Steven Johnson's Syndrome

Definition

A generalized hypersensitivity reaction, usually to a drug, in which skin and mucous membrane lesions are an early manifestation.



Once considered to be the same as erythema multiforme major, a severe form of erythema multiforme in which >1 mucosal surface was involved, but many now consider it to be a different disease with a more difficult course and a more ominous prognosis.
Stevens-Johnson syndrome (SJS) exists on a continuum with toxic epidermal necolysis (TEN).
Presents with characteristic targetoid cutaneous lesions on <10% of the body surface area (BSA)
Targetoid cutaneous lesion involvement of 10–30% of BSA is considered an overlap between SJS and TEN. Involvement of >30% of BSA is TEN, which has a high morbidity and up to 70% mortality (1).
System(s) affected: Cardiovascular; Hematologis/ Lymphatic/Immunologic; Nervous; Renal/Urologic; Skin/Exocrine
Synonym(s): Ectodermosis erosiva pluriorificialis; Febrile mucocutaneous syndrome; Herpes iris; Erythema polymorphe; Toxic epidermal necrolysis (TEN)
Dangerous progression

Patients with discrete skin lesions and >10% epidermal detachment are at risk of rapid progression to TEN.

Epidemiology
TEN has a greater mortality in older patients
Rare in children <3 years of age
More common in children and young adults
Pregnancy is a possible predisposing condition.
Incidence/prevalence in the US is difficult to estimate because there is no universally accepted definition of SJS.
1.1–7.1 and 0.4–1.2 cases/1 million person-years for SJS and TEN, respectively
Predominant age: SJS is more common in children and young adults.
Predominant sex: Male > Female (2:1)
Sex (% range of females): 33–62% for SJS and 61.3–64.3% for TEN
Age (average range): 25–47 years for SJS and 46–63 years for TEN

Risk Factors
Previous history of SJS
Immunocompromised status, including chronic viral infections with Epstein-Barr virus and HIV (2,3)
Patients with HIV infection may be predisposed to developing SJS in response to their medications.

•  - Human leukocyte antigen (HLA) subtypes A, B, and D
•  - Diseases that cause immune compromise (deficiencies, malignancy, etc.)
•  - Possibly radiation therapy or ultraviolet (UV) light

Associations with HLA-B*1501, HLA-B*1502, HLA-Bw44, HLA-B12, and HLA-DQB1*0601
Secondary prevention may be possible by avoiding exposure to offending medications or chemical agents.

Pathophysiology

- Erythematous papular lesions and keratinocyte necrosis are a consequence of cell-mediated immunity.

- Occurs 1–2 weeks after initial exposure to offending drugs and within 48 h on rechallenge.

- Accumulation and binding of reactive drug metabolites to mucocutaneous epithelial cells as haptens

- Drug haptens signal drug-specific CD8+ T-lymphocyte and macrophages, which infiltrate and express interleukin 2 (IL-2), tumor necrosis factor α (TNF-α), and interferon-γ, leading to keratinocyte activation.

- Cytokines enhance keratinocyte expression of soluble Fas ligand (sFasL) and Fas receptors, leading to apoptosis

Etiology

- 50% of cases are idiopathic.

- Associated with metabolism of parent drugs and metabolites

- Slow intrinsic acetylation rates

- Sulfonamides are the drugs most strongly associated with SJS and TEN. Then Cephalosporins, Quinolones, Aminopenicillins, Tetracyclines, Macrolides, Imidazole antifungals -HIV antiretrovirals (e.g., protease inhibitors, efavirenz, abacavir, amprenavir, fosamprenavir, atazanavir, darunavir, etravirine) , Anticonvulsants, especially carbamazepine, Nonsteroidal anti-inflammatory drugs (NSAIDs), especially oxicam, Allopurinol, Vaccines—dPT, BCG, oral polio, Mycoplasma pneumoniae infection, TEN is a dangerous progression of SJS, Mycoplasma pneumoniae may be an infectious precursor.

Investigation

History

Physical Exam

Usually a preceding illness for which the medication was given 1–3 weeks before initial cutaneous manifestations Sudden onset with rapidly progressive pleomorphic rash that includes petechiae, vesicles, bullae Considered to be SJS if epidermal detachments affect <10% of the skin Classified as TEN if epidermal detachments affect >30% or >10% in the absence of discrete skin lesions Burning sensation of the skin and sometimes of the mucous membranes Usually no pruritus Fever 39–40°C (102–104°F) Headache Malaise Arthralgias Cough productive of thick, purulent sputum

Recognized by the presence of several of the following features: Vesicles and ulcers on the mucous membranes, especially of the mouth and throat Erythematous macules with purpuric, necrotic centers and overlying blistering (4) Epidermal detachment with light lateral pressure (Nikolsky's sign) Fever 39–40°C (102–104°F) Crusted nares Conjunctivitis Corneal ulcerations Erosive vulvovaginitis or balanitis Cough productive of thick, purulent sputum Tachypnea/respiratory distress Arrhythmias Pericarditis Congestive heart failure (CHF) Mental status changes Seizures Coma Sepsis Patients with discrete skin lesions and 10–30% epidermal detachment are in the overlap between SJS and TEN.

Initial lab tests

Culture or serologic tests for suspected sources of infection

Electrolyte disturbance

Albuminuria/hematuriaFollow-Up & Special Considerations
Skin biopsy

Differential Diagnosis

Exfoliative dermatitis
Linear IgA bullous dermatosis
Staphylococcal scalded-skin syndrome
Pemphigus (paraneoplastic)
Generalized fixed drug eruption
Erythema multiforme major
Burns
Pressure blisters (coma, barbiturates)

Management
First Line

Corticosteroids are controversial. Early high-dose IV steroids may attenuate disease progression, reduce skin detachment, decrease inflammatory cytokine activity, and improve patient comfort. Withdraw if no benefit is seen in the first few days.
Experimental treatments that appear to have been useful include

- Recombinant granulocyte colony-stimulating factor

- Cyclophosphamide

- Cyclosporine

- IV immune globulin (IVIG) in HIV-positive patients; IVIG is considered beneficial treatment and prophylaxis, although not approved by the Food and Drug Administration (FDA) (3, 5,6).

- Contraindications: Avoid steroids in diabetic or immunosuppressed patients or those with chronic infections.

Second Line

- Acyclovir for herpetic infections

- Erythromycin or related antibiotic for Mycoplasma infections (empirical use of antibiotics is not recommended)

Additional Treatment
Withdraw all suspected medications, and treat any underlying disease.
Meticulous care of damaged skin
Supportive care, including moisture-retentive ointment, petroleum jelly, and sterile saline compresses
Catheter changing and culturing
Reverse isolation and temperature control with extensive epidermal loss
Maintenance of fluid, electrolyte, and protein balance
Plasmapheresis
Adequate calorie intake; parenteral nutrition, if necessary
Mouthwashes of warm saline or a solution of diphenhydramine, lidocaine, and kaolin suspension
Ophthalmologic consultation and monitoring for corneal damage
Venous thromboembolism prophylaxis with unfractionated heparin or low-molecular-weight heparin

Surgery/Other Procedures

Sterile débridement of areas of extensive epidermal loss
Application of biosynthetic dressings such as Biobrane to denuded areas
Damage to the vulva, vagina, or cornea: Consider surgical repair.

Admission Criteria

This disease progresses rapidly; all patients should be admitted.

Admission to a burn unit greatly improves the outcome for any patient who has sloughed skin over 10% or more of the body surface area.

ICU for bronchiolitis, acute respiratory distress syndrome (ARDS), or multiorgan damage

IV Fluids
Fluid management with saline and macromolecules is necessary in the 1st 24 h with decreasing IV fluid requirements as oral intake proceeds with nasogastric tube.

• Bed rest until clinically stabilized
• Avoid administration of topical silver sulfadiazine owing to association with sulfonamide and SJS.

Prognosis

Disease may have a rapid onset or may evolve slowly over 1–2 weeks with resolution over 4–6 weeks.
Often scarring of the skin or mucous membranes occurs, especially of the vulva.
Blindness or corneal opacities occur in 7–20% of patients.
The risk of recurrence is as high as 37%.
Death occurs in 5–15% of the patients with SJS and in up to 40% of patients with TEN.

Complications

Secondary infections
Sepsis
Pneumonia
ARDS
Bronchiolitis obliterans in children
Dehydration/electrolyte disturbance
Acute tubular necrosis
Corneal ulceration or iritis
Urethral erosions and genitourinary strictures
Arrhythmias
Venous thromboembolism
Disseminated intravascular coagulation (DIC)
Death in 15% of untreated cases of SJS and up to 40% of TEN cases