Toxic epidermal necrolysis

Synonym: Lyell's syndrome, after Alan Lyell who first described four cases of toxic epidermal necrolysis in 1956 as 'an eruption resembling scalding of the skin.'

What is toxic epidermal necrolysis?

Toxic epidermal necrolysis (TEN) 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, and sloughing of the skin and mucosa, involving internal and external surfaces.¹ 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 TEN.²

Definitions vary and another classification system works on the fact that SJS and TEN are related conditions which can be differentiated by the degree of skin involvement. Less of the epidermis sloughs off in SJS, whereas TEN may be defined as involving >30% of the total body surface area.³

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, it may be that erythema multiforme should not be classified as part of the same disease spectrum.⁴

Stevens–Johnson syndrome and toxic epidermal necrolysis are associated with significant morbidity and mortality, and early diagnosis and treatment is critical in achieving favourable outcomes for patients.⁵

What causes toxic epidermal necrolysis? (Aetiology)^{1 6}

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. Specifically, cytotoxic T lymphocytes cause keratinocyte damage and subsequent necrosis, mediated by granzyme B. Cytotoxic molecules including FasL and granulysin have been implicated as causing the widespread keratinocyte apoptosis.

Risk factors

• Certain drugs: usually the reaction begins within a few days to two months after starting a new drug. There are many culpable medications. More than 200 have been associated with SJS/TEN.² Those most commonly involved are:
  

  • Sulfonamides.

  • Ampicillin.

  • Quinolones.

  • Cefalosporins.

  • Anticonvulsants - phenobarbital, phenytoin, carbamazepine, lamotrigine and valproate.

  • Allopurinol.

  • Antiretrovirals.

  • Corticosteroids.

  • Non-steroidal anti-inflammatory drugs, especially 'oxicam' derivatives such as piroxicam and meloxicam.

• 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 and are known to trigger TEN without any drug exposure.

• Systemic lupus erythematosus (SLE) and malignancy are thought to increase the risk of TEN.

• In some cases there is no identifiable cause.

• Genetic factors seem to play a part in some cases, with study results varying geographically. For those of East Asian descent, in particular, it may be important to perform testing for HLA-B 1502 prior to starting treatment with carbamazepine.⁷

Toxic epidermal necrolysis epidemiology

• Worldwide incidence is 1-2 cases per million population per year.³

• It can affect all age groups but is more common in elderly people, perhaps due to the increased numbers of drugs that they are prescribed.

Toxic epidermal necrolysis symptoms (presentation)⁵

• There is a prodromal phase usually lasting 2-3 days with fever, symptoms similar to upper respiratory tract infection, conjunctivitis, pharyngitis, pruritus, malaise, arthralgia and myalgia.

• Mucous membrane involvement occurs early in 90% of cases and commonly precedes other symptoms.⁶ The conjunctivae, buccal, nasal, pharyngeal, tracheobronchial, perineal, vaginal, urethral and anal mucosae may all be involved.

• An ill-defined red 'burning/painful' macular or papular rash then develops, spreading from the face or the 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.

• Nikolsky's sign may be positive: if areas of seemingly normal skin between lesions are rubbed, the epidermis easily separates from its underlying surface.

Differential diagnosis

• Staphylococcal scalded skin syndrome (SSSS).

• 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 - may be due to infected menstrual tampons).

• Erythroderma/exfoliative dermatitis.

Investigations

• There are no confirmatory tests.

• Skin biopsy is used to distinguish from SSSS, and immunofluorescence staining is performed. There is full thickness epidermal necrosis in TEN plus epidermal detachment and sloughing.

• Percentage of body surface area affected distinguishes SJS from TEN.

• FBC, U&E, albumin, total protein and proteinuria must be closely monitored.

• Screening blood, urine and skin cultures should be collected.

Toxic epidermal necrolysis treatment and management⁵

A combination of intravenous immunoglobulin (IVIg) and corticosteroids is most effective for SJS/TEN overlap and TEN. However, optimal therapeutic options such as systemic corticosteroids, intravenous immunoglobulin, ciclosporin, and TNF-α antagonists are still controversial.⁸

Following cessation of the culprit trigger, management in a specialised burns unit is often essential. A multidisciplinary team is essential, and the involvement of dermatology, ear, nose, and throat surgery, ophthalmology, urology, colorectal surgery, and gynaecology may all be required.⁹

• Management involves identifying the causative agent early where possible, and withdrawing it, along with supportive care. Early cessation of the causative drug is associated with better outcomes.²

• Patients need transfer to a unit where they can receive intensive care, ideally a burns unit or HDU/ITU. Early admission to a burns or high dependency unit improves survival and reduces infection.²

• A great deal of supportive care is required. Fluid and electrolytes, infection and nutritional status all need very careful monitoring and treatment should be started as soon as possible.¹⁰

• 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.

• Dressings, emollients and saline may be applied to the affected skin. Use of 'anti-shear' therapy, which utilises a type of dressing that minimises the removal of delicate granulation tissue, may be helpful.¹¹

• Other treatments which have been used, but for which benefit remains uncertain, include:^{6 7}

  • Plasmapheresis.

  • Ciclosporin A.¹²

  • Tumour necrosis factor (TNF) antagonists - eg, infliximab, etanercept.^{13 14}

• Anticoagulation treatment reduces the risk of thromboembolism.

• Topical steroids may be useful when used early in ocular disease.¹⁵ Early ophthalmological advice is essential to reduce the risk of ophthalmological sequelae.

• 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.

Complications²

Acute phase

• Widespread skin sepsis and septicaemia.

• Pneumonia and respiratory failure.

• Dehydration (increased fluid loss, inability to drink if the mouth is involved).

• Hypovolaemic shock and multi-organ failure.

• Thromboembolism, including pulmonary embolism, and disseminated intravascular coagulopathy.

• Thermoregulatory disturbance.

Long-term

• Ocular complications, which may lead to blindness. 50% of those surviving TEN are said to develop ocular complications such as:⁶

  • Dry eyes or watery eyes (the most common - 46% of cases).

  • Conjunctivitis.

  • Corneal ulcers.

  • Symblepharon.

  • Ectropion and entropion.

  • Trichiasis.

  • Synechiae.

• Joint contractures.

• Loss of nails.

• Stomatitis and mucositis.

• Gastrointestinal haemorrhage.

• Oesophageal strictures and dysphagia.

• Phimosis.

• Gynaecological and obstetric complications - premature labour, long-term painful genitourinary lesions, vaginal stenosis, adenosis and telangiectasias.¹⁶

• Hypopigmentation or hyperpigmentation of skin; there may be scarring if infection has developed.

Prognosis

Mortality risk increases with the surface area involved, and is between 16-55%.³ It also depends on the quality of care and rapidity of diagnosis and treatment. A severity-of-illness score called the SCORTEN Scale is used, and has been demonstrated to have prognostic accuracy.¹⁷ 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 >10 mmol/L.

• Serum bicarbonate <20 mmol/L.

• Serum glucose >14 mmol/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%.

Prevention

Patients who survive must be warned which drugs to avoid in the future, and the reaction documented and highlighted in their records.