Toxic epidermal necrolysis
Toxic epidermal necrolysis (TEN) is a type of severe skin reaction.[2] Together with Stevens–Johnson syndrome (SJS) it forms a spectrum of disease, with TEN being more severe.[2] Early symptoms include fever and flu-like symptoms.[2] A few days later the skin begins to blister and peel forming painful raw areas.[2] Mucous membranes, such as the mouth, are also typically involved.[2] Complications include dehydration, sepsis, pneumonia, and multiple organ failure.[2]
Toxic epidermal necrolysis
Lyell syndrome, Lyell's syndrome[1]
Age > 40[3]
> 30% of the skin involved, skin biopsy[3]
Hospitalization, stopping the cause, pain medication[3]
1–2 per million per year (together with SJS)[2]
The most common cause is certain medications such as lamotrigine, carbamazepine, allopurinol, sulfonamide antibiotics, and nevirapine.[2] Other causes can include infections such as Mycoplasma pneumoniae and cytomegalovirus or the cause may remain unknown.[3][4] Risk factors include HIV/AIDS and systemic lupus erythematosus.[2] Diagnosis is based on a skin biopsy and involvement of more than 30% of the skin.[3] TEN is a type of severe cutaneous adverse reactions (SCARs), together with SJS, a SJS/TEN, and drug reaction with eosinophilia and systemic symptoms.[5] It is called SJS when less than 10% of the skin is involved and an intermediate form with 10 to 30% involvement.[3] Erythema multiforme (EM) is generally considered a separate condition.[6]
Treatment typically takes place in hospital such as in a burn unit or intensive care unit.[3][7] Efforts include stopping the cause, pain medication, and antihistamines.[3][4] Antibiotics, intravenous immunoglobulins, and corticosteroids may also be used.[3][4] Treatments do not typically change the course of the underlying disease.[3] Together with SJS it affects 1 to 2 persons per million per year.[2] It is more common in females than males.[3] Typical onset is over the age of 40.[3] Skin usually regrows over two to three weeks; however, recovery can take months and most are left with chronic problems.[3][4]
Signs and symptoms[edit]
Prodrome[edit]
TEN ultimately results in extensive skin involvement with redness, necrosis, and detachment of the top (epidermal) layer of the skin and mucosa. Before these severe findings develop, people often have a flu-like prodrome, with a cough, runny nose, fever, decreased appetite and malaise. A history of drug exposure exists on average 14 days (ranging from 1–4 weeks) prior to the onset of symptoms, but may result as early as 48 hours if it is a reexposure.[8]
Skin findings[edit]
Initial skin findings include red-purple, dusky, flat spots known as macules that start on the trunk and spread out from there. These skin lesions then transform into large blisters. The affected skin can then become necrotic or sag from the body and peel off in great swaths.[7]
Pathogenesis[edit]
The immune system's role in the precise pathogenesis of TEN remains unclear. It appears that a certain type of immune cell (cytotoxic CD8+ T cell) is primarily responsible for keratinocyte death and subsequent skin detachment. Keratinocytes are the cells found lower in the epidermis and specialize in holding the surrounding skin cells together. It is theorized that CD8+ immune cells become overactive by stimulation from drugs or drug metabolites. CD8+ T cells then mediate keratinocyte cell death through release of a number of molecules, including perforin, granzyme B, and granulysin. Other agents, including tumor necrosis factor alpha and Fas ligand, also appear to be involved in TEN pathogenesis.[6]
Confluent Epidermal Necrosis, low mag
Confluent Epidermal Necrosis, high mag
Treatment[edit]
The primary treatment of TEN is discontinuation of the causative factor(s), usually an offending drug, early referral and management in burn units or intensive care units, supportive management, and nutritional support.[7]
Current literature does not convincingly support use of any adjuvant systemic therapy. Initial interest in Intravenous immunoglobulin (IVIG) came from research showing that IVIG could inhibit Fas-FasL mediated keratinocyte apoptosis in vitro.[19] Unfortunately, research studies reveal conflicting support for use of IVIG in treatment of TEN.[20] Ability to draw more generalized conclusions from research to date has been limited by lack of controlled trials, and inconsistency in study design in terms of disease severity, IVIG dose, and timing of IVIG administration.[7]
Larger, high quality trials are needed to assess the actual benefit of IVIG in TEN.
Numerous other adjuvant therapies have been tried in TEN including, corticosteroids, ciclosporin, cyclophosphamide, plasmapheresis, pentoxifylline, acetylcysteine, ulinastatin, infliximab, and granulocyte colony-stimulating factors (if TEN associated-leukopenia exists). There is mixed evidence for use of corticosteroids and scant evidence for the other therapies.[7] A meta-analysis from 2002 concluded that there is no reliable evidence for the treatment of TEN.[21] Thalidomide did not show any benefit and was associated with increased mortality compared with placebo.[21]