Toxic epidermal necrolysis (TEN) and Stevens–Johnson syndrome (SJS): Experience with high-dose intravenous immunoglobulins and topical conservative approach: A retrospective analysis
Introduction
Toxic epidermal necrolysis (TEN) is an acute life-threatening exfoliative drug-induced skin pathology, having a clinical picture similar to extensive partial-thickness burns [1]. On this basis, burn units have been recently considered the ideal place for the management of TEN patients. Almost all the patients with TEN present associate mucosal lesions, including ubiquitous painful erosions and crusts [2].
About physiopathology, recently it has been demonstrated that TEN is due to alterations in the control of keratinocites apoptosis [3], [4] mediated by interaction between the cell-surface death receptor Fas and its ligand (Fas ligand: FasL or CD95L) [5]; up-regulation of keratinocyte FasL expression is the trigger for keratinocyte destruction during TEN [6].
More than 100 different drugs have been advocated as causes of TEN [7] but no skin or in vitro tests are actually available to demonstrate a clear correlation between TEN and the culprit drug and, at the same time, animal models are lacking.
Correlation between the illness and the drug intake is based on the recognition that TEN usually develops 1–3 weeks after administration of the offending drug [8]. Indeed a clear identification of the responsible drug is often presumptive, because there are several confounding factors frequently involved: for instance the frequent concomitant use of multiple different drug therapies.
Clinical diagnosis is based first on the presence of characteristic eruptions of erythematous confluent maculae together with positive Nikolsky's sign (dislodgement of epidermis by lateral pressure). Skin biopsy shows a typical histo-morphological picture of full-thickness epidermal necrosis with an only slightly altered underlying dermis. Immunohistochemistry confirms the clinical diagnosis excluding other cutaneous diseases (like blistered pemphigoid or drug-induced linear immunoglobulin A blistered disease or acute generalized exanthematous pustolosis) that clinically can mimic TEN [9], [10].
TEN incidence, in different national studies, has been estimated to be approximately 0.5–1.89 cases per one million people per year [11], 2.7 times higher among elderly than younger adults [12], probably due to a greater pharmaceutical use. Moreover, incidence in people with human immunodeficiency virus is much higher (0.01–0.1%) [13]. The mortality rate associated with TEN varies widely between the studies, ranging from 20% to 75% [14].
Treatment is based on the early removal of the suspected drug [15], [16]. Other associated clinical approaches include local management, fluid replacement, nutritional support and systemic treatments that aim to stop the progression of the skin disease. About local management some authors suggest to treat the wounds with the conservative method [6], [17], others with a more aggressive approach by means of mechanical debridement and coverage with skin substitutes [18], [19], including biological skin covers (auto-grafts, xenografts, cultured keratinocites, glycerol-preserved skin allografts [20]).
Concerning systemic treatments, high-dose corticosteroid therapy has been widely employed [21], [22], [23], [24] with uncertain results; recently other treatments (granulocyte colony stimulating factor [25], [26], cyclophosphamide [27], cyclosporin [19], [28], plasmapheresis [29], [30], N-acetylcysteine [31], anti-tumour necrosis factor-α antibodies [32] and ulinastatin [33]) have been attempted. Moreover, patients included in the cited series are few.
In 1998, on the basis of the identification of the mechanism of keratinocytes apoptosis [6] in SJS and TEN, a therapy based on the use of intravenous immunoglobulins (IVIG) was proposed with excellent results. It was demonstrated that IVIG have the capacity to inhibit Fas–Fas ligand-mediated apoptosis. Therapeutic effect of immunoglobulins is likely to involve inhibition of Fas-mediated keratinocyte death by naturally occurring Fas-blocking antibodies contained within human immunoglobulins preparations [6], acting directly on the Fas–Fas ligand system at the keratinocytes surface [34]. Other case-reports as in adults as in children successfully treated with IVIG have been published [11], [35], [36], [37], [38].
In this article it is reported our experience (1999–2005) using IVIG and conservative local approach in the treatment of TEN in comparison to our previous treatments (1993–1998), evaluating the complications occurred and the survival rate according to a TEN-specific severity of illness scale (SCORTEN) [39], [40], [41].
SCORTEN is calculated by giving 1 point for each of 7 independent risk factors (age > 40 years, presence of malignancy, body surface area involved > 10%, serum urea nitrogen level > 28 mg/dL, glucose level > 252 mg/dL, bicarbonate (HCO3) level < 20 mequiv./L, and heart rate > 120 beats/min) evaluated during the first 24 h of admission. The predicted mortality percentage is then based on the number of risk factors that each patient possesses. Patients with 0–1 risk factors have an expected mortality rate of 3.2%, 2 risk factors 12.1%, 3 risk factors 35.3%, 4 risk factors 58.3%, and 5 or more risk factors 90%.
Section snippets
Patients 1993–1998
All hospitalized patients to the Turin Burn Center with a diagnosis of SJS or TEN from January 1993 to January 1998 were included in this series. Diagnosis was made by dermatologists and confirmed by histopathological examination. In this period patients were primary admitted to a dermatological unit and transferred to the burn center only when their general clinical conditions were judged critical.
No specific pharmacological protocol was at that time used: six out of eight received
Patients 1993–1998
Eight subjects (six females and two males) all affected by TEN were admitted to our burn center with a delay of hospitalization of 7.4 ± 2.7 days. The average age was 55.6 ± 16.1 years and the TBSA percentage of skin slough 72.5 ± 20.4%. Pre-existing medical conditions and drugs taken in the 3 weeks’ period preceding the onset of TEN are reported in Table 1.
Of the eight patients, six died (75%) for septic shock and multiple organ failure (MOF). The average death time was 6 days after burn unit
Discussion
Toxic epidermal necrolysis (TEN) is a rare, potentially life-threatening acute exfoliative drug-induced skin and mucosal disorder. Nevertheless many patients take different drugs together in the period preceding the onset of clinical symptoms and there are no reliable tests to prove the link between a single case and a specific drug [44]. On the other hand, it has been reported that the withdrawn of the suspected drug may decrease mortality [15], [16]. Indeed a mean time of 14 days from initial
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Improving mortality outcomes of Stevens Johnson syndrome/toxic epidermal necrolysis: A regional burns centre experience
2018, BurnsCitation Excerpt :The percentage mortality of SJS/TEN overlap has been reported as low as less than 6% [21]. A systematic review has reported the mortality percentage of TEN when treated in a burns unit as 29% [22], although this figure ranges considerably in the literature from 10% to 75% [6,23]. A 15 year review of 40 patients with SJS/TENS overlap and TEN, with an average %TBSA of 45.9 (range 2–90) treated in a burn unit has demonstrated overall mortality rates of 10% [5].
SJS/TEN 2017: Building Multidisciplinary Networks to Drive Science and Translation
2018, Journal of Allergy and Clinical Immunology: In PracticeBurn Center Care of Patients with Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis
2017, Clinics in Plastic SurgeryCitation Excerpt :These promising findings led to numerous case reports, case series, and a variety of controlled and uncontrolled studies over the ensuing 15 years, which revealed mixed findings regarding benefit from IVIG. In 2012, a systematic review and meta-analysis by Huang and colleagues45 identified that only 6 controlled trials in adults46–51 (all retrospective) comparing IVIG to supportive care had been conducted since the initial observations of Viard and colleagues16 in 1998. These 6 trials involved a total of 243 subjects with SJS-TEN overlap or TEN and the pooled odds ratio (OR) for mortality in subjects treated with IVIG did not show a survival benefit compared with supportive care alone (OR 1.0, 95% CI 0.58–1.75).
UK guidelines for the management of Stevens-Johnson syndrome/toxic epidermal necrolysis in adults 2016
2016, Journal of Plastic, Reconstructive and Aesthetic SurgeryCitation Excerpt :In the conservative approach, detached epidermis is left in situ to act as a biological dressing for the underlying dermis. In cases where bullae are prominent, blister fluid should be aspirated or expressed and the blister roof allowed to settle onto the underlying dermis.44–46 Frequent application of a bland emollient to the whole skin is helpful during the acute phase of SJS/TEN to support barrier function, reduce transcutaneous water loss and encourage re-epithelialisation.44