Epidemiology of Ophthalmologic Disease Associated with Erythema Multiforme,Stevens‐Johnson Syndrome,and Toxic Epidermal Necrolysis in Hospitalized Children in the United States

The objective of the current study was to characterize the epidemiology and resource use of U.S. children hospitalized with ophthalmologic disease secondary to erythema multiforme (EM), Stevens‐Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). We studied children ages 5 to 19 years hospitalized in 2005 in 11 states, encompassing 38% of the U.S. pediatric population. Using International Classification of Diseases, Ninth Revision, Clinical Modification codes, we identified admissions of children with EM, SJS, or TEN and the presence of concurrent ophthalmologic disease, analyzed patient and hospitalization characteristics, and generated age‐ and sex‐adjusted national estimates. We identified 460 children admitted with EM, SJS, or TEN, corresponding to 1,229 U.S. hospitalizations in 2005. Of the children with EM, SJS, or TEN, 60 (13.0%) had ophthalmologic disease, primarily (90.0%) disorders of the conjunctiva. Children with the highest proportions of ophthalmologic disease included those with mycoplasma pneumonia (26.7%), herpes simplex virus (15.6%), upper respiratory infection (13.9%), and lower respiratory infection (13.7%). Individuals with EM, SJS, or TEN and ophthalmologic disease were more likely than those without ophthalmologic disease to receive intensive care unit care (28.3% vs 17.0%, p = 0.03) and to be admitted to a children's hospital (63.3% vs 48.8%, p = 0.03). Ophthalmologic disease was also associated with a significantly longer median length of stay (6.0 days, interquartile range [IQR] 3–9 days vs 3.0 days, IQR 2–6 days, p < 0.001) and median hospital cost ($7,868, IQR $3,539–$17,440 vs $2,969, IQR $1,603–$8,656, p < 0.001). In children with EM, SJS, or TEN, ophthalmologic disease was most common in those with concurrent Mycoplasma pneumoniae and herpes simplex virus infections. Ophthalmologic disease was associated with considerably higher inpatient resource use in this population. Children with EM, SJS, or TEN should be screened and treated early for ophthalmologic disease to prevent morbidity and minimize long‐term sequellae.     

Stevens‐Johnson syndrome and toxic epidermal necrolysis associated with the use of macrolide antibiotics: a review of published cases

Macrolides are one of the most commonly prescribed antibiotics. In several studies, their use was associated with the occurrence of Stevens‐Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). This review aimed to explore and summarize available cases of SJS/TEN suspected to be associated with the use of macrolide antibiotics reported in the literature. Electronic searches were conducted in PubMed/MEDLINE, Web of Science, Scopus, and Serbian Citation Index (SCIndeks). Twenty‐five publications describing a total of 27 patients were included. Cases of SJS/TEN which satisfied inclusion criteria were found for azithromycin (n = 11), clarithromycin (n = 7), erythromycin (n = 5), roxithromycin (n = 2), and telithromycin (n = 2). The age of the patients ranged from 2 to 77 years (median: 29 years). There were 14 female (51.9%) and 13 male (48.1%) patients. SJS was diagnosed in 16 patients (59.3%), TEN in 10 patients (37.0%), and SJS/TEN overlap in one patient (3.7%). Time to onset of the first symptoms ranged from 1 to 14 days (median: 3 days). All patients received some form of supportive and symptomatic care. Systemic corticosteroids were reported to be administered in 12 patients (44.4%) and intravenous immunoglobulin in five patients (18.5%). Three patients (11.1%) died. Considering that SJS/TEN is a severe and potentially life‐threatening reaction, physicians should be aware that they could be adverse effects of macrolide antibiotics and keep in mind that prompt recognition of SJS/TEN and discontinuation of the culprit drug in combination with supportive care is essential.     

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.     

Procalcitonin as a diagnostic indicator for systemic bacterial infections in patients with Stevens–Johnson syndrome/toxic epidermal necrolysis

Elevated serum procalcitonin (PCT) level has been reported to be a diagnostic index in systemic bacterial infections, but it can also increase in some non‐infectious inflammatory diseases. Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) is a rare immune‐mediated cutaneous mucosal reaction which is susceptible to bacterial infections and may have elevated PCT levels. The value of serum PCT has not been assessed in series of SJS/TEN patients. We aimed to investigate the PCT levels in SJS/TEN patients with systemic bacterial infections (systemic infected group), with skin surface bacterial infections (skin surface infected group) and without infections (non‐infected group), to assess whether PCT was a valuable indicator for systemic bacterial infections in SJS/TEN patients. The PCT and C‐reactive protein (CRP) levels of 42 inpatients with SJS/TEN were retrospectively analysis. The receiver–operator curve (ROC) was used to determine the diagnostic efficacy of PCT for systemic bacterial infections in SJS/TEN patients. The results demonstrated that PCT levels in the systemic infected group were significantly higher than those in the other two groups (P < 0.05). There was no significant difference in CRP between the three groups. The cut‐off PCT level of 0.65 ng/mL calculated by ROC had optimal diagnostic efficacy, with sensitivity and specificity of 84.6% and 89.7%, respectively. PCT and severity‐of‐illness score for toxic epidermal necrolysis were positively correlated (P < 0.05). In conclusion, PCT is a valuable index and superior to CRP in detecting systemic bacterial infections in SJS/TEN patients. The level of PCT can partially reflect the severity of the disease.     

Mycoplasma pneumoniae–Associated Mucocutaneous Disease in Children: Dilemmas in Classification

There is controversy regarding precise definitions for Stevens–Johnson syndrome (SJS) and erythema multiforme (EM) major because of overlap in clinical presentations. SJS and EM major associated with Mycoplasma pneumoniae have been reported to occur in children, but Mycoplasma is more commonly reported with SJS. We sought to further characterize Mycoplasma‐associated mucocutaneous disease. Through retrospective chart review over 10 years, six children hospitalized with a diagnosis of SJS who also tested positive for Mycoplasma infection were reviewed. Using documented physical examinations and photographs, diagnoses of SJS or EM major were retrospectively made based upon cutaneous lesional morphology employing the classification system proposed by Bastuji‐Garin et al. The majority of patients were boys, with limited acral cutaneous lesions. All patients required prolonged hospitalization because of mucosal involvement and had good short‐term outcomes. When the classification system was retrospectively applied, five of the six patients were reclassified with a diagnosis of EM major instead of SJS. Children with Mycoplasma‐associated EM major and SJS in our small retrospective series appeared to have significant mucosal involvement but more limited cutaneous involvement with lesional morphology, which is more characteristic of EM major.     

Efficacy of additional i.v. immunoglobulin to steroid therapy in Stevens–Johnson syndrome and toxic epidermal necrolysis

Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare and life‐threatening cutaneous adverse drug reactions. While there is no established therapy for SJS/TEN, systemic corticosteroids, plasma exchange and i.v. immunoglobulin (IVIG) have been used as treatment. The efficacy of IVIG is still controversial because total doses of IVIG used vary greatly from one study to another. The aim of this study was to evaluate the efficacy of IVIG, administrated for 5 days consecutively, in an open‐label, multicenter, single‐arm study in patients with SJS or TEN. IVIG (400 mg/kg per day) administrated for 5 days consecutively was performed as an additional therapy to systemic steroids in adult patients with SJS or TEN. Efficacy on day 7 of IVIG was evaluated. Parameters to assess clinical outcome were enanthema including ophthalmic and oral lesions, cutaneous lesions and general condition. These parameters were scored and recorded before and after IVIG. We enrolled five patients with SJS and three patients with TEN who did not respond sufficiently to systemic steroids before IVIG administration. All of the patients survived and the efficacy on day 7 of the IVIG was 87.5% (7/8 patients). Prompt amelioration was observed in skin lesions and enanthema in the patients in whom IVIG therapy was effective. Serious side‐effects from the use of IVIG were not observed. IVIG (400 mg/kg per day) administrated for 5 days consecutively seems to be effective in patients with SJS or TEN. IVIG administrated together with steroids should be considered as a treatment modality for patients with refractory SJS/TEN. Further studies are needed to define the therapeutic efficacy of IVIG.     

3 Severe cutaneous adverse reactions time latency between beginning of drug use and onset of reaction

Background Toxic epidermal necrolysis (TEN) and Stevens–Johnson syndrome (SJS) are acute life‐threatening severe cutaneous adverse reactions (SCAR) with an unclear pathogenesis mainly caused by drugs. Allopurinol and trimethoprim/sulphamethoxazole (TMS) are both well known to be associated with these conditions. In addition, TMS is known to induce generalized bullous fixed drug eruption (GBFDE), a less severe condition with a very short induction period that is clinically often confused with SJS or TEN. Aim We want to further investigate the risk profile of allopurinol and TMS for inducing SCAR, as the hazard functions of these substances are different. Furthermore, the re‐review of cases using more specific criteria to differentiate between SCAR and GBFDE should allow us to detect misclassification of cases. Methods 984 cases of SJS, SJS/TEN overlap and TEN were ascertained by a population‐based registry between 1990 and 1999. The following analysis is based on a random sample of 115 cases earlier accepted as SJS or TEN, which were exposed to either allopurinol or TMS, and 38 cases excluded in the previous review. An independent expert committee blinded for possible causes re‐reviewed these cases in clinical terms, as the original review process took place over a period of 10 years. In this analysis special emphasis is given to the time latency between beginning of drug use and onset of SCAR. Results Before re‐review 162/984 patients with SCAR reported the use of allopurinol and 131/984 the use of TMS within 2 weeks prior to the onset of the adverse reaction. After the re‐review the percentage of doubtful cases was higher for TMS (28/57) than for allopurinol (30/83). For definite cases of SJS or TEN the range between the lower and upper quartile of the time latency between beginning of drug use and onset of SCAR was 14–34 days for allopurinol, in contrast to 5–15 days for TMS. The time latency for doubtful and excluded cases after the use of TMS was much shorter (2.5 and 2 days, respectively). Conclusions The high numberof doubtful cases after the re‐review reveals the difficulty of applying approved detailed definitions to the variety of clinical patterns of cutaneous adverse reactions. We could confirm a high correlation of time latency between beginning of drug use and onset of SCAR and GBFDE for allopurinol and TMS, which may have an important impact on the risk profile of these and other suspected drugs, as well as on pathogenetic and therapeutic considerations of severe adverse events. When drug exposure occurs outside the relevant interval of time latency for SJS and TEN, other risk factors and/or differential diagnoses such as GBFDE should be considered.     

Erythema multiforme, Stevens–Johnson syndrome and toxic epidermal necrolysis in northeastern Malaysia

Background Previous studies have reported that drugs and infections are common causes of erythema multiforme (EM) and Stevens–Johnson syndrome (SJS). Toxic epidermal necrolysis (TEN) is mainly related to drugs. No study has been conducted in Kelantan, the northeastern state of Malaysia, to assess these cutaneous reactions. Methods A retrospective study of all hospitalized cases of EM, SJS, and TEN was conducted covering an 8-year period from 1987 to 1994. Results There were four cases (13.8%) of EM, 22 cases (75.9%) of SJS, and three cases (10.3%) of TEN. Drugs as a definitive cause was observed in one case (25%) of EM, 12 cases (54.5%) of SJS, and two cases (66.7%) of TEN. Drugs as a probable cause was observed in seven cases (31.8%) of SJS and one case (33.3%) of TEN. The male to female ratio was equal in EM and SJS. Antiepileptics were the commonest culprits, followed by antibiotics. One patient died of SJS and one patient died of TEN, giving mortality rates of 4.5% and 33.5% respectively. Fever was noted in 18 patients (62.1%). Leukocytosis was noted in 10 patients (34.5%), and nine patients (31.0%) had elevated liver transaminase enzymes. No significant correlation was noted between these biochemical changes and cutaneous eruption. Secondary infections were observed in 11 patients (37.9%): Staphylococcus aureus was the commonest isolated organism. Conclusions This study shows that drugs remain the commonest culprit in SJS and TEN. Despite adequate treatment, the mortality rate remains high, especially in TEN. These findings are similar to those of other reported studies.     

Open trial of ciclosporin treatment for Stevens–Johnson syndrome and toxic epidermal necrolysis

Background Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are acute mucocutaneous reactions associated with poor prognosis. The treatment is mainly symptomatic, based on supportive care. Until now, several curative treatments have been proposed without evidence of effectiveness. Objectives To evaluate the effect of ciclosporin on SJS and TEN after a short series had suggested a benefit. Methods We conducted an open, phase II trial to determine the safety and possible benefit of ciclosporin. Among the 45 consecutive patients admitted for SJS/TEN from March 2005 to September 2007, 29 fulfilled inclusion criteria. Ciclosporin was administered orally (3 mg kg^?1 daily for 10 days) and tapered over a month. Clinical and biological evaluations were performed sequentially. Predicted death rate was estimated with a validated prognostic score (SCORTEN). Results Twenty‐nine patients were included at a mean ± SD of 2·8 ± 1·8 days after onset. The final diagnosis was SJS (n = 10), SJS/TEN overlap (n = 12) and TEN (n = 7). One month of treatment was completed in 26. Ciclosporin was stopped after more than 10 days in three cases for side‐effects including posterior leucoencephalopathy (n = 1), neutropenia (n = 1) and nosocomial pneumopathy (n = 1). Ciclosporin dosage was tapered earlier than scheduled in two cases for alteration in renal function. The prognostic score predicted 2·75 deaths; none occurred (P = 0·1). Mean epidermal detachment remained stable in 18 of 29 cases (62%). The mean ± SD hospital stay was 16·2 ± 9·1 days. Conclusions Both the death rate and the progression of detachment seemed lower than expected, suggesting a possible usefulness of ciclosporin in SJS and TEN that needs to be confirmed.     

Erythema multiforme,Stevens–Johnson syndrome and toxic epidermal necrolysis: Frozen‐section diagnosis

Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) may be fatal. Although classified by body surface area skin detachment, initial stages of both may present with erythema multiforme (EM)‐like lesions. To diagnose and predict disease activity adequately as early as possible for patients revealing EM‐like lesions, we performed frozen‐section diagnosis. Thirty‐five patients clinically diagnosed as EM, SJS or TEN were biopsied to diagnose and predict disease progression within the initial‐visit day. Half of a histological section taken from a lesion was snap‐frozen and immediately cryostat‐sectioned, acetone‐fixed and stained with hematoxylin–eosin. Specimens were examined with light microscopy for presence of epidermal necrosis. A section from unaffected sites was also examined for 11 patients. Specimens were examined with light microscopy for presence of graft‐versus‐host reaction (GVHR)‐like findings: apoptotic keratinocytes and satellite cell necrosis. Epidermal necrosis was seen in nine patients. Initial diagnosis of the nine was one of overlap SJS‐TEN, four of SJS and four of EM, and final diagnosis of those was one of TEN, one of overlap SJS–TEN, four of SJS and three of EM. Dissociation between initial and final diagnosis was seen in three cases. GVHR‐like findings in the epidermis were observed in two patients finally diagnosed as overlap SJS–TEN and TEN. Frozen sections are useful not only to make a diagnosis of erythema multiforme but to assess a potential to exhibit more aggressive clinical behaviors (SJS or TEN).     

Combination therapy of intravenous immunoglobulin and corticosteroid in the treatment of toxic epidermal necrolysis and Stevens–Johnson syndrome: a retrospective comparative study in China

Background Toxic epidermal necrolysis (TEN) and Stevens–Johnson Syndrome (SJS) are drug‐induced diseases with no well‐established treatments. The application of corticosteroid therapy is controversial. Intravenous immunoglobulin (IVIG) therapy is emerging as a promising new method for the treatment of these two diseases. The efficacy of combination therapy of IVIG and corticosteroid in the treatment of TEN/SJS has seldom been reported. Methods Sixty‐five consecutive patients with either TEN or SJS, admitted over a 14‐year period from January 1993 to October 2007, were treated with corticosteroid and analyzed retrospectively using SCORTEN, a severity‐of‐illness scoring system for TEN/SJS prognosis, to evaluate efficacy. For patients admitted after January 2001, additional therapy with a dose of 0.4 g/kg/day of IVIG for 5 days was applied. Results In the 45 patients with TEN treated without IVIG, 8.63 patients were expected to die based on the SCORTEN system, but 10 deaths were observed. Standardized mortality ratio (SMR) analysis [(Σobserved deaths/Σexpected deaths) × 100] suggested that patients with TEN treated with systemic corticosteroid were 16% more likely to die than those treated with routine therapy (SMR = 1.16; 95% confidence interval, 0.56–2.13). In the further study of combination therapy, 12 patients with TEN and eight patients with SJS were admitted. There were two deaths in the TEN group and one death in the SJS group, with 3.51 deaths expected on the basis of the SCORTEN system. SMR analysis showed that combination therapy had a tendency to reduce the mortality rate of TEN (SMR = 0.85; 95% confidence interval, 0.18–2.50). Nevertheless, in both the TEN and SJS groups, the difference in mortality rate between the two therapies was not statistically significant (P = 0.651 and P = 1, respectively). In patients with TEN, combination therapy also reduced significantly the time of arrested progression (P = 0.019) and the total hospitalization time (P = 0.043), but could not reduce the time to the tapering of corticosteroid (P = 0.96). In SJS patients, the times of arrested progression and hospitalization were also reduced significantly (P = 0.019 and P = 0.0475, respectively). Likewise, the time to the tapering of corticosteroid was not reduced (P = 0.122). Conclusion Combination therapy with corticosteroid and IVIG exhibited a tendency to reduce the mortality rate in comparison with the solo administration of corticosteroid. The decrease in the mortality rate, however, was not statistically significant. Combination therapy also arrested progression earlier and decreased the hospitalization time, meaning that the total dose of corticosteroid may be reduced. Combination therapy, however, did not lead to earlier tapering of corticosteroid. No severe adverse effects of IVIG were found during treatment.     

Mycoplasma pneumoniae–Induced Recurrent Stevens–Johnson Syndrome in Children: A Case Report

Mycoplasma pneumoniae, the major pathogen of primary atypical pneumonia, is reported as the most common infectious agent associated with Stevens–Johnson syndrome (SJS) in children. For that reason it is important to consider mycoplasma infection also in the absence of classical pulmonary symptoms. SJS is a rare and acute, self‐limited disease, characterized by severe inflammation and necrosis of two or more mucous membranes. We report the case of a 12‐year‐old boy with a diagnosis of SJS induced by M. pneumoniae infection. The patient's SJS relapsed 8 months after discharge. When the condition is recurrent, it is important early on to identify the cause of a single episode to optimize care and therapeutic choices.     

Association of Early Systemic Corticosteroid Therapy with Mortality in Patients with Stevens–Johnson Syndrome or Toxic Epidermal Necrolysis: A Retrospective Cohort Study Using a Nationwide Claims Database

Background

Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe dermatologic disorders with high mortality. The role of systemic corticosteroids as an adjunctive therapy for SJS or TEN remains controversial.

Objective

The aim of this study was to determine whether treatment with early systemic corticosteroids impacts the in-hospital mortality of patients hospitalized with SJS or TEN.

Methods

Using the Japanese Diagnosis Procedure Combination Database, a large nationwide inpatient administrative claims database, we identified inpatients aged ≥ 18 years who were admitted with SJS or TEN. Treatment with early systemic corticosteroids was defined as starting treatment with systemic corticosteroids within 2 days (day 0 or day 1) of admission. The primary outcome was in-hospital mortality. We examined the association between early systemic corticosteroids and in-hospital mortality using propensity score (PS) analyses.

Results

We identified 1846 eligible patients with SJS or TEN, including 793 patients with early systemic corticosteroid use at ≤ 2 mg/kg/day, 558 patients with early systemic corticosteroid use at > 2 mg/kg/day, and 495 patients without early corticosteroid use. PS matching created 235 pairs (> 2 mg/kg/day vs. controls) and 332 pairs (≤ 2 mg/kg/day vs. controls). Early systemic corticosteroid use was not significantly associated with lower in-hospital mortality by PS matching (> 2 mg/kg/day vs. controls: relative risk [RR] 0.83, 95% confidence interval [CI] 0.37–1.85; ≤ 2 mg/kg/day vs. controls: RR 0.61, 95% CI 0.28–1.36) and by inverse probability of treatment weighting (> 2 mg/kg/day vs. controls: RR 0.99, 95% CI 0.45–2.19; ≤ 2 mg/kg/day vs. controls: RR 0.65, 95% CI 0.29–1.47).

Conclusion

Early systemic corticosteroid therapy for patients with SJS or TEN was not associated with lower in-hospital mortality. Further studies are needed to define the effect of corticosteroids for patients with SJS or TEN.

     

Association of HLA-B*1502 allele with carbamazepine-induced toxic epidermal necrolysis and Stevens-Johnson syndrome in the multi-ethnic Malaysian population

Background Carbamazepine (CBZ), a frequently used anticonvulsant drug, is one of the most common causes of life‐threatening cutaneous adverse drug reactions such as toxic epidermal necrolysis (TEN) and Stevens–Johnson syndrome (SJS). Recent studies have revealed a strong association between HLA‐B*1502 and CBZ‐induced TEN/SJS in the Taiwan Han Chinese population. Objectives This study is aimed to investigate the association between human leucocyte antigens (HLA) and CBZ‐induced TEN/SJS in the multi‐ethnic Malaysian population. Methods A sample of 21 unrelated patients with CBZ‐induced TEN/SJS and 300 race‐matched, healthy controls were genotyped for HLA‐A, ‐B and ‐DR using polymerase chain reaction (PCR). Allele frequencies were compared. Results HLA‐B*1502 was present in 75.0% (12/16) of Malay patients with CBZ‐induced TEN/SJS but in only 15.7% (47/300) of normal controls (odds ratio 16.15, 95% confidence interval 4.57–62.4; corrected P‐value = 7.87 × 10^?6), which suggests a strong association between HLA and CBZ‐induced TEN/SJS. Additionally, HLA‐B*1502 was found in all three Chinese and two Indian patients. Existing data show that frequencies of the HLA‐B*1502 allele are generally much higher in Asian populations than in White European populations, which explains the higher incidences of SJS and TEN in Asian countries. Conclusions HLA‐B*1502 is strongly associated with CBZ‐induced TEN/SJS in the Malay population in Malaysia, as has been seen in Han Chinese in Taiwan. This indicates that the genetic association apparent in the incidence of CBZ‐induced TEN/SJS is linked with the presence of HLA‐B*1502, irrespective of racial origin. Screening of patients for this genetic marker can help to prevent the occurrence of TEN/SJS.     

Epidermal necrolysis: 60 years of errors and advances

Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare conditions characterized by extensive epidermal detachment and mucositis. Both are associated with a high mortality rate and significant long‐term morbidity. Since the initial report introducing the term TEN in 1956, diagnosis of the condition has been fraught with difficulties that continue to exist today. The terms ‘erythema multiforme major’ (EMM) and SJS, and their relationship to TEN have also been confusing to clinicians. It is now recognized that EMM is a different entity from SJS and TEN in terms of demographics, causality and severity. SJS and TEN represent a continuum of disease, and differ only by the extent of epidermal detachment and therefore severity. The term ‘epidermal necrolysis’ (EN) is used in this article to describe the spectrum of disease that includes SJS and TEN. Important advances in understanding the pathomechanism and treatment of EN have been made over the years. These include the recognition of human leucocyte antigen (HLA) associations (e.g. HLA‐B*1502 with carbamazepine‐induced TEN) and understanding of the pathogenic roles of drug‐specific cytotoxic T cells and granulysin. It was previously believed that widespread keratinocyte death in EN is predominantly mediated by soluble Fas‐ligand and that intravenous immunoglobulin therapy is useful in blocking this mechanism with resultant survival benefits. Further studies have since proven these theories to be incorrect. This short review describes the key advances in the terminology, classification, causality and treatment of EN, and identifies future priorities and challenges in the understanding and management of this condition.     

Long‐term complications of Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN): the spectrum of chronic problems in patients who survive an episode of SJS/TEN necessitates multidisciplinary follow‐up

Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe adverse reactions to drugs that cause a life‐threatening eruption of mucocutaneous blistering and epithelial sloughing. While the acute complications of SJS/TEN are well described, it is increasingly recognized that survivors may develop delayed sequelae, some of which can be associated with significant morbidity. Studies of long‐term SJS/TEN outcomes mostly focus on mucocutaneous and ocular complications. However, other internal organs, such as the respiratory tract and gastrointestinal tract, can be affected. Psychological sequelae are also frequent following the trauma of widespread epidermal necrolysis. An appreciation of the ‘chronic’ phase of SJS/TEN is needed by clinicians caring for individuals who have survived the acute illness. This review aims to provide an update on the breadth and range of sequelae that can affect patients in the months and years following an acute episode of SJS/TEN.     

Distinguishing between erythema multiforme major and Stevens-Johnson syndrome/toxic epidermal necrolysis immunopathologically

The early clinical presentations of Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are similar to that of erythema multiforme major (EMM). Cytotoxic molecules, especially granulysin, are expressed in the skin lesions of SJS/TEN and cause extensive keratinocyte death. It is postulated that the function of regulatory T cells (Treg) in SJS/TEN is inadequate. This study examined whether an immunohistological examination of cytotoxic molecules and the immunophenotype of Treg is useful for discriminating SJS from EMM in the early period. Over the past 9 years, the lesional skin of 14 patients with SJS/TEN and 16 patients with EMM was biopsied. Double immunofluorescence labeling of CD8 and granulysin, perforin, or granzyme B was performed, and immunohistochemical analyses of granulysin, perforin, granzyme B, CD1a, CD3, CD4, CD8, CD68 and Foxp3 were conducted using a highly sensitive indirect immunoperoxidase technique. The number of cells positive for each antibody per five high‐power fields was counted. The proportions of granulysin⁺ cells/CD8⁺ cells (P = 0.012) and perforin⁺ cells/CD8⁺ cells (P = 0.037) in SJS/TEN were significantly higher than in EMM. The number of Foxp3⁺ cells/five high‐power fields in SJS/TEN was significantly lower than in EMM (P = 0.004). Similarly, the number of CD4⁺ cells/five high‐power fields in SJS/TEN was significantly lower than in EMM (P = 0.0017). These data suggest that these panels of antibodies for labeling cytotoxic molecules, CD4 and Treg are useful for discriminating early SJS/TEN and EMM with a skin biopsy.     

Piperacillin–tazobactam‐induced linear IgA bullous dermatosis presenting clinically as Stevens–Johnson syndrome/toxic epidermal necrolysis overlap

Linear IgA bullous dermatosis (LABD) is a subepidermal autoimmune bullous disease characterized by linear IgA deposition at the basement membrane zone, which is visualized by direct immunofluorescence. Patients with LABD typically present with widespread vesicles and bullae; however, this is not necessarily the case, as the clinical presentation of this disease is heterogeneous. LABD clinically presenting as Stevens–Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) is an infrequent, yet well‐described phenomenon. Most cases of LABD are idiopathic, but some cases are drug‐induced. Multiple drugs have been implicated in the development of LABD. We report a case of piperacillin–tazobactam‐induced LABD presenting clinically as SJS/TEN overlap. This is the first reported case of a strong causal association between piperacillin‐tazobactam and the development of LABD.     

The association of HLA B*15:02 allele and Stevens–Johnson syndrome/toxic epidermal necrolysis induced by aromatic anticonvulsant drugs in a South Indian population

Background

The presence of HLA‐B*15:02 allele is considered a risk factor for development of Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) in patients taking aromatic anticonvulsant drugs like carbamazepine and phenytoin. The genetic association is ethnicity specific. Testing for HLA‐B*15:02 allele is suggested as a prerequisite before starting carbamazepine in certain ethnic groups. There are only a few/no studies from south India on HLA association of SJS/TEN.

Aims

To identify any association between HLA‐B*15:02 allele and SJS/TEN induced by carbamazepine/phenytoin among native population.

Methods (including settings, design, and statistical analysis used)

A case–control study done in a tertiary care center at Kottayam in Kerala state of south India. Cases were 12 native patients who developed SJS/TEN owing to aromatic anticonvulsant drugs (phenytoin – 8; carbamazepine – 4), and controls were 11 persons tolerant to these drugs from unrelated families of the same ethnic group. HLA‐B typing was done by PCR SSP method.

Results

There was only one HLA‐B*15:02 carrier among cases and controls. He/she had SJS/TEN induced by carbamazepine.

Conclusions

Association of HLA‐B*15:02 with phenytoin‐induced SJS/TEN is rare in the population studied. The one limitation of the study was the small sample size.     

Fixed-drug eruption: A retrospective study in a single referral center in northern Taiwan

Background/ObjectiveFixed drug eruption (FDE) is a dermatosis characterized by recurrent patches or plaques at exactly the same sites with each administration of the causative drug. Vesicles or bullae may sometimes be found, and generalized bullous fixed drug eruption (GBFDE) may be confused with Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN). This study aimed to investigate the clinical and pathologic features of FDE in Taiwan.MethodsA retrospective analysis evaluated patients with FDE in a referral center in Taiwan covering a period of 11 years. Clinical data, suspected etiologies, and pathology/patch test results were collected. We also compared the GBFDE cases with SJS/TEN overlap or TEN cases to find differentiating clues.ResultsThere were 39 FDE patients, including nine GBFDE cases. The most frequent causative drugs were non-steroidal anti-inflammatory drugs (five cases, 12.8%) and antibiotics (four cases, 10.3%). Extremities other than the hands (71.8%) were the most frequently affected sites, followed by the trunk (51.3%), mucosa (38.5%), and hands (33.3%). The average age of FDE patients was 52.2 years (median, 56 years; range, 4–86 years). Patients with GBFDE were significantly older than non-GBFDE patients (69.1 ± 19.7 vs. 47.2 ± 23.6, p = 0.0124) and the trunk was more likely to be involved in GBFDE cases (88.9% vs. 40.0%, p = 0.0197). GBFDE cases also showed tendency to have more mucosal involvement (66.7% vs. 30.0%, p = 0.0631). Although similar to SJS/TEN, GBFDE cases had fewer constitutional symptoms, less mucosal involvement but had previous episodes. Histopathologically, the presence of more than two aggregated dyskeratotic keratinocytes (fire flag sign) in the epidermis was more frequently observed in SJS/TEN, whereas GBFDE had superficial and deep dermal infiltration of eosinophils and melanophages.ConclusionFDE is one of the specialized cutaneous drug reactions and GBFDE should be kept in mind and differentiated from SJS/TEN.