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Severe, blistering, adverse drug reactions involving the skin include Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Allopurinol, anticonvulsants, sulphonamide antibiotics and non-steroidal anti-inflammatory drugs in the oxicam class have been repeatedly described as triggers. Increasingly, immunotherapies are also coming into focus as triggers of severe skin reactions. Two patients with bullous skin symptoms after administration of the checkpoint inhibitor pembrolizumab are presented. As the clinical picture does not always allow an unequivocal classification, a histological assessment is often indispensable.Zu den schweren, blasenbildenden Arzneimittelreaktionen an der Haut gehören das Stevens-Johnson-Syndrom (SJS) und die toxisch epidermale Nekrolyse (TEN). Allopurinol, Antikonvulsiva, Sulfonamidantibiotika und nichtsteroidale Antirheumatika vom Oxicam-Typ sind wiederholt als Auslöser beschrieben. Zunehmend rücken auch Immuntherapien als Auslöser schwerer Hautreaktionen in den Fokus. Vorgestellt werden 2 Patienten mit bullösen Hauterscheinungen nach Gabe des Checkpointinhibitors Pembrolizumab. Da das klinische Bild nicht immer eine zweifelsfreie Einordnung zulässt, ist eine histologische Mitbeurteilung vielfach unverzichtbar.

Treatment of severe dermatological autoimmune diseases and toxic epidermal necrolysis (TEN) with high-dose intravenous immunoglobulin (IVIg) is a well-established procedure in dermatology. As treatment with IVIg is usually considered for rare clinical entities or severe cases, the use of immunoglobulin is not generally based on data from randomized controlled trials usually required for evidence-based medicine. Since the indications for the use of IVIg are rare, it is unlikely that such studies will be available in the foreseeable future. Because first-line use is limited by the high costs of IVIg, the first clinical guidelines on the use of IVIg in dermatological conditions were established in 2008 and renewed in 2011.The European guidelines presented here were prepared by a panel of experts nominated by the European Dermatology Forum (EDF) and European Academy of Dermatology and Venereology (EADV). The guidelines were developed to update the indications for treatment currently considered effective and to summarize the evidence for the use of IVIg in dermatological autoimmune diseases and TEN.The current guidelines represent consensual expert opinions and definitions on the use of IVIg reflecting current published evidence and are intended to serve as a decision-making tool for the use of IVIg in dermatological diseases.

Allergies to non-betalactam antibiotics: a challenge in practice

Warning symptoms skin: cutaneous manifestation of drug allergy

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are acutely occurring, unpredictable, often life-threatening reactions that are a huge challenge in clinical practice. They are characterized by extensive blistering of skin and mucosa and are considered as one disease entity of different severity. Thus, they are summarized as SJS/TEN or EN (for epidermal or epithelial necrolysis). The diagnosis can be confirmed through synopsis of clinical pattern and histopathological findings. To identify the inducing factors, it is crucial to obtain a detailed and thorough medication and infection history. Based on the results of large epidemiological studies, potentially inducing drugs can be narrowed down even in cases of multimedication and underlying diseases. Agents with a high risk for SJS/TEN are allopurinol, antibacterial sulfonamides, non-steroidal anti-inflammatory drugs of the oxicam-type, various antiepileptics and nevirapine. They alone explain more than half of the cases of SJS/TEN. Typically, the reaction occurs during the first continuous use of the medication, while the beginning of use most often is one to four weeks prior to reaction onset. However, a drug is not always the cause of the reaction, but in approximately 70-75% of the cases very likely. In other cases infections may be potential causes. If certain medications are thought to be the inducing factors, they should be withdrawn without delay. In addition, symptomatic treatment should be initiated. In case of progression, an additional immunomodulating therapy should be considered. In this respect, systematic reviews have shown best results for cyclosporine A and systemic steroids.

Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and a specific form of hypersensitivity syndrome which is nowadays called "drug reaction with eosinophilia and systemic symptoms" (DRESS) are severe, mainly drug-induced skin reactions. Whereas SJS/TEN is considered one reaction entity of different severity, DRESS has to be distinguished from SJS/TEN but also from other severe exanthems due to multiorgan involvement. Although SJS/TEN is generally referred to as drug reaction, in total only about three quarters of the cases are actually caused by drugs. After the clinical diagnosis is made, identification of the potential inducing factor is most important. In case medications are considered as causal, their withdrawal plays a key role in management. In order to identify and withdraw the inducing agent, a detailed and thorough medication history must be obtained. Agents identified or confirmed as inducers of SJS/TEN by pharmacoepidemiological studies are allopurinol, antibacterial sulfonamides, various antiepileptics, nevirapine and nonsteroidal anti-inflammatory drugs of the oxicam-type. Among drugs inducing DRESS are also various antiepileptics, but in addition allopurinol, sulfonamides and minocycline. Some cases of SJS/TEN and DRESS associated with the use of new medication, including targeted therapies and biologicals, have been observed.

Based on a representative case, which was treated in our center for severe burn injuries, the severity of the Waterhouse-Friderichsen syndrome and the complexity of the prolonged course of treatment are illustrated. Special attention is focused on the new treatment paradigm using the CytoSorb® adsorber.

Among severe drug reactions in children, besides Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), a specific form of hypersensitivity syndrome which is nowadays known as "drug reaction with eosinophilia and systemic symptoms" (DRESS) has to be mentioned. Whereas SJS/TEN is considered one reaction entity of different severity, DRESS has to be distinguished from SJS/TEN but also from other severe exanthems due to multiorgan involvement. Although SJS/TEN is generally referred to as a drug reaction, only about 75% of all cases are actually caused by medications and in children it is only about 50%. After a clear diagnosis has been made, specific therapeutic measures can follow, of which withdrawal of the inducing agent plays a key role, but further treatments differ substantially. In order to identify and withdraw the inducing agent, a detailed and thorough medication history must be obtained. Highly suspected drugs of SJS/TEN in children include, among others, antibacterial sulfonamides and various antiepileptics. DRESS in children and adolescents is also frequently induced by antiepileptics, but also by sulfonamides and minocycline. In contrast to adults, allopurinol is rarely found to be culprit in both conditions. Supportive therapy including appropriate topical treatments, pain therapy, ophthalmologic consultations, etc. is the gold standard in SJS/TEN, but a short-term immunomodulating therapy with cyclosporine A has shown very promising results in recent studies. In DRESS, however, systemic treatment with glucocorticosteroids slowly tapered over a longer period of time is recommended.

A 41 year old patient started treatment with 300 mg/d allopurinol for asymptomatic hyperuricaemia (9,2 mg/dl).4 weeks later he developed exfoliative skin lesions with haemorrhage, fever, eosinophilia and acute liver and renal failure, typical for an allopurinol hypersensitivity syndrome (AHS).An orthotopic liver-transplantation was performed.The AHS is a serious iatrogenic disease. 2 % of the treated patients develop a skin rash. 0,4 % of these patients experience suddenly and unforeseen a severe hypersensitivity with a mortality of 14-30 %. An early diagnosis is often very difficult. In the pathogenesis different causes are discussed. A hereditary component is involved. Of essential importance is the amount of the starting dose, the kidney function and concomitant drugs. In an asymptomatic hyperuricaemia the application of allopurinol is not indicated. If strong indications are present, the allopurinol therapy has to start with the lowest dose (100 mg/d). If required this dose should be increased under consequent supervision only.

Stevens-Johnson syndrome (SJS) and Toxic epidermal necrolysis (TEN) are characterized by extensive blistering of the skin and mucosa; they are considered as one disease entity with varying severity. They are rare but potentially life-threatening and accompanied by high mortality. A clear clinical diagnosis is needed to direct specific therapy, but supportive therapy remains most important. In order to identify and withdraw the inducing drug, a very detailed and thorough medication history has to be obtained. Among the highly suspected (strongly associated) agents are allopurinol, antibacterial sulfonamides, non-steroidal anti-inflammatory drugs of the oxicam type, various anti-epileptics and nevaripine. Together they account for more than half of the cases of SJS/TEN. Although a drug is not always the cause, it is considered very like in approximately 75% of cases. Infections have also to be considered as etiologic factors.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare severe and often life-threatening reactions of the skin and mucous membranes. They are considered as a single disease entity with different expressions of severity and are summarized under the term epidermal necrolysis (EN). There is a high risk of ocular involvement, which can lead to long-lasting eye problems and even blindness without immediate ophthalmological treatment. The acute occurrence, the unpredictable course and extreme variation in the manifestation of complications require an interdisciplinary approach. A rapid diagnosis of eye involvement and initiation of an intensive lubricating and anti-inflammatory surface treatment is of utmost importance for the long-term outcome. This article should help ophthalmologists to have a better understanding of this condition and therefore lead to substantial improvement in visual outcome and the quality of life of patients.Das Stevens-Johnson-Syndrom (SJS) und die toxisch epidermale Nekrolyse (TEN) sind seltene, schwere und oft lebensbedrohliche Reaktionen der Haut- und der Schleimhäute. Sie werden als eine Krankheitsentität verschieden schwerer Ausprägung angesehen und unter dem Begriff epidermale Nekrolyse zusammengefasst. Es besteht ein hohes Risiko okulärer Beteiligung, die ohne eine rasche, adäquate ophthalmologische Behandlung zu langwierigen Augenproblemen bis zur Erblindung führen kann. Das akute Auftreten, der unvorhersagbare Verlauf und die stark variierende Manifestation der Komplikationen erfordern einen interdisziplinären Ansatz. Eine rasche Diagnosestellung und Einleitung einer antiinflammatorischen oberflächenwirksamen Behandlung ist von großer Bedeutung für das Langzeitergebnis. Dieser Beitrag soll dem Verständnis dieser Reaktionsformen dienen und so zu einer Verbesserung der visuellen Rehabilitation und Lebensqualität der Patienten führen.

Toxic epidermal necrolysis (TEN) is associated with a high mortality. The need for mechanical ventilation is associated with an increased mortality in TEN patients. This study investigates the impact of the timing of initiation of the mechanical ventilation on the survival of TEN patients.A retrospective study of 26 TEN patients was carried out. Primary (on admission (group A) and secondary ventilation (1 day after admission (group B) were analysed for an association with mortality.8 patients did not require mechanical ventilation. 18 patients needed mechanical ventilation. In group A 8 patients with an epidermolytic body surface area (BSA) of 73 ± 16% and a mean SCORTEN of 3.2 ± 1.1 were analysed. In group B 10 patients with an epidermolytic BSA of 76 ± 19% and a mean SCORTEN of 3.8 ± 0.9 were evaluated. Statistical analysis showed an increased mortality in all mechanically ventilated compared with non-ventilated TEN patients (Odds ratio: 2.0; 95% CI: 1.26-3.17 p = 0.013).Mechanical ventilation in TEN patients is associated with an increased mortality rate, but the timing of initiation of mechanical ventilation does not affect the patient survival rates.

The coagulation system protects the body from uncontrolled blood loss by means of highly regulated processes. In case of an injury the coagulation system instantly switches from controlled blood flow to acute coagulation and thrombus formation with the goal of stopping the blood loss. Minor changes in this well-maintained equilibrium of coagulation and blood flow tip the balance towards uncontrolled blood loss or even fatal thromboembolic events. Iatrogenic manipulation of this highly regulated system is possible with a variety of therapeutic agents. We review the basics of coagulation physiology and then discuss dermatologically relevant aspects of thrombosis prevention, as well as the use of anticoagulants to treat dermatologic diseases.

The present report describes the case of a 67-year-old patient who developed an allopurinol-induced hypersensitivity syndrome (AHS) with toxic epidermal necrolysis and subsequently died of septic multiorgan failure. Considering the increasing prescription rate of allopurinol, the present case report intends to demonstrate the underestimated threat of AHS.

Introduction: In-hospital hypernatremia is associated with increased mortality rates. We want to elucidate the impact of in-hospital acquired hypernatremia in mortality of Toxic Epidermal Necrolysis (TEN). Purpose: Is there an association between hypernatremia and mortality in patients with TEN? Method: Retrospective study of 25 patients with TEN. Laboratory electrolyte results, diuresis and survival were analyzed. Patients were separated in two groups without (Group A) or with (Group B) hypernatremia. Results: In Group A 10 patients with a TBSA of 74±25% (mean ± standard deviation), and a SCORTEN-Score of 2.7±0.9 were summarized. Diuresis within the first 10 days after admission was 1±0.3 ml/kg/hour. In Group B 15 patients with a TBSA of 76±19%, and a SCORTEN-Score of 3.5±1 were included. Diuresis within the first 10 days after admission was 1.4±0.4 ml/kg/hour. Hypernatremia occurred on day 3.3±2.4 after admission and persisted for 5.3±2.9 days. Statistical analysis showed a significantly higher diuresis (p=0.007) and SCORTEN-Score (p=0.04) in the hypernatremic patients. One normonatremic and 8 hypernatremic patients died during ICU-stay (overall mortality rate 36%). A significantly higher mortality rate was found in Group B (odds ratio: 13,5; 95% confidence interval: 1.34–135.98; p=0.01) during ICU-stay. Conclusion: TEN patients with an in-hospital acquired hypernatremia have an increased mortality risk. Close electrolyte monitoring is advisable in these patients., GMS German Medical Science; 8:Doc30; ISSN 1612-3174

Summary Background: With an incidence of 1.5–1.8/1 million inhabitants per year, toxic epidermal necrolysis is a rare but life threatening disease. It is almost always drug-induced and its lethality is pronounced with up to 50 %. Several therapeutic options are described in literature; however, there is still lack of a universally accepted and specific therapy of toxic epidermal necrolysis. Methods: This survey considers 8 cases of toxic epidermal necrolysis diagnosed and treated in our clinic from 2003 to 2007. The epidermal sloughing was > 30 % of the body surface in each case. Results: After immediately discontinuing the drug suspected of being responsible for toxic epidermal necrolysis, we treated with systemic corticosteroids in an initial dose of up to 1.5 mg/kg. Moreover, special emphasis was put on basic measures such as control of vital parameters. With this treatment we reached good results; none of the patients died. Conclusions: Immediate beginning of therapy is essential for a successful treatment of toxic epidermal necrolysis. Besides systemic therapy with corticosteroids, certain basic measures such as isolation of patients at adequate room temperature to prevent hypothermia, strict control of circulation, temperature and laboratory parameters, daily smears of skin and mucous membranes and a diet rich in calories due to the catabolic metabolic status are very important for successful outcome.

Corneal ulcers with fornix shortening associated with late stages of cicatrizing trachoma contribute significantly to blindness in many developing countries. We report on the outcome of ocular surface and fornix reconstruction using amnion membrane transplantation.From 2001 to 2005, cryopreserved human amnion membrane without mitomycin C was grafted to 25 eyes of 17 patients with trophic corneal ulcers and symblepharon (cicatrizing trachoma: 19 eyes of 14 patients, Stevens-Johnson syndrome: 4 eyes of 2 patients, alkali burns: 2 eyes of 1 patient) in a controlled case series. Follow-up was done up to 6 months.Fischer's exact probability test.Of 25 eyes, 9 of 19 eyes with trachoma, 3 of 4 eyes with Stevens-Johnson syndrome, and 2 of 2 eyes with chemical burns showed complete reepithelialization and stromal recovery after 28-35 days (mean: 31+/-2.3 days). The primary success rate of trachoma eyes was not significantly different from the other indications (p=0.256). At 6 months post-op, 15 of 19 trachoma eyes (79%) compared to 2 of 6 non-trachoma eyes (33.3%) had developed a recurrence of symblephara (p=0.0592), and 13 of 15 eyes (86.6%) with a cicatricial trachoma compared to 1 of 6 with non-trachoma diagnosis experienced a recurrence of corneal vascularization (difference nonsignificant: p=0.1752). Persistent long-term reepithelialization was observed only in 1 of 19 trachoma eyes (5.3%) versus 4 of 6 non-trachoma eyes (66.7%, p=0.005); 3 of 19 trachoma eyes with a recurrence of ulcers had perforated after 6 months.Human amnion membrane without mitomycin C can be used for ocular surface reconstruction in selected patients with cicatrizing trachoma. Its efficacy in the long-term rehabilitation of cicatrizing trachoma seems to be limited due to the progressive scarring.

Toxic epidermal necrolysis (TEN) is the maximal variant of severe bullous drug reactions with a high mortality rate of 30-40%. Treatment should be interdisciplinary and is best provided in an intensive care setting. Since no specific therapy has been established, supportive intensive care and topical treatment are of crucial importance. Between 1995 and 2005, nine patients with TEN were treated in the anesthesiology intensive care unit in cooperation with dermatology in the University Hospital of Dresden. All patients initially received corticosteroids and five patients were additionally treated with intravenous immunoglobulins (IVIG). The overall mortality of 33% was underestimated by the SAPS II-Score, whereas it was overestimated by the TEN-specific SCORTEN. In more severely affected patients, other scoring systems in addition to SCORTEN should be used for prediction of prognosis and evaluation of therapy. The mortality rate of our IVIG treated patients was 20% vs. 50% compared to the non-IVIG-group. However, due to the small number of patients and contradictory results in the literature, IVIG cannot be generally recommended for the treatment of TEN, but should be considered in early stages of the disease.

Severe ocular surface diseases, such as Stevens-Johnson syndrome, ocular cicatricial pemphigoid or severe ocular burns may result in a significant loss of corneal stem cells, eventually leading to vision impairment or even corneal blindness. In case of unilateral involvement, limbal autografting, by means of transplanting limbal stem cells from the healthy fellow eye, has proved to be an effective procedure for restoring the integrity of the ocular surface. Limbal allografts may be performed in patients with bilateral disease, however, systemic immunosuppression is mandatory in these cases, with a long-term outcome that is frequently reduced compared to limbal autografts due to acute or chronic graft rejection. In recent years, amniotic membrane transplantation has been successfully employed as an additional tool in ocular surface reconstruction. The AlphaCor synthetic cornea, which is made of flexible acrylic may be considered as an alternative in patients with repeated corneal graft failures. Both limbal transplantation and the AlphaCor have been shown to be effective in eyes with an adequate tear film, but are most likely to fail in severe dry eyes or in patients with cicatrising diseases. Such conditions are the domain of keratoprostheses (KPros) with rigid optics, which certainly can be considered as the 'last resort' to restore vision in patients with profound corneal blindness not amenable to conventional corneal and limbal grafting. The osteo-odonto-keratoprosthesis according to Strampelli and modified by Falcinelli makes use of a "biological" support consisting of a longitudinal section of one of the patient's teeth that is also supported by the surrounding alveolar bone tissue. Compared to other devices favourable long-term results have been reported. In patients lacking any usable teeth, implantation of a keratoprosthesis with haptics made of Dacron (Pintucci-KPro) or tibial bone (Temprano-KPro) might be considered.

The antiepileptic carbamazepine can reduce aggressive behaviour and can be used as a mood stabilizer. We present a case report of a patient suffering from borderline personality disorder who was treated with carbamazepine and developed erythema multiforme.

Minor hypersensitivity reactions to allopurinol presenting as skin rash occur in approximately 2% of patients. A more severe, albeit rare, hypersensitivity reaction with fever, eosinophilia, dermatitis, renal failure, vasculitis and hepatic dysfunction carries a mortality of up to 20%. The incidence of this severe reaction can probably be reduced by adjusting the dose of allopurinol in patients with impaired renal function. Azathioprine and mercaptopurine are metabolised by xanthine oxidase, the enzyme that is inhibited by allopurinol. Concomitant administration can result in life-threatening neutropenia unless the dose of allopurinol is reduced by approximately 75%. The uricosuric agent benzbromarone has recently been withdrawn from the market because of several cases of fulminant hepatic failure with subsequent death of the patient or liver transplantation.