Role of nanocrystalline silver dressings in the management of toxic epidermal necrolysis (TEN) and TEN/Stevens–Johnson syndrome overlap

Toxic epidermal necrolysis (TEN) and Stevens–Johnson syndrome (SJS) are severe mucocutaneous eruptions. There is currently no defined optimal approach to wound care. The objective of this study was to evaluate silver dressings in the wound‐care management of TEN and SJS/TEN syndrome overlap with a retrospective case review of nine patients with TEN and SJS/TEN overlap presenting to our institution. Nanocrystalline silver dressings appear to be useful in the rapid commencement of healing in these patients. TEN and SJS/TEN overlap are rare conditions. This contributed to a relatively small number of cases included in the study. The ease of application, antimicrobial properties and low frequency of change make nanocrystalline silver dressings ideal in TEN/SJS.     

Critical factors differentiating erythema multiforme majus from Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN)

Erythema multiforme majus (EMM) and Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) are severe cutaneous reactions characterised by targetoid erythematous lesions and mucocutaneous involvement. The initial skin manifestations are similar, making early diagnosis difficult. We retrospectively reviewed 36 cases of EMM and 18 cases of SJS/TEN and also evaluated 6 patients with unclassified EMM. 13 patients in the EMM group and 16 patients in the SJS/TEN group presented with a high fever (>38.5?C; p<0.001). Two or more mucous membranes were affected in 6 patients in the EMM group and 18 patients in the SJS/TEN group. Significantly more SJS/TEN than EMM patients had high levels of C-reactive protein and severe hepatic dysfunction. Thirteen EMM and 13 SJS/TEN cases were caused by medications/drugs. Skin biopsy samples showed stronger mononuclear cell infiltration in the EMM than in the SJS/TEN group (p<0.001). The mean dose of initial systemic corticosteroid used to treat EMM was lower than that used to treat SJS/TEN. No patients died in either group. Clinically, the unclassified cases mostly behaved like EMM. The results of our investigation suggest that EMM and SJS/TEN are distinct conditions and they help in differentiating these syndromes at an early stage.     

Cyclosporine for SJS/TEN: a case series and review of the literature

Clear guidelines for the treatment of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are lacking due to its infrequency and the absence of large controlled studies. Systemic corticosteroids and intravenous immunoglobulin (IVIG) have received considerable attention, though reports of the use of these agents have demonstrated mixed success rates in improving morbidity and mortality from SJS/TEN. We present a case series of 4 patients with SJS/TEN who rapidly responded to treatment with cyclosporin A (CsA). We discuss the proposed mechanism of action and the rationale for the use of cyclosporin based on the currently understood pathophysiologic mechanism of TEN.     

Severe Stevens‐Johnson syndrome/toxic epidermal necrolysis overlap syndrome—beyond skin involvement

Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but serious dermatologic diseases with many potential multisystem complications. We describe the case of an 8‐year‐old girl who developed severe SJS/TEN overlap syndrome (25% of her body surface area was affected) complicated by pancreatitis and bronchiolitis obliterans. These rare complications emphasize the need for careful, intensive monitoring of possible complications and an interdisciplinary team approach to provide optimal treatment and follow‐up.     

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.     

Toxic epidermal necrolysis (TEN) Lyell's syndrome

Toxic epidermal necrolysis, a unique rapidly developing mucocutaneous reaction pattern, characterized by sheets of erythema, necrosis and bullous detachment of the epidermis, closely resembling that of scalding of the skin and rapidly fatal, was described by Lyell, and is now recognized as toxic epidermal necrolysis (TEN) Lyell's syndrome. The condition is indistinguishable from staphylococcal scalded skin syndrome (SSSS), and generalized fixed drug eruption. Hence, there has always been controversy as regards terminology. It is well conceived that TEN is equivalent to Stevens-Johnson syndrome (SJS), at its greatest severity. TEN, therefore, is a great challenge and warrants instant attention based on a thorough knowledgeable background covering several related facets including the recent advances in pathogenesis and management strategies. The details contained in the following text should prove very useful in the comprehension of a largely intractable entity.     

Erythema multiforme,Stevens‐Johnson syndrome/toxic epidermal necrolysis – diagnosis and treatment

Prior to the first international consensus classification published in 1993, the clinical distinction between erythema multiforme (EM), Stevens‐Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) had been subject to uncertainty and controversy for more than a century. Based on this classification, the three conditions are defined by the morphology of the individual lesions and their pattern of distribution. Etiopathogenetically, the majority of EM cases is caused by infections (primarily herpes simplex virus and Mycoplasma pneumoniae), whereas SJS/TEN are predominantly triggered by drugs. The SCORTEN (score of toxic epidermal necrolysis) can and should be used to assess disease prognosis in patients with SJS/TEN. While supportive treatment is generally considered sufficient for EM, there is still uncertainty as to the type of systemic therapy required for SJS/TEN. Given the lack of high‐quality therapeutic trials and (in some cases) conflicting results, it is currently impossible to issue definitive recommendations for any given immunomodulatory therapy. While there is always a trade‐off between rapid onset of treatment‐induced immunosuppression and an uptick in infection risk, there has been increasing evidence that cyclosporine in particular may be able to halt disease progression (i.e. skin detachment) and lower mortality rates. Assistance in diagnosis and management of the aforementioned conditions may be obtained from the Center for the Documentation of Severe Skin Reactions (dZh) at the Department of Dermatology, University Medical Center, Freiburg, Germany.     

Stevens-Johnson syndrome induced by doxycycline

Stevens-Johnson syndrome (SJS) is an acute mucocutaneous eruption nosologically related to erythema multiforme (EM) and toxic epidermal necrolysis (TEN). Medications are the most common triggering factors for SJS, with anticonvulsants, sulfonamides, penicillins, allopurinol, and nonsteroidal anti-inflammatory drugs (NSAIDs) most commonly implicated. SJS is very rarely associated with tetracyclines. We report a case of doxycycline-induced SJS in a 46-year-old man.     

Toxic epidermal necrolysis induced by human herpesvirus 7 treated with a tumor necrosis factor-α inhibitor

Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) is a life-threatening hypersensitivity reaction. Long-term sequelae include dry eyes, visual impairment and psychological complications. TEN is mostly induced by medication; however, viral infections, such as coxsackievirus A6, are known triggers of this disease. However, how to define the role of infection in SJS/TEN is still a problem. Most patients develop SJS/TEN over the course of symptoms of the infection first, and then take medication. Therefore, virus culture and nucleic acid detection at the acute stage cannot predict that the virus itself will indeed produce such a serious reaction. Furthermore, many SJS/TEN patients who are diagnosed with an infection are afraid of receiving the drug rechallenge test. Thus, we report the first case worldwide of a patient who suffered from TEN caused by herpesvirus 7 infection, which was confirmed by both real-time polymerase chain reaction and lymphocyte transformation test.     

The CD40/CD40 ligand system is expressed in the cutaneous lesions of erythema multiforme and Stevens-Johnson syndrome/toxic epidermal necrolysis spectrum

Background Erythema multiforme (EM) and Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) are determined by a dysregulation of cellular immunity. Objectives To evaluate the effector role of cellular immunity and the involvement of the CD40/CD40 ligand (CD40L) system in the pathogenesis of EM and SJS/TEN. Methods Biopsy specimens from eight patients with EM and six with SJS/TEN were stained for immunohistochemical examination using the alkaline phosphatase/antialkaline phosphatase method. The monoclonal antibodies used included those to CD1a, CD4, CD8, CD40, CD40L, CD68, Fas, Fas ligand (FasL) and myeloperoxidase. Results The cellular infiltrate in both EM and SJS/TEN lesions was composed mainly of T lymphocytes and CD68+ macrophages. We also detected large amounts of neutrophils. Fas and FasL were very highly expressed in SJS and TEN, but weakly in EM. CD40 staining was strong in all tissue sections; there were numerous CD40L+ cells in SJS/TEN but much fewer in EM. Conclusions Activated T lymphocytes and macrophages, but also neutrophils, are presumably the main triggers of mucocutaneous damage in the SJS/TEN disease spectrum. The Fas/FasL system is significantly expressed in SJS/TEN lesions, but not in EM, where this apoptotic pathway presumably does not play a pivotal role in the epidermal damage. We suggest that the CD40/CD40L system may represent an important pathway of induction of SJS/TEN lesions, while in EM it would contribute to the immunoinflammation only as a second‐line mechanism.     

Clinical manifestations and outcomes in 17 cases of Stevens–Johnson syndrome and toxic epidermal necrolysis

The clinical features and outcomes of 17 patients with Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) were retrospectively reviewed. There were 11 males and six females with an average age of 61.5 years. Ten patients with SJS (seven males, three females) and seven patients with TEN (four males, three females) were identified. Antibiotics, mainly beta-lactams, were the most common cause of SJS/TEN in this series. The mean skin loss in TEN was 45.7% total body surface area in contrast to the lesser skin loss (< 10%) observed in three patients with SJS. Complications included septicaemia, pneumonia and multi-organ failure, mainly in the TEN group. Two patients died from TEN-related complications and one patient with SJS died from unrelated causes. Ocular involvement and skin pigmentary changes represented the most significant long-term sequelae.     

Granulocyte colony‐stimulating factor in toxic epidermal necrolysis (TEN) and Chelsea & Westminster TEN protocol

Background: Toxic epidermal necrolysis (TEN) is a rare but life‐threatening, allergic drug reaction. Skin blistering with epidermal and mucosal necrolysis with subsequent detachment from an inflamed underlying dermis is a hallmark of the condition. The pathogenesis of TEN is not well understood, accounting for controversies about its management and significant delay in initiating potentially beneficial therapy. There are no management protocols based on a robust evidence base. Objectives: Prompt recognition of the diagnosis and consensus on early management initiatives are necessary in order to improve outcomes and survival in TEN. To date, TEN management has been directed at arresting the allergic reaction and treating the complications. We have identified a need for specific medical interventions to accelerate wound regeneration. This approach has not previously been adopted in the management of TEN. Methods: We observed that in two cases of severe TEN, dramatic re‐epithelialization and recovery coincided with the introduction of granulocyte colony‐stimulating factor (G‐CSF) for neutropenia. We explain how addition of the G‐CSF promotes recovery from TEN by enhanced bioregeneration of the damaged tissues through accelerated re‐epithelialization. Conclusion: G‐CSF has been used for severe neutropenia in TEN, but we recommend and explain why, as in our Chelsea and Westminster protocol, G‐CSF should be considered in treating severe TEN irrespective of the severity of neutropenia.     

Rapid remission of Stevens–Johnson syndrome by combination therapy using etanercept and intravenous immunoglobulin and a review of the literature

Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) are spectrum of rare, acute, and life‐threatening delayed‐type drug hypersensitivity reactions that are associated with high mortality rates. However, no therapeutic standard has been proposed for SJS/TEN. Here, we report a case of a patient diagnosed with Stevens–Johnson syndrome whose disease progression was halted by a single dose of etanercept and was treated successfully. In addition, we reviewed the literature reporting patients with SJS/TEN treated with similar regimens.     

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.     

Stevens-Johnson syndrome and toxic epidermal necrolysis in patients with lupus erythematosus: a descriptive study of 17 cases from a national registry and review of the literature

Background Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe cutaneous adverse reactions with high morbidity and mortality. Some expressions of lupus erythematosus (LE) may cause enormous difficulties in differentiating them from SJS and TEN by showing large areas of sheet‐like epidermal necrosis. Objective To evaluate clinically and histopathologically probable or definite cases of SJS/TEN with a history of systemic or other LE [(S)LE]. Methods This was a retrospective analysis of validated cases of SJS/TEN with a history of (S)LE, based on a large population‐based national registry. Results Among 1366 patients with SJS/TEN, 17 with a sufficiently documented history of (S)LE and representative histological material could be identified, suggesting a considerable over‐representation of LE in patients with SJS/TEN. Eight of these showed clinically and/or histopathologically some LE‐characteristic features interfering with the diagnosis of SJS/TEN. Differentiation could be elaborated on clinical and histopathological grounds: four patients were classified as SJS/TEN with a preceding (S)LE exacerbation and/or LE‐typical histopathological features, and four as ‘TEN‐like’ (S)LE. Conclusion Most patients with SJS/TEN and a history of (S)LE demonstrate clinical and histopathological properties allowing clear differentiation. However, occasionally acute cutaneous manifestations of (S)LE and SJS/TEN can be phenotypically similar, caused by extensive epidermal necrosis. Although no feature by itself is conclusive, a combination of recent (S)LE exacerbation, evident photodistribution, annular lesions and absent or only mild focal erosive mucosal involvement may favour LE over SJS/TEN clinically. Histopathologically, in particular, junctional vacuolar alteration, and the presence of solitary necrotic keratinocytes at lower epidermal levels, combined with moderate to dense periadnexal and perivascular lymphocytic infiltrates with a variable presence of melanophages, and mucin point to a LE‐related origin.     

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.     

Nonpigmenting fixed drug eruption as a possible abortive variant of toxic epidermal necrolysis: immunohistochemical and serum cytokine analyses

Nonpigmenting fixed drug eruption (NPFDE) is clinically indistinguishable from Stevens–Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) in its initial presentation. The traditional paradigm that epidermal changes are absent in NPFDE cannot be easily reconciled with the clinical resemblance to SJS/TEN. We therefore investigated whether NPFDE is pathogenetically different from pigmented FDE (PFDE) or SJS/TEN and which factors are responsible for the lack of hyperpigmentation. NPFDE lesions before challenge were characterized by larger numbers of CD8+ intraepidermal T cells associated with a paucity of melanocytes, compared with those in PFDE. Very high levels of serum interleukin (IL)‐10 were noted after clinical challenge. We conclude that NPFDE is a clinical syndrome with heterogeneous histological expression. NPFDE with epidermal involvement may be an abortive form of SJS/TEN, in which progression to TEN can be prevented by IL‐10.     

Bronchiolitis obliterans as a long‐term sequela of Stevens–Johnson syndrome and toxic epidermal necrolysis in children

Toxic epidermal necrolysis (TEN) and Stevens–Johnson syndrome (SJS) are characterized by widespread skin and mucosal blistering and necrosis. The triggers and long‐term sequelae in children may differ from those reported for adults. Bronchiolitis obliterans (BO) is an uncommon complication, with only 15 previously reported cases, but can lead to significant long‐term morbidity, requiring lung transplantation in some cases. We report three children with nondrug‐related SJS (n = 1) and TEN (n = 2) who developed BO. Two were treated with intravenous immunoglobulin therapy (2–2.4 g/kg) and all three survived. We highlight salient learning points from our cases and potential pitfalls in diagnosis of BO, including delayed onset, and we also review the literature.     

Efficacy and safety of cyclosporine in Stevens–Johnson syndrome and toxic epidermal necrolysis

Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but life threatening cutaneous reactions that are most commonly caused by exposure to medications. This review assesses the efficacy and safety of cyclosporine therapy for SJS, TEN, and SJS/TEN overlap. A literature review was conducted in PubMed using the MeSH terms TEN, SJS, and cyclosporine. Five case series and one meta‐analysis were analyzed. From review of the existing literature, cyclosporine appears to not only have a mortality benefit in the treatment of SJS/TEN, but also a relatively safe side effect profile.     

Use of etanercept to treat toxic epidermal necrolysis in a human immunodeficiency virus-positive patient

Toxic epidermal necrolysis (TEN) is an uncommon and severe cutaneous adverse drug reaction that causes disseminated necrosis of epidermal cells and mucocutaneous detachment. Here, we report the case of a 32-year-old man with human immunodeficiency virus infection who presented with generalized violaceous macules and blister formation 4 days after the administration of mefenamic acid and amoxicillin for a dental procedure. Additional symptoms included oral ulcers and conjunctivitis. Results of skin biopsy were compatible with Stevens–Johnson syndrome (SJS). SJS progressed to TEN within 2 days. Etanercept treatment showed a dramatic improvement in the symptoms of mucocutaneous lesions. To our knowledge, this is the first report on the treatment of TEN using etanercept in a human immunodeficiency virus-positive patient.