Dott. M.M. CIAMMAICHELLA Dirigente Medico UOC Medicina Interna I° per l'Urgenza (Direttore: Dott. G. Cerqua) A.C.O. S. Giovanni – Addolorata, Roma STEVENS-JOHNSON SYNDROME KEY-WORDS: Stevens-Johnson syndrome INTRODUCTION CLINICAL WORKUP TREATMENT MEDICATION FOLLOW-UP MISCELLANEOUS BIBLIOGRAPHY INTRODUCTION Background: Stevens-Johnson syndrome (SJS) is an immune-complex-mediated hypersensitivity reaction that is a severe expression of erythema multiforme. It is now also known as erythema multiforme major. SJS typically involves the skin and the mucous membranes. While minor presentations may occur, significant oral, nasal, eye, vaginal, urethral, gastrointestinal and lower respiratory tract mucous membranes may be develop in the course of the illness. Gastrointestinal and respiratory involvement may progress to necrosis. SJS is a serious systemic disorder with the potential for severe morbidity and even death. Pathophysiology: SJS is an immune mediated complex hypersensitivity disorder that may be caused by many drugs, viral infections and malignancies. In up to one-half of the cases, no specific etiology has been identified. Frequency: In the U.S.: Cases tend to have a propensity for the early spring and winter. Internationally: SJS occurs with a world-wide distribution similar in etiology and occurrence to U.S. cases. Mortality/Morbidity: Between 3-15% of patients with severe SJS will die. 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 there is extensive involvement of the esophagus. 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: Males are affected twice as often as females. Age: Most patients are in the second to fourth decade of their lives; however, cases have been reported in ages as young as 3 months. CLINICAL History: Typically, the disease process begins with a nonspecific upper respiratory tract infection. This is usually part of a 1-14 day prodrome during which there may be fever, sore throat, chills, headache and malaise. Vomiting and diarrhea are occasionally noted as part of the prodrome. Mucocutaneous lesions develop abruptly. Clusters of outbreaks last between 2-4 weeks. The lesions are typically non-pruritic. A history of fever or localized worsening should suggest a superimposed infection; however, fever has been reported to occur in up to 85% of all cases. Involvement of oral and/or mucous membranes may be severe enough that patients may not be able to eat or drink. Patients with GU involvement may complain of dysuria or an inability to void. A history of a previous outbreak of SJS or of erythema multiforme may be elicited. Recurrences may occur if the responsible agent is not eliminated or if the patient is re-exposed. Cough productive of a thick, purulent sputum Headache Malaise Arthralgia. Physical: The rash can begin as macules that develop into papules, vesicles, bullae, urticarial plaques or confluent erythema The center of these lesions may be vesicular, purpuric or necrotic. The typical lesion has the appearance of a target. The target is considered pathognomonic Lesions may become bullous and later rupture leaving denuded skin. The skin becomes susceptible to secondary infections. Urticarial lesions are typically not pruritic Infection may be responsible for the scarring associated with morbidity Although lesions may occur anywhere, the palms, soles, dorsum of hands and extensor surfaces are most commonly affected. The rash may be confined to any one area of the body, most often the trunk Mucosal involvement may include erythema, edema, sloughing, blistering, ulceration and necrosis Fever Orthostasis Tachycardia Hypotension Altered level of consciousness Epistaxis Conjunctivitis Corneal ulcerations Erosive vulvovaginitis or balanitis Seizures Coma. Causes: Drugs and malignancies are most often implicated as the etiology in adults and the elderly. Pediatric cases are more often related to infections. Over two-thirds of all patients had been prescribed a medication (e.g., sulfa, phenytoin, or penicillin). Over one-half report a recent upper respiratory tract infection. The 4 etiologic categories are infectious, drug-induced, malignancy related and idiopathic. Infectious diseases that have been reported include HSV, influenza, mumps, cat-scratch fever, Mycoplasma, LGV, histoplasmosis and cholera. In children, Epstein-Barr and enteroviruses have been identified. Drug etiologies include penicillins, sulfas, phenytoin (and related anticonvulsants), carbamazepine and barbiturates. Various carcinomas and lymphomas have been associated. Between 25-50% are idiopathic. WORKUP Lab Studies: There are no laboratory studies (other than biopsy) that can establish the diagnosis. A complete blood count (CBC) may reveal a normal white cell count or a non-specific leukocytosis. A severely elevated white blood cell (WBC) count indicates the possibility of a superimposed bacterial infection. Renal function should be determined and urine evaluated for blood. Electrolytes and other chemistries may be needed to help manage related problems. Blood, urine and wound cultures are indicated when an infection is clinically suspected. Imaging Studies: A chest radiograph may indicate the existence of a pneumonitis when clinically suspected. Otherwise, routine plain films are not indicated Other Tests: Skin biopsy is the definitive diagnostic study. It is not, however, an ED procedure. Skin biopsy demonstrates that the bullae are subepidermal Epidermal cell necrosis may be noted Perivascular areas are infiltrated with lymphocytes. TREATMENT Prehospital Care: Paramedics should recognize the presence of severe fluid loss and should treat SJS patients as they would victims of thermal burns. Emergency Department Care: Most cases present early and prior to obvious signs of hemodynamic compromise. Perhaps the single most important role for the ED physician is to detect SJS early and initiate the appropriate ED and inpatient management. Care in the ED must be directed to fluid replacement and electrolyte correction. Skin lesions are treated as burns. Cases of SJS should then be treated with special attention to airway and hemodynamic stability, fluid status, wound/burn care and pain control. Treatment of SJS is primarily supportive and symptomatic. Oral lesions should be managed with mouthwashes. Topical anesthetics are useful in reducing pain and allowing the patient to take in fluids. Areas of denuded skin must be covered with compresses of saline or Burow's solution. Underlying diseases and secondary infections must be identified and treated. Offending drugs must be stopped. The use of systemic steroids is controversial. Some authors believe that they are contraindicated. Treatment with systemic steroids has been associated with an increased incidence of complications. Tetanus prophylaxis should be addressed. Consultations: Consultants may help establish the diagnosis and direct inpatient care. Dermatology is most likely to help establish the diagnosis, with or without biopsy. Severe cases may require the involvement of a burn or plastic surgical 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 gastroenterology, pulmonary and nephrology may be helpful. MEDICATION There is no specific drug treatment for SJS. The choice of antibiotic will depend on the associated infection. The use of systemic corticosteroids is controversial. They are useful in high doses early in the reaction but morbidity and mortality may actually increase in association with corticosteroid use. FOLLOW-UP Further Inpatient Care: Saline compresses may be applied to the eyelids, lips and nose. Careful daily inspection is necessary to monitor for secondary superinfections. Prophylactic systemic antibiotics are not useful, especially in the current era of multiple drug resistance. Antimicrobials are indicated in cases of urinary tract or cutaneous infections, either of which may lead to bacteremia. Further Outpatient Care: Although patients with erythema multiforme minor may be managed as outpatients with topical steroids, those with erythema multiforme major (SJS) must be hospitalized. Cases of erythema multiforme minor must be followed closely. Some authors recommend daily follow up. Transfer: SJS patients are often critically ill. As such, they must be admitted to hospitals capable of delivering critical care. Some patients may deserve the services of a burn unit. Transfer criteria would be the same as for victims of thermal burns. Deterrence/Prevention: The patient must avoid any future exposure to agent(s) implicated in the occurrence of her/his case of SJS. Recurrences may occur. Complications: Ophthalmologic: Corneal ulceration, anterior uveitis, panophthalmitis, and blindness Gastroenterologic: Esophageal strictures Genitourinary: Renal tubular necrosis, renal failure, penile scarring, and vaginal stenosis Pulmonary: Tracheobronchial shedding with resultant respiratory failure Cutaneous: Scarring and cosmetic deformity, recurrences of infection through slow-healing ulcerations Prognosis: Individual lesions should typically heal within 1-2 weeks unless secondary infection occurs. The majority of patients recover without sequelae. Development of such serious sequelae, such as respiratory failure, renal failure and blindness, determine prognosis in those so afflicted. Up to 15% of all patients with the SJS will die. MISCELLANEOUS Medical/Legal Pitfalls: The gravity of the diagnosis must be recognized. As SJS patients who present early in the development of the disease may not yet be critically ill, the clinician may misdiagnose and discharge. SJS should be considered in all patients with target lesions and mucous membrane involvement. Provide close follow up and clear instructions. When discharging a patient home, clearly document the degree (%) of skin involvement, the absence of mucous membrane lesions and any clinical signs of toxicity. BIBLIOGRAPHY Bianchine JR, Macaraeg P, Lasagna L : Drugs as etiologic factors in the Stevens Johnson Syndrome. Am J Med 1968; 44: 390-394. Cohen B: The many faces of erythema multiforme. Contemporary Pediatrics 1994; 11: 19-39. Darmstadt GL, Lane A: Vesiculobullous disorders. Nelson's Textbook Of Pediatrics 1996; 1850-1852. Frieden IJ: Hypersensitivity reactions. Rudolph's Pediatrics 1996; 906-908. Ginsburg C: Stevens-Johnson syndrome in children. Pediatr Infec Dis 1982; 1: 155-161. Hurwitz A: Erythema multiforme: A review of its characteristics, diagnostic criteria and management. Pediatr Rev 1990; 11: 217-220.