Stevens Johnson Syndrome/Toxic Epidermal Necrolysis

OVERVIEW: What every practitioner needs to know#

Are you sure your patient has Stevens–Johnson syndrome/toxic epidermal necrolysis? What should you expect to find?

Stevens–Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe reactive blistering diseases along a continuum of disease severity. They are uncommon to rare conditions in the general population with increased incidence in the human immunodeficiency virus (HIV)-positive population. Though SJS/TEN is most commonly associated with exposure to medications, SJS is also associated with herpes virus or Mycoplasma. The onset of the disease ranges from 1 to 3 weeks after initiation of the culprit drug.

• Key symptoms:

  Prodrome: fever, sore throat, malaise, influenza-like symptoms; 2 to 3 days before skin manifestations

  Skin: rash, skin pain, blisters

  Mucous membranes (mouth, esophagus, eyes, urogenital, rectal/anal, respiratory): oral pain, odynophagia, decreased oral intake, photophobia, ocular pain, red eyes, dysuria, vaginal pain, painful defecation, nasal discharge/crusting, cough

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  Other: arthralgias

• Key physical findings:

  Skin (Figure 1):

  Several presentations may be seen:

  Erythematous, dusky, or purpuric macules progress to:

  atypical targetoid lesions with purpuric centers followed by desquamation

  desquamation without the atypical target stage

  Purpuric atypical targets coalesce into bullae followed by desquamation

  Confluent macular erythema or dusky redness is wide-spread on the trunk followed by gray discoloration as the epidermis necrosis then sloughs

  Blisters are flaccid when present (Figure 2)

  Face and trunk are initial sites of involvement most often, palms and soles may be an early site of involvement

  Symmetrical eruption

  Maximum body surface area (BSA) reached within 4 days

  Estimating BSA: count only skin that is currently denuded or “detachable” with or without Nikolsky’s sign, not purely erythematous skin

  SJS covers less than 10% of the patient’s BSA

  SJS/TEN overlap covers 10 to 30% of the BSA

  TEN covers more than 30% of the BSA

  Nikolsky’s sign (slight rubbing of seemingly intact skin results in exfoliation) is positive

  Mucous membranes: SJS nearly always has two or more mucous membrane surfaces involved

  Oropharyngeal:

  Erythema

  Hemorrhagic crust on vermilion lips

  Erosions and/or ulcers on any surface

  Ocular:

  Conjunctivitis, often purulent

  Crusting along lid margins

  Vaginal/Penile:

  Erythema

  Erosions, ulcers, vesicles, bullae

  Perianal:

  Erythema

  Erosions, ulcers, vesicles, bullae

  Respiratory:

  Hemorrhagic crust at nares

  Erythema, erosions, ulcers of nasal mucosae

  Inspiratory crackles, rhonchi with auscultation

  Other:

  Hypovolemia to shock

  Ill- to toxic-appearing

  Generalized lymphadenopathy

  May have hepatosplenomegaly

  Swollen, tender joints

How did the patient develop Stevens–Johnson syndrome/toxic epidermis necrolysis?

• Nearly all cases of TEN and most of cases of SJS are caused by exposure to a medication, prescribed or over-the-counter. Some cases of SJS, less than 50%, are caused by infection; herpes or Mycoplasma being the most common.

• Incidence:

  SJS: 1.2 to 6.0 cases per million person-years

  TEN: 0.4 to 1.2 cases per million person-years

  HIV: 100 to 1,000 times more common per drug exposure

• Drugs implicated: (this is a short list of more common culprits)

  Sulfonamides: sulfamethoxazole, sulfadoxine, sulfadiazine, sulfasalazine

  Nevirapine

  Anticonvulsants: lamotrigine (1 in 1,000 adults), carbamazepine (14 in 100,000 adults), phenytoin, barbiturates

  Allopurinol (most common cause in Europe)

  Aminopenicillins

  Nonsteroidal anti-inflammatory drugs (NSAIDs): piroxicam, ibuprofen, naproxen

Which individuals are of greater risk of developing Stevens–Johnson syndrome/toxic epidermal necrolysis?

• HIV-positive patients

  cluster of differentiation (CD)4 count 25 to 200

• Human leukocyte antigen (HLA)-DRB1*0101 patients

  Associated with nevirapine induced SJS/TEN and other severe drug reactions

• HLA-B*1502

  5 to 10% of Asians (not associated in other ethnicities)

  Associated with carbamazepine induced SJS/TEN

• HLA-B*5801

  Han Chinese, Japanese, Thai, and less so in Europeans

  Associated with SJS/TEN from allopurinol

• Women are at greater risk of SJS/TEN than men

• Older age (likely related to exposure to more medications)

Beware: there are other diseases that can mimic Stevens–Johnson syndrome/toxic epidermal necrolysis:

• Staphylococcal scalded skin syndrome

  More common in newborns and young children

  Spares mucous membranes and palms and soles

  Caused by an exotoxin directed toward desmoglein resulting in superficial erosions

• Acute graft-versus-host disease (GVHD)

  Allogeneic stem cell transplantation recipients are at a substantially greater risk of acute GVHD than autologous stem cell transplantation recipients.

  Can be difficult to differentiate clinically and histologically

• Acute generalized exanthematous pustulosis (AGEP)

  Drug-induced skin eruption

  Quick onset: 1 to 11 days after exposure

  Scarlatiniform erythema; rapid evolution of numerous small nonfollicular pustules

  Rarely: purpuric atypical targets; histopathology suggests AGEP over SJS/TEN

  Mucous membrane involved but it is nonerosive; typically only one region

  Face may be involved

  Superficial desquamation occurs in approximately 2 weeks

  Fever

  Not associated with sulfonamides

• Paraneoplastic pemphigus

  Underlying non-Hodgkin lymphoma, chronic lymphocytic leukemia, Castleman disease, sarcoma, thymoma

  Severe oropharyngeal erosions/ulcerations

  Skin may have erythematous macules, lichenoid papules, targetoid lesions, vesicles/bullae, or erosions

  Histopathology and direct immunofluorescence are helpful in establishing the diagnosis

• Erythema multiforme

  Red papules progress to “target lesions”

  Pruritic or burning

  Usually not painful

  Acral predominance (hands, feet, palms, soles)

  Prodrome is uncommon

  Oral lesions tend to be discrete and may appear “targetoid”

What laboratory studies should you order and what should you expect to find?

Results consistent with the diagnosis of SJS/TEN

• Complete blood count with differential

  Leukocytosis is common; may have leukopenia

  Eosinophilia (approximately 20%)

  Anemia

• Complete metabolic panel

  Elevated aspartate aminotransferase and/or alanine transaminase may be seen

  Elevated glucose

  Elevated blood urea nitrogen and creatinine

  Decreased bicarbonate indicating metabolic acidosis

• Urinalysis

  Proteinuria

  Microscopic hematuria

• Other

  Elevated sedimentation rate

  Cultures if indicated

  Blood, urine, skin, sputum

Results that confirm the diagnosis

The diagnosis of TEN is most commonly made clinically. However, in cases where the diagnosis is unclear for either SJS or TEN, skin biopsy may be helpful. When the diagnosis is needed quickly, frozen sections can be invaluable.

• Histopathology of skin biopsy specimen

  Scattered necrotic keratinocytes to full thickness epidermal necrosis

  Lymphocytic inflammatory infiltrate: sparse to dense

What imaging studies will be helpful in making or excluding the diagnosis of Stevens–Johnson syndrome/toxic epidermal necrolysis?

There are no standard radiologic studies for SJS/TEN. Imaging should be based on symptoms and signs on a case-by-case basis.

What consult service or services would be helpful for making the diagnosis and assisting with treatment?

• Dermatology can be extremely helpful in evaluating patients with suspected SJS/TEN. Dermatology will help establish the diagnosis clinically or obtain a skin biopsy sample and will aid in determining the culprit drug. Hospitals with established inpatient dermatology consult services experienced in treating patients with SJS/TEN may have improved outcomes.

• Intensive care unit (ICU) care in a specialized “burn unit” has shown improved mortality and transfer to such care should be strongly considered when greater than 15% of BSA is involved.

• Ophthalmology should be consulted to evaluate for corneal ulcerations and for treatment recommendations.

• Gynecology may be consulted for evaluation of the vaginal mucosae.

If you decide the patient has SJS/TEN, what therapies should you initiate immediately?

Key principles of therapy:

• Discontinued offending agent as soon as possible (estimated reduced mortality by 30% per day when the offending drug is stopped early)

  In general medications that were started within the 4 weeks prior to symptom onset are the likely culprit

  Stop ALL nonessential medications

  If doubt exists regarding the culprit drug, stop ALL medications

• Obtain consultations early

• Transfer to specialized “burn” ICU if greater than 15% of BSA is involved; likely reduces infection and mortality

• Supportive therapy is essential: intravenous fluids, electrolyte replacement, temperature regulation, and nutritional support

• Gentle skin care with as little manipulation and movement as possible

• Pay particular attention to mucous membranes’ treatment

• Monitor for infection/sepsis and treat early if present

• Use of systemic medications for treatment is controversial

  Immunosuppressives, if used, should be

  Initiated very early in the disease process (once most of the skin has been lost, these medications only contribute to increased mortality)

  Considered as a short course to arrest progression

  Discontinued if progression of disease is seen

  Intravenous immunoglobulin

• Use of systemic antibiotics should be reserved for those with documented infections or signs/symptoms of sepsis.

Supportive care

• Fluid replacement

  Dependent on surface area involved

  Peripheral intravenous catheters (placed in uninvolved skin if possible) are preferred to central lines in the hopes of decreasing catheter-related bacteremia

• Maintain warm environment: 30 to 32°C

• Nutritional support

  Utilization of the gastrointestinal tract with a feeding tube for example is preferred to parenteral feeding

• Analgesia with opiates may be required, particularly when the involved BSA is large

• Monitor for signs/symptoms of sepsis: hypotension, hypo- or hyperthermia, altered mental status, worsening glucose control, etc.

• Monitor for respiratory compromise: dyspnea and marked hypoxemia even in the setting of a normal chest radiograph may indicate bronchial injury and the need for mechanical ventilation.

• Monitor complete blood count, renal function, liver transaminases, and electrolytes frequently

Skin care

• General care:

  Limit movement and manipulation, limit shearing forces

  Bed with controlled pressure (avoid foam and water mattresses) and thermoregulation may be helpful (e.g., air-fluidized bed from Clinitron^®)

  Removal of necrotic epidermis to reduce risk of infection and subsequent sepsis

  Commonly occurs in the operating room using warm saline or sterilized water without detergent

• Denuded areas:

  Topical antibiotic application

  Silver-sulfadiazine 1% cream is commonly used directly on the wounds

  Theoretical risk of renal failure; may delay epithelialization

  If sulfonamide is culprit drug, recommend NOT using this cream

  Mupirocin 2% ointment

  Safety when applied to greater than 20% of BSA has not been established

  Silver impregnated dressings are another option

  Cover with petrolatum impregnated gauze (Vaseline^®, Xeroform^®—3% bismuth tribromophenate)

  Changed daily

  Gentle cleansing with (0.05% chlorhexidine, 0.5% silver nitrate, boric acid, aluminum acetate, or gentian violet) solution with dressing changes

  Skin substitutes

  Synthetic/semisynthetic

  Biobrane^®: bilaminar membrane applied after initial debridement of necrotic epidermis then left in place

  Reduces pain, improves mobilization, and decreases infection in elderly patients with TEN

  Suprathel^®

  Calcium-sodium alginate dressings

  Can be left in place for 2 to 3 days

  Nanocrystalline silver dressings (Acticoat^®, Aquacel^®-Ag)

  Left in place for 5 to 7 days

  Antibacterial properties

  Biologic

  Porcine xenografts

  Applied in the operative room after debridement of necrotic epidermis; small areas may be covered at the bedside

  Stapled in place

  Monitored daily for dehiscence and subxenograft purulent material indicting infection

  Left in place until dessicated when it is trimmed as epithelialization occurs beneath the xenograft

  Human allografts

  Glycerol-preserved homologous donor skin is applied at bedside or operating room

  Stitched or stapled in place

  Covered by petrolatum impregnated gauze that is changed daily

Mucous membranes

• Eyes:

  Daily cleansing of eyelids with warm sterile saline

  Liberal use of lubricants; may contain antibiotic

  Topical antibiotic eye drops: gentamicin

• Oropharyngeal:

  Saline compresses to lips followed by petrolatum or antibiotic ointment to reduce crusting

  Rinse mouth several times per day with chlorhexidine solution and/or sterile saline

  Viscous lidocaine to reduce pain

• Vulva/vaginal:

  Liberal use of petroleum jelly or petroleum impregnated gauze to erosions on vulva/labia to prevent scarring

• Respiratory:

  Daily cleansing of nostrils with warm sterile saline using a cotton tipped swab

  Apply topical antibiotic ointment to nares (e.g., mupirocin)

  Nebulized saline

  Physiotherapy

  Bronchodilators

  Humidified oxygen when required

If I am not sure what pathogen is causing the infection what anti-infective should I order?

Medications and other treatments used in an attempt to arrest progression of the disease are summarized in
Table I. The use of these treatment modalities is controversial.