techial rash that rapidly progresses to full thickness skin loss. Oftentimes, patients will present with fevers and non-specific flu-like symptoms with development of systemic purpura within 12 to 96 hours of onset of symptoms [79]. Over the course of the next few days the rash will progress to symmetrical, ecchymotic skin lesions involving the lower extremities [74]. Mortality rates are as high as 33–40% in some reports with approximately 90% of patients requiring full thickness skin grafting or amputation at some point during their hospitalization [69, 79]. Once recognized, patients should be transferred to a burn center for definitive care [76, 80, 81].

Management

Management consists of aggressive fluid resuscitation, supportive care through the use of vasopressors and ventilators, intense wound management, systemic anticoagulation and prompt initiation of broad-spectrum antibiotics. Some studies reported success in disease treatment with administration of activated protein C [82, 83]. The full thickness wounds in patients with PF are similar to those seen in patients with full thickness burn wounds which has led many burn centers to adopt a similar treatment algorithm for patients with NF including serial staged surgical debridement with allografting and full thickness skin grafting once patients have been adequately resuscitated [76, 83–85]. Due to the degree of resuscitative [65–67] volume delivered to these patients on admission, some studies support the implementation of early fasciotomies to increase chances of limb salvage [69, 76]. Due to the extent of skin loss in patients with PF, nutritional optimization is also paramount in these patients to allow for wound healing. These patient’s long-term care is similar to that of NF, requiring long-term nutrition, psychosocial, physical and occupational therapy. As many of these patients will be discharged with physical deformities, close follow-up care with a multidisciplinary team is absolutely required.

Exfoliative diseases of the skin

While exfoliative diseases of the skin are believed to originate from a similar pathologic mechanism, the

degree of clinical morbidity and mortality associate with each can vary significantly. In general, these diseases are typically precipitated by a either a specific drug or metabolite or a viral infection leading to a highly variable degree of soft tissue involvement with sloughing of skin at the dermoepidermal junction, which tends to be the hallmark feature of this disease entity [86]. It is believed that this disease process is the result of a hypersensitive, deregulated immune reaction to the inciting drugs due to an inherent inability to detoxify drug-reactive metabolites [87–89].

The two most common exfoliative diseases of the skin encountered are Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN). Both SJS and TENS are severe, acute, potentially lifethreatening diseases characterized by extensive epidermal detachment and erosions of the mucous membranes. Inciting factors are innumerable, with viral infections and drugs generally listed as the most common culprits in SJS and TENS, respectively. Nonetheless, prompt referral and transfer to a tertiary burn center is encouraged as the mainstay in treatment.

Stevens-Johnson syndrome

Stevens-Johnson syndrome (SJS) is an immunocomplex mediated hypersensitivity complex first described in 1922 [90]. Presently, most experts agree that SJS and toxic epidermal necrolysis (TEN) are different manifestations of the same disease. Ste- vens-Johnson Syndrome (SJS) is a rare condition, with a reported incidence of around 2.6 to 6.1 cases per million people per year. While the majority of cases of Stevens-Johnson syndrome is associated with a hypersensitivity to certain drugs, viral infections and malignancies have also been implicated in the pathogenesis of SJS [91]. Certain infections have been noted to have an increased associated incidence, including herpes simplex virus, influenza, mumps, cat-scratch fever, histoplasmosis, EpsteinBarr virus and mycoplasma pneumoniae [92].

As such, SJS and TEN tend to be considered in the differential diagnosis when presented with a significant desquamating process of the skin and mucous membranes. While minor presentations may occur, significant involvement of oral, nasal, eye,

vaginal, urethral, GI, and lower respiratory tract mucous membranes may develop in the course of the illness. Although several classification schemes have been reported, the simplest breakdown depends on the total body surface area involved [90]:

1.Stevens-Johnson syndrome – A “minor form of TEN,” with less than 10% body surface area (BSA) detachment

2.Overlapping Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) – Detachment of 10–30% BSA

3.Toxic epidermal necrolysis – Detachment of more than 30% BSA

as is the case with TEN, the clinical features typically associated with SJS includes a prodrome of 2–3 days characterized by fever, cough, sore throat, and general malaise before the cutaneous manifestations of SJS become apparent [93]. The acute phase, which is typically associated with the first 8–12 days, is characterized by an acute macular exanthema, with rapidly spreading necrosis of the mucus membranes at first, followed by similar events in the epidermis, e. g. the skin.

Prompt referral to a tertiary burn care center is highly encouraged and has been demonstrated to improve survival in extensive cases of SJS and TENS. Given the degree of overlap in clinical manifestation, SJS is treated in much the same way as TENS. As such, diagnosis and treatment strategies will be discussed in the TENS section.

Toxic epidermal necrolysis

Ruskin first described a condition similar to TEN in 1948, and in 1956 Lyell reported 4 more patients who had an acute rash followed by skin detachment and mucus membrane involvement [94, 95]. While clinically similar in presentation to staphylococcal scalded skin syndrome (SSSS), i. e. sloughing of epidermal sheets, SSSS and TEN can be differentiated from a histologic perspective, which underlies the importance of the skin biopsy at the time of presentation. In SSSS, there is superficial detachment involving the upper epidermal layers, whereas in TEN there is pan-epidermal necrosis. Recognition of SSSS is as important as treatment considerations are distinct, including the use of antibiotics, rather than viewing antibiotics as causing the disease, as is often the case

for TEN. On the other hand, the histologic difference between Steven-Johnson syndrome (SJS) and TEN is less pronounced. While SJS and TEN are believed to be the same disorder of different severities, with SJS representing an attenuated form of TEN, a significant proportion of SJS cases are not associated with drug ingestion. Despite a similar clinical presentation and course to TEN, the mortality associated with SJS ranges between 1% and 3% [96, 97].

The estimated annual incidence of TEN is reported between 0.4 and 1.3 cases per million per year, and can occur in all age groups, including newborns and the elderly [98–100]. Those patients with HIV and AIDS have been found to be at approximately 1000 fold increase of developing TEN when compared to the normal population [101]. Reported mortality varies from 30–50%, with the primary cause of death being infection and multi-system organ failure[102]. Antibiotics, NSAIDS and analgesics are the most common drugs identified in cases of TEN, with anticonvulsants reported in 18% of drug induced cases of TEN [88, 103–105].

Clinical presentation

The clinical features typically associated with TEN include a prodrome of 2–3 days characterized by fever, cough, sore throat, and general malaise before the cutaneous manifestations of TEN become apparent [93]. The acute phase, which is typically associated with the first 8–12 days, is characterized by an acute macular exanthema, with rapidly spreading necrosis of the mucus membranes at first, followed by similar events in the epidermis, e. g. the skin [106]. At the time of skin involvement, Nikolsky sign is universally present – epidermal separation induced by gentle lateral pressure on the skin surface [107]. Mucous membranes, including conjunctival, pharyngeal, tracheal and esophageal, are involved in nearly all reported cases. Typically, the dermis remains undamaged, and dermatologic recovery takes 1 to 3 weeks, depending on the extent of skin detachment (Fig. 6). However, mucosal lesions, including the ocular manifestations of TEN, generally require a longer time to heal [108].

Fig. 6. Patient with TENS with characteristic epidermal sloughing at areas of high friction

Diagnosis

The diagnosis of TEN can often times be made clinically, but differentiating TEN from SJS remains a point of contention. While several proposed diagnostic criteria for SJS and TEN exist, authors do not agree on a universally accepted model. Pathologic examination of perilesional skin can be used to support or exclude a clinical diagnosis of TEN. Characteristic histologic features include extensive keratinocyte death through the apoptotic pathway with separation of the epidermis from the dermis at the dermoepidermal junction. A paucicellular infiltrate, in which macrophages and dendrocytes predominate, has been commonly described. TEN has been characterized immunopathologically by an increased ratio of dermal dendrocytes to dermal lymphocytes, in contrast to the opposite pattern seen in EM where lymphocytes predominate [109].

The mortality associated with TEN ranges from 30–50%, which is significantly higher than episodes of SJS (1–3%). The primary cause of death in TEN is infection and multi-system organ failure. As in burn patients, age and extent of skin detachment are still considered major prognostic factors. However, after controlling for extent of skin detachment, a diagnosis of TEN generally carries a worse prognosis. The SCORTEN (severity-of-illness score for TEN) is a validated model of disease severity which has been shown to accurately predict mortality from TEN based on a seven point checklist [110]. Table 1(a) and (b) demonstrate the seven variables identified

and predicted mortality, respectively. The SCORTEN value is calculated by giving one point to each of the variables present in the first 24h after admission. However, given the lack of consensus on what constitutes a standardized protocol of care, there still remains significant heterogeneity in the treatment of TEN patients [111].

Treatment

Once the diagnosis of SJS or TEN is suspected, prompt withdrawal of potential causative drug(s) should be the priority, as this particular course of action is one therapeutic technique that has been shown to decrease mortality and improve prognosis [112]. In general, any medication initiated within 3–4 weeks prior to the onset of symptoms should be suspected, and should be strictly avoided, especially in the course of treatment. Principles guiding the care of treatment of SJS and TEN patients are similar to those in extensive thermal burns [113]. The treatment of patients with extensive SJS or TEN is most appropriately provided in intensive care units, or more specifically, burn centers, where staff

Table 1a. The SCORTEN scoring system

SCORTEN Variables

1.Extent of Epidermal detachment > 10%

2.Age > 40 years

3.Heart rate > 120/min

4.Bicarbonate > 20 mmol/L

5.Serum urea nitrogen > 28 mg/dL

6.Glucose > 252 mg/dL

7.History of Malignancy

Table 1b. Predicting mortality in TEN based on SCORTEN

is familiar with managing complex epidermal loss and associated complications, i. e. mechanical ventilation, pressor support and wound care [114, 115]. Given the current confusion regarding the pathophysiologic mechanisms responsible for SJS and TENS, it should not be surprising that therapeutic approaches are diverse and relatively ineffective. Presently, there is a lack of consensus on specific treatments for SJS and TEN. As such, patients are treated symptomatically and supportively. Supportive therapies include attention and protection of eroded mucosal surfaces, prevention, early detection and treatment of infection, nutritional support and monitoring of fluid and electrolyte balances.

Given the low incidence of TEN, randomized controlled trials comparing potential therapeutics are rare. Recent therapeutic interventions in TEN are based on the proposed molecular mechanisms involved in the clinical manifestations of TEN, i. e. apoptosis of keratinocytes. As such, the majority of reports in the literature involve single case observations or small, uncontrolled studies. To date, only one prospective, randomized-controlled clinical trial has been reported in the literature [116]. Theoretically, effective treatment strategies should focus on halting keratinocyte apoptosis, either by acting on the keratinocytes directly, or the effectors mediating the process. Table 2 offers a mechanistic overview of reported therapeutic efforts investigated. Needless to say, treatment with corticosteroids remains controversial – early retrospective studies suggested that corticosteroids increased hospital stays and complication rates. As such,

corticosteroids are not recommended in the management of either SJS or TEN.

Of particular interest in the treatment of TEN is the use of IVIg. The in-vitro studies of Viard et al. showed that up-regulation of keratinocyte FasL expression is the critical trigger for keratinocyte destruction during TEN[117]. Furthermore, this induced apoptosis could be completely abrogated by the addition of pooled IVIg, which contained naturally occurring anti-FasL antibody. Others speculate that IVIg may also contain products involved in the inhibition of inflammatory cytokines. Following the in-vitro study, the group demonstrated the efficacy in 10 consecutive TEN patients with IVIg doses ranging from 0.2 to 0.75g/kg/day with marked clinical improvement. Treatment of TEN with IVIg has been reported in several case studies with wide variation in patients and treatment protocols. As a consequence, results have been inconsistent and, at times, conflicting. Several case series support the use of IVIg, suggesting that mortality rates are improved in IVIg treated cohorts [118–121]. Other groups have demonstrated no improvement in outcome [122–124]. Given such conflicting results, it is difficult to draw a conclusion on the efficacy of IVIg in the treatment of TEN. Much of the conflicting results may be attributable to the inconsistency of pooled IVIg lots. Several questions remain unanswered, including what is the optimal neutralizing titer that is necessary to halt the progression, and, more importantly, what is the true target that is affected with pooled IVIg. Well designed prospective studies are needed to address whether IVIg does improve outcome.