Toxic epidermal necrolysis L51.2

Maximum variant of a drug-induced, inflammatory systemic reaction characterized by extensive, truncal, necrolytic detachment of the skin (>30% of the KOF) and mucous membranes, severe systemic side effects and high mortality (20-50%). The risk of toxic epithelial necrolysis is highest between the 4th and 28th day after initiation of drug therapy. The disease is considered a maximum variant of epidermal necrolysis (EN) - see also 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 in HIV-infected persons is 100/100,000 per year).

The pathogenesis is unknown. Clinical and histological similarities to severe cutaneous graft-versus-host reactions suggest a common pathogenesis.

There is evidence that drugs can trigger toxic epidermal necrolysis, even after long-term use. These include:

• Cotrimoxazole and other sulfonamides
• aminopenicillins
• cephalosporins
• Antiepileptic drugs
• Allopurinol (probably the most common cause!)
• Oxicam (non-steroidal anti-inflammatory drug)
• Psychotropic drugs
• Anticonvulsants (e.g. carbamzepine, phenytoin, phenobarbital, valproic acid, lamotrigine)
• Serotonin reuptake inhibitors (e.g. fluoxetine)

trigger a TEN.

No evidence of an increased risk has been found for widely used drugs such as beta-blockers, ACE inhibitors, calcium channel blockers, thiazides, furosemide, sulfonylureas and insulin.

Vaccinations ( measles, mumps, rubella) have occasionally been described in the literature as triggers. A significant risk could be calculated for specific concomitant diseases such as HIV, collagenoses, tumor diseases, radiotherapy and acute infections within the last 4 weeks.

Women are predominantly affected (up to 10 times more frequently than men).

The average age is 60-70 years.

Children and adolescents are very rarely affected.

Initially fine-spotted, later confluent, extensive initially macular, subsequently maculo-papular and finally vesicular exanthema. Furthermore: extensive epidermal detachment (epidermal necrolysis) with skin that can be pushed off like a towel.

Early involvement of upper and lower eyelids with hemorrhagic encrusting erosions.

Conjunctivitis with a tendency to form symblepharon.

Oral and genital mucosa: inflammatory reddening, erosions, ulcerations, hemorrhagic incrustation, possibly adhesions.

General: high fever, possibly somnolence, fatigue

Often rapid need for intensive care!

Extensive necrolysis of the epidermis with intra- and subepidermal blistering. Blister contents are usually hemorrhagic. Edematized dermis, epitheliotropic round cell infiltrates and vasodilatation are also seen.

Cryostat section: For rapid diagnosis, a biopsy with a fresh blister cover formed by the entire epidermis is required.

Staphylococcal scalded skin syndrome: here there is intraepidermal blistering and therefore significantly reduced blister thickness. The absence of mucosal involvement is typical.

Erythema exsudativum multiforme (EM-majus): Exanthema emphasizing the extremities, typical and atypical cockades, skin blisters <10% of the body surface area (KOF).

Paraneoplastic pemphigus: Frequently acute onset with painful erosions and ulcers of the oral mucosa. The stomatitis is unusually severe and resistant to treatment (painful extensive erosions and ulcers are visible). Furthermore, therapy-resistant inflammations occur on other transitional mucous membranes (rhinitis, pharyngitis, bronchitis, brochiolitis: note: in contrast to other types of pemphigus, an acantholytic loss of adhesion of the bronchial epithelium may also occur, balanitis and vulvitis). Detection of AK pemphigus!

Stevens-Johnson syndrome: As with TEN, trunk exanthema, atypical cockades, skin blisters <10% of the body surface area (KOF).

Skin: scarring, pigment disorders, 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 changes in the oropharynx, genitals or anal region.

Eyes: Initial mucopurulent inflammation, conjunctival necrosis (destruction of goblet cells, keratinization), corneal ulcers. Late effects are scarring with trichiasis, keratoconjunctivitis sicca or synechiae.

Kidneys: Tubular necrosis.

Lungs: Respiratory failure in 40% of patients; 25-30% require mechanical ventilation.

Gastrointestinal tract: Bleeding.

Blood: leukopenia

other parameters: fluid, electrolyte and protein losses.

General guidelines for the therapy of TEN:

Intensive care in appropriately equipped therapy units.

Discontinuation of the medication in question.

Isolation/protection against infection (set up an airlock).

Aseptic protective clothing: protective gowns, face masks, gloves for medical and nursing staff.

Adequate heat supply (precise temperature control).

Ensure sufficient humidity in the room air.

Use a special bed for decubitus prophylaxis and position on metal foil.

If necessary, insert bladder catheter, urine and fluid balancing.

Document the findings (extent, severity on intensive care treatment sheets).

Swab wound surfaces daily (culture with resistance behavior; risk of Pseudomonas colonization and other superinfections).

Treatment of complications (sepsis, bleeding).

Regular antiseptic wound treatment with antiseptic solutions or gels should be carried out to reduce the risk of infection. The antiseptics should be warmed. Solutions containing polihexanide and octenidine are recommended.

• In the case of minor skin detachment, the epidermis should be left in situ.
• If blisters form, they should be relieved by puncture. The blister cover remains in situ.
• In the case of extensive skin detachment, careful removal of the detached skin should be considered.

If no systemic treatment with glucocorticoids is given, topical glucocorticoid externals can be applied for a maximum of 5 days (glucocorticoids class III/IV in adults and corticoids class III in children and adolescents). They should be applied to lesional but not yet eroded areas of skin.

For the treatment of eroded areas of the skin, they should be applied to non-stick, non-adherent silicone spacers or greasy gauze to cover the wound. Silver-containing topicals and wound dressings are also used in acute care (silver sulphadiazine). Limitations include the increased risk of absorption of silver-containing particles (monitoring of leukocytes, liver and kidney values) and the possible causal triggering of toxic epidermolysis by sulfmethoxazole or sulfasalazine when silver sulfadiazine is used.

The frequency of topical antiseptic treatment is based on the frequency of dressing changes.

Topical antibiotics and antibiotic wound washes should be avoided.

Lip and oral mucosa involvement (frequent infestation): White kerosene or an ointment containing dexpanthenol should be applied to the erosive lip skin several times a day. Alternatively, white beeswax or a local anesthetic ointment would be indicated. Antiseptic mouthwashes should be carried out regularly. Rinsing with dexpanthenol or ointment solutions is also useful. Prophylactic administration of antibiotics or antiviral substances is not necessary.

Eye involvement (50-80% involvement): Preservative-free wetting agents should be used 1-2 hourly during the day to care for the ocular surfaces, regardless of severity. Ocular ointments should be used at night. If the ocular surface is intact, a preservative-free topical corticosteroid (e.g. 1% prednisolone) should be applied. If anti-inflammatory topical treatment is necessary for >2-4 weeks, a switch to topical calcineurin inhibitors (Ciclosporin A, Tacrolimus) is recommended.

Genital involvement (up to 70% involvement): In patients with erosive involvement of the genital mucosa or dysuria, a urinary catheter (Foley catheter) should be inserted. Gentle cleansing of the urogenital area with sterile water and physiological saline solution. Basic protective care (e.g. white kerosene ointment) should be applied several times a day. Topical corticosteroids can be applied for a maximum duration of 5 days (glucocorticoids class III/IV in adults and corticoids class III in children and adolescents). They should be applied to lesional but not yet eroded areas of skin. Covering the lesions with non-adherent fat gauze is recommended.

If the female genitals are involved, vaginal stents/phantoms should be used to avoid synechiae. Menstrual suppression may be considered.

Anal region involvement: Antiseptic sitz baths e.g. with potassium permanganate (light pink) and glucocorticoid creams (see above). Administration of mild laxatives to soften the stool; if necessary, switch to a strained or liquid diet; parenteral nutrition if necessary.

Caution! Eye involvement: treatment by an ophthalmologist. Symblepharon formation is possible!

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

Ciclosporin A: Previously controversially discussed, a large Spanish study (n=26 patients) demonstrated a significant reduction in the risk of mortality compared to a collective not treated with Ciclosporin A (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 (every 4 weeks) over several months in cases of resistance to therapy with other regimens. Data situation: The efficacy of IVIG therapy is controversially discussed on the basis of 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 antibiotic treatment according to antibiogram.

Pain therapy: Analgesia should be given according to the general recommendation for the treatment of perioperative and post-traumatic pain. Indicated are: Morphine (e.g. MST Tbl.) 10-30 mg every 8 hours or opioids such as Tramadol (Tramal) 100 mg every 4-6 hours (max. 400 mg/day).

Fluid balancing: In severe cases, initiate fluid balancing and parenteral nutrition. Dosage regimen per day:

• Colloidal solution 1 ml/kg bw x affected KO.
• Electrolyte solution (physiological saline solution) 1 ml/kg x affected KO.
• After stabilization: switch to high-calorie liquid food (e.g. Meritene). Later diet with strained food; no spices, no fruit acids.

Remember! Check intravenous accesses regularly (high risk of contamination)!

• Remember! When administering glucocorticoids and treatment with Ciclosporin A, a bacterial cause of TEN (staphylogenic Lyell syndrome) must be ruled out!

The mortality rate is approx. 20-25%, in smaller studies up to 60%. Intensive measures are necessary. The skin changes usually heal without scars. Bastuji-Garin et al. have developed a score that should allow a predictive statement on mortality - see below. SCORTEN.

Toxic epidermal necrolysis and Stevens-Johnson syndrome (SJS) were previously regarded as severe forms of erythema multiforme due to similarities in their clinical appearance. This assessment is now considered outdated. Instead, SJS and TEN are now regarded as variants of a disease entity with varying degrees of severity, which is referred to as epidermal necrolysis (EN). SJS is defined as a skin detachment of <10 % in relation to the body surface area (KOF), with an epidermal detachment of > 30 % KOF the diagnosis of TEN is made. A skin detachment between 10 and 30 % KOF is referred to as SJS/TEN transitional form.

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