Toxic epidermal necrolysis L51.2

Severe maximum variant of drug reaction characterized by extensive detachment of the skin as well as mucous membranes, severe systemic concomitant symptoms and by high mortality (20-50%). The risk of TEN is highest between days 4 and 28 after initiation of drug therapy. The disease is considered to be the maximum variant of SJ syndrome ( Stevens-Johnson syndrome) with a minimum involvement of > 30% of the body surface.

• Incidence: About 0.15-0.18/100,000 inhabitants/year.
• More common in patients with manifest AIDS (incidence is 100/100,000 per year for those infected with HIV).

• The pathogenesis is unknown. Clinical and histologic similarities to severe cutaneous graft-versus-host reactions suggest a common pathogenesis. Evidence suggests that various drugs such as cotrimoxazole and other sulfonamides, antiepileptic drugs, allopurinol (probably the most common cause!), oxicam (nonsteroidal anti-inflammatory drug), psychotropic drugs, anticonvulsants (e.g. phenytoin and phenobarbital), serotonin reuptake inhibitors (e.g. fluoxetine) trigger TEN.
• No evidence of increased risk has been demonstrated for widely used medications such as beta-blockers, ACE inhibitors, calcium channel blockers, thiazides, furosemide, sulfonylureas, and insulin.
• Vaccinations ( measles, mumps, rubella) have been described sporadically in the literature as a trigger. For specific concomitant diseases such as HIV, collagenoses, tumor diseases, radiation therapy and acute infections within the last 4 weeks a significant risk could be calculated.

• Predominantly women are affected (up to 10 times more frequently than men).
• The average age is 60-70 LJ.
• Children and young people are very rarely affected.

• Initially fine-spotted, later confluent, large-area initially macular, subsequently maculo-papular and finally vesicular exanthema. Furthermore: extensive epidermal detachment (epidermal necrolysis) with towel-like detachable skin.
• Early involvement of upper and lower eyelids with hemorrhagic crusted erosions.
• Conjunctivitis with tendency to symblepharon formation.
• Oral and genital mucosa: inflammatory redness, erosions, ulcerations, hemorrhagic crusting, possible adhesions.
• General: high fever, possibly somnolence, exhaustion.
• Often rapid need for intensive care!

• Extensive necrolysis of the epidermis with intra- and subepidermal blister formation. Bladder contents are mostly hemorrhagic. Oedematized dermis, epitheliotropic round cell infiltrates and vasodilatation are also observed.
• Cryostat section: For a quick diagnosis a biopsy with a fresh blister cover, which is formed by the entire epidermis, is necessary.

• Staphylococcal Scalded Skin Syndrome: here, intraepidermal blister formation and therefore significantly reduced blister thickness. Typical is the absence of mucosal involvement.
• Erythema exsudativum multiforme (major forms)
• Paraneoplastic pemphigus.

• Skin: scarring, pigmentary disorder, nail growth disorders(Beau-Reil's transverse furrows of the nails, nail loss). Diffuse toxic alopecia (usually reversible) (see alopecia). Bacterial or viral infections of the skin. Risk of sepsis with development of shock and multiple organ failure (most common cause of death). Mucosal lesions of oropharynx, genitals or anal region.
• Eyes: Initial mucopurulent inflammation, conjunctival necrosis (goblet cell destruction, cornification), corneal ulcers. Late sequelae are scarring with trichiasis, keratoconjunctivitis sicca or synechiae.
• Kidneys: Tubular necrosis.
• Lungs: Respiratory failure.
• Gastrointestinal: Hemorrhage.
• Blood: Leukopenia.
• Fluid, electrolyte and protein losses.

• Intensive care in appropriately equipped therapy units.
• Discontinuation of the medication in question.
• Isolation/protection against infection (set up airlock).
• Aseptic protective clothing: protective gowns, mouthguards, gloves for medical and nursing staff.
• Sufficient heat supply (exact temperature control).
• Ensure sufficient moisture content of the room air.
• Use special bed for decubitus prophylaxis and store on metal foil.
• If necessary, place a bladder catheter, urine and fluid balancing.
• Documentation of the collected findings (extent, severity on intensive care treatment sheets).
• If necessary, take swabs of the wound surfaces (culture with resistance behaviour; danger from Pseudomonas colonisation and other superinfections).
• Therapy of complications (sepsis, bleeding).

Glucocorticoids: The use of systemic glucocorticoids is controversial. Some studies indicate a worse prognosis with high-dose glucocorticoid medication. Nevertheless, short-term shock therapy is still recommended (1000-250-100-20 mg prednisolone i.v. on day 1 to 4). Ulcer prophylaxis with ranitidine (e.g., Zantic) 150 mg/day.

Ciclosporin A: Previously controversial, a larger Spanish study (n=26 pat.) demonstrated a significant reduction in mortality risk compared to a non-ciclosporin A-treated collective (IVIG therapy) (Gonzales-Herrada C et al. (2017).

IVIG: Initial 1.0 g/kg bw for 4 days and maintenance therapy of 0.5 g/kg bw (4-week cycle) for several months in case of resistance to therapy with other regimens. Data situation: The efficacy of IVIG therapy is controversial based on evidence level IIA studies.

Antibiotics (only for superinfection): Antibiotic coverage with cephalosporins such as cefotaxime (e.g. Claforan) 2 times/day 2 g i.v., if necessary in combination with gentamicin (e.g. Refobacin) 240 mg/day i.v. Daily swabs on the wound surfaces and if necessary change of antibiosis according to antibiogram.

Pain therapy: Morphine (e.g. MST Tbl.) 10-30 mg every 8 hrs or opioids such as tramadol (Tramal) 100 mg every 4-6 hrs (max. 400 mg/day).

• Fluid balancing: In severe courses, initiate fluid balancing and parenteral nutrition. Dosage regimen per day:
  • Colloidal solution 1 ml/kg bw x affected KO.
  • Electrolyte solution (physiologic saline) 1 ml/kg times affected KO.
    At stabilization: transition to high caloric liquid diet (e.g. Meritene). Later diet with passaged food; no spices, no fruit acids.

• Reminder. Check intravenous lines regularly (high risk of contamination)!

• Reminder. In case of glucocorticoid administration and therapy with ciclosporin A, a bacterial cause of TEN (staphylogenic Lyell syndrome) must be safely excluded!

Remember! Report to the Documentation Centre of Severe Skin Reactions, Dermatological Clinic of the University of Freiburg, Hauptstr. 7, 79104 Freiburg. Web: http://www.ukl.uni-freiburg.de/haut/dzh/homede.htm

1. Bachot N et al (2001) Physiopathology and treatment of severe drug eruptions. Curr Opin Allergy Clin Immunol 1: 293-298
2. Boujeau JC et al (1990) Toxic epidermal necrolysis (Lyell syndrome). Arch Dermatol 126: 37-42
3. Campione E et al (2003) High-dose intraveous immunoglobulin for severe drug reactions: efficacy in toxic epidermal necrolysis. Acta Derm Venerol 83: 430-432
4. González-Herrada C et al (2017) Cyclosporine Use in Epidermal Necrolysis Is Associated with an ImportantMortality
   Reduction: Evidence from Three Different Approaches. J Invest Dermatol 137:2092-2100.
5. Halvey e t al (2008) Allopurinol is the most common cause of Stevens-Johnson syndrome and toxic epidermal necrolysis in Europe in Israel. JAAD 58: 25-32
6. Hanken et al (2010) Primary care and drug treatment of patients with toxic epidermal necrolysis. JDDG 8: 341-347
7. Luther H, Kastner U, Altmeyer P (1999) Comment on the contribution by Lyell A (1956) Toxic epidermal necrolysis: An eruption resembling scaling of the skin. Br J Dermatol 68: 355-361
8. Mockenhaupt M et al (2008) Stevens-Johnson syndrome and toxic epidermal necrolysis: assessment of medication risks with emphasis on recently marketed drugs. The EuroSCAR-study. J Invest Dermatol 128: 35-44
9. Nassif A et al (2002) Drug specific cytotoxic T-cells in the skin lesions of a patient with toxic epidermal necrolysis. J Invest Dermatol 118: 728-733
10. Prins C et al Treatment of toxic epidermal necrolysis with high-dose intravenous immunoglobulins: multicenter retrospective analysis of 48 consecutive cases. Arch Dermatol 139: 26-32
11. Roujeau JC et al (1990) Toxic epidermal necrolysis (Lyell syndrome). J Am Acad Dermatol 6: 1039-1062
12. Schöpf E et al (1991) Toxic epidermal necrolysis and Stevens-Johnson syndrome. Arch Dermatol 127: 839-842
13. Spornraft-Ragaller P et al (2007) Treatment of toxic epidermal necrolysis. Experiences in nine patients considering intravenous immunoglobulins. skin 2: 62-68
14. Trent JT et al (2003) Analysis of intravenous immunoglobulin for the treatment of toxic epidermal necrolysis using SCORTEN: The University of Miami Experience. Arch Dermatol 139: 39-43
15. Wolff K et al (2003) Treatment of toxic epidermal necrolysis: the uncertainty persists but the fog is dispersing. Arch Dermatol 139: 85-86