A 58-year-old man presents to the ED with a rash. He was seen three days prior for a “spider bite,” and was started empirically on clindamycin for suspected community acquired-MRSA.
Two days later he developed a diffuse non-puritic erythematous rash, and his internist switched him to ciprofloxacin. Overnight the patient developed skin blistering. He has had malaise and chills for two days with no fever and no mouth or eye dryness. What is your diagnosis? See p. 20.
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are characterized by a severe mucocutaneous reaction. The distinction between TEN and SJS primarily is based on the severity of the reaction and the percentage of body surface area involved.
Both are characterized by skin involvement one to three days following an abrupt flu-like prodrome of fever and malaise. SJS, however, is a less severe reaction; erythmatous lesions evolve quickly to epidermal necrosis, and sloughing is limited to less than 10 percent of the body surface area. (Arch Dermatol 1993;129:92.)
Mucous membranes are affected in 92 percent or more of patients, typically at two or three distinct sites, most commonly the oropharynx, the eyes, and the genitalia. (Ann Allergy Asthma Immunol 2005;94:419.)
TEN, or Lyell's syndrome, has a similar presentation to SJS, but half of cases begin as painful diffuse skin erythema versus discrete lesions. This quickly progresses to full thickness epidermal necrosis from massive keratinocyte apoptosis and desquamation of more than 30 percent of the body surface area with mucosal involvement seen in nearly all cases. (Arch Dermatol 1975;111:1135.) Interestingly, even in severe cases, the scalp is generally not involved. (Clin Dermatol 1993;11:493.)
Classically patients have separation of large sheets at the dermal-epidermal junction, mimicking thermal burn injury. Progression of skin lesions is variable. One in seven patients will have massive necrolysis of the entire skin surface within 24 hours, but lesions typically erupt over a two- to 15-day period. (J Am Acad Dermatol 2007;56:181.) Inflammation of internal mucosal surfaces, including the respiratory (up to 30 percent of cases [Dermatol Clin 2007;25(2):245]) and gastrointestinal tracts, occurs frequently. (J Dermatol 1998;25:533.)
SJS largely occurs in children and adolescents; TEN occurs in patients of all ages. (Brit J Dermatol 2005;152:150.) SJS and TEN combined result in approximately two cases per million people per year (J Clin Epidemiol 1996;49:769) with SJS cases outnumbering TEN by three to one. (Brit J Dermatol 1996;135:6.) Patients infected with human immunodeficiency virus are affected more frequently.
The exact pathophysiological mechanism of these diseases is not well understood. (One theory is that they are the result of a T-cell mediated phenomenon.) Controversy exists about whether these are independent diseases or part of the same continuum. Several classification systems exist, but the most widely accepted is by Bastuji-Garin, et al (Arch Dermatol 1993;129:92), which divides the spectrum into five categories:
- ▪ Bullous erythema multiforme: Epidermal detachment involving less than 10 percent body surface coupled with localized typical targets or raised atypical targets.
- ▪ SJS: Epidermal detachment of less than 10 percent body surface in association with widespread erythematous or purpuric macules or flat atypical targets.
- ▪ SJS/TEN overlap: Epidermal detachment of 10 to 30 percent body surface plus widespread purpuric macules or flat atypical targets.
- ▪ TEN with spots: Epidermal detachment of more than 30 percent body surface coupled with widespread purpuric macules or flat atypical targets.
- ▪ TEN without spots: Large sheets of epidermal detachment involving more than 10 percent body surface without purpuric macules or target lesions. (J Am Acad Dermatol 2007;56:181.)
SJS and TEN virtually always result from a medication reaction, typically occurring within eight weeks of therapy onset. Less than five percent of patients report no history of medication use. More than 220 medications have been implicated, but the major offenders are sulfonamide antibiotics (2.6 per 100,000 exposures [Dermatol Clin 2007;25(2):245]), anticonvulsants, beta-lactam antibiotics, abacavir, nonsteroidal anti-inflammatory drugs, tetracyclines, and quinolones (especially ciprofloxacin). (J Am Acad Dermatol 2007;56:181.) Infections, vaccinations, autoimmune diseases, chemical exposures, herbal medicines, and foods also have been identified as precipitants.
Possible risk factors for SJS and TEN include a genetic predisposition secondary to certain HLA-types, “slow acetylation” metabolism, and immuncompromised individuals (malignancy, HIV).
Patients will likely present to the ED complaining of fever and a rash with classic skin lesions characterized by erythematous ill-shaped macules often with a purpuric center, which progress to vesicles and flaccid bulla. Pressure on bulla and vesicles causes lateral spreading of the lesion with easy separation of the epidermis from the basal layer, also known as Nikolsky's sign. Lesions may be painful, particularly with TEN, or associated with a burning sensation.
Some may present with diffuse skin erythema, urticaria, tongue swelling, or mucous membrane crusting or erosions. Conjunctival lesions have been reported in 85 percent of patients (Arch Dermatol 1987;123:1160), with involvement ranging from scleral injection to scarring between the conjunctiva and sclera. Patients may complain of photophobia, eye dryness, and a foreign body sensation.
SJS and TEN are clinical diagnoses verified histologically. No diagnostic laboratory test exists, but anemia and lymphopenia are common. (Clin Dermatol 1998;16:399.)
The differential diagnosis of SJS and TEN include Staphylococcal scalded skin syndrome, toxic shock syndrome, drug-induced pemphigoid, acute generalized exanthematous pustulosis, erythematous drug eruptions, pustular drug eruptions, acute graft-versus-host disease, Kawasaki disease, and phototoxic eruptions.
Supportive care is the mainstay of treatment. Immediate removal of the offending agent or medication, if known, is critical. Therapeutic interventions should include analgesia and follow standard burn therapy and fluid resuscitation protocols. The role of steroids, intravenous gammaglobulin, cylophosphamide/cyclosporine, TNF-alpha inhibitors, and plasmapheresis remain controversial with more research needed.
Patients should be transferred to a critical care burn unit. The rapidity with which a patient is admitted to a burn unit is directly proportional to survival. (J Am Acad Dermatol 2007;56:181.) Early ophthalmologic consultation should be obtained to identify potential ocular involvement.
Patients are particularly susceptible to bacteremia and sepsis, which are the leading cause of mortality. The overall mortality rate for SJS has been reported to be as low as one to three percent. (Ann Allergy Asthma Immunol 2005;94:419.) Unfortunately, TEN has a much worse prognosis with a mortality rate of approximately 30 percent. The SCORTEN score can be used to predict mortality. (J Am Acad Dermatol 2007;56:181.) Prognosis tends to be worse for those over 40 and with significant cutaneous involvement.
For those who survive, skin scarring, hyper/hypopigmentation, abnormal nail growth, alopecia, pulmonary complications, and vaginal, urethral, and anal strictures can occur. The most serious potential long-term complications are ocular, including synechiae, corneal ulcers, Meibomian gland dysfunction, panopthalmitis, and blindness. (Ophthalmology 2005;112:904.)