Basics
Description
- Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe, potentially fatal, mucocutaneous drug reactions characterized by epidermal necrosis involving skin and at least 2 mucous membranes.
- The cutaneous necrosis leads to widespread epidermal detachment and loss of skin barrier function.
- Given the potential risk for infection and fluid and electrolyte imbalances with widespread denudation, SJS and TEN are considered medical emergencies.
Epidemiology
Incidence
- Overall annual risk of 0.5 " “1.9 per million in the general population
- The precise incidence in children is unknown.
- Patients with HIV have a 1,000-fold increased risk.
Risk Factors
- Exposure to inciting medications
- Infection with Mycoplasma pneumoniae, HIV
- Genetic background
- Coexistence of cancer
- Concomitant radiotherapy
Genetics
- Recently, strong associations have been made between HLA alleles and SJS/TEN.
- Associations are ethnic population " “specific and therefore universal screening of HLA alleles is rarely recommended.
- The FDA recommends checking for HLA-B*1502 in Asian populations where this HLA subtype is highly prevalent before prescribing carbamazepine.
General Prevention
Once SJS/TEN has occurred, the inciting medication and any cross-reacting medications should be avoided. ‚
Pathophysiology
- Widespread keratinocyte and mucosal cell death occurs secondary to CD8+ T-cell " “mediated apoptosis via Fas and Fas ligand pathways and/or direct granulysin secretion. Fas receptors are located on keratinocytes and, when activated with Fas ligand, induce apoptosis and therefore necrosis of epidermal cells. Granulysin is released from cytotoxic T cells and induces apoptosis by creating holes in target cell membranes.
- The exact mechanism by which the implicated drug or infection triggers activation of cytotoxic T cells and the upregulation of the Fas/FasL pathway is unknown.
- Soluble Fas ligand is increased in patients with SJS/TEN.
- IVIG theoretically acts to block the Fas " “FasL connection, thereby interrupting keratinocyte death and epidermal necrosis. Trials that show a benefit of IVIG use demonstrate improvement of disease severity but not complete abolition of symptoms; this incomplete effect may be due to IVIG being started too late in the disease progression or due to a potential alternative pathway to keratinocyte destruction.
Etiology
- <5% of cases have no known cause.
- Medications
- Over 100 medications have been implicated in causing SJS/TEN.
- High-risk drugs include aromatic amine anticonvulsants such as carbamazepine, phenobarbital and phenytoin, lamotrigine, ˇ ²-lactam antibiotics, sulfa medications (including trimethoprim-sulfamethoxazole and sulfasalazine), minocycline, cephalosporins, quinolones, NSAIDs (especially peroxicam and meloxicam), allopurinol, and nevirapine.
- Acetaminophen (very rare)
- Recently, the FDA issued a warning about the risk of acetaminophen-related SJS/TEN.
- Although SJS/TEN is a very rare occurrence in patients taking acetaminophen, the ubiquity of acetaminophen in prescription and OTC products prompted the requirement for new labeling.
- A greater risk of developing SJS/TEN is seen in the first 8 weeks of treatment with these medications, with the highest risk being 1 " “3 weeks after exposure.
- M. pneumoniae
- A well-established nondrug cause of SJS/TEN
- More commonly implicated in children and adolescents
- There is scant evidence that vaccines, neoplastic syndromes, and autoimmune disease such as SLE may play a role in etiology.
- Herpes simplex virus " “associated erythema multiforme (EM) was historically categorized on the spectrum with SJS and TEN, but new classification schemes place it as a separate entity.
Diagnosis
History
- Prodromal period for 1 " “7 days of low-grade fever, sore throat or upper respiratory infection or dysphagia, and general malaise; patient may also complain of pain or stinging in the eyes.
- Subsequent development of targetoid red papules and plaques with dusky, blistered, or eroded center as well as mucosal (lip, intraoral, conjunctival, urethral, anal) pain with blistering and erosions
- Recent initiation of high-risk agent (see earlier list) or upper respiratory symptoms such as cough indicative of Mycoplasma infection
Physical Exam
- Acute phase
- Early skin lesions are erythematous targetoid macules and patches with a dusky center that then vesiculate.
- The eruption usually starts on the face, presternal area of chest, and palms and soles. >90% of patients also have ocular and/or genital mucosa involvement consisting of erythema and erosions as well as hemorrhaging, crusting, and blisters.
- Skin and mucosal lesions are very tender.
- Intraoral lesions may precede the cutaneous findings.
- Ocular involvement at the onset of disease is common. Early ocular disease ranges from acute conjunctivitis, eyelid edema, and ocular discharge to pseudomembrane formation and corneal erosion.
- Secondary phase
- Over hours to days, necrosis, blistering, and sloughing cause large areas of epidermal detachment.
- Lesions are characterized by a positive Nikolsky sign (epidermal detachment upon mechanical stress).
- Extensive mucosal involvement may include the esophagus, distal gastrointestinal (GI) tract, and respiratory epithelium.
- Occasionally Mycoplasma-induced SJS can involve only the mucosal surfaces with little or no cutaneous involvement.
Alert
- The progression of disease to sheets of widespread epidermal necrosis and sloughing may be hours. This is a medical emergency.
- The systemic severity of SJS and TEN is often underestimated based on the severity of skin disease.
- Ocular involvement is often early and severe.
Diagnostic Tests & Interpretation
Lab
Initial Lab Tests
- CBC with differential, metabolic panel, hepatic function test, coagulation studies, urinalysis, mycoplasma serology, or PCR if indicated
- Anemia and lymphocytopenia are common and portend a poor prognosis.
Imaging
Symptom-directed imaging may be indicated depending on the extent of mucosal and systemic involvement. ‚
Clinical Diagnosis
- The diagnosis of SJS and TEN is largely clinical based on history and physical exam.
- By definition, <10% affected body surface area (BSA) is SJS; 10 " “30% affected BSA is SJS/TEN overlap; >30% affected BSA is TEN.
Diagnostic Procedures/Other
- Skin biopsy with cryosection can be performed to confirm the clinical diagnosis if in doubt.
- Histologic examination with direct immunofluorescence (DIF) can be performed to rule out other autoimmune blistering diseases such as paraneoplastic pemphigus if in doubt.
Pathologic and Diagnostic Findings
- Skin biopsy shows full-thickness epidermal necrosis and few inflammatory cells; the skin biopsy may additionally show separation at the subepidermal level.
- DIF shows no immunoglobulin or complement deposition in the epidermis or in the epidermal " ”dermal zone.
Differential Diagnosis
- Staphylococcal scalded skin syndrome (SSSS)
- Linear IgA dermatosis
- Paraneoplastic pemphigus, pemphigus vulgaris, and bullous pemphigoid
- Acute generalized exanthematous pustulosis
- Disseminated fixed bullous drug eruption
- Drug-induced hypersensitivity syndrome (drug reaction with eosinophilia and systemic symptoms [DRESS])
Treatment
Medication
First Line
- Stop all potentially offending medications.
- Early admission to burn unit or pediatric intensive care unit for initial stabilization and management of fluid, electrolytes, and nutrition; airway stability; and eye care
- Prompt ophthalmology and dermatology consultation
- Otolaryngology, urology, or gynecology consultation may be needed based on extent of mucosal involvement.
- Meticulous wound care with bland emollients; avoid silver sulfadiazine as it may cause SJS owing to its sulfa moiety.
- Topical antibiotics should be used in areas of superinfection. The prophylactic use of topical antibiotics is somewhat controversial. Most agree that they should be applied to areas with a higher risk of superinfection, such as the perioral, periocular, and intertriginous areas.
- IVIG: 0.5 " “1 g/kg/dose given in 2 " “4 doses for a total of 2 " “3 g/kg total
- There have been variable results from a limited number of quality studies looking at the effects of IVIG. Multiple studies have demonstrated a beneficial effect especially if started early in the course.
- Adverse effects of IVIG include acute renal failure, DIC, osmotic nephrosis, anaphylaxis, serum sickness, aseptic meningitis, and thrombosis, among others.
- Steroids (prednisolone, dexamethasone, methylprednisolone) were the mainstay of therapy in the 1990s but now are less commonly used because of the increased risk of sepsis, infection, and other complications especially when used in TEN with widespread epidermal loss.
- Thalidomide, cyclosporine, TNF antagonists, plasmapheresis, and cyclophosphamide have been studied in the treatment of SJS/TEN, primarily in adults and some limited data may support their use.
- Prophylactic systemic antibiotics are not recommended, as they place the patient at an increased risk of candidemia and resistant infections.
Additional Therapies
- Pain control is key to patient comfort.
- Good oral care using agents such as "magic mouthwash " ¯ helps debride dead skin and provide oral anesthesia.
Surgery/Other Procedures
- Surgical debridement. Studies have shown that surgical debridement of wounds prior to wound care yielded no additional benefit.
- Lysis of synechiae and vaginal adhesion
- Ocular amniotic membrane transplantation
Discharge Criteria
When afebrile, the loss of skin is clearly done, and reepithelialization has occurred; cleavage of synechiae in the eyes is no longer needed; and the patient can eat and drink appropriately ‚
Ongoing Care
Follow-up Recommendations
Follow-up with a dermatologist and/or wound care specialist. Reepithelialization often starts within days and may take up to 3 weeks to be completed. ‚
Patient Monitoring
- SCORTEN is a well-validated, widely used scoring system in adults used for its predictive value, which is best at day 3. Variables include age, percentage BSA affected, BUN, serum glucose, HR, serum bicarbonate, and associated malignancy.
- Monitor for skin, urinary tract, and pulmonary infections; synechiae in the eyes; and vaginal and urethral adhesions.
Prognosis
- Mortality is 1 " “5% in SJS and up to 25 " “35% in TEN (although most of this data is from the adult literature and likely the mortality is lower in children).
- Prognosis depends on BSA affected, time to cessation of offending medication, and time to initiation of supportive care.
Complications
- Mucosal complications occur in >70% of patients with acute-phase mucosal involvement. Ocular complications occur in 50% of patients with TEN.
- Systemic: sepsis, multiorgan failure, major metabolic dysregulation
- Mucosal: respiratory failure, pneumonia, pulmonary embolus, UTI, GI hemorrhage, obstruction, and perforation
- Cutaneous: skin infections, scarring, hypo-/hyperpigmentation, nail dystrophies
- Ocular: synechiae, dry eyes, bacterial conjunctivitis, suppurative keratitis, endophthalmitis, impaired tear ducts, corneal ulcers, vision loss
Additional Reading
- Bastuji-Garin ‚ S, Rzany ‚ B, Stern ‚ RS, et al. Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme. Arch Dermatol. 1993;129(1):92 " “96. ‚ [View Abstract]
- Del Pozzo-Magana ‚ BR, Lazo-Langner ‚ A, Carleton ‚ B, et al. A systematic review of treatment of drug-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in children. J Popul Ther Clin Pharmacol. 2011;18:e121 " “e133. ‚ [View Abstract]
- Ferrandiz-Pulido ‚ C, Garcia-Patos ‚ V. A review of causes of Stevens-Johnson syndrome and toxic epidermal necrolysis in children. Arch Dis Child. 2013;98(12):998 " “1003. ‚ [View Abstract]
- Karlin ‚ E, Phillips ‚ E. Genotyping for severe drug hypersensitivity. Curr Allergy Asthma Rep. 2014;14(3):418. ‚ [View Abstract]
- Levi ‚ N, Bastuji-Garin ‚ S, Mockenhaupt ‚ M, et al. Medications as risk factors of Stevens-Johnson syndrome and toxic epidermal necrolysis in children: a pooled analysis. Pediatrics. 2009;123(2):e297 " “e304. ‚ [View Abstract]
- Treat ‚ J. Stevens-Johnson syndrome and toxic epidermal necrolysis. Pediatr Ann. 2010;39(10):667 " “674. ‚ [View Abstract]
Codes
ICD09
- 695.13 Stevens-Johnson syndrome
- 695.14 Stevens-Johnson syndrome-toxic epidermal necrolysis overlap syndrome
- 695.15 Toxic epidermal necrolysis
ICD10
- L51.1 Stevens-Johnson syndrome
- L51.3 Stevens-Johnson synd-tox epdrml necrolysis overlap syndrome
- L51.2 Toxic epidermal necrolysis [Lyell]
SNOMED
- 73442001 Stevens-Johnson syndrome (disorder)
- 124911000119100 Stevens-Johnson syndrome - toxic epidermal necrolysis overlap (disorder)
- 402744003 toxic epidermal necrolysis due to drug (disorder)