Stevens-Johnson Syndrome

Stevens-Johnson Syndrome

Background:
Stevens-Johnson syndrome (SJS) is an immune-complex?mediated hypersensitivity complex that is a severe expression of erythema multiforme. It is now known also as erythema multiforme major. 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. SJS is a serious systemic disorder with the potential for severe morbidity and even death.

Pathophysiology:
SJS 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. In up to half of cases, no specific etiology has been identified.
Frequency:
In the US: Cases tend to have a propensity for the early spring and winter.
Internationally: SJS occurs with a worldwide distribution similar in etiology and occurrence to that in the US.

Mortality/Morbidity:
Patients with severe SJS die in 3-15% of cases.
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: Male-to-female ratio is 2:1.
Age: Most patients are in the second to fourth decade of their lives; 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.
This usually is part of a 1- to 14-day prodrome during which fever, sore throat, chills, headache, and malaise may be present.
Vomiting and diarrhea occasionally are noted as part of the prodrome.
Mucocutaneous lesions develop abruptly. Clusters of outbreaks last from 2-4 weeks. The lesions typically are 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 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:
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 infection.
Urticarial lesions typically are 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.
The following signs may be noted on examination:
Fever
Orthostasis
Tachycardia
Hypotension
Altered level of consciousness
Epistaxis
Conjunctivitis
Corneal ulcerations
Erosive vulvovaginitis or balanitis
Seizures
Coma

Causes:
Drugs and malignancies most often are implicated as the etiology in adults and the elderly.
Pediatric cases are related more often to infections than to malignancy or a reaction to a drug.
A medication such as sulfa, phenytoin, or penicillin had previously been prescribed to more than two thirds of all patients with SJS.
More than half of the patients with SJS report a recent upper respiratory tract infection.
The 4 etiologic categories are (1) infectious, (2) drug-induced, (3) malignancy-related, and (4) idiopathic.
Infectious diseases that have been reported include herpes simplex virus (HSV), influenza, mumps, cat-scratch fever, mycoplasmal infection, lymphogranuloma venereum (LGV), histoplasmosis, and cholera.
In children, Epstein-Barr virus and enteroviruses have been identified.
Drug etiologies include penicillins, sulfas, phenytoin (and related anticonvulsants), carbamazepine, and barbiturates. In late 2002, the US Food and Drug Administration (FDA) and the manufacturer Pharmacia noted that SJS had been reported in patients taking the cyclooxygenase-2 (COX-2) inhibitor valdecoxib.
Various carcinomas and lymphomas have been associated.
SJS is idiopathic in 25-50% of cases.

DIFFERENTIALS :
Burns, Chemical
Burns, Ocular
Burns, Thermal
Dermatitis, Exfoliative
Erythema Multiforme
Staphylococcal Scalded Skin Syndrome
Toxic Epidermal Necrolysis
Toxic Shock Syndrome
Other Problems to be Considered:
Acute generalized exanthematic pustulosis
Pemphigus

WORKUP :

Lab Studies:
No laboratory studies (other than biopsy) exist that can aid the physician in establishing the diagnosis.

A complete blood count (CBC) may reveal a normal white blood cell (WBC) count or a nonspecific leukocytosis. A severely elevated WBC count indicates the possibility of a superimposed bacterial infection.
Determine renal function and evaluate urine for blood.
Electrolytes and other chemistries may be needed to help manage related problems.
Cultures of blood, urine, and wounds are indicated when an infection is clinically suspected.

Imaging Studies:
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 but is not 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 patients with SJS as they would patients with 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.
Patients with SJS then should 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.
Manage oral lesions 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 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.
Address tetanus prophylaxis.

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 gastroenterology, pulmonary, and nephrology may be helpful.

MEDICATION :
No specific drug treatment exists for SJS. The choice of antibiotic depends 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 actually may 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 treated as outpatients with topical steroids, those with erythema multiforme major (ie, SJS) must be hospitalized.
Cases of erythema multiforme minor must be followed closely. Some authors recommend daily follow-up.

Transfer:
Patients with SJS are often critically ill; therefore, they must be admitted to hospitals capable of delivering critical care.
Some patients may require the services of a burn unit.
Transfer criteria would be the same as for patients with thermal burns.

Deterrence/Prevention:
Patients must avoid any future exposure to agent(s) implicated in the occurrence of SJS. Recurrences are possible.

Complications:
Ophthalmologic – Corneal ulceration, anterior uveitis, panophthalmitis, blindness
Gastroenterologic – Esophageal strictures
Genitourinary – Renal tubular necrosis, renal failure, penile scarring, vaginal stenosis
Pulmonary – Tracheobronchial shedding with resultant respiratory failure
Cutaneous – Scarring and cosmetic deformity, recurrences of infection through slow-healing ulcerations

Prognosis:
Individual lesions typically should heal within 1-2 weeks, unless secondary infection occurs. The majority of patients recover without sequelae.
Development of serious sequelae, such as respiratory failure, renal failure, and blindness, determines prognosis in those affected.
Up to 15% of all patients with SJS die as a result of the condition.

MISCELLANEOUS:
Medical/Legal Pitfalls:
The gravity of the diagnosis must be recognized. Because patients with SJS 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:

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 Feb; 20(2): 219-23[Medline].
Bianchine JR, Macaraeg PV Jr, Lasagna L, et al: Drugs as etiologic factors in the Stevens-Johnson syndrome. Am J Med 1968 Mar; 44(3): 390-405[Medline].
Brett AS, Philips D, Lynn AW: Intravenous immunoglobulin therapy for Stevens-Johnson syndrome. South Med J 2001 Mar; 94(3): 342-3[Medline].
Cohen B: The many faces of erythema multiforme. Contemp Pediatr 1994; 11: 19-39.
Cunha BA: Antibiotic side effects. Med Clin North Am 2001 Jan; 85(1): 149-85[Medline].
Darmstadt GL, Lane A: Vesiculobullous disorders. In Nelson WE, et al, eds. Nelson Textbook Of Pediatrics. 15th ed. Philadelphia: WB Saunders; 1996:1850-2.
Frieden IJ: Hypersensitivity reactions. In Rudolph AM et al. Rudolph’s Pediatrics. 20th ed. Stamford, Conn: Appleton & Lange; 1996:906-8.
Ginsburg CM: Stevens-Johnson syndrome in children. Pediatr Infect Dis 1982 May-Jun; 1(3): 155-8[Medline].
Hofbauer GF, Burg G, Nestle FO: Cocaine-related Stevens-Johnson syndrome. Dermatology 2000; 201(3): 258-60[Medline].
Hurwitz S: Erythema multiforme: a review of its characteristics, diagnostic criteria, and management. Pediatr Rev 1990 Jan; 11(7): 217-22[Medline].
Metry DW, Lahart CJ, Farmer KL, Hebert AA: Stevens-Johnson syndrome caused by the antiretroviral drug nevirapine. J Am Acad Dermatol 2001 Feb; 44(2 Suppl): 354-7[Medline].
Prais D, Grisuru-Soen G, Barzilai A, Amir J: Varicella zoster virus infection associated with erythema multiforme in children. Infection 2001 Jan-Feb; 29(1): 37-9[Medline].
Sane SP, Bhatt AD: Stevens-Johnson syndrome and toxic epidermal necrolysis-challenges of recognition and management. J Assoc Physicians India 2000 Oct; 48(10): 999-1003[Medline].

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