Toxic Epidermal Necrolysis

Synonym: Lyell's Syndrome, after Alan Lyell who first described 4 cases of Toxic Epidermal Necrolysis in 1956 as " an eruption resembling scalding of the skin".¹

Toxic Epidermal Necrolysis is an acute onset, potentially life-threatening, idiosyncratic mucocutaneous reaction, usually occurring after commencement of a new medication.

Widespread full-thickness epidermal necrosis develops producing erythema, large blisters and/or exfoliation of large sheets of skin leaving a raw base.² The skin has an appearance similar to a scald. It usually affects the trunk, face and one or more mucous membranes.

It is considered by some as being part of a spectrum of disease which includes, in order of severity, erythema multiforme, Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN). However, others argue that as erythema multiforme is associated with infections including herpes simplex virus and Mycoplasma pneumoniae, whereas SJS and TEN are necrolytic bullous reactions to certain drugs, erythema multiforme should not be classified as part of the same disease spectrum.²

Another classification system works on the fact that SJS and TEN are related conditions that can be differentiated by the degree of skin involvement. Less than 10% of the epidermis sloughs off in Stevens-Johnson syndrome as compared to >30% in TEN.³

There is thought to be an immune-complex mediated hypersensitivity reaction to the presence of toxic drug metabolites which accumulate in the skin. This reaction results in the destruction of keratinocytes.

Infection, malignancy and vaccination have also been suggested as other possible aetiologies.⁴ There may be no obvious trigger (idiopathic TEN).

• Certain drugs: Usually the reaction begins within 4 to 8 weeks after starting a new drug. There are many culprit medications. Those most commonly involved are:
  • Sulphonamides
  • Ampicillin
  • Anticonvulsants, especially phenobarbitone, phenytoin, carbamazepine, valproate
  • Allopurinol
  • Antiretrovirals
  • Corticosteroids
  • NSAIDs, especially 'oxicam' derivatives such as piroxicam
• The reaction is more rarely triggered by some immunisations and following bone marrow or organ transplantation. The skin manifestations of graft-versus-host disease are thought to have a similar aetiology to TEN.
• Infections such as mycoplasma and HIV are also associated.
• SLE and malignancy are thought to increase the risk of TEN.

• Worldwide incidence is 0.5 to 1.4 cases per million population per year.⁴
• Females are more commonly affected.⁴
• It can affect all age groups but is more common in elderly people, probably due to the increased numbers of drugs that they are prescribed.

• There is a prodromal phase lasting from 2-3 days to up to 3 weeks with fever, symptoms similar to URTI, rash, conjunctivitis (32%), pharyngitis (25%), pruritis (28%), malaise, arthralgia and myalgia.²
• Mucous membrane involvement occurs early in 90% of cases and commonly precedes other symptoms. The conjunctivae, buccal, nasal, pharyngeal, tracheo-bronchial, perineal, vaginal, urethral and anal mucosa may all be involved.
• An ill-defined red "burning/painful" macular or papular rash then develops spreading from the face or upper trunk. Bullae form and then coalesce. They generally increase in number over 3-4 days (sometimes hours). The epidermis can then slough in sheets.
• There may be hyperpyrexia.
• Hypotension and tachycardia can develop secondary to dehydration and hypovolaemia.
• The Nikolsky sign: If areas of seemingly normal skin between lesions are rubbed, the epidermis easily separates from its underlying surface.

Staphylococcal scalded skin syndrome (SSSS)

This differs from TEN in that there is a focal infection with staphylococcus. A circulating toxin produced by the bacteria causes intraepidermal blistering. Oropharyngeal involvement is rare and systemic illness tends to be less severe in SSSS. It more commonly affects children. It rarely affects adults, as they usually have sufficient antibodies to the exfoliative exotoxin, and are better able to excrete the toxin via the kidneys. Treatment is supportive as for burns, and with antibiotics. Mortality in children is around 4% (~50% in adults). This condition is differentiated from TEN on the basis of skin biopsy/frozen section of sloughed skin. In TEN cleavage is deeper in the dermis than in SSSS.

Other differential diagnoses

• Burns (chemical, light or heat)
• Bullous impetigo
• Pemphigus, pemphigoid (generally of slower onset)
• Epidermolysis bullosa hereditaria
• SLE
• Scarlet fever (desquamation but no bullae)
• Other drug eruptions
• Erythema multiforme
• Bullous lichen planus
• Toxic shock syndrome (toxin mediated reaction to staphylococcal infection - check for infected tampons)
• Exfoliative dermatitis

• There are no confirmatory tests.
• Skin biopsy and immunofluorescence staining should be considered if pemphigus/pemphigoid are suspected. There is full thickness epidermal necrosis in TEN plus epidermal detachment and sloughing.
• FBC, U&E, albumin, total protein and proteinuria must be closely monitored.
• Screening blood, urine and skin cultures should be collected.
• Multiple organ involvement occurs as TEN progresses.

• There is currently no generally accepted specific treatment regimen.⁵
• Patients need transfer to a unit where they can receive intensive care, ideally a burns unit or HDU/ITU.
  A multidisciplinary approach to care is needed including dermatologists, general physicians, surgeons, nurses and physiotherapists.
• Detection and withdrawal of potential causative agents is needed.⁴
• Treatment is largely supportive. Fluid and electrolytes, infection and nutritional status all need very careful monitoring. Dressings, emollients and saline may be applied to the affected skin.
• Debridement of necrotic areas of skin may be needed. The exposed dermis needs protecting with skin grafting to prevent fluid and protein loss and infection as well as to control pain.
• Antibiotics are generally not given prophylactically.
• Oral hygiene and opthalmological treatment, including lubricants and topical antibiotics are needed.
• Anticoagulation treatment reduces the risk of thromboembolism.
• High dose steroids are sometimes used⁵, but firm justification for their use is lacking, and some studies have shown increased mortality with their use.⁶
• Intravenous human immunoglobulins showed positive results in some trials^7,8,9 but this finding has been challenged.^10,11
• Other therapies that have been used include plasmapheresis, cyclophosphamide, pentoxyfilline, thalidomide, anti-TNF-alpha antibodies and cyclosporin A with mixed outcomes.¹⁰
• Small numbers involved in trials and the difficulty of enrolling critically ill patients mean that definitive evidence is hard to come by. Multicentre randomised controlled trials are needed to look at the treatments for TEN.⁹

• Widespread skin sepsis and septicaemia (50% of deaths in TEN are attributed to this).⁴
• Pneumonia and respiratory failure.
• Dehydration (increased fluid loss, inability to drink if mouth involved).
• Hypovolaemic shock and acute tubular necrosis.
• Thermoregulatory disturbance.
• Ocular damage, corneal involvement and visual loss (5-9% of patients with TEN become blind).⁴
• Stomatitis and mucositis.
• Gastrointestinal haemorrhage.
• Pulmonary embolism.
• Oesophageal strictures and dysphagia.
• Genitourinary lesions and erosion.
• Hypo or hyperpigmentation of skin; there may be scarring if infection has developed.

Mortality is between 10–70%.⁴ It depends on the quality of care and rapidity of diagnosis and treatment. A severity-of-illness score has been developed called SCORTEN.⁴ A score of one is given to each of the following prognostic factors if they are present:

• Age >40
• Heart rate >120 bpm
• The presence of cancer or haematological malignancy
• Involved body surface area >10%
• Serum urea >10mmol/L
• Serum bicarbonate <20mmol/L
• Serum glucose >14mmol/L

A mortality risk can then be attributed to the scores achieved:

• Score 0-1: 3.2%
• Score of 2: 12.1%
• Score of 3: 35.3%
• Score of 4: 58.3%
• Score of ≥ 5: 90%

Patients who survive must be warned which drugs to avoid in the future.