Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis
CADRs are classified by the WHO as severe when they are life-threatening, require hospitalization, or lead to permanent disability. Stevens-Johnson Syndrome (SJS) (Fig. 107-4) and toxic epidermal necrolysis (TEN) (Fig. 107-5) are rare, serious CADRs, with calculated incidences of 1 to 6 and 0.4 to 1.2 cases per million person-years, respectively.48 SJS and TEN are histopathologically identical diseases that are differentiated by the extent of epidermal detachment: less than 10% in SJS, 10% to 29% in transitional SJS/TEN, and greater than 30% in TEN. In addition to the hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms, SJS and TEN constitute the major groups of severe CADRs49 (Table 107-7).
Table 107–7. Classification of Severe Cutaneous Adverse Drug Reactions ||Download (.pdf)
Table 107–7. Classification of Severe Cutaneous Adverse Drug Reactions
|Erosions||Several sites||Several sites||Mouth and lips|
|Detachment of epidermis||Yes||Yes||No|
|Respiratory tract||Bronchial erosions/ARDS||Bronchial erosions/ARDS||Interstitial pneumonitis|
|Liver||Hepatitis 10%||Hepatitis 10%||Hepatitis 60%|
|Lymph node enlarged||No||No||Usual|
Stevens-Johnson syndrome/toxic epidermal necrolysis. Erosive involvement of lips and oral mucosa. (Courtesy Dr. Iris K. Aronson collection.)
Toxic epidermal necrolysis: >30% of the body surface area involved. Necrotic epidermis sloughs, revealing moist, bright red dermis. (Courtesy Dr. Iris K. Aronson collection.)
Fever, sore throat, cough, and burning eyes may precede painful skin eruptions resembling burns for 1 to 3 days. Lesions usually appear within 3 weeks of drug administration and begin as irregularly defined, painful erythematous macules with purpuric centers that tend to coalesce. Within a few hours or days, blisters appear and epidermal detachment extends over the body. Lesions in the mucosae are characteristic, occasionally preceding skin lesions by several days. However, initial presentation of SJS and TEN may be very similar to less serious CADR, that is, a maculopapular rash. Involvement of the epithelium of the trachea, bronchi, or gastrointestinal tract increases morbidity rate.
TEN is the most severe form of drug eruption known, with a mortality rate of approximately 30%.50 Mortality is mainly a result of respiratory complications or sepsis. Prognosis is influenced by age (>60 years), the presence of comorbidities, sepsis, and extent of body surface area involved.9,50,51 TEN is caused almost exclusively by medications, although it may be a manifestation of severe acute GVHD.52 The implicated medication is usually started within 3 weeks of the eruption. An increased risk for SJS and TEN has been found with the use of the following drugs: anticonvulsants (phenytoin, valproic acid, phenobarbital, and carbamazepine), antibiotics (sulfonamides and aminopenicillins), NSAIDs (oxicam derivatives), chlormezanone, allopurinol, and, interestingly, corticosteroids.48 Drugs with long-half lives, known to be frequent culprits, have been associated with higher fatality rates.53 TEN occurs more frequently in HIV-infected individuals, especially those receiving sulfonamides and/or nevirapine. This may be related to the concurrence of the glutathione S-transferase M1 null and the slow acetylator genotypes.54 Precipitation of SJS and TEN by infectious agents is much less common. Infection with Mycoplasma pneumoniae is the best documented55 (Table 107-8).
Table 107–8. Factors Associated with SJS and TEN ||Download (.pdf)
Table 107–8. Factors Associated with SJS and TEN
|Drugs||Infections (isolated cases)|
| • Sulfonamides
| • Aminopenicillins
| • Cephalosporins
| • Quinolones
| • Phenobarbital||Yersiniosis|
| • Phenytoin||Adenovirus|
| • Valproic acid||Gram-negative septicemia|
| • Carbamazepine|
| • Proxicam|
| • Tenoxicam|
The pathogenesis of SJS and TEN remains unclear. Humoral and cell-mediated cytotoxicities, drug metabolites, and apoptotic mechanisms have been implicated, with inconsistent data. Experimental data suggest that activation of Fas (CD95) through its ligand, FasL (CD95L), results in caspase-mediated keratinocyte apoptosis, possibly an important pathophysiologic mechanism in TEN.56 Fas (CD95) is a cell surface receptor expressed on keratinocytes and most cells and can be activated by FasL, which is expressed by natural killer cells and activated T lymphocytes.57 FasL can also exist in a soluble form (sFasL), capable of inducing apoptosis.58 Soluble FasL results from metalloproteinase-mediated cleavage of cell surface FasL and stimulation of peripheral blood mononuclear cells by an offending drug results in upregulated sFasL expression. Sera from SJS and TEN patients can induce Fas-FasL–mediated keratinocyte apoptosis in vitro and contain elevated concentrations of sFasL when compared with control patients.59
Initially, patients develop pain, tenderness, or a burning sensation in the skin. These symptoms often begin abruptly and are associated with fever and general malaise. Over the next 1 to 3 days, ill-defined erythematous macules or a diffuse erythema develop over the trunk and extremities. As the red areas enlarge, central dusky necrotic sites develop with subsequent bullae formation. Bullae result from edema occurring beneath the necrotic epidermis. As the disease progresses, sheets of full-thickness epidermis slough off, revealing dark red, moist dermis (resembling severe second-degree burns). The Nikolsky sign (separation of the skin with lateral traction) is positive and an important diagnostic clue.
Mucous membrane involvement occurs in 85% to 95% of patients and may be the presenting sign.60 The oropharynx and conjunctivae are most affected, resulting in severe erosions and pain. Keratitis, ocular erosions, and symblepharon may result in blindness. Dysuria is a sign of urethral involvement. Erosions in the lower respiratory tract and the intestine have also been described.61
Hematologic studies may show anemia, eosinophilia, neutropenia, lymphopenia, thrombocytopenia, and an elevated erythrocyte sedimentation rate. Lymphopenia is seen early in the course of disease in up to 90% of cases and is a result of depletion of CD4 T lymphocytes. Neutropenia is seen in up to 30% of cases and carries a poor prognosis.62 Serum chemistries show evidence of extensive fluid and protein loss, hypoalbuminemia, and hypocalcemia.63 Taking a small piece of tender erythematous skin for frozen section may help make a rapid diagnosis. This will show the level of the separation within the skin and, in TEN, reveals full-thickness necrosis of the epidermis, with an intact dermis with little or no inflammation. Alternatively, a skin biopsy in an area immediately adjacent to and overlapping a blister may be sent for routine histology. The irregular presence of necrotic keratinocytes along the dermal-epidermal junction is a hallmark of early lesions, whereas diffuse epidermal necrosis with subepidermal clefting is present in late lesions. There is minimal dermal inflammation. Immunofluorescence findings are nondescript, with no significant complement or antibody deposition, suggesting that cell-mediated cytotoxicity is an important mechanism.
The clinical differential diagnosis includes staphylococcal scalded skin syndrome, acute GVHD, scarlet fever, erythema multiforme, and pemphigus vulgaris. In all these cases, full-thickness epidermal necrosis is rare (except in GVHD, in which epidermal necrosis is accompanied by an abundant lymphocytic infiltrate).
Erythema multiforme (previously referred to as erythema multiforme minor), is an acute, self-limited reaction characterized by asymptomatic, annular erythematous, or urticarial plaques with central areas of blistering and necrosis, resulting in the so-called target lesions. Lesions usually develop on the extensor surfaces of the extremities and mucosae and cover less than 10% of the body surface area. Outbreaks last for 1 to 4 weeks. Relapses are frequent. It is associated with recurrent herpes simplex virus infections in the great majority of cases and with M. pneumoniae infection in a smaller subset.
Treatment for SJS and TEN includes pain management and prompt withdrawal of any agents that are not essential for the maintenance of life. This latter has been shown to decrease mortality rate in TEN by about 30% per day, despite some progression of the mucocutaneous involvement.64 Fluid resuscitation, treatment of infections, and meticulous skin and eye care are most appropriately managed in an isolation room in a burn unit, where the staff is trained in topical wound and skin care. Severe airway involvement may necessitate intubation and ventilation. An ophthalmologic consultation should be obtained to assess eye involvement, which is usually treated with topical antibiotics and lubricants. If symblepharon occurs, early lysis must be performed. Fluid and electrolyte imbalances are related to the percentage of body surface area involved; however, fluid loss tends to be less than in severe burn patients. Topical therapy includes gentle debridement of necrotic skin followed by the application of nonadherent dressings to the areas of skin erosion, a wrapping of a thin silver-impregnated dressing, and an outer linen covering to hold all in place. Antibiotic ointments are widely used, although their value is unproved. It is important to avoid the sulfonamide derivatives (silver sulfadiazine cream, topical mafenide acetate, and ophthalmic sodium sulfacetamide) because of potential significant absorption and the possibility of inducing SJS.65 A variety of other dressings may be used to decrease fluid loss and pain and promote wound healing, and may be useful adjuncts to therapy. These include porcine xenografts66 and synthetic dressings such as Omniderm, OpSite, Vigilon, Mepitel, and Biobrane. Systemic antibiotics should be used only when there is documented infection or neutropenia.
The use of corticosteroids and immunosuppressive agents in the treatment of TEN is controversial. The rationale for such an approach is based on the assumption that TEN is an immune-mediated event. There are no case-controlled studies supporting the use of corticosteroids; however, several case reports have advocated their use.67,68 In most cases in which steroids were found effective, they were started very early in the course of the disease. More recent literature has indicated a higher mortality rate, increased time to recovery, and increased length of hospital stay in patients treated with systemic corticosteroids.69,70 Patients undergoing long-term glucocorticoid therapy who develop TEN may have a delay in onset, but the severity of disease is unaffected.71 Based on this information, corticosteroids should not be used routinely in TEN and should only be considered in patients who present early in the course of disease. Intravenous immunoglobulin therapy in TEN aims to decrease Fas-mediated keratinocyte apoptosis by sequestering Fas available for binding to CD95. Four nonrandomized, uncontrolled studies have shown that large-dose intravenous immunoglobulin decreases mortality rate and progression of TEN,72–75 whereas one prospective study showed no benefit.49 Hence, there is no consensus, and controlled, randomized trials are needed. The use of plasmapheresis and immunosuppressive drugs remains controversial due to the lack of strong clinical data.
Hypersensitivity Syndrome/Drug Reaction with Eosinophilia and Systemic Symptoms
A severe hypersensitivity syndrome consisting of fever, rash, lymphadenopathy, and variable organ (usually liver) involvement may appear after several weeks of drug ingestion. When associated with eosinophilia and systemic symptoms, the term drug reaction with eosinophilia and systemic symptoms is used (see Table 107-7). The most common precipitants are the aromatic anticonvulsants (e.g., phenytoin, phenobarbital, and carbamazepine). Faulty metabolism of these drugs is thought to precipitate the disease process, which has also been associated with the initiation or reactivation of infection with human herpes virus type 6.76 There is a 75% incidence of cross-reactivity between these anticonvulsants; therefore, once one of these drugs has caused a reaction, further exposure to any of them should not be attempted. Other medications known to cause this syndrome include dapsone, sulfonamides, allopurinol and minocycline.77
The cutaneous component of this ADR varies from a maculopapular eruption to frank erythroderma. Discontinuation of the offending agent and the administration of moderate to large doses of systemic steroids are the treatments of choice and have shown benefit in multiple case reports. Supportive care, similar to that for SJS and TEN, in an ICU or burn unit, must be instituted when life-threatening visceral manifestations are present, whereas topical steroids alone may be sufficient for mild disease.