• FUNDAMENTALS
  • PATHOLOGY & AETIOLOGY
  • CLINICAL FEATURES
  • DIAGNOSIS & INVESTIGATIONS
  • MANAGEMENT

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Introduction & Definitions

What are Stevens Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN)? What is the difference between the two?
  • SJS and TEN are severe muco-cutaneous reactions characterized by erythema, extensive epidermal necrosis, and widespread bullous epidermal detachment. They are most commonly triggered by drugs and affect all age groups
  • Widespread skin loss from these conditions leads to ‘acute skin failure’ which is comparable with any other major organ dysfunction
  • Although rare, these conditions have high mortality rates, long critical care stays, and are associated with significant chronic morbidity
  • SJS and TEN are variants of the same disease spectrum, but distinguished chiefly by severity:
    • SJS is the less severe form, affecting <10% total body surface area (TBSA)
    • TEN is more severe and affects >30% TBSA
    • Cases which affect 10–30% are referred to as SJS/TEN overlap.
  • In total, 90% of cases involve mucous membranes of the mouth, eyes, and genital tract.

Epidemiology, Clinical Course & Prognosis

How common is SJS / TEN?
  • This rare condition has an annual estimated incidence of 0.4–1.2 cases per million
What is the prognosis in SJS / TEN?
  • The overall mortality rate for SJS is 10%, but increases to 30–50% in TEN
  • The main cause of in-hospital mortality is multi-organ failure from sepsis

Aetiology

What are the causes of SJS / TEN?
  • Drugs (Most common, 4-28 days after initiation)
    • Allopurinol
    • Anticonvulsants
    • Cotrimoxazole
    • ‘Sulfa’ drugs
    • Oxicam NSAIDs
    • Nevirapine
  • Infections:
    • HIV
    • CMV
    • Mycoplasma
  • Malignancy
  • Bone marrow transplant
  • Genetic predisposition
Which drugs are known to cause SJS / TEN?
Score
High Risk
Low Risk
Doubtful Risk
Antimicrobials
  • Sulfonamides
  • Nevirapine
  • Aminopenicillins
  • Cephalosporins
  • Quinolones
  • Macrolides
  • Tetracyclines
Anticonvulsants
  • Lamotrigine
  • Phenobarbital
  • Phenytoin
  • Carbamazepine
Analgesics
  • Oxicam NSAIDs
  • Acetic acid NSAIDs
  • Paracetamol
  • Pyrazolone analgesics
  • Other NSAIDs
Other
  • Sulfasalazine
  • Thiacetazone

Pathophysiology

What are the normal functions of the skin that can be lost in TEN?
Protection
  • Barrier function of stratum corneum protects against environmental, chemical, and microbial hazards
  • Limitation of inward and outward passage of water and electrolytes ensures the conservation of the internal milieu
  • Durability and elasticity of dermis contributes to protection against physical injury
  • Melanin production protects against ultra-violet radiation
Regulation
  • Temperature homeostasis is maintained by alteration of skin blood flow, sweating, and pilo-erection
  • Minor role in maintaining fluid balance by avoiding excessive evaporative water loss that would otherwise cause dehydration and cooling
Immune
  • Dynamic role in innate and acquired defense systems
Metabolic
  • Role in Vitamin D synthesis
  • Capability in transformation of some drugs
Neurosensory
  • Terminal fibres of sensory nerves and specialized sensory receptors lying within the dermis enable skin to act as a large sensory organ
Social
  • Visible portion of body covering

Yau et al.

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What are the pathological mechanisms underlying SJS / TEN?
  • Characterized histologically by keratinocyte apoptosis and separation of the epidermis from the dermis at the dermo-epidermal junction (black arrows)
  • Leads to extensive epidermal destruction
  • Proposed mediators are:
    • Cytokines including fas-fas ligand and tumour necrosis factor alpha
    • Direct toxic effect of drug triggering an immune reaction involving CD8+ lymphocytes

Presentation

How does SJS / TEN present?
  • Usually presents with prodrome for 2–3 days of fever, flu-like illness and malaise
  • Features can be described as those affecting: the skin, mucous membranes (involvement is characteristic of SJS / TEN) and extra-cutaneous sites
Skin

Initial Phase:

  • Erythematous, dusky red, flat macules
  • Lesions symmetrically distributed on face, trunk and limbs

Late Phase:

  • Lesion coalesce to form flaccid blisters
  • Epidermal detachment
Mucous Membranes
  • Eyelid oedema, redness and discharge
  • Buccal erosive haemorrhagic lesions, white pseudomembranous crust
  • Crust on lips
  • Genital erosive haemorrhagic lesions, painful urination
Extracutaneous Sites
  • Respiratory Tract: Respiratory distress
  • GI Tract: Nausea, diarrhoea, malabsorption, colonic perforation
  • Renal Tract: Proteinuria, haematuria

Differential Diagnosis

What is the differential diagnosis for SJS / TEN?
  • Erythema multiforme major
  • Acute generalized erythematous pustulosis
  • Intermediate burns
  • Generalized Fixed Bullous Drug Eruption
  • Staphylococcal Scalded Skin Syndrome
  • Edematous erythroderma
  • Bullous pemphigoid
  • Paraneoplastic pemphigus
  • Linear IgA Bullous Dermatosis
  • Lupus erythematosus
  • Exfoliative dermatitis

Work-Up Summary

How do you work up the patient with suspected SJS / TEN?
To Determine Diagnosis
  • Usually clinical diagnosis based upon characteristic features and identification of known trigger
  • Skin biopsy gold standard but usually used only in equivocal cases
To Determine Aetiology
  • Drug cause: Full drug history (prescription and over the counter medication)
  • Infectious cause: HIV screen, CMV, Mycoplasma
To Assess Severity
  • SCORTEN score: urea, blood gas / bicarbonate, glucose
    (Should be calculated within the first 24 hours)

Severity & Prognostic Scoring

Which score can be used to assess prognosis in SJS / TEN?

  • The SCORTEN is a validated scoring system to predict mortality

  • This should be scored within 24 hours of admission.

    • Age >40

    • Malignancy

    • Initial area greater >10%

    • Heart rate >120

    • Serum urea >10

    • Serum glucose >14

    • Serum bicarbonate <20

Score
Predicted Mortality (%)
0-1
3.2
2
12.1
3
35.3
4
58.3
5 or more
90

Management Summary

How do you manage the patient with SJS /TEN?

Key Principles

  • Early recognition and withdrawal of offending agents
  • Multidisciplinary supportive care in burns centre
  • Strict infection control as per BAD guidelines
Initial Resuscitation & Supportive Care
  • ABC approach treating abnormalities as found:
    • May require intubation if significant airway involvement
    • Careful fluid assessment and resuscitation with ongoing maintenance
    • IV access through non-lesioned skin, regularly replace
  • Maintenance fluids calculated with Parkland formula or more restrictive variant
  • Multimodal analgesia with opiate sparing agents
  • Multidisciplinary approach towards supportive care:
    • Strict asepsis, nurse in side room
    • Regular infection surveillance
    • Attention to thromboprophylaxis
Specific Management
  • Withdraw offending agent and treat underlying cause
  • Management of skin lesions:
    • Regularly cleanse wounds and intact skin by irrigation
    • Apply emollients and topical antimicrobial
    • Leave detached epidermis in situ
    • Necrotic lesions may need surgical debridement and skin grafting
  • Careful MDT approach to management of ocular, oral, genital and respiratory tract lesions:
    • Vigilant care of eyes with lubricants and drops
  • Experimental treatment - centre dependent:
    • IVIG
    • Ciclosporin
    • Corticosteroids (generally not recommended)
Monitoring, Referral & Deposition
  • Skin area >10% should be managed in a burns centre or medical ICU
  • Senior MDT approach:
    • Burns surgeon
    • Dermatologist
    • Ophthalmologist

Critical Care Admission and Specialist Referral

Which patients with SJS / TEN should be referred to the regional centre? What are the benefits of transfer?
  • Transfer to a regional burns centre should be considered for patients with:
    1. TEN (>30% BSA epidermal loss)
          and
    2. Evidence of any one of:
      • Clinical deterioration
      • extension of epidermal detachment,
      • sub-epidermal pus,
      • local sepsis,
      • wound conversion and/or delayed healing.
  • Transfer to a burns centre allows:
    • Supportive care provided by an experienced multidisciplinary team
    • Surgical intervention to allow debridement of necrotic or infected tissue

Specific Management

Which therapies have been used in the management of SJS / TEN and what is the evidence for their efficacy?
Therapy
Evidence
Intravenous Immunoglobulin (IVIg)
  • Proposed mechanism of action is antagonization of fas-fas ligand activity
  • No controlled studies have been performed with current evidence conflicted on its efficacy
  • A summary of current evidence has been produced by French et al
  • Despite this the use of IVIg is considered as a ‘Red’ indication for short term use by the department of Health Guidelines - considered the highest priority because of a risk to life without treatment
Corticosteroids
  • Although widely trialled shown to have no significant beneficial effect at best, and at worst be harmful, with some small studies reporting increased mortality with steroid use
  • Summary of current evidence has been produced but Law et al
  • They are currently not recommended for routine treatment
Ciclosporin
  • Proposed mechanism of action is suppressant of T-cell function reducing keratinocyte apoptosis
  • Data is scarce and of poor quality limiting recommendations

Law et al.

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French et al.

R

Supportive Management

How should skin be managed in SJS/TEN?
  • Skin should be handled gently with limitation of trauma
  • Conservative approach generally standard of care:
    • Necrotic loose tissue removed
    • Blisters pierced and loose dermis left in place to act as a biological dressing
    • Wounds and intact skin cleansed regularly
    • Regular application of emollient to whole skin and topical antibacterial to sloughy areas only
    • Non-adhesive antibacterial dressing used to cover lesions
  • Surgical debridement may be indicated, particularly if:
    • Local sepsis / subepidermal pus
    • Extensive epidermal detachment
How should mucosal lesions (ocular/ oral /genital / respiratory) be managed in SJS/TEN?
Treatment of Eye Involvement
  • Early ophthalmology review and review daily thereafter during acute illness
  • Frequent application of lubrication (hyaluronate or carmellose eye drops 2 hourly)
  • Corticosteroid drops (dexamethasone 0.1% twice a day) may reduce damage
  • If evidence of ulceration topical antibiotic prophylaxis should be used (e.g. moxifloxacin drops four times a day)
Treatment of Mouth Involvement
  • Manage lips with soft white soft paraffin ointment every 2 hours
  • Clean the mouth daily with an oral sponge
  • Use regular mouthwashes:
    • Anti-inflammatory: rinse or spray containing benzydamine hydrochloride every three hours
    • Anti-septic: rinse containing chlorhexidine twice a day
    • Corticosteroid: mouthwash (e.g. betamethasone sodium phosphate) four times a day
Treatment of Urogenital Involvement
  • Daily review is required during the acute illness
  • Corticosteroid cream should be administered to involved but non-eroded surfaces
  • Gynaecology review recommended for females to consider need for vaginal dilators
Treatment of Airway Involvement
  • Mechanical ventilation may be required if pulmonary infiltrates and respiratory failure develops
  • Fibreoptic bronchoscopy is useful to washout of necrotic bronchial epithelium
How can infection be prevented in SJS /TEN?
  • Wounds should be handled in a sterile manner whenever possible
  • Antimicrobial solutions for disinfection recommended
  • Use of bowel management systems may prevent wound soiling
  • No evidence for prophylactic use of antibiotics
  • Frequent wound swabs should be sent for surveillance and to guide antimicrobial therapy
How should fluid replacement be managed for patients with SJS/TEN?
  • Traditionally patients have been managed as burns patients:
    • Parkland formula applied for involvement >15%
    • Can result in overaggressive fluid replacement and related complications
  • Alternative regime of 2 mL/kg/ body weight / % BSA epidermal detachment / 24 hours has been suggested
  • Should be guided by urine output, lactate and other markers of tissue perfusion

Shiga et al.

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Author

The Guidewire
Trainee in ICM & Anaesthesia

Reviewer

The Guidewire
Trainee in ICM & Anaesthesia

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