Infectious Diseases

Stevens Johnson Syndrome/Toxic Epidermal Necrolysis

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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

    • 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

Figure 1.

SJS-TEN overlap: note purulent discharge and oral erosions; crusting at the eyelid margins with conjunctival injection

Figure 2.

SJS/TEN overlap: Large flaccid bullae are present with an ulceration

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.

Table I.

Treatment options for Stevens–Johnson syndrome/toxic epidermis necrolysis.
Treatment Comments
Corticosteroids When used early in the disease process and at high pulsed doses (dexamethasone 100mg IV daily for 3 to 4 days, methylprednisolone 30mg/kg/day IV for 3 days), they may provide minimal benefit in SJS/TEN. There are case series suggesting benefit, those suggesting no benefit, and those showing detrimental effects including increased mortality.The use of corticosteroids is not recommended by most in patients with TEN.
IVIg The available data suggest that when used early in the disease and reaching a total dose of >2g/kg over 3 to 4 days, there may be a reduction in mortality. One such regimen would include the following: 1g/kg IV daily for 3 to 4 days.Be sure to check for IgA deficiency prior to the use of IVIg to prevent anaphylaxis.
Ciclosporin Case reports and one case series of patients with TEN suggest that this treatment may lead to arrest of progression of skin disease within 36 hours of initiation of the medication and the epidermis may re-epithelialize more quickly. Treatment regimens vary from 3-5mg/kg orally or IV daily from 8 to 24 days. There is theoretical biological basis for its use but more data is needed to recommend it routinely.
Plasmapheresis Small case series results are mixed and this treatment modality cannot be recommended with confidence.
TNF-α inhibitors ThalidomideEtanerceptInfliximab One randomized study using thalidomide 400mg daily for 5 days was stopped early due to excess mortality in the thalidomide group.Anecdotal evidence exists for etanercept and infliximab in the setting of TEN showing prompt termination of disease progression. In all cases treated with etanercept and all but two with infliximab, the patients were also treated with corticosteroids.More data is needed to establish TNF-α inhibitors as beneficial in SJS/TEN.

Evaluation of the literature regarding the treatment of SJS/TEN is limited by lack of adequate control data, uniformity in treatment regimens, and small sample sizes.

There are no studies specifically evaluating the treatment of SJS/TEN in those who are infected with HIV.

What complications could arise as a consequence of Stevens–Johnson syndrome/toxic epidermal necrolysis?

  • Death

  • Infection—including sepsis

    • Staphylococcus aureus

    • Pseudomonas

    • Enterococcus

    • Klebsiella

    • Others

    • Initiate appropriate antibiotics for documented infection

    • Empiric antibiotics should cover primarily Staphylococcus aureus

  • Electrolyte imbalance

    • Hypokalemia

    • Hyponatremia

    • Hypophosphatemia

  • Eyes: approximately 50% of patients will experience some ocular sequelae

    • Sicca symptoms

    • Symblepharon or ankyloblepharon

    • Ectropion and entropion

    • Photophobia

    • Aberrant lashes may cause corneal abrasions

    • Blindness

  • Skin and Nails

    • Scarring

    • Postinflammatory hyperpigmentation/hypopigmentation

    • Dystrophic nails

  • Vaginal/penile

    • Vaginal stenosis

    • Labial scarring

    • Phimosis

  • Pulmonary

    • Adult respiratory distress syndrome (ARDS)

    • Pneumonia (at times ventilator associated)

    • Chronic decreased diffusion capacity

  • Acute renal failure

    • Tubulonecrosis

    • Glomerulonephritis

  • Gastrointestinal

    • Stenosis leading to dysphagia and ileus-like symptoms

    • Pancreatitis

What should you tell the family about the patient's prognosis?

The prognosis depends on several factors including BSA involved, comorbidities, age, and several signs of systemic disease at the time of admission.

Score of toxic epidermal necrosis (SCORTEN) scale: 1 point is given for each risk factor (Table II).

Table II.

Score of toxic epidermal necrosis (SCORTEN) scale.
Prognostic factor Points SCORTEN Mortality rate (%)
Age >40 years 1 0-1 3.2
Heart rate >120 beats per minute 1 2 12.1
Cancer or hematologic malignancy 1 3 35.8
Body surface area >10% on day 1 1 4 58.3
Serum urea >10mmol/L 1 > or = 5 90
Serum bicarbonate <20mmol/L 1
Serum glucose >14mmol/L 1
  • Overall mortality ranges from 1 to 9% in SJS and 25 to 35% in TEN.

  • Respiratory tract involvement is another poor prognostic indicator.

  • The most common cause of death in patients with SJS/TEN is infection.

Once the initial insult has occurred and the skin has sloughed, re-epithelialization typically begins fairly quickly from the edge of the ulcerations and from adnexal structures. The average time to re-epithelialization is 3 weeks.

How do you contract Stevens–Johnson syndrome/toxic epidermal necrolysis and how frequent is this disease?

  • 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

  • Though SJS is most commonly caused by exposure to medications, it can be seen in the setting of infection as well.

    • Most common:

      • Herpes

      • Mycoplasma pneumoniae

    • Bacterial

      • Yersinia

      • Mycobacterium tuberculosis

      • Chlamydia

      • Treponema pallidum

      • Streptococcus

    • Fungal

      • Coccidioidomycosis

      • Histoplasmosis

    • Other Viral

      • Enteroviruses

      • Measles

      • Adenovirus

      • Influenza

What is responsible for this disease?

Though the exact pathophysiology of SJS/TEN is only partially understood, evidence suggests that cytotoxic T cells initiate the disease resulting in keratinocyte apoptosis followed by necrosis and sloughing. The cell-mediated immune response is felt to be the result of an antigenic complex composed of drug metabolites and host tissues. Granzyme B has been implicated but this requires cell-to-cell contact for killing and in most histologic sections of SJS/TEN, the cellular infiltrate is minimal compared to the level of epidermal necrosis. As such, a soluble cytokine likely plays a role. The most likely culprits include Fas ligand (FasL) and granulysin. FasL and its cognate death receptor Fas, are both upregulated on keratinocytes in TEN. Granulysin, secreted by cytotoxic T cells, natural killer (NK) cells, and NKT cells, is a cytolytic protein and is likely involved in keratinocyte death in TEN. Tumor necrosis factor (TNF) is also elevated in patients with TEN which may explain why TNF-α inhibitors have shown some success in treatment.

In HIV+ patients, there is a relative decrease in CD4+ Tcells, including regulatory Tcells, compared with non-HIV infected patients. This may contribute to the significantly increased risk of developing SJS/TEN in HIV+ patients.

What other clinical manifestations may help me to diagnose and manage Stevens–Johnson syndrome/toxic epidermal necrolysis?

It is very important when seeing a patient with SJS/TEN to meticulously evaluate all medications used in the past 4 to 6 weeks. If the culprit drug cannot be identified, stopping ALL medications should strongly be considered.

What other additional laboratory studies may be ordered?

  • Should be directed by signs and symptoms

How can Stevens–Johnson syndrome/toxic epidermal necrolysis be prevented?

  • If prescribing carbamazepine to a patient of Asian ethnicity (except Japanese), obtain HLA testing for HLA-B*1502

  • In HIV-positive patients it is felt that starting at lower doses of nevirapine may be helpful

WHAT'S THE EVIDENCE for specific management and treatment recommendations?

Lebargy, F, Wolkenstein, P, Gisselbrecht, M. "Pulmonary complications in toxic epidermal necrolysis: a prospective clinical study". Intensive Care Med. vol. 23. 1997. pp. 1237-44.

(Prospective trial showing that a normal chest radiograph when accompanied by other signs or symptoms may still portend a poor prognosis and ventilation requirement.)

Chave, TA, Mortimer, NJ, Sladden, MJ, Hall, AP, Hutchinson, PE. "Toxic epidermal necrolysis: current evidence, practical management, and future directions". Br J Dermatol. vol. 153. 2005. pp. 241-53.

(Review of TEN including pathophysiology and treatment options.)

Boorboor, P, Vogt, PM, Bechara, FG, Alkandari, Q, Aust, M, Gohritz, A, Spies, M. "Toxic epidermal necrolysis: use of Biobrane for skin coverage reduces pain, improves mobilization and decreases infection in elderly patients". Burns. vol. 34. 2008. pp. 487-92.

(Comparative study of Biobrane and paraffin gauze in 14 patients with TEN.)

Barvaliya, M, Sanmukhani, J, Patel, T, Paliwal, N, Shah, H, Tripathi, C. "Drug-induced Stevens–Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and SJS-TEN overlap: a multicentric retrospective study". J Postgradmed. vol. 57. 2001. pp. 115-19.

(Review of tertiary care hospitals cases of SJS/TEN focusing on causative drugs, clinical outcome, and cost.)

James, WD, Berger, TG, Elston, DM. "Andrews' Diseases of the Skin". Saunders-Elsevier. 2011. pp. 297-301.

(Excellent review of SJS/TEN based on the literature.)

Reiger, A, Chen, TM, Cockerell, CJ, Bolognia, JL, Jorizzo, JL, Rapini, RP. "Chapter 77. Cutaneous manifestations of HIV infection and HIV-related disorders". Dermatology. vol. 1171. Mosby-Elsevier. 2008.

(Detailed review of SJS/TEN including pathophysiology, epidemiology, clinical manifestations, and treatment.)

Williams, J, Coulson, I, Lebwohl, MG, Heymann, WR, Berth-Jones, J. "Treatment of Skin Disease Comprehensive Therapeutic Strategies". Seborrheic eczema. Saunders-Elsevier. 2010. pp. 694-6.

(This book evaluates the evidence for treatments for many different diseases of the skin. It grades them as A: double-blind studies, B: clinical trial with greater than or equal 20 subjects, C: clinical trial with less than 20 subjects, D: case series of more than four subjects, and E: anecdotal case reports.)

Paquet, P, Piérard, G. "Topical treatment options for drug-induced toxic epidermal necrolysis (TEN)". Expert Opin Pharmacother. vol. 11. 2010. pp. 2447-58.

(Excellent review of peer-reviewed literature on topical therapies used in the treatment of TEN.)

The typical length of stay will depend on BSA involved and complications that occur during the hospitalization. Hospitalizations ranging from 5 to 30 days are commonly reported.

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