Stevens-Johnson syndrome Introduction

Background First described in 1922, Stevens-Johnson syndrome (SJS) is an immune-complex–mediated hypersensitivity complex that is a severe expression of erythema multiforme. It is known by some as erythema multiforme major, but disagreement exists in the literature. Most authors and experts consider Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) different manifestations of the same disease. For that reason, many refer to the entity as SJS/TEN. SJS typically involves the skin and the mucous membranes.

While minor presentations may occur, significant involvement of oral, nasal, eye, vaginal, urethral, GI, and lower respiratory tract mucous membranes may develop in the course of the illness. GI and respiratory involvement may progress to necrosis. Stevens Johnson Syndrome (SJS) is a serious systemic disorder with the potential for severe morbidity and even death. Missed diagnosis is common.

 

Although several classification schemes have been reported, the simplest breaks the disease down as follows:

1 • Stevens-Johnson syndrome - A "minor form of TEN," with less than 10% body surface area (BSA) detachment

• Overlapping Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) - Detachment of 10-30% BSA

• Toxic epidermal necrolysis - Detachment of more than 30% BSA Pathophysiology Stevens-Johnson syndrome is an immune-complex–mediated hypersensitivity disorder that may be caused by many drugs, viral infections, and malignancies. Cocaine recently has been added to the list of drugs capable of producing the syndrome.

Additionally, the antidepressant mirtazapine and tumor necrosis factor (TNF) – alpha antagonists infliximab, etanercept, and adalimumab have been reported as causes.

In up to half of cases, no specific etiology has been identified. Although not currently relevant to the practice of emergency medicine, research into the pathophysiology of SJS/TEN may soon allow for the development of tests to aid in the diagnosis as well as to identify those at risk. Pathologically, cell death results causing separation of the epidermis from the dermis. The death receptor, Fas, and its ligand, FasL, have been linked to the process, as has TNF-alpha.

Researchers have found increased soluble FasL levels in the sera of patients with SJS/TEN before skin detachment or inset of mucosal lesions.

2 Others have also linked inflammatory cytokines to the pathogenesis. A "killer effector molecule" has been identified that may play a role in the activation of cytotoxic lymphocytes.

3 There is also strong evidence for a genetic predisposition to severe cutaneous adverse drug reactions such as SJS. The US FDA and Health Canada advise screening for a human leukocyte antigen, HLA-B*1502, in patients of southeastern Asian ethnicity before starting treatment with carbamazepine. (The risk is much lower in other ethnic populations, making screening impractical in them).

Another HLA antigen, HLA-B*5801, confers a risk of allopurinol-related reactions. Pretreatment screening is not readily available.

4 Mortality/Morbidity • Mortality is determined primarily by the extent of skin sloughing. When BSA sloughing is less than 10%, the mortality rate is approximately 1-5%.

However, when more than 30% BSA sloughing is present, the mortality rate is between 25% and 35%, and may be as high as 50%.5,4 Bacteremia/sepsis may also contribute to mortality.

6 • See SCORTEN for a more complete discussion of severity of illness and mortality.

• Lesions may continue to erupt in crops for as long as 2-3 weeks. Mucosal pseudomembrane formation may lead to mucosal scarring and loss of function of the involved organ system. Esophageal strictures may occur when extensive involvement of the esophagus exists. Mucosal shedding in the tracheobronchial tree may lead to respiratory failure.

• Ocular sequelae may include corneal ulceration and anterior uveitis. Blindness may develop secondary to severe keratitis or panophthalmitis in 3-10% of patients. Vaginal stenosis and penile scarring have been reported. Renal complications are rare.

Race A Caucasian predominance has been reported. Sex In Stevens-Johnson syndrome, the male-to-female ratio is 2:1.

Age Most patients are in the second to fourth decade of life; however, cases have been reported in children as young as 3 months. Clinical History

• Typically, the disease process begins with a nonspecific upper respiratory tract infection.

o This usually is part of a 1- to 14-day prodrome during which fever, sore throat, chills, headache, and malaise may be present.

o Vomiting and diarrhea are occasionally noted as part of the prodrome.

• Mucocutaneous lesions develop abruptly. Clusters of outbreaks last from 2-4 weeks. The lesions are typically nonpruritic.

• A history of fever or localized worsening should suggest a superimposed infection; however, fever has been reported to occur in up to 85% of cases.

• Involvement of oral and/or mucous membranes may be severe enough that patients may not be able to eat or drink.

• Patients with genitourinary involvement may complain of dysuria or an inability to void.

• A history of a previous outbreak of Stevens-Johnson syndrome (SJS) or of erythema multiforme may be elicited. Recurrences may occur if the responsible agent is not eliminated or if the patient is reexposed.

• Typical symptoms are as follows: o Cough productive of a thick purulent sputum o Headache o Malaise o Arthralgia Physical

• The rash can begin as macules that develop into papules, vesicles, bullae, urticarial plaques, or confluent erythema.

o The center of these lesions may be vesicular, purpuric, or necrotic.

o The typical lesion has the appearance of a target. The target is considered pathognomonic. However, in contrast to the typical erythema multiforme lesions, these lesions have only two zones of color. The core may be vesicular, purpuric, or necrotic; that zone is surrounded by macular erythema. Some have called these targetoid lesions.

o Lesions may become bullous and later rupture, leaving denuded skin. The skin becomes susceptible to secondary infection. Extensive sloughing is shown in the image below.

o Note extensive sloughing of epidermis from Stevens-Johnson syndrome. Courtesy of David F. Butler, MD.

o Urticarial lesions typically are not pruritic. o Infection may be responsible for the scarring associated with morbidity.

o Although lesions may occur anywhere, the palms, soles, dorsum of the hands, and extensor surfaces are most commonly affected. Desquamation on the foot is shown in the image below.

o Sheetlike desquamation on the foot in a patient with toxic epidermal necrolysis. Courtesy of Robert Schwartz, MD.

o The rash may be confined to any one area of the body, most often the trunk.

o Mucosal involvement may include erythema, edema, sloughing, blistering, ulceration, and necrosis. An example of this type of involvement is shown in the image below.

o Hemorrhagic crusting of the mucous membranes in toxic epidermal necrolysis. Similar lesions are seen in Stevens-Johnson syndrome. Courtesy of Robert Schwartz, MD.

o Although some have suggested the possibility of Stevens-Johnson syndrome (SJS) without skin lesions, most believe that mucosal lesions alone are not enough to establish the diagnosis. Some are now calling cases without skin lesions "atypical" or "incomplete."7 This group of authors suggested that the combination of urethritis, conjunctivitis, and stomatitis made the diagnosis of SJS in a patient with Mycoplasma pneumoniae -induced signs and symptoms. • The following signs may be noted on examination:

o Fever

o Orthostasis

o Tachycardia

o Hypotension

o Altered level of consciousness

o Epistaxis

o Conjunctivitis

o Corneal ulcerations

o Erosive vulvovaginitis or balanitis

o Seizures, coma

Causes

• Drugs and malignancies are most often implicated as the etiology in adults and elderly persons.

• Pediatric cases are related more often to infections than to malignancy or a reaction to a drug.

• Oxicam NSAIDs and sulfonamides are most often implicated in western nations. In Southeast Asia, allopurinol is most common.4

• A medication such as sulfa, phenytoin, or penicillin had previously been prescribed to more than two thirds of all patients with Stevens-Johnson syndrome (SJS). The anticonvulsant oxcarbazepine (Trileptal) has also been implicated.

Hallgren et al reported ciprofloxacin-induced Stevens-Johnson syndrome in young patients in Sweden and commented on several others.

8 Metry et al reported Stevens-Johnson syndrome in 2 HIV patients treated with nevirapine and mentioned one other in the literature.

9 The authors speculated that the problem may extend to other non-nucleoside reverse transcriptase inhibitors.

9 Indinavir has been mentioned.

• More than half of the patients with Stevens-Johnson syndrome report a recent upper respiratory tract infection.

• The 4 etiologic categories are (1) infectious, (2) drug-induced, (3) malignancy-related, and (4) idiopathic. o Viral diseases that have been reported include herpes simplex virus (HSV), AIDS, coxsackie viral infections, influenza, hepatitis, mumps, lymphogranuloma venereum (LGV), rickettsial infections, and variola. o Bacterial etiologies include group A beta streptococci, diphtheria, Brucellosis, mycobacteria, Mycoplasma pneumoniae, tularemia, and typhoid.

An "incomplete" case was recently reported after Mycoplasma pneumoniae infection.7,10 o Coccidioidomycosis, dermatophytosis, and histoplasmosis are the fungal possibilities.

o Malaria and trichomoniasis have been reported as protozoal causes. o In children, Epstein-Barr virus and enteroviruses have been identified.

o Antibiotic etiologies include penicillins and sulfa antibiotics. Anticonvulsants including phenytoin, carbamazepine, valproic acid, lamotrigine, and barbiturates have been implicated.

Mockenhapupt et al stressed that most anticonvulsant-induced SJS occurs in the first 60 days of use.11 In late 2002, the US Food and Drug Administration (FDA) and the manufacturer Pharmacia noted that Stevens-Johnson syndrome (SJS) had been reported in patients taking the cyclooxygenase-2 (COX-2) inhibitor valdecoxib.

In 2007, the US FDA reported SJS/TEN in patients taking modafinil (Provigil). Allopurinol has recently been implicated as the most common cause in Europe and Israel.12

o The most recent additions to possible drug-induced cases include the antidepressant mirtazapine13 and the TNF-alpha antagonists infliximab, etanercept, and adalimumab14 .

o Various carcinomas and lymphomas have been associated. o Stevens-Johnson syndrome (SJS) is idiopathic in 25-50% of cases. Treatment Prehospital Care Paramedics should recognize the presence of severe fluid loss and should treat patients with Stevens-Johnson syndrome (SJS) as they would patients with thermal burns. Emergency Department Care Most patients present early and prior to obvious signs of hemodynamic compromise. The single most important role for the ED physician is to detect Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) early and initiate the appropriate ED and inpatient management. Withdrawal of the suspected offending agent is critically important. Timing of withdrawal has been linked to outcome.

• Care in the ED must be directed to fluid replacement and electrolyte correction.

• Skin lesions are treated as burns.

• Patients with SJS/TEN should be treated with special attention to airway and hemodynamic stability, fluid status, wound/burn care, and pain control.

• Treatment is primarily supportive and symptomatic. Some have advocated corticosteroids, cyclophosphamide, plasmapheresis, hemodialysis, and immunoglobulin.

o Manage oral lesions with mouthwashes.

o Topical anesthetics are useful in reducing pain and allowing the patient to take in fluids. o Areas of denuded skin must be covered with compresses of saline or Burow solution.

o Address tetanus prophylaxis.

• Underlying diseases and secondary infections must be identified and treated. Offending drugs must be stopped.

• The use of systemic steroids remains controversial. Some authors believe that they are contraindicated, especially because there may be some question about the diagnosis. Patients with infection-induced erythema multiforme do worse when steroids are given. (Note that the differentiation between SJS and EM should be possible even in the acute stage.)15

Treatment with systemic steroids has been associated with an increased prevalence of complications. The ophthalmology literature contains several papers that advocate systemic and topical steroids to minimize ocular morbidity.16,17 Authors have cited sight salvage when pulse steroid therapy has been given.15,17

Others have concluded that IV steroids and immunoglobulin treatment do not improve outcome.18

The ophthalmology literature also mentions concurrent coverage of the involved eye(s) with amniotic membrane.19

• In a large European study designed to evaluate the efficacy of various treatments, the EuroSCAR Study "found no sufficient evidence of a benefit for any specific treatment."20

The group looked at mortality in patients treated with IV immunoglobulins and corticosteroids. However, in a letter to the editor, Pehr disagreed with the findings in the EuroSCAR study citing inadequate doses of IVIG and corticosteroids in that study.21

Consultations Consultants may help establish the diagnosis and direct inpatient care. A dermatologist is the most likely clinician to establish the diagnosis, with or without biopsy.

• Severe cases may require the involvement of a burn specialist or plastic surgery specialist.

• Internal medicine, critical care, or pediatrics consultants direct inpatient care.

• Ophthalmology consultation is mandatory for those with ocular involvement.

• Depending on organ system involvement, consultations with a gastroenterologist, pulmonologist, and nephrologist may be helpful. Medication No specific drug treatment has been consistently shown to be beneficial in the treatment of Stevens-Johnson syndrome. The choice of antibiotic for infectious causes depends on the cause of that infection.

Clinical and laboratory evidence suggesting bloodstream infection mandates the use of antibiotics. The most common organisms include Staphylococcus aureus, Pseudomonas aeruginosa, and Enterobacteriaceae species.6

The use of systemic corticosteroids is controversial, but may be useful in high doses early in the disease. Morbidity and mortality actually may increase in association with corticosteroid use.

Human intravenous immunoglobulin has been described as both treatment and prophylaxis. In the latter setting, one group used IVIG in a patient who underwent cardiac catheterization but who had 4 previous Stevens-Johnson syndrome (SJS) episodes after intravenous contrast injection.22