Toxic epidermal necrolysis and Stevens–Johnson syndrome

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Toxic epidermal necrolysis and Stevens–Johnson syndrome

Nicholas M. Craven and Daniel Creamer

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

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Toxic epidermal necrolysis (TEN) and Stevens–Johnson syndrome (SJS) form a spectrum of rare, potentially life-threatening conditions manifesting widespread erythematous macules or atypical target lesions and severe erosions of mucous membranes. Confluence of cutaneous lesions leads to epidermal loss, which by definition involves less than 10% of total body surface area in SJS, 10–30% in overlap cases, and more than 30% in TEN. Complications develop similar to those seen after burns. In most cases TEN and SJS can be attributed to a drug reaction.

Management Strategy

The causative drug should be identified and discontinued. In general, drugs introduced in the 4 weeks before the onset of symptoms are usually responsible. If in doubt, all drugs should be stopped if possible.

The patient should be managed in a burns unit or appropriate high-dependency unit. Supportive therapy is directed at fluid replacement, maintaining a warm environment to reduce heat loss, topical antiseptic preparations, hydrocolloid dressings or skin substitutes to reduce colonization of the skin, and regular monitoring for sepsis. Fluid replacement requirements depend on the extent of involvement of the skin and mucous membranes, and may be 5–7 L in the first 24 hours. Peripheral lines are preferable to central lines, which increase the risk of sepsis. Nutritional support may require fine-bore nasogastric tube feeding until the oral mucosa has healed. All lines should be checked daily for signs of infection, changed at least every 3 days, and the tips of all discarded lines and catheters sent for culture. Antibiotics should not be given routinely as this may promote resistance. If signs of sepsis develop (rising or falling temperature, rigors, hypotension, fall in urine output, deterioration of respiratory status, diabetic control, or level of consciousness), initial antibiotic therapy can be guided by the results of swabs taken from the skin and mucous membranes. Necrolytic epidermis should be removed gently once it starts to fold over to reduce the risk of infection.

Ophthalmologic review should be obtained as soon as possible after diagnosis to minimize the risk of conjunctival scarring and blindness. Regular instillation of antiseptic eye drops and separation of newly forming synechiae are required. Oral and nasal debris should be cleaned regularly and an antiseptic mouthwash used several times a day.

Analgesia with opiates is often required, and care should be taken to monitor for respiratory depression. Respiratory failure may develop, requiring ventilation in an intensive care facility.

The use of systemic corticosteroids in the management of TEN and SJS remains controversial (see below). Several reports suggest that the use of corticosteroids increases morbidity and mortality, usually by increasing the risk of sepsis. Conversely, a number of case reports and short studies advocate the use of high-dose corticosteroids in the early stages of the evolution of these conditions. It is therefore possible that high-dose corticosteroids may prove beneficial in aborting further epithelial loss in patients with evolving SJS/TEN, but this has not yet been tested in a randomized controlled trial. Nevertheless, it is generally accepted that continuing administration of corticosteroids is counterproductive once extensive skin loss has occurred.

Several other potential disease-modifying treatments (intravenous immunoglobulin (IVIG), cyclosporine, pentoxifylline, plasmapheresis, cyclophosphamide) have been reported in small numbers of patients, but there is currently no strong evidence base for recommending any specific intervention other than supportive care.

Survivors of TEN and SJS and their close relatives should avoid exposure to the culprit drug and related compounds.

Specific investigations

Established TEN can usually be diagnosed clinically. Biopsy and immunofluorescence of an affected area of skin can exclude conditions such as staphylococcal scalded skin syndrome and paraneoplastic pemphigus. Histologic examination of the roof of a fresh blister (even on frozen section specimens) may be adequate to distinguish TEN from staphylococcal scalded skin syndrome.

Supportive care involves regular monitoring of full blood count, urea, creatinine, electrolytes (including calcium and phosphate), transaminases, glucose, blood gases, swabs from infected areas and flexures, blood and urine cultures, and urine output.

First-line therapies

image Supportive measures E
image Withdrawal of culprit drug E
image Analgesia E
image Bioengineered skin substitute C

Toxic epidermal necrolysis: use of Biobrane for skin coverage reduces pain, improves mobilization and decreases infection in elderly patients.

Boorboor P, Vogt PM, Bechara FG, Alkandari Q, Aust M, Gohritz A, et al. Burns 2008; 34: 487–92.

A comparative study of two dressing regimens in 14 TEN patients managed in a burns unit. In eight patients, denuded skin was covered with paraffin gauze which was changed daily; in six patients the exposed dermis was covered with Biobrane, a biosynthetic wound dressing, which was left undisturbed following application. Assessment of a range of clinical parameters demonstrated a significant reduction in pain and significantly enhanced mobility in the Biobrane group compared to the control group. Speed of re-epithelialization, duration of hospital stay, and mortality were not significantly different in the two groups.

Second-line therapies

image Cyclosporine C
image Systemic corticosteroids C
image Intravenous immunoglobulin C

Treatment of toxic epidermal necrolysis with cyclosporine A.

Arévalo JM, Lorente JA, González-Herrada C, Jiménez-Reyes J. J Trauma 2000; 48: 473–8.

An improved outcome is reported in 11 consecutive patients with TEN treated with cyclosporine 3 mg/kg daily, compared to six historical controls treated with cyclophosphamide and corticosteroids. Both groups were of comparable age, with similar extent of skin loss and delay between onset of TEN and admission. Patients treated with cyclosporine had more rapid re-epithelialization, were less likely to suffer multiorgan failure, and had a lower mortality (0 of 11 vs three of six).

There are now several reports of the successful use of cyclosporine in TEN. Because most of the hazards of this drug are associated with long-term use it seems logical to use this drug in TEN, as treatment will only be needed for a few days.

Corticosteroid therapy in an additional 13 cases of Stevens–Johnson syndrome: a total series of 67 cases.

Tripathi A, Ditto AM, Grammer LC, Greenberger PA, McGrath KG, Zeiss CR, et al. Allergy Asthma Proc 2000; 21: 101–5.

Latest in a series of reports from this group. Thirteen patients with SJS were treated with intravenous methylprednisolone 160–240 mg daily on admission to the unit (1–14 days after onset of symptoms). One patient died from unrelated causes; all others survived. This extends to 67 the authors’ series of patients with SJS treated with corticosteroids.

Clinical descriptions are incomplete, but surprisingly few of the patients had bullous lesions. It is possible that a significant number of these 67 patients would be classified by dermatologists as having hypersensitivity syndrome rather than SJS.

Intravenous immunoglobulin does not improve outcome in toxic epidermal necrolysis.

Shortt R, Gomez M, Mittman N, Cartotto R. J Burn Care Rehab 2004; 25: 246–55.

Outcome data for 16 patients with TEN treated with IVIG were compared with those of 16 historical controls treated without IVIG. The mortality rate of the IVIG group was 25%, compared to 38% in the control group (not statistically significant). There were no significant differences between the groups with respect to the duration of hospital stay, duration of ventilation, the incidence of sepsis, or time to healing. There was a trend towards less severe wound progression in patients who received IVIG.

As with all data on treatment of TEN, interpretation of the available literature is limited by lack of uniformity in the treatment regimens used, by the lack of adequate control data, and/or by the relatively small size of the studies.

Third-line therapies

image Plasmapheresis C
image Pentoxifylline E

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