was recovered at high frequency (greater than 85%) from the saliva of both healthy individuals and those infected with the human immunodeficiency virus (HIV). The level of isolation mirrored the high prevalence of antibodies to HHV-6 found in sera obtained from residents of diverse areas of the world. Seroconversion occurred between 1 and 3 years of age; seroprevalence ranged between 80% and 100% among adults under 40 and decreased to 35% between ages 62 and 88. Serum titres in healthy individuals remained stable during periods of virus shedding. Immune cellular dysfunction in patients was associated with high geometric mean HHV-6 antibody titres. These observations suggest that HHV-6 infection takes place within the first 3 years of life, and strongly implicate oral shedding as a common means of transmission of this newly described herpesvirus.
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Saliva and peripheral blood samples from 20 healthy adults were examined for the presence of human herpesvirus-6 (HHV-6) DNA sequences using the polymerase chain reaction. Eighteen out of 20 whole saliva samples contained detectable HHV-6 genomes. The majority of peripheral blood samples were also positive; however, the results suggest that only a rare cell in the peripheral blood is infected. Serological studies did not reveal any correlation between HHV-6 antibody titre and the ability to detect HHV-6 DNA. The data indicate that HHV-6 genomes persist in the peripheral blood and oropharynx or salivary glands of most healthy individuals following primary infection.
Article
Although human herpesvirus 6 (HHV-6) is known to reactivate during hematopoietic stem cell transplantation (HSCT), the clinical significance of this finding is controversial. We used a quantitative PCR test for HHV-6 to assay plasma samples prospectively collected from a cohort of 110 allogeneic HSCT recipients to evaluate the clinical effects of HHV-6 infection. A retrospective review of medical records was performed to determine clinical end points. HHV-6 reactivation occurred in 52 (47%) of the 110 subjects. Factors that increased the risk of subsequent HHV-6 reactivation were hematologic malignancy that occurred at a time other than the first remission (adjusted P = .002), a mismatch in the sexes of donor and recipient (adjusted P=.05), younger age (adjusted P = .01), and the receipt of glucocorticoids (adjusted P = .06). HHV-6 reactivation was associated with subsequent all-cause mortality (adjusted hazard ration [HR], 2.9; 95% confidence interval [CI], 1.1-7.5), grade 3-4 graft-versus-host disease (GVHD) (adjusted HR, 4.9; 95% CI, 1.5-16), a lower probability of monocyte engraftment (adjusted HR, 0.42; 95% CI; 0.22-0.80), a lower probability of platelet engraftment (adjusted HR, 0.47; 95% CI, 0.21-1.1; P = .05) and a higher platelet transfusion requirement (adjusted P = .02). A higher level of HHV-6 DNA was associated with subsequent central nervous system (CNS) dysfunction (HR, 21; 95% CI, 1.8-249). HHV-6 reactivation is common after allogeneic HSCT and is associated with subsequent delayed monocyte and platelet engraftment, increased platelet transfusion requirements, all-cause mortality, grade 3-4 GVHD, and CNS dysfunction.
Article
A 66-year-old man developed a fever of 38 degrees C and generalized pruritic rash about one month after mexiletine hydrochloride administration for ventricular tachycardia. The rash appeared as edematous erythema and papules with purpura on the lower extremities. Liver dysfunction, leukocytosis, and atypical lymphocytes were also present. Elevated antibody titer against human herpes virus 6 (HHV-6) was detected during the course of the disease (1:20 -> 1:640). The patient was diagnosed as having drug-induced hypersensitivity syndrome (DIHS) due to mexiletine. Discontinuation of the mexiletine administration and systemic corticosteroid treatment led to a temporary improvement, but tapering the corticosteroid dose twice led to recrudescence. Simultaneous with the recrudescence, elevated antibody titers against HHV-6 and cytomegalovirus were detected, as well as viral DNA in the blood, suggesting that these two viruses may have been involved in the recrudescence. The patient died of myocarditis, most likely related to cytomegalovirus. Our case indicates that, in addition to HHV-6, other herpes viruses such as cytomegalovirus can be reactivated in DIHS and may modify the clinical disease activity.
Article
Drug-induced hypersensitivity syndrome (DIHS) is characterized by a severe multiorgan hypersensitivity reaction that usually appears after a 3-6-week exposure to certain drugs, including anticonvulsants. There are some reports showing that serum IgG levels often decrease at the early stage of DIHS. Reactivation of human herpesvirus (HHV)-6 has been reported in patients with DIHS, and some other DIHS patients showed reactivation of cytomegalovirus (CMV) or Epstein-Barr virus (EBV). To determine whether reactivation of HHV-6, HHV-7, CMV and/or EBV occurs in patients with DIHS. Titres of IgG and IgM antibodies to HHV-6 and HHV-7 were determined using an indirect immunofluorescence antibody assay on admission and at various times after admission. Anti-CMV IgG and IgM antibody titres and anti-EBV capsid antigen IgG, IgA, IgM, and EBV nuclear antigen and EBV early antigen IgG titres were determined by enzyme immunoassay. Polymerase chain reaction (PCR) procedures for HHV-6, HHV-7, CMV and EBV DNAs were performed using serum samples. IgG antibody titres to HHV-6, HHV-7, CMV and EBV were increased after the onset in seven, six, seven and two of seven patients, respectively. IgG antibody titres to HHV-6 and HHV-7 were elevated simultaneously 21-38 days after the onset. IgG antibody titres to CMV and EBV were elevated 10-21 days after the elevation of HHV-6 and HHV-7 antibody titres. PCR showed that HHV-6, HHV-7, CMV and EBV DNAs became positive in six, five, seven and two of seven patients, respectively. HHV-6 and HHV-7 DNAs were detected 21-35 days after the onset, and CMV DNA was detected 10-21 days after detection of HHV-6 and HHV-7 DNAs. The present study suggests that in addition to HHV-6 reactivation, reactivation of HHV-7, CMV and/or EBV may also occur following drug eruption in some patients with DIHS.
Article
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). We attempted to determine whether sequential herpesvirus reactivation could be detected in four patients with severe DIHS, as observed in patients with GVHD, and be coincident with various clinical manifestations that developed after discontinuation of the causative drugs. Detection and quantification of viral DNA [cytomegalovirus (CMV), Epstein-Barr virus (EBV), HHV-6 and HHV-7] in sequential blood samples were performed using real-time polymerase chain reaction assays, based on TaqMan technology. In these patients, the cascade of virus reactivation initiated by HHV-6 or EBV extended to EBV or HHV-7, and eventually to CMV. Clinical manifestations of this syndrome followed by failure of various organs occurring despite discontinuation of the drug were coincident with these herpesvirus reactivations. These results suggest that various herpesviruses can reactivate in the setting of severe drug reactions in a similar sequential order to that described in GVHD. The sequential reactivation of these herpesviruses is responsible for the development of multiorgan failure occurring after discontinuation of the causative drug.
Article
To delineate the clinical manifestations in different age groups and to define the viral load in patients with Epstein-Barr virus-associated infectious mononucleosis (EBV-associated IM). We reviewed data on 69 children with EBV-associated IM from November 2001 to October 2005. Clinical features were evaluated among four age groups: <3 years, 3 to 5 years, 6 to 9 years and 10 to 18 years. EBV viral load was measured by quantitative real-time polymerase chain reaction (PCR) in 13 patients with 15 specimens. Majority of the children were younger than 7 years of age (76.8%) and the male-to-female ratio was 1.6:1. The symptoms and signs included fever (91.3%), tonsillopharyngitis (88.4%), lymphadenopathy (78.3%) and hepatitis (75.4%). The younger age group had higher monocyte count, lower occurrence of hepatitis, and lower glutamic-oxaloacetic transaminase (GOT) and glutamic-pyruvic transaminase (GPT) levels than the older age group. The median (range) EBV viral load of peripheral blood mononuclear cells (PBMCs) and plasma in IM patients was 738 (0-7455) copies/mug DNA and 51 (0-957) copies/mL plasma, respectively. The PBMC detection rate was high in the early (within 10 days after onset) and late phase (>10 days after onset) [90-100%]. The plasma detection rate in the early phase (66.7%) was higher than that in the late phase (40%). The younger age group of EBV-associated IM patients had higher monocyte count, lower occurrence of hepatitis, and lower GOT and GPT levels than the older age group. The PBMC detection rate was almost equally high in both the early and late phases, while the plasma detection rate was higher in the early phase. Quantitative real-time PCR of EBV DNA is useful for diagnosing and monitoring EBV-associated IM, especially in younger children.
Article
Drug-induced hypersensitivity syndrome (DIHS) is an adverse reaction with clinical signs of fever, rash and internal organ involvement. In the vast majority of patients in Japan, the causative drugs for DIHS are limited to the following eight: carbamazepine, phenytoin, phenobarbital, zonisamide, mexiletine, dapsone, salazosulfapyridine and allopurinol. The association of human herpesvirus (HHV)-6 reactivation with DIHS has been reported by various groups. To confirm the relationship between the flaring and severity of DIHS and HHV-6 reactivation. We evaluated 100 patients with drug rash and systemic symptom(s) caused by the drugs associated with DIHS. HHV-6 reactivation was examined by serological antibody assay and quantitative real-time polymerase chain reaction assay of serial serum samples. Anti-HHV-6 IgG titres increased in 62 of 100 patients, 14-28 days after the onset of symptoms. These patients suffered from severe organ involvement and a prolonged course compared with 38 patients showing no reactivation of HHV-6. Significant amounts of HHV-6 DNA were detected in serum samples from 18 of the 62 patients. Flaring of symptoms such as fever and hepatitis was closely related to HHV-6 reactivation in these 18 patients. It should be emphasized that all five patients with fatal outcome and 10 patients with renal failure were in the HHV-6 reactivation group. A combination of immunological reaction to a drug and HHV-6 reactivation results in the severe course of DIHS. The demonstration of HHV-6 reactivation is a useful marker of diagnosis as well as prognosis in DIHS.
Article
Background Recently, human herpesvirus 6 (HHV-6) reactivation has been frequently observed in patients with drug-induced hypersensitivity syndrome or drug rash with eosinophilia and systemic symptoms but not in patients with other types of drug eruptions, eg, Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN). This finding suggests that there is a close relationship between HHV-6 reactivation and drug-induced hypersensitivity syndrome.Observations A 71-year-old man who was not immunocompromised developed TEN because of zonisamide therapy. After the onset of the rash, significant increases in HHV-6 IgG titers and HHV-6 DNA levels were observed in the patient's whole blood samples, indicating that an HHV-6 reactivation had occurred. Furthermore, the patient's clinical manifestations of TEN appeared to recur concurrently with HHV-6 reactivation.Conclusion Our case suggests that HHV-6 reactivation may also occur in several types of drug eruptions, including Stevens-Johnson syndrome and TEN.
Article
The relationship between herpesvirus reactivation and graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (allo-SCT) is unclear. We sought to examine the relationship between human herpesvirus (HHV) reactivation and rash/GVHD after allo-SCT by prospective evaluation. Fifteen patients who had received allo-SCT underwent prospective serial examinations for human herpesvirus 6 (HHV-6), HHV-7, cytomegalovirus, and Epstein-Barr virus DNA in the blood by polymerase chain reaction and real-time polymerase chain reaction. Serum interferon gamma, interleukins 4 and 10, tumor necrosis factor alpha, and soluble interleukin 2 receptor (sIL-2R) were also measured. In 10 of 15 patients, macular/papular eruptions were seen after allo-SCT and GVHD was diagnosed. In 8 patients with rash, HHV-6 DNA levels correlated with the cutaneous manifestation. Interleukin 10 and sIL-2R also increased in association with rash. The number of patients in our study was relatively small. Not all patients were examined for cytokines and sIL-2R. HHV-6 reactivation may be involved in the pathogenesis of rash/GVHD after allo-SCT.
Relationships among human herpesvirus 6 reactivation, serum interleukin 10 levels, and rash/graft-versus-host disease after allogeneic stem cell transplantation
  • K Kitamura
  • H Asada
  • H Iida
  • Etal
Clinical manifestations and quantitative analysis of virus load in Taiwanese children with Epstein-Barr virus-associated infectious mononucleosis
  • Cc Cheng
  • Ly Chang
  • Pl Shao
  • Etal
Fluctuation of blood and skin plasmacytoid dendritic cells in drug-induced hypersensitivity syndrome
  • K Sugita
  • M Tohyama
  • H Watanabe
  • Etal
High rate of reactivation of human herpesvirus 6 in children with dengue hemorrhagic fever
  • K Balachandra
  • K Chimabutra
  • P Supromajakr
  • Etal
The nature of the principal type 1 interferon-producing cells in human blood
  • Fp Siegal
  • N Kadowaki
  • M Shodell
  • Etal
anticonvulsant hypersensitivity syndrome and human herpesvirus 6 reactivation and hypogammaglobulinemia
anticonvulsant hypersensitivity syndrome and human herpesvirus 6 reactivation and hypogammaglobulinemia. Arch Dermatol 2004; 140: 183-188.