Toxic Epidermal Necrolysis

8/17/2007

Question:  What are current effective therapies for toxic epidermal necrolysis?

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<1>

Unique Identifier [PMID]: 16684642

Authors: Mills E. Cooper C. Wu P. Rachlis B. Singh S. Guyatt GH.

Institution: Centre for International Health and Human Rights Studies, North York, Ontario, Canada. emills@cihhrs.org

Title: Randomized trials stopped early for harm in HIV/AIDS: a systematic survey. [Review] [41 refs]

Source: HIV Clinical Trials. 7(1):24-33, 2006 Jan-Feb.

Abstract: PURPOSE: The decision to stop trials early because of the harmful effects of the intervention is complex and requires weighing statistical, logistical, and ethical considerations. We assessed the prevalence of randomized clinical trials (RCTs) stopped early for harm in HIV/AIDS and determined the quality of reporting of methods to inform the decision to stop the trial. METHOD: We searched 11 electronic databases and major conference abstract databases, contacted trialist and advocacy groups, and searched the Internet. We selected RCTs stopped early for harm. We extracted data on journal and year of publication, reporting of methods and funding, planned sample size, number and planning of interim analyses, stopping rules, and effect size of the harm outcomes. RESULTS: We found 10 RCTs stopped early for harm (median, n = 85; range, 7-1227). Most interventions (n = 9) were antiviral drugs; one trial studied vitamins to prevent vertical transmission of HIV. Five studies reported a priori defined adverse events, and only 1 trial reported planned stopping guidelines. The primary harm outcomes reported across trials included toxicity, death, and increased mother-to-child transmission. Two trials were stopped due to sudden unanticipated adverse events (Stevens-Johnson syndrome, death, and encephalopathy). Relative risk point estimates for harm ranged from 1 to 6.18. Six studies reported the presence of a data safety and monitoring board. CONCLUSION: The reporting of methods to inform the decision to stop trials for harm in this population is deficient in a variety of ways, including lack of stopping guidelines. Clinicians should interpret RCTs stopped early for harm with caution and interpret the results in light of related evidence. Trialists should improve the transparency of their decision-making regarding early stopping for harmful effects. [References: 41]

Publication Type: Journal Article. Review.

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Unique Identifier [PMID]: 16566534

Authors: Oplatek A. Brown K. Sen S. Halerz M. Supple K. Gamelli RL.

Institution: Department of Surgery, Burn & Shock Trauma Institute, Stritch School of Medicine, Loyola University Medical Center, Maywood, Illinois 60153, USA.

Title: Long-term follow-up of patients treated for toxic epidermal necrolysis.

Source: Journal of Burn Care & Research. 27(1):26-33, 2006 Jan-Feb.

Abstract: Patient outcomes concerning toxic epidermal necrolysis (TEN) have improved over the years as a better understanding of the pathophysiology of the illness has been gained and enhancements have been made in the care of the acutely ill. With increase in survival, long-term complications these patients experience are beginning to be recognized. In this study, we analyzed the outcomes of a cohort of TEN survivors treated at our burn unit and sought to determine the impact of clinical variables from the initial hospitalization on mortality after discharge. We performed a retrospective review of data from patients with TEN treated at our burn unit from March 1993 to September 2002. Follow-up data on new health problems were collected on patients who were alive at discharge via questionnaire. Survival was estimated using the Kaplan-Meier method with Cox regression model. During the study period, of the 64 patients treated for TEN, 46 survived. After discharge, 15 patients died, whereas the remaining 31 patients continued to suffer from ocular (54%), skin (81%), and renal (23%) problems. Median survival for the whole cohort has not been reached, with an estimated 5-year survival of 65%. No patient in either group had a TEN recurrence. Seventy-nine percent of the patients with ocular involvement in the acute phase of TEN had long-term ocular complications, and 73% of patients with mucosal involvement had persistent mucosal lesions. Five individual factors were found to be predictors of postdischarge mortality on univariate analysis: age at diagnosis of TEN>or=60 years, SCORTEN 3 to 6, % maximal TBSA slough>or=50%, days from onset of symptoms to admission to a burn unit>or=5 days, and presence of multiple comorbidities at diagnosis of TEN. In multivariate analysis, only SCORTEN of 3 to 6 (P=.003) and days to admission>or=5 (P=.027) maintained significance as predictors of mortality and may be used to heighten surveillance during postdischarge care of patients with TEN.

Publication Type: Journal Article.

<3>

Unique Identifier [PMID]: 16361748

Authors: Agrawal S. Agarwalla A.

Institution: Department of Dermatology and Venereology, B.P. Koirala Institute of Health Sciences, Dharan, Nepal.

Title: Dapsone hypersensitivity syndrome: a clinico-epidemiological review.

Source: Journal of Dermatology. 32(11):883-9, 2005 Nov.

Abstract: Diaminodiphenyl sulphone (dapsone) is a drug of choice in the treatment of leprosy. It is also useful for the treatment of many neutrophilic and other dermatoses. Dapsone hypersensitivity syndrome is a rare but well recognized serious adverse effect characterized by fever, skin rashes, generalized lymphadenopathy, hepatitis, and hepato-splenomegaly. Twenty-six patients with dapsone hypersensitivity syndrome were studied for clinical profile, outcome, and prognosis. The male:female ratio was 2.2:1, and the mean age was 33.19 years (range 13 to 64 years). The interval between start of dapsone therapy and appearance of symptoms varied from 2-7 weeks (mean 29.82 days). Twenty-four patients received dapsone as a part of multi-drug therapy for leprosy; the other two patients received dapsone for lichen planus and acne vulgaris. Exfoliative dermatitis was the most common cutaneous manifestation followed by erythematous maculo-papular eruption and Stevens-Johnson syndrome-like lesion. The other common systemic manifestations were: fever (26 cases), itching (22 cases), lymphadenopathy (21 cases), jaundice (21 cases), pallor (20 cases), hepatomegaly (19 cases), and pedal edema (14 cases). Investigation profile revealed elevated levels of serum liver enzymes in 100% of patients, elevated erythrocyte sedimentation rate in 92.3%, raised bilirubin in 84.6%, leucocytosis in 69.23%, low hemoglobin (<9 gm/dl) in 46.15% and hypoproteinemia in 42.3%. Eosinophilia, hemolytic anemia, and reticulocytosis count were found in 4 patients each. All the patients had favorable outcomes except three who died due to hepatic failure. Medical personnel must be aware of this potentially fatal syndrome, because it can cause considerable morbidity and mortality.

Publication Type: Journal Article.

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Unique Identifier [PMID]: 16086734

Authors: Chave TA. Mortimer NJ. Sladden MJ. Hall AP. Hutchinson PE.

Institution: Department of Dermatology, Leicester Royal Infirmary, University Hospitals of Leicester NHS Trust, Leicester LE1 5WW, UK. toby.chave@rcht.cornwall.nhs.uk

Title: Toxic epidermal necrolysis: current evidence, practical management and future directions.[see comment]. [Review] [148 refs]

Source: British Journal of Dermatology. 153(2):241-53, 2005 Aug.

Abstract: Toxic epidermal necrolysis (TEN) is a rare disorder characterized by extensive epidermal death. Almost all cases appear to be caused by an idiosyncratic drug reaction. Proposed pathogenic mechanisms are conflicting, and the evidence for the benefits of individual treatments is inadequate, and in some cases contradictory. The mortality rate remains high. We review the literature pertaining to the pathogenesis of TEN and drug reactions in general. The rationale for therapeutic interventions, together with reported evidence of efficacy, are considered. We present a composite model of TEN, based on previous work and suggested pathogeneses of TEN, mechanisms of drug reactions and reported cytotoxic lymphocyte (CTL) cytolytic pathways. In this system, TEN, like some other cutaneous drug eruptions, is an HLA class I-restricted, specific drug sensitivity, resulting in clonal expansion of CD8+ CTLs. Cytotoxicity is mediated by CTL granzyme and possibly death receptor (DR) ligand (DR-L), probably Fas ligand (FasL). Particular to TEN, there is then an amplification sequence involving further DR-L expression. FasL is likely to be particularly important but tumour necrosis factor (TNF) may well contribute, via the TNF receptor 1 (TNF-R1) death pathway. Alternatively, we suggest the possibility of upregulation of an antiapoptotic TNF-R1-nuclear factor kappaB pathway, which would proscribe treatments which downregulate this pathway. None of the published data on individual treatment efficacies is sufficiently strong to suggest a definitive single treatment. Currently a multifaceted regimen appears indicated, targeting various likely intermediary mechanisms, including elimination of residual drug, immunosuppression, inhibition of DR pathways, general antiapoptotic strategies, and aggressive supportive care. Particular attention has been directed at avoiding potential conflicts between different treatments and avoiding agents that theoretically might have a net proapoptotic rather than antiapoptotic effect. Nursing on a specialized unit is of paramount importance. [References: 148]

Publication Type: Journal Article. Review.

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Unique Identifier [PMID]: 12533160

Authors: Prins C. Kerdel FA. Padilla RS. Hunziker T. Chimenti S. Viard I. Mauri DN. Flynn K. Trent J. Margolis DJ. Saurat JH. French LE. TEN-IVIG Study Group. Toxic epidermal necrolysis-intravenous immunoglobulin.

Institution: Department of Dermatology, Geneva University Medical School, Switzerland.

Title: Treatment of toxic epidermal necrolysis with high-dose intravenous immunoglobulins: multicenter retrospective analysis of 48 consecutive cases.[see comment].

Source: Archives of Dermatology. 139(1):26-32, 2003 Jan.

Abstract: OBJECTIVE: To evaluate the effect of high-dose intravenous immunoglobulin (IVIG) in toxic epidermal necrolysis (TEN), parameters that may affect response to treatment, and the effect of different IVIG batches on Fas-mediated cell death. DESIGN: Multicenter retrospective analysis of 48 consecutive TEN patients treated with IVIG. SETTING: Fourteen university hospital dermatology centers in Europe and the United States. PATIENTS: Forty-eight patients with TEN (skin detachment >10% of their body surface [mean, 44.8%; range, 10%-95%]). INTERVENTIONS: Infusion of IVIG in all patients (range, 0.8-5.8 g/kg), and analysis of the ability of different IVIG batches to inhibit Fas-mediated cell death. MAIN OUTCOME MEASURES: Objective response to IVIG treatment, final outcome at day 45, parameters that may affect response to IVIG treatment, and tolerance. RESULTS: Infusion of IVIG (mean total dose, 2.7 g/kg [range, 0.65-5.8 g/kg]; mean consecutive days, 4 [range, 1-5 days]) was associated with a rapid cessation (mean, 2.3 days [range, 1-6 days]) of skin and mucosal detachment in 43 patients (90%) and survival in 42 (88%). Patients who responded to IVIG had received treatment earlier in the course of disease and, on average, higher doses of IVIG. Furthermore, analysis of 35 IVIG batches revealed significant batch-to-batch variations in the capacity of IVIG to inhibit Fas-mediated cell death in vitro. CONCLUSIONS: Early infusion of high-dose IVIG is safe, well tolerated, and likely to be effective in improving the survival of patients with TEN. We recommend early treatment with IVIG at a total dose of 3 g/kg over 3 consecutive days (1 g/kg per day for 3 days).

Publication Type: In Vitro. Journal Article. Multicenter Study. Research Support, Non-U.S. Gov't.

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Unique Identifier [PMID]: 12519556

Authors: Majumdar S. Mockenhaupt M. Roujeau J. Townshend A.

Institution: 16 Ariel Close, Basford, Nottingham, UK, NG6 0EH. sammajumdar@hotmail.com

Title: Interventions for toxic epidermal necrolysis. [Review] [28 refs]

Source: Cochrane Database of Systematic Reviews. (4):CD001435, 2002.

Abstract: BACKGROUND: Toxic epidermal necrolysis is a rare condition where a drug reaction induces skin loss, similar to that seen in extensive burns. It is associated with high morbidity and mortality and there is no clear agreement on effective treatment. OBJECTIVES: To assess the effects of all interventions for the treatment of toxic epidermal necrolysis. SEARCH STRATEGY: We searched the Cochrane Skin Group Specialised Register (March 2001), the Cochrane Controlled Trials Register (March 2001), MEDLINE (1966 to December 2001), EMBASE (1980 to December 2001), DARE (4th Quarter 2001) and CINAHL (1982 to October 2001). SELECTION CRITERIA: Randomised controlled trials of therapeutic and supportive interventions that included participants clinically diagnosed with toxic epidermal necrolysis were included. DATA COLLECTION AND ANALYSIS: Two independent reviewers carried out study selection and assessment of methodological quality. MAIN RESULTS: Only one randomised controlled trial of treatment was identified. This trial compared the effectiveness of thalidomide with placebo and included 22 patients, 12 in the treatment group and 10 in the placebo group. Patients on the treatment arm received thalidomide 200 mg twice daily for 5 days. The main end point was the measurement of the progression of skin detachment after 7 days. Other end points were the overall mortality and severity of the disease evaluated with the simplified acute physiology score. The study was terminated as the mortality on the treatment arm was 83% compared to 30% on the control arm (relative risk 2.78, 95% confidence interval 1.04 to 7.40). No randomised controlled trials of the most commonly used current treatments i.e. systemic steroids, cyclosporin A and intravenous immunoglobulins were found. REVIEWER'S CONCLUSIONS: Treatment with thalidomide was not shown to be effective and was associated with significantly higher mortality than placebo. There is no reliable evidence on which to base treatment for toxic epidermal necrolysis, a disease commonly associated with mortality rates of around 30%. More research is required to understand the mechanisms of toxic epidermal necrolysis. International multi-centre studies are needed in the form of randomised controlled trials, to evaluate treatments for toxic epidermal necrolysis, especially those using high doses of steroid and intravenous immunoglobulins. [References: 28]

Publication Type: Journal Article. Review.

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Unique Identifier [PMID]: 12172137

Authors: Ducic I. Shalom A. Rising W. Nagamoto K. Munster AM.

Institution: Division of Plastic Surgery, Georgetown University Medical Center, 3800 Reservoir Road NW, Washington, D.C. 20007, USA. iducic@aol.com

Title: Outcome of patients with toxic epidermal necrolysis syndrome revisited.

Source: Plastic & Reconstructive Surgery. 110(3):768-73, 2002 Sep 1.

Abstract: Toxic epidermal necrolysis syndrome is an uncommon, acute, life-threatening, medication-induced disorder with a reported mortality rate of 20 to 60 percent. Different variables have been identified as risk factors. The extent to which these variables, when combined, affect the mortality and outcome in toxic epidermal necrolysis syndrome patients has not yet been reliably defined. Because of the high mortality rate, the logistic analysis of studied variables was performed to see whether a prognostic algorithm could be developed to aid the management of these patients. Thus, a retrospective review of 56 consecutive toxic epidermal necrolysis syndrome patients treated over a period of 13 years was undertaken in the authors' burn center. The demographics included age, sex, race, and total body surface area involved. The other variables studied were comorbidities, sepsis, steroid administration, and the interval between onset of rash and burn center admission. Data were subjected to Fisher's exact test and logistic analysis. Thirty-six patients (64.3 percent) were alive and 20 (35.7 percent) died. Univariate analysis indicated that the male/female ratio was 12:24 for survivors and 9:11 for nonsurvivors (p = 0.4). The white/nonwhite ratio was 80 percent for survivors and 54 percent for nonsurvivors (p = 0.58). The median age was 48.4 +/- 22.8 years (survivors, 41.7 +/- 22.0; nonsurvivors, 60.5 +/- 19.5; p = 0.002). Total body surface area involvement for survivors was 56.9 +/- 32 and 77.7 +/- 21 for nonsurvivors (p = 0.005). The presence of one or more comorbidities between the two groups differed (53 percent survivors and 90 percent nonsurvivors, p = 0.007), indicating eight times higher odds of dying in their presence. The average time between the onset of symptoms and admission to the burn unit was 5.25 +/- 3.4 days for survivors and 7.15 +/- 4.5 days for nonsurvivors (p = 0.08). The presence of sepsis (19.4 percent survivors, 95 percent nonsurvivors, p < 0.001) decreased odds for survival by a factor of 79. Steroids given as a single dose or multiple doses before the patient's transfer to the burn unit were not significantly associated with death (44 percent survivors, 65 percent nonsurvivors, p = 0.14). A multivariate logistic regression model yielded odds ratios of 1.11 (95 percent confidence interval, 1.03 to 1.19) for age in years, 304 (95 percent confidence interval, 8.83 to 10,400) for the presence of sepsis, and 1.03 (95 percent confidence interval, 0.99 to 1.08) for body surface area in percent. All those entering the burn unit with sepsis died. Equivalently, no survivors had sepsis before admission to the burn unit, whereas 55 percent of nonsurvivors had sepsis before admission and 40 percent developed sepsis after admission. When investigating the effect of age and sepsis, no patients over age 60 ever having sepsis survived, whereas all those who were under 60 and without sepsis survived. Likewise, all patients whose age was over 60 and whose total body surface area involved was over 60 percent died. The main factors contributing to the mortality from toxic epidermal necrolysis syndrome, when considering covariates separately, are the presence of sepsis at any time (odds ratio, 79), the presence of comorbidities (odds ratio, 8.05), age, and total body surface area, whereas multivariate models suggested age (odds ratio per year of additional age, 1.11), total body surface area (odds ratio per additional percent of body surface area, 1.03), and the presence of sepsis (odds ratio, 304). By using the actual coefficients in the logistic model, the log odds that the patient will die as the result of his or her condition can be summarized in the following formula: -11.5 + (10 percent of the patient's age + 3 percent of total body surface area + 5.75 if sepsis is present). The awareness of the importance of these covariates, and their early recognition as risk factors, should offer a focused approach to the patients' management and improve their outcome.

Publication Type: Journal Article.

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Unique Identifier [PMID]: 12164739

Authors: Auquier-Dunant A. Mockenhaupt M. Naldi L. Correia O. Schroder W. Roujeau JC. SCAR Study Group. Severe Cutaneous Adverse Reactions.

Institution: Department of Biostatistics and Epidemiology, Institut Gustave-Roussy, Villejuif, France.

Title: Correlations between clinical patterns and causes of erythema multiforme majus, Stevens-Johnson syndrome, and toxic epidermal necrolysis: results of an international prospective study.

Source: Archives of Dermatology. 138(8):1019-24, 2002 Aug.

Abstract: BACKGROUND: It was proposed that Stevens-Johnson syndrome and toxic epidermal necrolysis differed from erythema multiforme majus by the pattern and localization of skin lesions. OBJECTIVE: To evaluate the validity of this clinical separation. DESIGN: Case-control study. SETTINGS: Active survey from 1989 to 1995 of 1800 hospital departments in Europe. PATIENTS: A total of 552 patients and 1720 control subjects. METHODS: Cases were sorted into 5 groups (erythema multiforme majus, Stevens-Johnson syndrome, Stevens-Johnson syndrome-toxic epidermal necrolysis overlap, toxic epidermal necrolysis, and unclassified erythema multiforme majus or Stevens-Johnson syndrome) by experts blinded as to exposure to drugs and other factors. Etiologic fractions for herpes and drugs obtained from case-control analyses were compared between these groups. RESULTS: Erythema multiforme majus significantly differed from Stevens-Johnson syndrome, overlap, and toxic epidermal necrolysis by occurrence in younger males, frequent recurrences, less fever, milder mucosal lesions, and lack of association with collagen vascular diseases, human immunodeficiency virus infection, or cancer. Recent or recurrent herpes was the principal risk factor for erythema multiforme majus (etiologic fractions of 29% and 17%, respectively) and had a role in Stevens-Johnson syndrome (etiologic fractions of 6% and 10%) but not in overlap cases or toxic epidermal necrolysis. Drugs had higher etiologic fractions for Stevens-Johnson syndrome, overlap, or toxic epidermal necrolysis (64%-66%) than for erythema multiforme majus (18%). Unclassified cases mostly behaved clinically like erythema multiforme. CONCLUSIONS: This large prospective study confirmed that erythema multiforme majus differs from Stevens-Johnson syndrome and toxic epidermal necrolysis not only in severity but also in several demographic characteristics and causes.

Publication Type: Journal Article. Research Support, Non-U.S. Gov't.

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Unique Identifier [PMID]: 10724207

Authors: Stern RS.

Title: Improving the outcome of patients with toxic epidermal necrolysis and Stevens-Johnson syndrome.[comment]. [Review] [16 refs]

Source: Archives of Dermatology. 136(3):410-1, 2000 Mar.

Publication Type: Comment. Editorial. Review.

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Unique Identifier [PMID]: 10724193

Authors: Garcia-Doval I. LeCleach L. Bocquet H. Otero XL. Roujeau JC.

Institution: Department of Dermatology, Hospital Provincial de Pontevedra, Spain.

Title: Toxic epidermal necrolysis and Stevens-Johnson syndrome: does early withdrawal of causative drugs decrease the risk of death?[see comment].

Source: Archives of Dermatology. 136(3):323-7, 2000 Mar.

Abstract: BACKGROUND: Withdrawal of the drug(s) that cause severe cutaneous adverse reactions is usually recommended without proof that it alters the course of those reactions. OBJECTIVE: To determine whether the timing of causative drug withdrawal is related to the prognosis of patients with toxic epidermal necrolysis (TEN) or Stevens-Johnson syndrome (SJS). DESIGN: A 10-year observational study (January 1, 1987, through October 30, 1997) of patients admitted to a dermatological intensive care unit, using binary logistic regression analysis. SETTING: A single referral unit in a university hospital. PATIENTS: Consecutive sample of 203 patients with TEN or SJS. Exclusion criteria included causative drug undetermined, lack of information on disease evolution, the date of causative drug(s) withdrawal, or the date when the first definite sign of TEN or SJS appeared. MAIN OUTCOME MEASURE: Death before hospital discharge. RESULTS: One hundred thirteen patients were included; 74 had TEN and 39 had SJS; 20 died. The drug causing TEN or SJS was withdrawn early in 64 patients and late (after the first definite sign of TEN or SJS) in 49 patients. After adjustment for confounding variables (age, maximum extent of detachment, admission year, human immunodeficiency virus status), our model showed that the earlier the causative drug was withdrawn, the better the prognosis (odds ratio, 0.69 for each day; 95% confidence interval, 0.53-0.89). Patients exposed to causative drugs with long half-lives had an increased risk of dying (odds ratio, 4.9; 95% confidence interval, 1.3-18.9). The variables did not interact. CONCLUSIONS: Prompt withdrawal of drug(s) that are suspected to cause SJS or TEN may decrease mortality. Prompt withdrawal of causative drugs should be a priority when blisters or erosions appear in the course of a drug eruption.

Publication Type: Journal Article.

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Unique Identifier [PMID]: 9680896

Authors: Schmidt-Westhausen A. Grunewald T. Reichart PA. Pohle HD.

Institution: Abteilung fur Oralchirurgie und zahnarztliche Rontgenologie, Universitatsklinikum Charite, Humboldt Universitat zu Berlin, Germany.

Title: Oral manifestations of toxic epidermal necrolysis (TEN) in patients with AIDS: report of five cases.

Source: Oral Diseases. 4(2):90-4, 1998 Jun.

Abstract: OBJECTIVE: To describe oral findings in HIV-infected individuals with toxic epidermal necrolysis (TEN). PATIENTS: In a retrospective study over a 10 year period the medical histories of 931 hospitalised HIV-infected patients were reviewed for the occurrence of TEN. RESULTS: Five cases of TEN were diagnosed (three men, two women; median age: 41 years; median CD4+ T lymphocyte count: 20/microliter). Four patients had been treated with biweekly pyrimethamine/sulfadoxine for prophylaxis against Pneumocystis carinii pneumonia and toxoplasmosis. In one patient flucloxacillin was administered. Signs of TEN with cutaneous epidermolysis occurred and patients showed oral lesions characterized as oropharyngeal blisters and bullae on the palate, buccal mucosa, tongue and floor of the mouth initially. Antibiotics and corticosteroids were administered; none of the patients died. CONCLUSION: Longacting sulfonamides and antibiotics have been implicated as the cause of severe mucocutaneous reactions. Since rash and oral blisters may be the first signs of TEN in patients receiving these it is mandatory to follow up these patients closely to detect oral or cutaneous changes indicating the development of TEN.

Publication Type: Case Reports. Journal Article.

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Unique Identifier [PMID]: 9425690

Authors: Smith KJ. Skelton HG. Yeager J. Ledsky R. Ng TH. Wagner KF.

Institution: United States Army Medical Research Institute for Chemical Defense, Aberdeen, Maryland, USA.

Title: Increased drug reactions in HIV-1-positive patients: a possible explanation based on patterns of immune dysregulation seen in HIV-1 disease. The Military Medical Consortium for the Advancement of Retroviral Research (MMCARR).

Source: Clinical & Experimental Dermatology. 22(3):118-23, 1997 May.

Abstract: Drug reactions are common in HIV-1 disease, with the incidence having been reported to increase with increasing stage and with CD4+ T-cell counts below 200/microliters. However, there have been numerous reports of patients in which rechallenge, dosing changes or continued therapy have resulted in no recurrence or else clearing of the eruption. We followed 974 HIV-1-positive patients for 46 months as a part of a military study of HIV-1 disease. Within this group there were a total of 283 drug eruptions, with cutaneous manifestations in 201 patients in which clinical characteristics were noted and 86 patients in which cutaneous biopsies were performed. Serological evidence of reactivation or acute Epstein-Barr virus (EBV) or cytomegalovirus (CMV) infections were also noted, as well as peripheral eosinophilia. The incidence of drug eruptions significantly increased with increasing Walter Reed stage and decreasing CD4 counts and CD4/CD8 ratio, as well as with increasing age and in patients with increased numbers of other dermatological diagnoses. In addition, white patients had significantly more drug eruptions than did black. Serological or culture evidence of acute or reactivated EBV or CMV was significantly increased in patients with drug eruptions. The majority of the eruptions were maculopapular or morbilliform with a predominantly perivascular mononuclear cell infiltrate. HIV-1 positive patients have an increased incidence of drug reactions, the incidence having been reported to increase in patients with less than 200 CD4+ T cells/microliter. However, at very low T4 counts, especially those less than 25/microliter, and at a CD4/CD8 ratio of less than 0.10, the probability of reactions to trimethoprim-sulphamethoxazole (TMP-SMZ) is decreased in late-stage HIV-1 patients. Maculopapular or morbilliform eruptions are the most common clinical presentations, often accompanied by one or more of the following: fever, arthralgias, eosinophilia, and serum transaminase elevation. Histologically the majority of these eruptions show a perivascular mononuclear cell infiltrate, sometimes with focal interface changes and apoptotic, necrotic cells within the epidermis. Acute hypersensitivity reactions and toxic epidermal necrolysis (TEN) or Stevens-Johnson's syndrome (SJS) with diffuse epidermal apoptosis and necrosis have also been less commonly described. In a study of cutaneous manifestations in an HIV-1 positive military population, drug reactions were evaluated in terms of clinical features, histopathology, demographic features and laboratory findings.

Publication Type: Journal Article. Research Support, U.S. Gov't, P.H.S..

<13>

Unique Identifier [PMID]: 7477149

Authors: Fine JD.

Institution: Department of Dermatology, University of North Carolina at Chapel Hill 27599, USA.

Title: Management of acquired bullous skin diseases.[see comment]. [Review] [112 refs]

Source: New England Journal of Medicine. 333(22):1475-84, 1995 Nov 30.

Publication Type: Journal Article. Research Support, U.S. Gov't, P.H.S.. Review.

<14>

Unique Identifier [PMID]: 7778917

Authors: Guibal F. Bastuji-Garin S. Chosidow O. Saiag P. Revuz J. Roujeau JC.

Institution: Department of Dermatology, Hopital Henri Mondor, Universite Paris XII, Creteil, France.

Title: Characteristics of toxic epidermal necrolysis in patients undergoing long-term glucocorticoid therapy.[see comment].

Source: Archives of Dermatology. 131(6):669-72, 1995 Jun.

Abstract: BACKGROUND AND DESIGN: The usefulness of steroid therapy in toxic epidermal necrolysis (TEN) remains controversial. Up to 5% of the TEN cases occur in patients who undergo long-term steroid therapy. We, thus, looked for the potential effect of long-term glucocorticosteroid therapy before the onset of TEN on altering the progression of the disease. The records of 179 patients were reviewed. The characteristics of the 13 patients who were undergoing long-term glucocorticosteroid therapy were compared with those of 166 other patients with TEN. The following parameters were studied: age, mortality, delay between the introduction of the suspect drug and the onset of TEN, length of hospital stay, body surface area involved, time elapsed between the first symptom of TEN and hospital admission, number of medications taken by the patients before the onset of TEN, lymphocyte count, granulocyte count, platelet count, glycemia, serum aspartate aminotransferase level, and total disease duration. RESULTS: Patients who were undergoing long-term glucocorticosteroid therapy differed from other patients with TEN in the administration of more drugs, longer delay between the introduction of the suspect drug and the onset of TEN, and a longer time elapsed between the first symptom of TEN and hospital admission. We observed no differences for the other parameters that were studied. CONCLUSION: Our study shows that long-term steroid therapy may delay the onset of TEN, but it does not halt its progression.

Publication Type: Comparative Study. Journal Article.

<15>

Unique Identifier [PMID]: 8038322

Authors: Pertel P. Hirschtick R.

Institution: Division of Infectious Diseases, Northwestern University, Medical School, Chicago, Illinois 60611.

Title: Adverse reactions to dapsone in persons infected with human immunodeficiency virus.

Source: Clinical Infectious Diseases. 18(4):630-2, 1994 Apr.

Abstract: Dapsone is used in prophylaxis for and treatment of Pneumocystis carinii pneumonia. We present a case of Stevens-Johnson syndrome that was likely induced by administration of dapsone. A review of charts at the HIV Treatment Center of Northwestern University (Chicago) revealed that 40.3% of patients treated with trimethoprim-sulfamethoxazole could not tolerate the medication, while 25.2% of those treated with dapsone were intolerant of the drug. We also found a higher rate of adverse reactions to dapsone among patients with prior intolerance to trimethoprim-sulfamethoxazole than among patients without such a history; however, the difference was not significant.

Publication Type: Case Reports. Journal Article. Research Support, Non-U.S. Gov't.

<16>

Unique Identifier [PMID]: 1453334

Authors: Bayard PJ. Berger TG. Jacobson MA.

Institution: Department of Family and Community Medicine, San Francisco General Hospital, CA 94110.

Title: Drug hypersensitivity reactions and human immunodeficiency virus disease. [Review] [108 refs]

Source: Journal of Acquired Immune Deficiency Syndromes. 5(12):1237-57, 1992 Dec.

Abstract: Drug hypersensitivity reactions are often observed by clinicians treating patients infected with the human immunodeficiency virus (HIV). For certain drugs, the incidence of these reactions appears to be higher than previously reported in the general population. The best example is trimethoprim-sulfamethoxazole, associated with rash, fever, hematologic disturbances, transaminase elevation, and, less frequently, more severe reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and anaphylactic-like reactions. Other sulfa congeners, pentamidine, antituberculosis regimens containing isoniazid and rifampin, amoxicillin-clavulanate, clindamycin, and thalidomide also have been associated with an increased incidence of adverse reactions, some of which could involve allergic mechanisms. Effective dosage and management strategies are needed to prevent or ameliorate hypersensitivity reactions when they occur. [References: 108]

Publication Type: Journal Article. Research Support, U.S. Gov't, P.H.S.. Review.

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Unique Identifier [PMID]: 1899814

Authors: Levy M. Shear NH.

Institution: Division of Clinical Pharmacology, Department of Paediatrics, Hospital for sick Children, Toronto, Ontario, Canada.

Title: Mycoplasma pneumoniae infections and Stevens-Johnson syndrome. Report of eight cases and review of the literature. [Review] [59 refs]

Source: Clinical Pediatrics. 30(1):42-9, 1991 Jan.

Abstract: On the basis of a literature review and eight cases of our own, we analyzed 37 cases of Mycoplasma pneumoniae (MP) infection and Stevens-Johnson syndrome (SJS). Our clinical and laboratory findings do not differ from those reported in the literature for MP infection with no exanthem or for SJS of various etiologies. Eighty percent of the children presented with symptoms of upper respiratory tract infection (URTI) (cough, fever, sore throat, malaise, headache), with a mean of 10 days (range 1 to 30) before skin rash broke out. Skin manifestations occurred in 94.2% of the patients after 3 to 21 days (mean 10.3 days) of fever. The exanthem, composed predominantly of maculopapular and vesicular, was distributed chiefly on the trunk and extremities and lasted less than 14 days in 87.8% of the patients. Stomatitis was observed in 91.6% of the patients and conjunctivitis in 50%. No consistent pattern seems to emerge by which one could predict the existence of MP infection causing SJS. The complications of SJS associated with MP seem less frequent (2.7%) and much less severe than in cases where SJS arises from other reported causes. Because coincidence cannot be excluded from the assessments of the degree and rate of improvement for the few patients treated with corticosteroid, from the low frequency of complications, and from the mortality rate of zero in this series of patients, the use of corticosteroids for SJS associated with MP infection is questionable. [References: 59]

Publication Type: Journal Article. Research Support, Non-U.S. Gov't. Review.

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Unique Identifier [PMID]: 2187719

Authors: Tegelberg-Stassen MJ. van Vloten WA. Baart de la Faille H.

Institution: Department of Dermatology, Zeister Algemeen Ziekenhuis, The Netherlands.

Title: Management of nonstaphylococcal toxic epidermal necrolysis: follow-up study of 16 case histories.[see comment]. [Review] [28 refs]

Source: Dermatologica. 180(3):124-9, 1990.

Abstract: In this study the clinical and laboratory data of 14 patients who experienced 16 attacks of nonstaphylococcal toxic epidermal necrolysis (TEN) are presented. All patients were treated in the Department of Dermatology of the University Hospital of Utrecht. Only 1 patient died. Attention is focused on a successful management consisting of reversed barrier nursing, painstakingly executed skin care, timely use of antibiotics and a therapy consisting of high dosages of corticosteroids. Thorough management in centers experienced in the treatment of TEN is essential for good treatment results. Further investigations concerning the use of corticosteroids in treating TEN are needed. [References: 28]

Publication Type: Journal Article. Review.

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Unique Identifier [PMID]: 3658330

Authors: de Felice GP. Caroli R. Autelitano A.

Institution: Eye Clinic, University of Milan, Ospedale San Paolo, Italy.

Title: Long-term complications of toxic epidermal necrolysis (Lyell's disease). Clinical and histopathologic study.

Source: Ophthalmologica. 195(1):1-6, 1987.

Abstract: A case of toxic epidermal necrolysis had been observed in a 4-year-old child. This patient has been reexamined by us 21 years later. At that time a biopsy of conjunctival material and a histopathologic and ultrastructural study were done. The long-term ocular complications of the disease caused severe visual impairment with a remarkable sicca syndrome due to extensive scarring and keratinization, as confirmed also by light- and electron-microscopic features. These findings, concerning a particularly long follow-up, suggest that the ocular sequelae of this disease require continuous ophthalmological supervision many years after the acute stage of the disease.

Publication Type: Case Reports. Journal Article.

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Unique Identifier [PMID]: 836697

Authors: Elias PM. Fritsch P. Epstein EH.

Title: Staphylococcal scalded skin syndrome. Clinical features, pathogenesis, and recent microbiological and biochemical developments.

Source: Archives of Dermatology. 113(2):207-19, 1977 Feb.

Abstract: The essential clinical features of staphylococcal scalded skin syndrome (SSSS) and otherforms of toxic epidermal necrolysis (TEN) are contrasted. Whereas TEN is a devastating disease of multiple causes and of high fatality affecting all age groups, SSSS comprises many clinical entitles that occur primarily in early childhood and is caused by certain phage group 2 staphylococci. Because of the high cleavage plane, the barrier is only translently perturbed, and rapid recovery is the rule. Although the early stages of SSSS may resemble other widespread dermatoses clinically, the correct diagnosis is suggested, even prior to frank exfoliation, by the presence of cutaneous tenderness and a positive Nikolski sign. However, rapid bedside confirmation is now possible with exfoliative cytology and frozen sections. Recent availability of in vivo and in vitro animal models of SSSS have advanced the knowledge of the disease: the responsible epidermolytic toxin has been characterized, and the purely extracellular pathogenesis of SSSS has been established. The epidermolytic toxin is strikingly species and tissue specific, attacking only certain keratinizing epithelia of mice, hamsters, monkeys, and man. The lower incidence of SSSS in adults is primarily due to a supreior capacity to metabolize and excrete the toxin, as well as more efficient immune capabilities. The mechanisms of epidermolytic toxin action and the molecular site of action are still the focus of active investigation.

Publication Type: Journal Article.

<21>

Unique Identifier [PMID]: 4226103

Authors: Koblenzer PJ.

Title: Acute epidermal necrolysis (Ritter von Rittershain-Lyell). A clinicopathologic study.

Source: Archives of Dermatology. 95(6):608-17, 1967 Jun.

Publication Type: Journal Article.