stevens-johnson

Stevens-Johnson syndrome and toxic epidermal necrolysis in adults

//SJS and TEN are distinguished chiefly by severity and percentage of body surface involved.//

prodrome of malaise and fever, erythematous or purpuric macules and plaques epidermal necrosis and sloughing (show picture 1A-1B).

//Skin sloughing is limited to less than 10 percent of the body surface [1].

//Mucosal membranes are affected in 92 to 100 percent of patients,

//usually at two or more distinct sites (ocular, oral, and genital) [3].

// Toxic epidermal necrolysis (TEN), or Lyell's syndrome

prodrome of fever and malaise. Temperatures often exceed 39 degrees Celsius. erythematous macules and patches or diffuse erythema pain out of proportion to clinical findings full thickness epidermal necrosis //full-thickness epidermal necrosis leads to sloughing of greater than 30 percent of the body surface area [1] //Mucous membranes are involved in nearly all cases [7].

SJS/TEN overlap syndrome — SJS/TEN overlap syndrome describes patients with involvement of greater than 10 percent, but less than 30 percent of body surface area [1].

Because the pathogenesis of these disorders is not well-understood, there is a lack of consensus regarding whether SJS and TEN represent different severities of the same condition or separate disorders. Likewise, there are differing opinions about the degree to which SJS overlaps with severe erythema multiforme (EM), a condition with similar presentation. The most widely employed criteria, which are presented herein, propose a continuum between TEN and SJS, and distinguish SJS from severe EM (show table 1) [1,3,8]. The nosologic controversies surrounding these disorders are discussed briefly; however, this review places emphasis on the clinical presentation, diagnosis, and management of SJS and TEN. (See "Nosologic controversies" below).

ETIOLOGIES

In adults — Medications are the most common inciting etiologic factor in both SJS and TEN in adults, causing 30 to 50 percent of cases of SJS and up to 80 percent of cases of TEN [1,6,8-10]. Infections are the next most common trigger of adult SJS (up to 15 percent). In contrast, infectious causes of TEN are unusual [7,11,12]. Rare causes of SJS and TEN include vaccinations, systemic diseases, chemical exposure, herbal medicines, and foods [8,13-15].

Medications — The following groups of agents are most commonly implicated (show table 2) [16-18] :

Anti-gout agents (especially allopurinol) Antibiotics (sulfonamides >> penicillins > cephalosporins) Antipsychotics and anti-epileptics (including carbamazepine, dilantin, lamotrigine, and phenobarbital) Analgesics and non-steroidal anti-inflammatory agents (especially piroxicam) A 2007 multinational study from Europe and Israel indicated that allopurinol was the most common cause of SJS and TEN in these areas [19]. An earlier case control study quantified the relative risk of SJS/TEN corresponding with common medications (show table 3) [20]. Newer drugs that have been associated with SJS and TEN include nevirapine, lamotrigine, sertraline, pantoprazole, and tramadol [21].

In children — Infections, particularly Mycoplasma pneumonia, are associated with a greater proportion of pediatric cases of SJS [22], although medications are the leading cause across all age groups. In a series of 32 pediatric cases of SJS or TEN, the most common cause was a combination of azithromycin and ibuprofen, followed by ibuprofen alone. Ibuprofen was involved in 47 percent of all cases, and statistical analysis demonstrated a significant correlation between ibuprofen administration during treatment and disease complications. The authors advised caution when giving ibuprofen to children with suspected SJS or TEN [23].

HISTORY AND CLINICAL PRESENTATION — Exposure commonly precedes the onset of symptoms by one to three weeks (average 14 days) in medication-related cases [24]. Reexposure may result in onset of symptoms in as little as 48 hours.

Prodrome — SJS and TEN typically have a prodrome of fever and influenza-like symptoms one to three days before the development of mucocutaneous lesions [25]. Fever is usually higher with TEN [24]. Skin tenderness, photophobia, and conjunctival itching or burning may be early symptoms in both conditions.

Signs and symptoms

Skin - The skin lesions typically begin as ill-defined erythematous macules with purpuric centers. Occasional targetoid lesions may develop, particularly in SJS. The skin may be painful, particularly in TEN [24]. A burning sensation or other paresthesias may be reported. Lesions are symmetrically distributed, and start upon the face and thorax before spreading to other areas [6]. The scalp is typically spared, and palms and soles are less involved [26,27]. Vesicles and flaccid bullae then form, which spread laterally with pressure. The skin begins to slough within days. Sloughing progresses rapidly, but typically ceases to progress after two to three days [28]. Fulminant cases of TEN have been described, in which nearly 100 percent of the epidermis sloughed over a matter of hours [26,27].

The following signs and symptoms, when present early in the course of a reaction, should alert clinicians to a potentially serious eruption that may progress to SJS/TEN [25] :

– Confluent erythema (erythroderma) – Facial edema or central facial involvement – Skin pain – Palpable purpura – Skin necrosis – Blisters and/or epidermal detachment – Mucous membrane erosions and crusting – Urticaria (in the setting of other suggestive symptoms) – Swelling of tongue

Mucosa - Mucous membranes are involved in 92 percent or more of SJS/TEN [3]. Painful crusts and erosions may occur upon any mucosal surface, including the genitalia [24,25]. Urethritis may result in dysuria or even urinary retention [8]. The gastrointestinal and respiratory tracts may also be involved [29]. Ophthalmologic - Conjunctival lesions have been reported in 85 percent of patients [24,30]. Ocular involvement may range from simple hyperemia and congestion of vessels to scarring with the development of synechiae between the eyelids and conjunctiva [6,30]. Long-term ophthalmologic sequelae include photophobia, visual impairment, ingrown eyelashes (trichiasis), neovascularization of the cornea, keratitis, and corneal scarring leading to blindness [20,30-32]. Pulmonary - Pulmonary complications of TEN may include dyspnea, hypoxia, bronchial hypersecretion, tracheobronchitis, pulmonary edema, bacterial pneumonitis, and bronchiolitis obliterans [33,34]. Laboratory abnormalities — Hematologic abnormalities, particularly anemia and lymphopenia, are common in TEN patients [6]. Neutropenia is noted in about one-third of patients, and is correlated with a poor prognosis [6,35]. (See "Prognosis" below). Despite the strong association of TEN with drug ingestion, eosinophilia is unusual. Glucocorticoids can cause demarginalization and mobilization of neutrophils into the circulation, and this must be considered in patients who received these agents prior to testing.

Mild elevations in serum aminotransferase levels (two to three times normal) are present in about one-half of patients with TEN, while overt hepatitis occurs in just 10 percent [24].

Resolution — The time course of severe SJS/TEN, from prodrome to hospital discharge in the absence of significant complications, is typically two to four weeks. Reepithelialization may begin within several days of lesion onset, although it typically takes two to three weeks [36]. Skin that had remained attached during the acute process may peel gradually and nails may be shed.

EPIDEMIOLOGY

Incidence — The incidence of SJS, SJS/TEN overlap, and TEN considered together is approximately two cases per million people per year [37]. Cases of SJS appear to outnumber those of TEN by as much as three to one [38]. The epidemiology of SJS and TEN is also clouded by differences in disease definitions.

The mean age of patients with SJS has varied from 25 to 47 years, depending upon the series, although it can occur in all age groups [16,32,39]. Women have comprised 33 to 62 percent of reported cases [40]. One study reviewed Medicaid billing data in three states for the period of 1980 to 1984, using several related diagnostic codes, and reported incidence rates of between 2.6 and 7.1 cases per million population per year [41]. Data from West Germany, employing a more narrow definition of SJS, reported an incidence of 1.1 cases per million population per year [16].

The mean age of patients with TEN has been reported to be between 46 and 63 years, although, like SJS, TEN can occur in patients of any age [16,42]. The proportion of women affected has been estimated to be just over 60 percent [16]. One study examined discharge diagnoses in the greater Seattle area, from 1972 to 1986, and reported an incidence of TEN of 0.5 per million population per year [43]. Investigators in Sweden reported an incidence for TEN of 0.4 per million population per year, while a French group reported 1.2 cases of TEN per million population per year [42].

Risk factors — The following have been identified as possible risk factors for SJS/TEN:

Certain HLA-types (show table 4) [44-48]. As an example, patients with HLA-B* 1502 are at sufficiently increased risk for SJS/TEN due to carbamazepine, that the United States Food and Drug Administration has suggested screening patients of Asian and South Asian ancestry (in whom the prevalence of this allele is significant) if use of carbamazepine is under consideration [49]. Polymorphisms in the IL4 receptor gene, which are biologically linked to Th2 cytokine-driven inflammatory mediators [50] Lower N-acetylation capacity ("slow acetylators") [51] Malignancy may increase the risk of SJS and TEN, although data are conflicting as to whether underlying malignancy truly increases the risk, or is simply associated with increased exposure to causative medications [6,52,53]. Higher doses and more rapid introduction of medications may increase the risk of SJS or TEN. As examples, allopurinol doses below 200 mg/dL were associated with a lower risk of SJS/TEN than higher doses [19]. Similarly, lamotrigine was associated with high rates of severe skin reactions when it was initially introduced [54]. Recommendations were subsequently made for gradual titration when beginning therapy, and more recent studies suggest much lower rates of SJS/TEN [55]. Coincidental viral infections or other coingestants [56] Physical stimuli, such as ultraviolet light or radiation therapy, may be co-factors in some cases [52,57,58] HIV-infected patients — Patients with HIV infection have been reported to be at three times increased risk for SJS/TEN. The reasons for this susceptibility are not fully understood, although exposure to multiple medications, including sulfonamides, "slow acetylation" status, immune dysregulation, and the presence of concomitant infections may contribute [51,59,60].

A 40-fold increased risk for SJS/TEN due to trimethoprim-sulfamethoxazole was observed in HIV-infected patients, as compared to the risk among the general population taking this same medication [61]. Toxic hydroxylamine metabolites and depleted systemic glutathione reserves have been implicated in this toxicity [62]. Despite this heightened risk, however, the advantages of this medication (efficacy, availability, and low cost) outweigh the risks for SJS/TEN in most patients with HIV-AIDS who require treatment or prophylaxis for pneumocystis infections.

NOSOLOGIC CONTROVERSIES — The categorization, or nosology, of SJS, TEN, and severe EM, is an area of ongoing controversy that will only be resolved once the pathophysiology of these disorders has been revealed. An understanding of the controversy requires a brief historical review.

Erythema multiforme, the least severe of the disorders, was described by von Hebra in 1866 as acral (peripheral), targetoid, edematous papules and/or plaques without mucosal involvement (show picture 3) [63]. It is associated with infections, particularly herpes simplex virus [64].

Stevens-Johnson syndrome was subsequently described as a pediatric affliction by Stevens and Johnson in 1922 [2]. These authors reported on two cases consisting of a "generalized eruption with continued fever, inflamed buccal mucosa, and severe purulent conjunctivitis." The cases were distinguished from EM (von Hebra) by the "character of the lesions...the prolonged high fever and the terminal heavy crusting."

Two categories of EM were later suggested: erythema multiforme minor (von Hebra), and a severe form, erythema multiforme major (EM major), which encompassed SJS [65]. Subsequently, SJS came to be used synonymously with EMM [66]. A substantial number of dermatologists still consider EM major and SJS to be the same disease [5].

However, this categorization did not address cases with predominantly acral, targetoid eruptions, characteristic of EM minor (von Hebra), but with mucosal involvement more characteristic of EM major. To encompass this variant, it was proposed that EM major and SJS be considered distinct conditions with the term EM being restricted to acral, targetoid lesions, either with or without mucosal involvement, and the term SJS applied to mucous membrane involvement and widespread vesicles arising upon erythematous skin, without classic targetoid lesions [1,9]. Distinguishing the two conditions is also consistent with observations about etiology, as there is a strong association between herpes virus infections and EM, while SJS is more often associated with exogenous agents (eg, drugs) [10]. While differing slightly in definitional characteristics of the diseases, studies of the expression of IL-13 and other cytokines lends further support to the notion that SJS and TEN are diseases akin to one another, but distinct from classic erythema multiforme [67,68].

TEN was first described in 1948, with a small series appearing a decade later [4]. TEN was distinguished by an acute, diffuse, erythematous rash followed by widespread full-thickness epidermal sloughing, and was initially believed to be distinct from SJS.

It was later proposed that SJS and TEN were varying degrees of the same process, differing only in the extent of involvement [26,69]. However, this unifying concept has not been universally accepted. Some have cited subtle histologic differences between SJS and TEN [38]. In addition, one report demonstrated that serum from TEN patients was directly cytotoxic to cultured keratinocytes, while serum from SJS patients was toxic only in the presence of lymphocytes [70]. This observation supported the original hypothesis that the conditions were different, with a toxic metabolite triggering TEN and an immunologic cellular response mediating SJS [4].

Summary — Severe EM (EM major) and SJS are viewed by many experts as separate entities, based on etiologic and clinical distinctions. In contrast, the concept that SJS and TEN exist along a continuum of a single disease process appears well-supported by the majority of evidence and is accepted by most, although not all.

PATHOGENESIS — The pathologic mechanisms that induce skin damage in SJS/TEN are incompletely understood. The shortened interval upon reexposure to symptoms is suggestive of an immunologic process, although a precise mechanism has not been demonstrated [24].

A role for reactive drug metabolites has been supported by the finding that many patients with SJS and TEN demonstrate altered metabolic capabilities, such as slow N-acetylation [51,59,71]. This may result in prolonged exposure to toxic and/or immunogenic metabolites in these individuals.

Other hypothesized mechanisms for SJS/TEN have involved mixed drug-induced and immunologically-mediated phenomenon. Keratinocytes normally express the death receptor, CD95 (fas). When fas interacts with its ligand (fas ligand), the affected cell undergoes apoptosis, a highly-controlled process that eliminates unwanted cells without creating an inflammatory reaction. Mass triggering of apoptosis among keratinocytes may explain the pauci-inflammatory nature of the epidermal necrosis observed in SJS/TEN. (See "Histology" below).

The source of fas ligand in this proposed mechanism is less clear. Keratinocytes from TEN patients may express fas ligand as well as fas. Fas ligand expression has been induced by drug exposure in vitro [72]. Alternatively, fas ligand was shown to be secreted by peripheral blood mononuclear cells of patients with TEN and SJS upon in vitro exposure to the causative drug [73].

Perforin, TNF-a, and granzyme B, which are involved in distinct non-apoptotic cell death pathways, were also found in the high concentrations in the peripheral mononuclear cells and blister fluid of SJS/TEN patients [74]. However, elevations in these mediators were not specific to SJS/TEN.

DIAGNOSIS — SJS and TEN are clinical diagnoses supported by compatible histologic findings. Histology is not independently diagnostic.

Histology — The earliest histologic finding in SJS is a perivascular mononuclear inflammatory infiltrate comprised primarily of T-lymphocytes [75,76]. This infiltrate is not diagnostic, and it may be seen in a wide variety of conditions, including a simple drug-induced exanthem. A sparse infiltrate of lymphocytes develops at the dermoepidermal junction, with lymphocytes clustered around dying basal keratinocytes ("satellitosis") [38]. As the lesions progress, frank subepidermal vesiculation develops, with full thickness epidermal necrosis. Fully developed SJS is distinguished by full thickness epidermal detachment with splitting above the basement membrane, minimal inflammatory infiltrate, and normal immunofluorescence.

The histopathology of TEN is similar. In addition, abnormalities of the underlying sweat ducts have been described in TEN, including lymphocytic infiltration, basal cell hyperplasia, and necrosis [77].

Differential diagnosis — The differential diagnosis of SJS/TEN includes:

Erythematous drug eruptions Pustular drug eruptions Phototoxic eruptions Staphylococcal scalded skin syndrome (SSSS) Toxic shock syndrome (TSS) Acute generalized exanthematous pustulosis (AGEP) Skin biopsy is useful in excluding or including many of these conditions. An appropriate sample may be obtained using a large (>4 mm) punch biopsy or by deep shave biopsy ("saucerization") technique.

Erythematous drug eruptions - Erythematous drug reactions are commonplace. The generalized and symmetric maculopapular erythema of a drug eruption can mimic early SJS/TEN. However, erythematous drug eruptions lack mucosal involvement as well as the ill-defined but prominent skin pain of TEN, which is often out of proportion to the clinical findings. Treatment of erythematous drug reactions includes withdrawal and supportive measures (eg, antihistamines for pruritus). (See "Drug eruptions"). Pustular drug eruptions - Pustular drug reactions, such as acute generalized exanthematous pustulosis (AGEP), may also mimic early SJS/TEN. AGEP is an eruption consisting of non-follicularly centered pustules that often begin on the neck and intertriginous areas. Most commonly, AGEP is caused by beta-lactam antibiotics, occurring within a few days of ingestion. The lesions are not associated with pain, and mucosal involvement is rare. The pustules of AGEP may coalesce and slough, but this occurs during resolution of the disorder, and is not present during the evolving phase of the disease. Treatment of pustular drug reactions includes withdrawal and supportive measures. Phototoxic eruptions - Phototoxic eruptions are caused by direct interaction of a chemical with sunlight to yield a byproduct toxic to the skin. The most common phototoxic reactions to be confused with SJS/TEN are those that are due to oral ingestants. As an example, fluoroquinolones may yield a phototoxic reaction, which can lead to widespread epidermal sloughing. The clinical history, known phototoxic qualities of the suspected ingestant, and a clear photodistribution to the eruption represent key points of discrimination. When sloughing is marked, the patient with a severe phototoxic reaction is managed in a burn unit, much like a patient with SJS/TEN. (See "Drug eruptions"). Toxic shock syndrome - Toxic shock syndrome (TSS) is classically caused by Staphylococcus aureus. A similar form of streptococcal toxic shock syndrome has been attributed to toxin-elaborating strains of Group A streptococci. (See "Staphylococcal toxic shock syndrome" and see "Epidemiology, clinical manifestations, and diagnosis of streptococcal toxic shock syndrome"). The clinical manifestations of TSS are caused by elaboration of specific bacterial toxin(s) that act as superantigens, non-specifically activating large numbers of T lymphocytes [78]. The clinical manifestations of streptococcal TSS are similar.

TSS develops acutely in healthy individuals, particularly young women, sometimes within days of menstruation or surgical procedures. Presentation includes fever, hypotension, skin manifestations, non-pitting edema of the face and hands, and multi-organ failure. Systemic signs and symptoms include diarrhea and vomiting in the early phases, myalgias with elevations of creatinine phosphokinase, elevated transaminases, elevated creatinine, and mental status changes. Thus, compared to SJS/TEN, TSS presents with more prominent involvement of multiple organ systems.

Cutaneous manifestations may include a diffuse red macular rash resembling sunburn that may involve the palms and soles. This eruption may be subtle or fleeting (show picture 4). Petechiae, vesicles, and bullae may develop in severe cases. Desquamation occurs one to two weeks after the onset of illness and chiefly affects the palms and soles (show picture 5). Mucosal involvement in TSS includes hyperemia of the vaginal and oropharyngeal mucosa and conjunctival-scleral suffusion and hemorrhage (show picture 6) [79]. (See "Staphylococcal toxic shock syndrome" and see "Treatment of streptococcal toxic shock syndrome").

Staphylococcal scalded skin syndrome - Staphylococcal scalded skin syndrome (SSSS), also known as Ritter's disease, is caused by epidermolytic toxins produced by certain strains of Staphylococci [80]. This toxin is distributed systemically and results in dissolution of keratinocyte attachments in only the upper layer of the epidermis (stratum granulosum). SSSS usually affects newborns and children [81]. Adults are less commonly affected because improved renal function allows for clearance of the toxins from the body, although adults with renal failure are more susceptible [82]. (See "Vesiculobullous and pustular lesions in the newborn"). SSSS presents with fever, irritability, and a generalized, erythematous, micromacular to maculopapular rash (show picture 7 and show picture 8) [80-82]. The exfoliative phase is heralded by perioral exudation and crusting with large radial fissures, likened to an "unhappy clown," appearing around the mouth. There is usually no history of drug exposure.

SSSS is distinguished clinically from SJS/TEN chiefly by its epidemiology. The diagnosis is supported by histologic examination, which reveals sloughing of only the upper layers of the epidermis. Frozen section examination of sloughing epidermis can often distinguish SSSS from TEN as histology in TEN will reveal a subepidermal split with full thickness epidermal necrosis, while only partial thickness epidermal sloughing and minimal keratinocyte necrosis will be noted in SSSS [83,84].

Treatment of SSSS involves eradication using intravenous antibiotics [80]. (See "Vesiculobullous and pustular lesions in the newborn").

PROGNOSIS — Age at diagnosis and extent of skin detachment are the main prognostic factors for both SJS and TEN [42,85]. Children have a more favorable prognosis than elderly patients.

Stevens-Johnson syndrome — The overall mortality rate for SJS has been reported to be as low as 1 to 3 percent [3]. Prompt removal of the causative drug decreases mortality [86].

Toxic epidermal necrolysis — For TEN, the prognosis is more guarded. Mortality has ranged from 10 to 70 percent in past series, with more recent studies citing overall rates of 25 to 35 percent [24,87,88]. Early identification and withdrawal of the offending medication improves prognosis [86].

A prognostic scoring system (SCORTEN) based upon seven independent and easily measured clinical and laboratory variables has been advocated and validated for use on day one and day three of hospitalization for SJS/TEN (show table 5) [89-91]. A Kaplan-Meier curve corresponding to the SCORTEN analysis for day one has been developed and is useful to clinicians when discussing a patient's prognosis with family members or medical staff (show figure 1) [91]. The interpretation of Kaplan-Meier curves is reviewed elsewhere. (See "Glossary of common biostatistical and epidemiological terms").

Reepithelialization — Reepithelialization may begin after several days, but typically it takes two to three weeks; the usual duration of hospitalization in severe cases [36]. Dermatologic sequelae are common and include scarring, irregular pigmentation and eruptive nevi, abnormal regrowth of nails, and alopecia [24,30,92,93].

Long-term sequelae — Dermatologic sequelae are common and include scarring, irregular pigmentation and eruptive nevi, abnormal regrowth of nails, and alopecia [30,88,94,95]. Long-term pulmonary complications have also been reported [96]. In multivariate analysis, a SCORTEN of 3 to 6 (p = .003) and days to admission to a burn unit (≥5 days) (p = .027) were significant predictors of mortality during the postdischarge period for patients with TEN [97].

TREATMENT — The primary interventions for both SJS and TEN are removal of the offending medication (if applicable) and supportive care administered in a burn unit [98].

Prompt removal of offending agent — For patients with SJS or TEN, early identification and withdrawal of the offending medication improves prognosis [86]. This should be the initial intervention in any patient with an adverse drug reaction that involves signs or symptoms suggestive of SJS or TEN. Any agents that could be causative should be immediately discontinued. (See "Signs and symptoms" above).

The impact of early removal of the causative medications on mortality was evaluated in a 10-year observational study of 113 patients with TEN or SJS [86]. Late withdrawal of the causative drug was defined as removal after the first definite sign of TEN or SJS. Logistic regression showed that the earlier the causative drug was removed, the better the prognosis (odds ratio [OR] = 0.69 for each day), after adjustment for confounding variables (age, maximum extent of detachment, admission year, human immunodeficiency virus status). In addition, causative drugs with long half-lives conferred an increased risk of dying (OR = 4.9).

Transfer to a burn unit — SJS and TEN involve massive loss of the epidermis, and the principles of emergency management are similar to those of burn victims. Prompt transfer to a burn unit should be arranged whenever possible. A retrospective multicenter review of 199 patients with TEN treated at burn care centers documented an overall mortality rate of 32 percent [99]. However, the mortality of the subset of patients transferred to a burn center more than one week after onset of disease was 51 percent.

Supportive care — Supportive care includes wound care, fluid and electrolyte management, nutritional support, ocular care, temperature management, and monitoring for and treatment of superinfections.

Wound care - Non-adherent nanocrystalline gauze materials containing silver are being increasingly utilized in the care of SJS and TEN wounds, replacing petrolatum-impregnated gauze, although controlled trials comparing the two have not been performed [100]. Silver ions exert broad antimicrobial effects by interfering with the respiratory chain of cytochromes [101]. Such dressings may be left in place for longer durations (up to seven days), thereby decreasing the frequency of painful dressing changes. Fluid management - Fluid and electrolyte imbalances may occur due to increased transepidermal water loss, but replacement volumes are typically less than those of burn victims [102]. Nutritional support - Oral feedings, via a nasogastric tube, should be initiated early. These may sometimes be introduced after just the second day of care [6]. Ocular care - Immediate and ongoing attention to ocular involvement is recommended to avoid permanent ocular complications. (See "Signs and symptoms" above). We suggest obtaining a baseline ophthalmologic consultation when possible, with regular exams by nursing staff, and additional consultation should eye complications be suspected later in the course [98]. Temperature management - Other measures of overall care include increasing the room temperature to 30 to 32º C, and/or the use of heated-air body warmers to prevent excessive caloric expenditures due to epidermal loss [3]. Fluidized air beds are useful when the patient's backside is significantly denuded [28,103]. Monitoring and treatment of superinfections - Patients with SJS/TEN are at high risk of infection and sepsis remains a prominent cause of mortality [3,24]. Sterile handling and reverse-isolation procedures are essential [102,104]. Routine cultures of the skin, and also of blood, catheters, and gastric or urinary tubes should be performed [3]. Signs of infection include increases in the quantity of bacteria cultured from the skin, a sudden decrease in temperature, or general deterioration [3]. The initial choice of antibiotics is based upon culture results [103]. Colonization with Staphylococcus aureus occurs in the first few days of illness, while gram-negative rods, particularly Pseudomonas aeruginosa, are problematic later in the course [6,105]. (See "Pseudomonas aeruginosa skin, soft tissue, and bone infections").

Prophylactic systemic antibiotics are NOT employed by the majority of burn units [99]. In contrast, topical antibiotics are commonly used. Silver sulfadiazine is usually avoided because of the strong association of SJS/TEN with sulfonamides, although silver nitrate and newer silver-imbued nanocrystalline gauze materials are used successfully, as discussed previously [101].

Additional therapies — There are no universally accepted and uniformly effective treatment regimens for SJS or TEN beyond supportive care [106]. Several therapies have been utilized in these disorders, however, with variable success. Unfortunately, none have been evaluated with randomized controlled prospective studies, except thalidomide, which was found to be harmful. Controlled trials are essential, however, because the prognosis with supportive care alone is favorable [107]. The treatments that have been studied are presented in this section and summarized in the table (show table 6).

Glucocorticoids — The data regarding use of glucocorticoids in both SJS and TEN are mixed. One large series and several case reports have described positive outcomes in patients with SJS and TEN treated with systemic glucocorticoids, compared to those treated with supportive care only [39,108,109] :

In a series of 54 consecutive patients at one center, all received intravenous methylprednisolone at the time of diagnosis, at doses of 160 to 240 mg per day and there were no deaths or significant adverse outcomes [108]. Glucocorticoid doses were reduced upon clinical evidence of improvement. A multinational study of 379 patients with verified SJS or TEN demonstrated a nonsignificant trend towards diminished mortality with the administration of glucocorticoids [85]. Patients received various glucocorticoids, including prednisone, methylprednisolone, and dexamethasone, either orally or intravenously, at widely varying doses. In France, where the mean maximum dose administered was 60 mg daily, the odds ratio (OR) for death was 0.9 (95% CI, 0.2-4.2), while in Germany, where the mean maximum dose was 250 mg daily, the OR for death was 0.2 (CI, 0.1-0.9). In theory, however, glucocorticoids could increase the risk of sepsis, increase protein catabolism, and decrease the rate of epithelialization, and other studies have found that administration of systemic glucocorticoids was associated with increased morbidity and mortality, particularly if these agents were administered for prolonged periods [25,110-114].

SJS - While recognizing that the evidence is inadequate, we suggest administration of glucocorticoids to patients in whom the SJS has been diagnosed promptly (eg, within 24 to 48 hours). We administer prednisone, 1 to 3 mg/kg daily (or an equivalent amount of prednisolone or methylprednisolone, and do not continue therapy beyond four to seven days. We discontinue treatment sooner if there is any sign of infection. There is a clinical impression that glucocorticoids are more effective in cases in which the biopsy shows inflammatory changes (more lymphocytes), compared to those cases in which the biopsy is paucicellular, although this difference has not been formally documented and cannot be considered evidence-based. TEN - In contrast, we do not generally administer glucocorticoids to patients with TEN, although this is no conclusive evidence of harm. Intravenous gammaglobulin — Data surrounding the use of intravenous immunoglobulin (IVIG) for SJS/TEN are limited and conflicting [94,95,115,116] . Most early reports involved administration of 1.0 to 1.5 mg/kg in a single infusion. Later reports favored "high-dose" regimens of 1 gram/kg per day for three days (ie, a total dose of 3 grams/kg), although these are largely in small series of patients at single centers [72,117-121].

The largest series in which IVIG was used was a multicenter, retrospective review of 48 patients with TEN [119]. The mean total dose was 2.7 grams/kg (with doses ranging from 0.65 to 5.8 grams/kg divided over one to five days). Patients received IVIG seven days after onset of symptoms, on average. In 90 percent, skin and mucosal detachment ceased in two to three days and survival was 88 percent. Poor outcomes were associated with lower doses of IVIG and more days of symptoms before initiation of IVIG, as well as the presence of underlying conditions and greater body surface area affected [88,119].

In contrast, the multinational study described previously concluded that IVIG was not superior to supportive care, although the median IVIG dose was 1.9 g/kg (interquartile range 1.3 to 2.1 g/kg) supplied over one to seven days, a dose lower than most of the reports which found a benefit [85].

While the efficacy of IVIG for SJS or TEN has not been demonstrated convincingly and the best approach to therapy is unknown, we favor administration and would suggest total doses >2 grams/kg [88].

Combined therapy — Glucocorticoids and IVIG have been administered in combination to patients with SJS and TEN [85]. This is not our practice, however.

Plasmapheresis — Plasmapheresis has been reported effective in several studies regarding the acute care of patients with TEN [87,122-125]. Removal of a toxin, such as a drug, drug metabolite, or other cytotoxic mediator, has been proffered to be the mechanism of action. Yet another series demonstrated no difference in mortality, length of stay in hospital, or time to reepithelialization with plasmapheresis [126]. Thus, this treatment modality is also in need of further study.

Harmful agents — Thalidomide is a potent inhibitor of TNF-alpha. When this cytokine was found to be potentially upregulated in TEN, thalidomide was proposed as a potential therapy. Treatment with thalidomide was studied in a double-blinded randomized placebo controlled study of TEN patients, but the trial had to be stopped because of increased mortality among those given the active agent [127]. The exact mechanism by which thalidomide worsens TEN is not understood, but its use is firmly contraindicated.

PATIENT EDUCATION — Patients who survive SJS or TEN triggered by a medication must be carefully educated about future avoidance and understand that reexposure may be fatal. Relevant information should be inscribed on a medical information bracelet or necklace and worn at all times. Patients should learn all the names for the causative medication, be able to report that they have a history of SJS or TEN, and be able to recognize closely-related medications that should also be avoided.

SUMMARY AND RECOMMENDATIONS

Clinical characteristics

SJS and TEN represent disorders of uncertain etiology that are characterized by desquamative lesions of the skin and mucous membranes. (See "Introduction and terminology" above). The most widely recognized diagnostic criteria proposes a spectrum of disease for SJS and TEN. Cases with less than 10 percent epidermal involvement are classified as SJS; those with 30 percent or more involvement are classified as TEN; cases with between 10 and 30 percent involvement are considered overlap SJS/TEN. (See "Introduction and terminology" above). The signs and symptoms of SJS and TEN begin with a prodrome of fever and influenza-like symptoms one to three days before the development of mucocutaneous and skin lesions. Characteristic vesicular and bullous skin lesions then appear and progress over several days, followed by sloughing. There may be multiorgan involvement. Hospital discharge is usually possible within two to four weeks in the absence of complications. (See "History and clinical presentation" above). TEN is almost invariably drug-induced, while SJS is associated with infections, as well as drug administration. (See "Etiologies" above). The diagnosis of SJS or TEN is clinical. Histology is supportive, but not independently diagnostic. (See "Diagnosis" above). The prognosis in SJS is favorable, with a reported mortality of 1 to 3 percent. The prognosis in TEN is worse, with mortality ranging from 25 to 35 percent. Predictors of mortality include older age at onset and greater extent of skin involvement. (See "Prognosis" above). Management — Essential components in the management of both SJS and TEN are early recognition and immediate withdrawal of any potential causative agents, and prompt transfer to a burn unit whenever possible. (See "Treatment" above).

Sepsis is the major cause of death. Silver-impregnanted nanocrystalline gauze is useful in topical wound care, and routine cultures of possible sites of superinfection are recommended. Prophylactic systemic antibiotics are not utilized by the majority of burn centers, although antimicrobials must be administered at the first sign of infection with choice of agent guided by specific culture data. (See "Supportive care" above). Adjunctive therapies — A number of adjunctive interventions have been proposed, including glucocorticoids, IVIG, and plasmapheresis, yet there is currently insufficient evidence to establish the benefit of any of these therapies (show table 6). The approach at our center is described below. (See "Additional therapies" above).

SJS — For patients in whom the diagnosis of SJS has been made within a day or two of symptoms onset, we suggest administration of systemic glucocorticoids. We initiate this therapy as soon as possible after diagnosis, and discontinue it after four to seven days or at the first sign of infection. We administer prednisone, 1 to 3 mg/kg daily or an equivalent amount of prednisolone or methylprednisolone. (See "Glucocorticoids" above).

In severe cases of SJS, we suggest administering IVIG. We administer a dose of 1 gram/kg daily for three consecutive days. We generally do not combine IVIG and glucocorticoids in the treatment of SJS. (See "Intravenous gammaglobulin" above). TEN — We suggest administering IVIG to patients with TEN. We propose a dose of 1 gram/kg daily for three consecutive days. (See "Intravenous gammaglobulin" above).

We do not typically administer glucocorticoids or employ plasmapheresis in the treatment of TEN. (See "Glucocorticoids" above and see "Plasmapheresis" above).

Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES

Bastuji-Garin, S, Rzany, B, Stern, RS, et al. Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme. Arch Dermatol 1993; 129:92. Stevens, AM, Johnson, FC. A new eruptive fever associated with stomatitis and ophthalmia: a report of two cases in children. Am J Dis Child 1922; 24:526. Letko, E, Papaliodis, DN, Papaliodis, GN, et al. Stevens-Johnson syndrome and toxic epidermal necrolysis: a review of the literature. Ann Allergy Asthma Immunol 2005; 94:419. Lyell, A. Toxic epidermal necrolysis: an eruption resembling scalding of the skin. Br J Dermatol 1956; 68:355. Fritsch, PO, Ruiz-Maldonado, R. Erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. In: Fitzpatrick's dermatology in general medicine (6e), Freedberg, IM, et al (Eds), McGraw-Hill Inc., New York 2003. p.544. Roujeau, JC, Chosidow, O, Saiag, P, et al. Toxic epidermal necrolysis (Lyell syndrome). J Am Acad Dermatol 1990; 23:1039. Rasmussen, JE. Toxic epidermal necrolysis. A review of 75 cases in children. Arch Dermatol 1975; 111:1135. Roujeau, JC. Stevens-Johnson syndrome and toxic epidermal necrolysis are severity variants of the same disease which differs from erythema multiforme. J Dermatol 1997; 24:726. Roujeau, JC. What is going on in erythema multiforme?. Dermatology 1994; 188:249. Assier, H, Bastuji-Garin, S, Revuz, J, Roujeau, JC. Erythema multiforme with mucous membrane involvement and Stevens-Johnson syndrome are clinically different disorders with distinct causes. Arch Dermatol 1995; 131:539. Lyell, A. Toxic epidermal necrolysis (the scalded skin syndrome): a reappraisal. Br J Dermatol 1979; 100:69. de Groot, R, Oranje, AP, Vuzevski, VD, Mettau, JW. Toxic epidermal necrolysis probably due to Klebsiella pneumoniae sepsis. Dermatologica 1984; 169:88. Chowdhury, AD, Oda, M, Markus, AF, et al. Herbal medicine induced Stevens-Johnson syndrome: a case report. Int J Paediatr Dent 2004; 14:204. Nethercott, JR, Choi, BC. Erythema multiforme (Stevens-Johnson syndrome)--chart review of 123 hospitalized patients. Dermatologica 1985; 171:383. Ball, R, Ball, LK, Wise, RP, et al. Stevens-Johnson syndrome and toxic epidermal necrolysis after vaccination: reports to the vaccine adverse event reporting system. Pediatr Infect Dis J 2001; 20:219. Schopf, E, Stuhmer, A, Rzany, B, et al. Toxic epidermal necrolysis and Stevens-Johnson syndrome. An epidemiologic study from West Germany. Arch Dermatol 1991; 127:839. Mockenhaupt, M, Kelly, JP, Kaufman, D, Stern, RS. The risk of Stevens-Johnson syndrome and toxic epidermal necrolysis associated with nonsteroidal antiinflammatory drugs: a multinational perspective. J Rheumatol 2003; 30:2234. Devi, K, George, S, Criton, S, et al. Carbamazepine--the commonest cause of toxic epidermal necrolysis and Stevens-Johnson syndrome: a study of 7 years. Indian J Dermatol Venereol Leprol 2005; 71:325. Halevy, S, Ghislain, PD, Mockenhaupt, M, et al. Allopurinol is the most common cause of Stevens-Johnson syndrome and toxic epidermal necrolysis in Europe and Israel. J Am Acad Dermatol 2007; :. Roujeau, JC, Kelly, JP, Naldi, L, et al. Medication use and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis. N Engl J Med 1995; 333:1600. Mockenhaupt, M, Viboud, C, Dunant, A, et al. Stevens-Johnson syndrome and toxic epidermal necrolysis: assessment of medication risks with emphasis on recently marketed drugs. The EuroSCAR-study. J Invest Dermatol 2008; 128:35. Leaute-Labreze, C, Lamireau, T, Chawki, D, et al. Diagnosis, classification, and management of erythema multiforme and Stevens-Johnson syndrome. Arch Dis Child 2000; 83:347. Dore, J, Salisbury, RE. Morbidity and Mortality of Mucocutaneous Diseases in the Pediatric Population at a Tertiary Care Center. J Burn Care Res 2007; :. Revuz, J, Penso, D, Roujeau, JC, et al. Toxic epidermal necrolysis. Clinical findings and prognosis factors in 87 patients. Arch Dermatol 1987; 123:1160. Roujeau, JC, Stern, RS. Severe adverse cutaneous reactions to drugs. N Engl J Med 1994; 331:1272. Ruiz-Maldonado, R. Acute disseminated epidermal necrosis types 1, 2, and 3: study of 60 cases. J Am Acad Dermatol 1985; 13:623. Revuz, J, Roujeau, JC, Guillaume, JC, et al. Treatment of toxic epidermal necrolysis. Creteil's experience. Arch Dermatol 1987; 123:1156. Heimbach ,DM, Engrav, LH, Marvin, JA, et al. Toxic epidermal necrolysis. A step forward in treatment. JAMA 1987; 257:2171. Roupe, G, Ahlmen, M, Fagerberg, B, Suurkula, M. Toxic epidermal necrolysis with extensive mucosal erosions of the gastrointestinal and respiratory tracts. Int Arch Allergy Appl Immunol 1986; 80:145. Sheridan, RL, Schulz, JT, Ryan, CM, et al. Long-term consequences of toxic epidermal necrolysis in children. Pediatrics 2002; 109:74. Ortiz, JE, Horn, MS, Peterson, HD. Toxic epidermal necrolysis-case report and review of the literature. Ann Plast Surg 1982; 9:249. Power, WJ, Ghoraishi, M, Merayo-Lloves, J, et al. Analysis of the acute ophthalmic manifestations of the erythema multiforme/Stevens-Johnson syndrome/toxic epidermal necrolysis disease spectrum. Ophthalmology 1995; 102:1669. Lebargy, F, Wolkenstein, P, Gisselbrecht, M, et al. Pulmonary complications in toxic epidermal necrolysis: a prospective study. Intensive Care Med 1997; 23:1237. Kim, MJ, Lee, KY. Bronchiolitis obliterans in children with Stevens-Johnson syndrome: follow-up with high resolution Ct. Pediatr Radiol 1996; 26:22. Westly, ED, Weschler, HL. Toxic epidermal necrolysis. Granulocytic leucopenia as a prognostic indicator. Arch Dermatol 1984; 120:721. Jordan, MH, Lewis, MS, Jeng, JG, Rees, JM. Treatment of toxic epidermal necrolysis by burn units: another market or another threat? J Burn Care Rehabil 1991; 12:579. Rzany, B, Mockenhaupt, M, Baur, S, et al. Epidemiology of erythema exsudativum multiforme majus, Stevens-Johnson syndrome, and toxic epidermal necrolysis in Germany (1990-1992): structure and results of a population-based registry. J Clin Epidemiol 1996; 49:769. Rzany, B, Hering, O, Mockenhaupt, M, et al. Histopathological and epidemiological characteristics of patients with erythema exudativum multiforme major, Stevens-Johnson syndrome and toxic epidermal necrolysis. Br J Dermatol 1996; 135:6. Patterson, R, Miller, M, Kaplan, M, et al. Effectiveness of early therapy with corticosteroids in Stevens-Johnson syndrome: experience with 41 cases and a hypothesis regarding pathogenesis. Ann Allergy 1994; 73:27. Bagot, M, Charue, D, Heslan, M, et al. Impaired antigen presentation in toxic epidermal necrolysis. Arch Dermatol 1993; 129:721. Strom, BL, Carson, JL, Halpern, AC, et al. Using a claims database to investigate drug-induced Stevens-Johnson syndrome. Stat Med 1991; 10:565. Roujeau, JC, Guillaume, JC, Fabre, JP, et al. Toxic epidermal necrolysis (Lyell syndrome). Incidence and drug etiology in France, 1981-1985. Arch Dermatol 1990; 126:37. Chan, HL, Stern, RS, Arndt, KA, et al. The incidence of erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. A population-based study with particular reference to reactions caused by drugs among outpatients. Arch Dermatol 1990; 126:43. Roujeau, JC, Huynh, TN, Bracq, C, et al. Genetic susceptibility to toxic epidermal necrolysis. Genetic susceptibility to toxic epidermal necrolysis. Arch Dermatol 1987; 123:1171. Chung, WH, Hung, SI, Hong, HS, et al. Medical genetics: a marker for Stevens-Johnson syndrome. Nature 2004; 428:486. Hung, SI, Chung, WH, Liou, LB, et al. HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol. Proc Natl Acad Sci U S A 2005; 102:4134. Hung, SI, Chung, WH, Jee, SH, et al. Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions. Pharmacogenet Genomics 2006; 16:297. Shirato, S, Kagaya, F, Suzuki, Y, Joukou, S. Stevens-Johnson syndrome induced by methazolamide treatment. Arch Ophthalmol 1997; 115:550. www.fda.gov/medwatch/safety/2007/safety07.htm#carbamazepine (Accessed on December 12, 2007). Ueta, M, Sotozono, C, Inatomi, T, et al. Association of IL4R polymorphisms with Stevens-Johnson syndrome. J Allergy Clin Immunol 2007; 120:1457. Dietrich, A, Kawakubo, Y, Rzany, B, et al. Low N-acetylating capacity in patients with Stevens-Johnson syndrome and toxic epidermal necrolysis. Exp Dermatol 1995; 4:313. Sommers, KR, Kong, KM, Bui, DT, et al. Stevens-Johnson syndrome/toxic epidermal necrolysis in a patient receiving concurrent radiation and gemcitabine. Anticancer Drugs 2003; 14:659. Gravante, G, Delogu, D, Marianetti, M, et al. Toxic epidermal necrolysis and Steven-Johnson syndrome in oncologic patients. Eur Rev Med Pharmacol Sci 2007; 11:269. Schlienger, RG, Shapiro, LE, Shear, NH. Lamotrigine-induced severe cutaneous adverse reactions. Epilepsia 1998; 39 Suppl 7:S22. Mockenhaupt, M, Messenheimer, J, Tennis, P, Schlingmann, J. Risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in new users of antiepileptics. Neurology 2005; 64:1134. Chosidow, O, Bourgault, L, Roujeau, JC. Drug rashes. What are the targets of cell-mediated cytotoxicity?. Arch Dermatol 1994; 130:627. Fritsch, PO, Sidoroff, A. Drug-induced Stevens-Johnson syndrome/toxic epidermal necrolysis. Am J Clin Dermatol 2000; 1:349. Duncan, KO, Tigelaar, RE, Bolognia, JL. Stevens-Johnson syndrome limited to multiple sites of radiation therapy in a patient receiving phenobarbital. J Am Acad Dermatol 1999; 40:493. Wolkenstein, P, Carriere, V, Charue, D, et al. A slow acetylator genotype is a risk factor for sulphonamide-induced toxic epidermal necrolysis and Stevens-Johnson syndrome. Pharmacogenetics 1995; 5:255. Slatore, CG, Tilles, SA. Sulfonamide hypersensitivity. Immunol Allergy Clin North Am 2004; 24:477. Rotunda, A, Hirsch, RJ, Scheinfeld, N, Weinberg, JM. Severe cutaneous reactions associated with the use of human immunodeficiency virus medications. Acta Derm Venereol 2003; 83:1. Gruchalla, RS, Drug allergy. J Allergy Clin Immunol 2003; 111:S548. von Hebra, F. Atlas der Hautkrankheiten. Vienna: Kaiserliche Akademie der Wissenchaften Wien, 1866. Forman, R, Koren, G, Shear, NH. Erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis in children: a review of 10 years'experience. Drug Saf 2002; 25:965. Thomas, BA. The so-called Stevens-Johnson syndrome. Br Med J 1950; 4667:1393. Huff, JC, Weston, WL, Tonnesen, MG. Erythema multiforme: a critical review of characteristics, diagnostic criteria, and causes. J Am Acad Dermatol 1983; 8:763. Caproni, M, Torchia, D, Schincaglia, E, et al. Expression of cytokines and chemokine receptors in the cutaneous lesions of erythema multiforme and Stevens-Johnson syndrome/toxic epidermal necrolysis. Br J Dermatol 2006; 155:722. Quaglino, P, Caproni, M, Osella-Abate, S, et al. Serum interleukin-13 levels are increased in patients with Stevens-Johnson syndrome/ toxic epidermal necrolysis but not in those with erythema multiforme. Br J Dermatol 2007; :. Lyell, A. Requiem for toxic epidermal necrolysis. Br J Dermatol 1990; 122:837. Bennion, S, Fitzpatrick, JE. Serum from patients with toxic epidermal necrosis is directly toxic to cultured keratinocytes. (Poster). American Academy of Dermatology 45th Annual Meeting, New Orleans, Louisiana December 6-11th, 1986. Shear, NH, Spielberg, SP, Grant, DM, et al. Differences in metabolism of sulfonamides predisposing to idiosyncratic toxicity. Ann Intern Med 1986; 105:179. Viard, I, Wehrli, P, Bullani, R, et al. Inhibition of toxic epidermal necrolysis by blockade of CD95 with human intravenous immunoglobulin. Science 1998; 282:490. Abe, R, Shimizu, T, Shibaki, A, et al. Toxic epidermal necrolysis and Stevens-Johnson syndrome are induced by soluble Fas ligand. Am J Pathol 2003; 162:1515. Posadas, SJ, Padial, A, Torres, MJ, et al. Delayed reactions to drugs show levels of perforin, granzyme B, and Fas-L to be related to disease severity. J Allergy Clin Immunol 2002; 109:155. Foster, CS, Fong, LP, Azar, D, Kenyon, KR. Episodic conjunctival inflammation after Stevens-Johnson syndrome. Ophthalmology 1988; 95:453. Villada, G, Roujeau, JC, Clerici, T, Bourgault, I, Revuz, J. Immunopathology of toxic epidermal necrolysis. Keratinocytes, HLA-DR expression, Langerhans cells, and mononuclear cells: an immunopathologic study of five cases. Arch Dermatol 1992; 128:50. Akosa, AB, Elhag, AM. Toxic epidermal necrolysis. A study of the sweat glands. J Cutan Pathol 1995; 22:359. Chuang, YY, Huang, YC, Lin, TY. Toxic shock syndrome in children: epidemiology, pathogenesis, and management. Paediatr Drugs 2005; 7:11. Chesney, PJ, Davis, JP, Purdy, WK, et al. Clinical manifestations of toxic shock syndrome. JAMA 1981; 246:741. Patel, GK, Finlay, AY. Staphylococcal scalded skin syndrome: diagnosis and management. Am J Clin Dermatol 2003; 4:165. Dobson, CM, King, CM. Adult staphylococcal scalded skin syndrome: histological pitfalls and new diagnostic perspectives. Br J Dermatol 2003; 148:1068. Cribier, B, Piemont, Y, Grosshans, E. Staphylococcal scalded skin syndrome in adults. A clinical review illustrated with a new case. J Am Acad Dermatol 1994; 30:319. Honig, PJ, Gaisin, A, Buck, BE. Frozen section differentiation of drug-induced and staphylococcal-induced toxic epidermal necrolysis. J Pediatr 1978; 92:504. Amon, RB, Dimond, RL. Toxic epidermal necrolysis. Rapid differentiation between staphylococcal- and drug-induced disease. Arch Dermatol 1975; 111:1433. Schneck, J, Fagot, JP, Sekula, P, et al. Effects of treatments on the mortality of Stevens-Johnson syndrome and toxic epidermal necrolysis: A retrospective study on patients included in the prospective EuroSCAR Study. J Am Acad Dermatol 2008; 58:33. Garcia-Doval, I, LeCleach, L, Bocquet, H, et al. Toxic epidermal necrolysis and Stevens-Johnson syndrome: does early withdrawal of causative drugs decrease the risk of death?. Arch Dermatol 2000; 136:323. Sakellariou, G, Koukoudis, P, Karpouzas, J, et al. Plasma exchange (PE) treatment in drug-induced toxic epidermal necrolysis (TEN). Int J Artif Organs 1991; 14:634. French, LE, Trent, JT, Kerdel, FA. Use of intravenous immunoglobulin in toxic epidermal necrolysis and Stevens-Johnson syndrome: Our current understanding. Int Immunopharmacol 2006; 6:543. Bastuji-Garin, S, Fouchard, N, Bertocchi, M, et al. SCORTEN: a severity of illness score for toxic epidermal necrolysis. J Invest Dermatol 2000; 115:149. Trent, JT, Kirsner, RS, Romanelli, P, Kerdel, FA. Use of SCORTEN to accurately predict mortality in patients with toxic epidermal necrolysis in the United States. Arch Dermatol 2004; 140:890. Guégan, S, Bastuji-Garin, S, Poszepczynska-Guigné, E, et al. Performance of the SCORTEN during the first five days of hospitalization to predict the prognosis of epidermal necrolysis. J Invest Dermatol 2006; 126:272. Ringheanu, M, Laude, TA. Toxic epidermal necrolysis in children--an update. Clin Pediatr (Phila) 2000; 39:687. Sheridan, RL, Weber, JM, Schulz, JT, et al. Management of severe toxic epidermal necrolysis in children. J Burn Care Rehabil 1999; 20:497. Prins, C, Vittorio, C, Padilla, RS, et al. Effect of high dose intravenous immunoglobulin therapy in Stevens-Johnson syndrome: a retrospective, multicenter study. Dermatology 2003; 207:96. Faye, O, Roujeau, JC. Treatment of epidermal necrolysis with high-dose intravenous immunoglobulins (IV Ig): clinical experience to date. Drugs 2005; 65:2085. Kamada, N, Kinoshita, K, Togawa, Y, et al. Chronic pulmonary complications associated with toxic epidermal necrolysis: report of a severe case with anti-Ro/SS-A and a review of the published work. J Dermatol 2006; 33:616. Oplatek, A, Brown, K, Sen, S, et al. Long-term follow-up of patients treated for toxic epidermal necrolysis. J Burn Care Res 2006; 27:26. Imahara, SD, Holmes JH, 4th, Heimbach, DM, et al. SCORTEN overestimates mortality in the setting of a standardized treatment protocol. J Burn Care Res 2006; 27:270. Palmieri, TL, Greenhalgh, DG, Saffle, JR, et al. A multicenter review of toxic epidermal necrolysis treated in U.S. burn centers at the end of the twentieth century. J Burn Care Rehabil 2002; 23:87. Dalli, RL, Kumar, R, Kennedy, P, et al. Toxic epidermal necrolysis/Stevens-Johnson syndrome: current trends in management. ANZ J Surg 2007; 77:671. Dunn, K, Edwards-Jones, V. The role of Acticoat with nanocrystalline silver in the management of burns. Burns 2004; 30 Suppl 1:S1. Pruitt, BA Jr. Burn treatment for the unburned. JAMA 1987; 257:2207. Meneux, E, Wolkenstein, P, Haddad, B, et al. Vulvovaginal involvement in toxic epidermal necrolysis: a retrospective study of 40 cases. Obstet Gynecol 1998; 91:283. Tompkins, RG, Burke, JF. Burn therapy 1985: acute management. Intensive Care Med 1986; 12:289. Khoo, AK, Foo, CL. Toxic epidermal necrolysis in a burns center: a 6-year review. Burns 1996; 22:275. Khalili, B, Bahna, SL. Pathogenesis and recent therapeutic trends in Stevens-Johnson syndrome and toxic epidermal necrolysis. Ann Allergy Asthma Immunol 2006; 97:272. Hynes, AY, Kafkala, C, Daoud, YJ, Foster, CS. Controversy in the use of high-dose systemic steroids in the acute care of patients with Stevens-Johnson syndrome. Int Ophthalmol Clin 2005; 45:25. Tripathi, A, Ditto, AM, Grammer, LC, et al. Corticosteroid therapy in an additional 13 cases of Stevens-Johnson syndrome: a total series of 67 cases. Allergy Asthma Proc 2000; 21:101. Kakourou, T, Klontza, D, Soteropoulou, F, Kattamis, C. Corticosteroid treatment of erythema multiforme major (Stevens-Johnson syndrome) in children. Eur J Pediatr 1997; 156:90. Kim, PS, Goldfarb IW, Gaisford, JC, et al. Stevens-Johnson syndrome and toxic epidermal necrolysis: a pathophysiologic review with recommendations for a treatment protocol. J Burn Care Rehabil 1983; 4:91. Halebian, PH, Corder, VJ, Madden MR, et al. Improved burn center survival of patients with toxic epidermal necrolysis managed without corticosteroids. Ann Surg 1986; 204:503. Kelemen JJ, 3rd, Cioffi, WG, McManus, WF, et al. Burn center care for patients with toxic epidermal necrolysis. J Am Coll Surg 1995; 180:273. Herndon, DN. Toxic epidermal necrolysis: a systemic and dermatologic disorder best treated with standard treatment protocols in burn intensive care units without the prolonged use of corticosteroids. J Am Coll Surg 1995; 180:340. Chave, TA, Mortimer, NJ, Sladden, MJ, et al. Toxic epidermal necrolysis: current evidence, practicalmanagement and future directions. Br J Dermatol 2005; 153:241. Metry, DW, Jung, P, Levy, ML. Use of intravenous immunoglobulin in children with Stevens-Johnson syndrome and toxic epidermal necrolysis. Pediatrics 2003; 112:1430. Morici, MV, Galen, WK, Shetty, AK, et al. Intravenous immunoglobulin therapy for children with Stevens-Johnson syndrome. J Rheumatol 2000; 27:2494. Campione, E, Marulli, GC, Carrozzo, AM, et al. High-dose intravenous immunoglobulin for severe drug reactions: efficacy in toxic epidermal necrolysis. Acta Derm Venereol 2003; 83:430. Trent JT, Kirsner RS, Romanelli P, Kerdel FA. Analysis of intravenous immunoglobulin for the treatment of toxic epidermal necrolysis using SCORTEN: The University of Miami Experience. Arch Dermatol 2003; 139:39. Prins, C, Kerdel, FA, Padilla, RS, et al. Treatment of toxic epidermal necrolysis with high-dose intravenous immunoglobulins: multicenter retrospective analysis of 48 consecutive cases. Arch Dermatol 2003; 139:26. Tristani-Firouzi, P, Petersen, MJ, Saffle, JR, et al. Treatment of toxic epidermal necrolysis with intravenous immunoglobulin in children. J Am Acad Dermatol 2002; 47:548. Stella, M, Cassano, P, Bollero, D, et al. Toxic epidermal necrolysis treated with intravenous high-dose immunoglobulins: our experience. Dermatology 2001; 203:45. Egan, CA, Grant, WJ, Morris, SE, et al. Plasmapheresis as anadjunct treatment in toxic epidermal necrolysis. J Am Acad Dermatol 1999; 40:458. Kamanabroo, D, Schmitz-Landgraf, W, Czarnetzki, BM. Plasmapheresis in severe drug-induced toxic epidermal necrolysis. Arch Dermatol 1985; 121:1548. Bamichas, G, Natse, T, Christidou, F, et al. Plasma exchange in patients with toxic epidermal necrolysis. Ther Apher 2002; 6:225. Chaidemenos, GC, Chrysomallis, F, Sombolos, K, et al. Plasmapheresis in toxic epidermal necrolysis. Int J Dermatol 1997; 36:218. Furubacke, A, Berlin, G, Anderson, C, Sjoberg, F. Lack of significant treatment effect of plasma exchange in the treatment of drug-induced toxic epidermal necrolysis?. Intensive Care Med 1999; 25:1307. Wolkenstein, P, Latarjet, J, Roujeau, JC, et al. Randomised comparison of thalidomide versus placebo in toxic epidermal necrolysis. Lancet 1998; 352:1586.