Drug‐induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms due to lamotrigine differs from that due to other drugs

Drug‐induced hypersensitivity syndrome (DIHS), also referred to as drug reaction with eosinophilia and systemic symptoms (DRESS), is a multi‐organ systemic drug reaction characterized by hematological abnormalities and reactivation of human herpesvirus‐6 (HHV‐6). DIHS/DRESS is typically associated with a limited number of drugs, such as the anticonvulsants. Our group has treated 12 patients for DIHS/DRESS due to lamotrigine (LTG), but their presentation differed from that of patients with DIHS/DRESS caused by other drugs. The aim of the present study was to identify significant differences between DIHS/DRESS caused by LTG versus other drugs. We retrospectively reviewed data of 12 patients with DIHS/DRESS caused by LTG and 32 patients with DIHS/DRESS due to other drugs. The increase in alanine aminotransferase level was significantly milder in the LTG group than the DIHS/DRESS group due to other drugs. The percentage of atypical lymphocytes in the blood during DIHS/DRESS was lower in the LTG group. Serum levels of lactate dehydrogenase and thymus and activation‐regulated chemokine were also lower in the LTG group. There were fewer DIHS/DRESS patients with HHV‐6 reactivation in the LTG group than in the group treated with other drugs. Lymphocyte transformation after DIHS/DRESS onset was faster in the LTG group. The two groups did not differ with respect to the interval from first drug intake to rash, white blood cell count, blood eosinophilia or DRESS score. There were no significant histopathological differences between the two groups. The features of LTG‐associated DIHS/DRESS and DIHS/DRESS due to other drugs differ.     

Facial pustules due to drug‐induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms may histopathologically mimic eosinophilic pustular folliculitis: A case report

Pustules with facial and/or neck edema is one characteristic feature of drug‐induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS) at the early stage. Although several retrospective histopathologic studies on DIHS/DRESS have been reported, the detailed histopathologic findings of facial pustules for DIHS/DRESS are unavailable. We herein report a case of DIHS/DRESS with facial pustules that was histopathologically similar to eosinophilic pustular folliculitis (EPF). Eosinophilic infiltration into expanded follicles and sebaceous glands, which is highly characteristic of EPF, was detected in pustules due to DIHS/DRESS in this case. There are numerous pathophysiological similarities between DIHS/DRESS and EPF, which may cause their histopathologic similarity. Our findings suggest that facial pustules of DIHS/DRESS may histopathologically mimic EPF.     

Pustular‐type drug‐induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms due to carbamazepine with systemic muscle involvement

Drug‐induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe reaction usually associated with maculopapular eruptions and systemic involvement. Here we report the first case, to our knowledge, of DIHS/DRESS due to carbamazepine with acute generalized pustular bacterid‐like (AGPB‐like) eruptions and skeletal muscle involvement. Reviewing our case and the published work, we discuss pustular‐type DIHS/DRESS which, in most cases, involves acute generalized exanthematous pustulosis (AGEP)‐like skin eruptions in response to carbamazepine. Pustular eruptions may appear in relatively few cases of DIHS/DRESS, in particular, when the causative drug is carbamazepine and, even in cases of intractable pustular bacterid‐like eruptions, a reaction to a drug should be suspected. Skeletal muscle involvement may be associated with DIHS/DRESS as one of its systemic manifestations.     

Late-onset interstitial nephritis in a patient with drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms

Drug-induced hypersensitivity syndrome (DIHS), also referred to as drug reaction with eosinophilia and systemic symptoms (DRESS), is a severe hypersensitivity drug reaction affecting the skin and multiple internal organ systems. We report a 47-year-old man with DIHS/DRESS and comorbidities (fulminant type 1 diabetes mellitus, valsartan-induced photosensitivity, vitiligo and acute interstitial nephritis). Although acute interstitial nephritis usually appears in the early phase, his is a rare case of acute interstitial nephritis more than 2 years after the onset of DIHS/DRESS.     

Case of lamotrigine‐induced drug adverse reaction under tocilizumab treatment with clinical and virological features of drug‐induced hypersensitivity syndrome

The pathological mechanisms and immunological kinetics of drug‐induced hypersensitivity syndrome (DIHS), including the relevance of interleukin (IL)‐6, remain unclear. We report a case of drug adverse reaction that does not fulfill the diagnostic criteria of DIHS but mimics its characteristic features. Because the patient was under anti‐IL‐6 therapy at the onset, some symptoms typically seen in DIHS were absent, such as fever and leukocyte count abnormalities. However, the characteristic features of DIHS were clearly observed in the subsequent course, including the repeated recurrence of skin rash, prolonged liver dysfunction and reactivation of herpes viruses. This case suggested that IL‐6 role at the onset is not a main factor to determine the subsequent pathomechanism of DIHS and attention should be paid to the preceding therapy for achieving accurate diagnosis.     

Long-term outcome of patients with severe cutaneous adverse reactions

Visceral involvement associated with Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS) is well documented. However, little is known about the long-term outcomes of severe drug eruptions due to a lack of long-term follow-up. Long-term sequelae may arise in patients who survive the acute complications of severe drug reactions. In SJS/TEN, extensive scarring that result from the healing of mucocutaneous ulcerative lesions may interfere with organ function. Severe sequelae include visual impairment and pulmonary obliterative disease that impair patients' quality of life. In DIHS/DRESS, recent observations suggest that fulminant type 1 diabetes mellitus (FT1D) and autoimmune diseases such as autoimmune thyroiditis and lupus erythematosus can occur after a disease-free period of several months to years. Thus, DIHS/DRESS may lead to the development of autoimmune diseases, which may be overlooked. Dermatologists need to be aware of the sequelae that may arise following resolution of severe cutaneous adverse reactions and should be vigilant for manifestations of autoimmune disease during follow-up.     

药物超敏综合征的遗传易感性研究进展

药物超敏综合征是一类严重的药物不良反应,患者有发热、皮肤损害、嗜酸粒细胞升高、淋巴结肿大及肝脏受累等,流行病学调查发现其死亡率高达10%~20%。近年来,研究发现药物超敏综合征的发生与个体的遗传易感性,尤其是某些人类白细胞抗原(HLA)等位基因有关。本文综述了卡马西平,别嘌呤醇,氨苯砜,阿巴卡韦及奈韦拉平所致药物超敏综合征的遗传易感性研究进展。     

Influence of corticosteroid therapy on viral reactivation in drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms

Drug-induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe adverse drug reaction characteristically associated with sequential reactivation of herpesviruses, such as human herpesvirus 6 (HHV-6), Epstein-Barr virus (EBV), and cytomegalovirus (CMV). Since systemic corticosteroids are thought to result in viral reactivation due to their immunosuppressive effects, we clarified the influence of systemic corticosteroid therapy on viral reactivation in DIHS/DRESS. Viral DNA in peripheral whole blood and serum sIL-2R level were measured during the disease course in twenty DIHS/DRESS patients. Six of seven patients treated without corticosteroids experienced HHV-6 viremia associated with elevated serum sIL-2R levels. In contrast, high-dose corticosteroids started within 1 week after onset tended to inhibit the occurrence of HHV-6 reactivation with remarkable suppression of serum sIL-2R level. Low-dose corticosteroids or late-start high-dose corticosteroids did not suppress occurrence of HHV-6 viremia and the increase of sIL-2R levels. HHV-6 load in the blood was clearly correlated with the serum sIL-2R level. On the other hand, increased CMV load were found in patients treated with corticosteroids regardless of the start time. The frequency of detection of EBV DNA in peripheral blood was similarly observed in all groups. In conclusion, high-dose corticosteroids started within 1 week tended to suppress HHV-6 reactivation through suppression of T cell activation. However, CMV proliferation was promoted by corticosteroids regardless of the start time. These observations suggested that careful consideration should be given to the dose and timing of administration of systemic corticosteroids in the treatment of DIHS/DRESS.     

Drug reaction with eosinophilia and systemic symptoms: A drug-induced hypersensitivity syndrome with variable clinical features

Drug reaction with eosinophilia and systemic symptoms (DRESS) or drug-induced hypersensitivity syndrome (DIHS) involves a unique and severe adverse drug reaction. Patients present with fever, rash, lymphadenopathy, hematological abnormalities, systemic illness, and may suffer from prolonged courses. Although the precise pathogenesis of DRESS/DIHS is not fully understood, it is widely considered to be an immunological reaction to a drug or drug metabolites. In this review article, we discuss the historical aspects of nosology, variable clinical and histopathological features, advantages and disadvantages of using an international Registry of Severe Cutaneous Adverse Reactions (RegiSCAR) and Japanese DIHS criteria, pathogenesis, treatment, and long-term sequelae of DRESS/DIHS. Early recognition of this syndrome, withdrawal of suspected culprit drugs, and adequate supportive care are mainstays of improving patient prognosis and reducing morbidities and mortality. Moreover, some DRESS/DIHS patients may develop long-term sequelae, especially autoimmune diseases and end organ failure. Physicians should be aware of these possibilities in patients after DRESS/DIHS and cautiously follow-up symptoms and laboratory tests for early detection of these sequelae.     

Patch testing is an effective method for the diagnosis of carbamazepine‐induced drug reaction,eosinophilia and systemic symptoms (DRESS) syndrome in an 8‐year‐old girl

Drug reaction, eosinophilia and systemic symptoms (DRESS) is an acute and life‐threatening disease, characterised by fever, rash and systemic symptoms, including lymphadenopathy, abnormal liver function, interstitial nephritis, pulmonary and cardiac infiltrates and haematological abnormalities with eosinophilia and atypical lymphocytes. The drugs mostly associated with DRESS are anticonvulsants, allopurinol, minocycline and sulfonamides. This syndrome is rarely seen in childhood even though a large number of children have anticonvulsant treatment. An 8‐year‐old girl was admitted with fever, lymphadenopathy and skin eruptions on her trunk. Her medical history was notable for epilepsy and carbamazepine treatment had been started 5 weeks previously. Laboratory studies showed a white cell count of 6200/µL (normal, 4100–11 200/µL) with 22% eosinophils and a γ‐glutamyl transpeptidase level of 296 U/L (normal, 0–23 U/L). Laboratory tests for infections and collagen diseases were in the normal range. Persistence of fever and maculopapular eruption with generalised desquamation and the appearance of cheilitis and facial angioedema suggested a hypersensitivity reaction to carbamazepine. The carbamazepine was replaced with levetiracetam. All clinical symptoms improved within a week with corticosteroids and antihistamine treatment. Six weeks after complete recovery an epicutaneous patch test with carbamazepine was performed and a carbamazepine‐induced positive skin reaction was observed at 48‐h. Carbamazepine‐induced DRESS syndrome is a rare entity in children. An epicutaneous patch test is a useful tool for identifying the inducing agent for the DRESS syndrome and for identifying a safe anticonvulsant drug.     

Cerebral vasculitis and multi‐focal neurological deficits due to allopurinol‐induced hypersensitivity syndrome

Drug‐induced hypersensitivity syndrome (DIHS) is a multi‐system syndrome resulting from an idiosyncratic reaction to medication. While it commonly results in multi‐organ involvement, particularly the liver, there are few reports of DIHS causing cerebral vasculitis and neurological deficits. We report the case of a 63‐year old woman with DIHS secondary to allopurinol leading to multiple neurological deficits with magnetic resonance imaging findings consistent with a cerebral vasculitis.     

Case of vitiligo universalis as a sequela of drug‐induced hypersensitivity syndrome

Drug‐induced hypersensitivity syndrome (DIHS) is a type of severe drug adverse reaction with high morbidity and mortality. DIHS patients have been reported to subsequently develop autoimmune disease, which may be followed by end‐organ decompensation. We report a 47‐year‐old woman who presented with fever, generalized maculopapular eruption, facial edema and eosinophilia with liver function impairment after taking celecoxib and sulfasalazine for 1 month. The patient was diagnosed with definite DIHS. The patient was treated with immunosuppressants including systemic corticosteroid for approximately 1.5 years due to recurrent episodes. Reactivation of human herpesvirus 6 and possible reactivation of cytomegalovirus were detected. Generalized hypopigmentation of the skin and leukotrichia were noted 4 months after the onset of DIHS. Histopathological examination confirmed the diagnosis of vitiligo. Some spontaneous repigmentation was noted 4 years after DIHS without specific treatment. Further immunoserology study showed elevated plasma C‐X‐C motif chemokine 10 level, which is related to vitiligo activity, in our patient. The occurrence of widespread vitiligo after DIHS is an extremely rare condition. This case provides an important reminder for physicians to monitor such severe complications after DIHS.     

Stevens–Johnson syndrome and toxic epidermal necrolysis due to anticonvulsants share certain clinical and laboratory features with drug‐induced hypersensitivity syndrome,despite differences in cutaneous presentations

Background. Drug‐induced hypersensitivity syndrome (DIHS)/drug rash with eosinophilia and systemic symptoms (DRESS) syndrome is characterized by late disease onset, fever, rash, hepatic dysfunction, haematological abnormalities, lymphadenopathy and often, human herpesvirus (HHV) reactivation. The diagnosis of DIHS is based on the combined presence of these findings. Anticonvulsants are a major cause of DIHS and may also cause Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). We examined whether SJS/TEN due to anticonvulsants display similar clinical and laboratory features seen in DIHS. Methods. Patients diagnosed with SJS or TEN due to anticonvulsants (n = 8) were examined and their clinical features and laboratory findings were compared with patients with anticonvulsant‐related DIHS (n = 6). Results. Seven of the eight patients with SJS/TEN developed symptoms > 3 weeks after starting anticonvulsants. Hepatic dysfunction was present in six patients with SJS/TEN and five patients with DIHS. Leucocytosis and/or eosinophilia was noted in seven patients with SJS/TEN and four patients with DIHS. Only one patient in the SJS/TEN group had atypical lymphocytosis; this was present in four patients with DIHS. Reactivation of HHV‐6 was detected in one of the four patients tested in the SJS/TEN group, although it was seen in five of the six patients with DIHS. Conclusions. TSJS/TEN due to anticonvulsants may exhibit some clinical and laboratory features of DIHS. The nature of the cutaneous involvement should be emphasized in the diagnosis of DIHS.     

Severe drug‐induced skin reactions: clinical pattern,diagnostics and therapy

The spectrum of severe drug‐induced skin reactions includes not only Stevens‐Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) but also generalized bullous fixed drug eruption (GBFDE), acute generalized exanthematous pustulosis (AGEP) and hypersensitivity syndrome (HSS), also called drug reaction with eosinophilia and systemic symptoms (DRESS). These reactions differ in clinical presentation as well as prognosis, causative agents and therapy. Therefore, the appropriate diagnostic measures should be undertaken rapidly, in order to prove the diagnosis. In addition to a thorough clinical examination, a skin biopsy should be taken and specific laboratory investigations should be done if AGEP or HSS/DRESS is suspected. Since these reactions are drug‐induced, the causative agent should be rapidly identified and withdrawn. Besides adequate supportive therapy, systemic immunomodulatory treatments may be considered. Despite intensive care management, the prognosis in SJS and TEN is often poor and influenced by the amount of skin detachment as well as the age of the patients and the pre‐existing underlying conditions. Severe sequelae may develop in survivors and affect especially mucosal sites. The prognosis of GBFDE is better but recurrent events may lead to more severe involvement. In HSS/DRESS sequelae have been also described as well as long lasting and recurrent courses, whereas AGEP usually heals without problems.     

Syndrome of inappropriate secretion of antidiuretic hormone associated with limbic encephalitis in a patient with drug-induced hypersensitivity syndrome

Drug-induced hypersensitivity syndrome (DIHS)/drug rash with eosinophilia and systemic symptoms (DRESS) is a severe multiorgan reaction with reactivation of herpesviruses. Various features are often seen during the course of the disease. Many aspects of this syndrome suggest close similarities between DIHS/DRESS and graft-versus-host disease. We describe a patient with phenobarbital-induced hypersensitivity syndrome who revealed syndrome of inappropriate secretion of antidiuretic hormone (SIADH) associated with limbic encephalitis during the course of the disease. In view of previous reports that SIADH and limbic encephalitis are caused by reactivation of latent herpesviruses after transplantation, both conditions may be secondarily caused by reactivation of latent herpesviruses, which is typically observed in DIHS/DRESS. These neurological symptoms should be added to a growing list of important complications of DIHS/DRESS because of the high mortality rate associated with them.     

Drug‐induced hypersensitivity syndrome due to carbapenem antibiotics

Drug‐induced hypersensitivity syndrome (DIHS) is characterized by a serious adverse systemic reaction that usually appears after a 3–6‐week exposure to certain drugs, for example, anticonvulsants. Many different precipitating factors have been reported, but the pathophysiology of DIHS remains unknown. However, reactivation of members of the human herpesvirus (HHV) family, and of HHV‐6 in particular, has been reported in patients with DIHS. We report the case of a 64‐year‐old man who developed a generalized erythematous rash, fever, hepatic failure, lymphadenopathy and an increased number of atypical lymphocytes. In addition, reactivation of HHV‐6 and cytomegalovirus (CMV) was demonstrated by real‐time quantitative amplification by polymerase chain reaction. The patient was given a diagnosis of DIHS due to carbapenem antibiotics based on his clinical course, laboratory data, and results of lymphocyte‐stimulation tests with various drugs. This is the first report, to our knowledge, of DIHS induced by carbapenem antibiotics.     

Ethosuximide‐induced drug reaction with eosinophilia and systemic symptoms with mediastinal lymphadenopathy

Lymphadenopathy is a common sign for drug reaction and eosinophilia with systemic symptoms (DRESS) syndrome, but hilar and mediastinal lymphadenopathy may be underreported. We describe a 7‐year‐old boy who started taking ethosuximide for absence seizures and presented with diffuse rash, fever, elevated transaminases, facial swelling, and hilar and mediastinal lymphadenopathy. His mediastinal lymphadenopathy was concerning for lymphoma, which led to more invasive testing to rule out malignancy. This report highlights an unusual and likely underreported presenting sign of DRESS syndrome in children.     

Drug‐induced hypersensitivity syndrome due to minocycline complicated by severe myocarditis

A 60‐year‐old woman presented with a 13‐day history of a generalized erythematous rash accompanied by fever, periorbital edema and axillary lymphadenopathy. Prior to the appearance of the rash, the patient had been treated with intermittent courses of oral minocycline for cystitis. The patient was diagnosed with drug‐induced hypersensitivity syndrome (DIHS) due to minocycline. During the admission, infectious endocarditis was suspected and the patient was treated with i.v. gammaglobulin (0.4 g/kg per day). The following day, the patient suffered from systemic deterioration and symptomatic low blood pressure that prompted repeat echocardiography which revealed an ejection fraction of 10%. DIHS‐associated myocarditis was suspected and management with circulation assistance devices and steroid pulse therapy were started, resulting in satisfactory resolution. A rise in titer of human herpesvirus‐6, cytomegalovirus and Herpes simplex virus‐1 antibodies was detected. Although minocycline‐induced myocarditis is rare, this severe drug reaction should be considered with DIHS.     

Severe cutaneous adverse drug reactions

The clinical manifestations of drug eruptions can range from mild maculopapular exanthema to severe cutaneous adverse drug reactions (SCAR), including drug‐induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms, Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) which are rare but occasionally fatal. Some pathogens may induce skin reactions mimicking SCAR. There are several models to explain the interaction of human leukocyte antigen (HLA), drug and T‐cell receptor (TCR): (i) the “hapten/prohapten” theory; (ii) the “p‐i concept”; (iii) the “altered peptide repertoire”; and (iv) the “altered TCR repertoire”. The checkpoints of molecular mechanisms of SCAR include specific drug antigens interacting with the specific HLA loci (e.g. HLA‐B*15:02 for carbamazepine‐induced SJS/TEN and HLA‐B*58:01 for allopurinol‐induced SCAR), involvement of specific TCR, induction of T‐cell‐mediated responses (e.g. granulysin, Fas ligand, perforin/granzyme B and T‐helper 1/2‐associated cytokines) and cell death mechanism (e.g. miR‐18a‐5p‐induced apoptosis; annexin A1 and formyl peptide receptor 1‐induced necroptosis in keratinocytes). In addition to immune mechanism, metabolism has been found to play a role in the pathogenesis of SCAR, such as recent findings of strong association of CYP2C9*3 with phenytoin‐induced SCAR and impaired renal function with allopurinol SCAR. With a better understanding of the mechanisms, effective therapeutics and prevention for SCAR can be improved.     

Clinicopathlogical features and prognosis of drug rash with eosinophilia and systemic symptoms: a study of 30 cases in Taiwan

Background  Drug rash with eosinophilia and systemic symptoms (DRESS), a group of non-blistering severe cutaneous adverse drug reactions (SCADRs), is characterized by skin rash and multiorgan involvement. Details of this reaction have not been reported in the literature so far.
Aim  We investigate clinical and pathological features and prognosis of DRESS and hope this study will provide data concerning this disorder in Taiwan.
Methods  From January 2001 to June 2006, a total of 30 patients, diagnosed with DRESS, were enrolled and evaluated for demographic characteristics, pathological findings, complications and outcome.
Results  Patient ages ranged from 13 to 78, with an equal sex ratio. The most common offending drug was allopurinol followed by carbamazepine. Pathologic changes observed were lichenoid dermatitis, erythema multiforme, pseudolymphoma and vasculitis. Impairment of liver and renal functions and blood dyscrasia were frequent complications. Active infection or reactivation of HHV-6 was observed in 7 of 11 patients studied serologically. Two patients developed type 1 diabetes mellitus. The mortality rate was 10% (3 of 30).
Conclusions  DRESS is a heterogeneous group of life-threatening conditions. The leading drug in DRESS in Taiwan is allopurinol. High eosinophil count and multiple underlying diseases are poor prognostic factors in patients with DRESS.