On the surface, these exfoliative disorders may mimic the symptoms of a partial-thickness thermal injury, specifically in relation to the involvement of the skin. However, these diseases also affect all epithelial surfaces, thus increasing the risk and incidence of infections, other complications, and death. Patients suffering from particularly complicated cases of SJS may benefit from the expertise of a burn center, although these patients are generally referred on an as-needed basis. In contrast, those diagnosed with TEN carry a specific set of severe and complicated medical needs that are clearly best addressed in the context of a specialized burn center.

Mortality of TEN ranges from 25% to 80%, with morbidity being reported as high as 65%. However, reports are variable and usually based only on small patient populations. ^{, ,} Death may occur early in the course of the disease, with sepsis being the most frequent cause. Pseudomonas aeruginosa and Staphylococcus aureus are the predominant organisms involved. Pulmonary embolism and gastrointestinal hemorrhage are other causes of death.

Mortality is increased significantly in those patients at the extremes of age and in relation to the percentage of denuded skin and serum urea nitrogen levels. ^{, ,} Bastuji-Garin et al. in 2000 created the Score of Toxic Epidermal Necrolysis (SCORTEN), a scoring system to predict mortality in the adult population presenting with TEN. The scoring system uses seven independent risk factors to predict mortality by allotting 1 point for each variable :

• a.

  Age older than 40

• b.

  Heart rate greater than 120 beats per minute

• c.

  Comorbid malignancy

• d.

  Epidermal detachment of greater than 10% of body surface area (BSA) on day 1

• e.

  Blood urea nitrogen greater than 28 mg/dL

• f.

  Glucose greater than 252 mg/dL

• g.

  Bicarbonate less than 20 mEq/L

The scoring system should be performed on day 1 and day 3 postadmission to maximize its predictive value. Mortality from TEN increases from 3.2% for a score of 0 or 1 to 90% for a score greater than 5 ( Table 36.2 ).

Although originally developed for adults, the scoring system has been validated in the pediatric population, but overall it has been challenged for its lack of incorporating no more than one morbidity (malignancy) in its calculation. ^, Although other investigators have developed formulas based on logistic regression analysis (i.e., ABCD 10), the SCORTEN system is the most accurate and widely used.

SJS is associated with a mortality rate of 0% to 38%. ^, EM rarely causes death.

TEN appears to be driven by immunologic reactions to foreign antigens, often referred to as triggers. Medications are by far the most commonly identified trigger, implicated in 77% to 94% cases of TEN. Antimicrobials, anticonvulsants, analgesics, and nonsteroidal antiinflammatory agents of the oxicam type have been implicated. ^, Naturally, the particular profile of TEN instigators will vary from population to population depending on the epidemiology of medication exposures in any given population.

Attempts to identify drugs suspected of having caused exfoliative necrolysis by skin test and laboratory tests seldom have been successful. Although some assays are trialed in research settings, there are currently no fully vetted, reliable methods available for identifying the inciting trigger in a patient with TEN. Historically, the medication-specific trigger for any given case of TEN was ultimately a matter of speculation. However, Sassolas et al. in 2010 developed an algorithm of drug causality for epidermal necrolysis termed ALDEN. The algorithm assigns a score of 1 to 10 for each drug based on six parameters. The score is then categorized as very probable (>6), probable (4–5), possible (2–3), unlikely (0–1), and very unlikely (<0) ( Table 36.3 ). The results of this algorithm were compared with a case-controlled analysis of the European Study of Severe Cutaneous Adverse Reactions (EuroSCAR) and found to have good accordance. ^, The use of ALDEN in the clinical setting may greatly improve the ability for clinicians and researchers to link medication-specific triggers and TEN.

Although advances have been made in correlating medications as the causative agent of TEN, the role of nonmedication triggers in the etiology of TEN remains murky. Upper respiratory tract infections, pharyngitis, otitis media, or viral illness are frequently reported as preceding or coinciding with the development of TEN in some patients. ^, Mycoplasma pneumoniae and herpes viruses (cytomegalovirus, Epstein-Barr virus, herpes simplex, and varicella zoster) have been implicated in the cause of EM and SJS, but not TEN. ^{, ,} Quantifying the association between TEN and antecedent viral syndromes is complicated by the rarity of TEN and the similarities between prodromal symptoms and other more common disorders. This leads to patients presenting with relatively prominent prodromal symptoms who are typically misdiagnosed as having a simple viral syndrome. Because of the delay between early prodromal symptoms and the more specific TEN rash, it is often impossible to determine in retrospect whether the pertinent symptoms were actually prodromal or if the patient had an antecedent viral infection. Furthermore, these prodromal symptoms are often treated with medications before the TEN diagnosis is considered. As such, medications used to treat prodromal symptoms are frequently misinterpreted as TEN triggers.

Genetics clearly plays an important role in the pathophysiology of TEN, with multiple alleles identified as potent risk factors. Interestingly, the genetic risk factors identified thus far all appear to be trigger specific. That is, a particular allele may place a person at risk for developing TEN in response to one drug, but not increase that same person’s risk for developing TEN in response to a different medication. The majority of those alleles identified thus far appear to increase risk through two separate mechanisms: drug-antigen metabolism and antigen presentation. As early as 1986, Shear et al. identified a pattern of “slow” sulfonamide metabolism in patients with a history of severe cutaneous sulfonamide reactions. Insights and technologies developed through the maturation of the field have allowed pharmacogeneticists to trace such associations with polymorphisms in genes encoding for components of the cytochrome P450 machinery. Investigators studying TEN patients’ genotypes have assembled a sizable catalog of cytochrome P450C variants that convey an increased risk for developing TEN, with each polymorphism associated with a specific trigger agent. The largest family of genes with a documented association with TEN include polymorphisms at a number of human leukocyte antigen (HLA) loci that have been associated with drug-specific risks for TEN. These polymorphisms presumably alter the morphology of the HLA molecules on antigen-presenting cells, making them more or less inclined to “recognize” a particular antigen. The “antigen” may be the medication molecule, a drug metabolite, a by-product of drug metabolism, or a hapten created by the binding of the drug, metabolite, or by-product to another peptide.

The clinical application of these genetic markers is complicated by the fact that their predictive value varies widely when applied to populations of different ethnic makeups. An example of this strong association between HLA, drug sensitivity, and ethnic background was discovered by Chung et al. They demonstrated a strong association between HLA-B*1502, SJS, and carbamazepine in Han Chinese. This unique relationship was later observed in a Thai population but was absent in the Japanese and European populations. In fact, RegiSCAR, a large European study, suggested that HLA-B*1502 is not a marker for carbamazepine, sulfamethoxazole, lamotrigine, or NSAID oxicam-type–induced SJS or TEN.

Although the HLA-B*1502 and carbamazepine association demonstrated significant ethnic variance, this is not the observation for all HLA-medication interactions. A second strong relationship among HLA, drug sensitivity, and SJS/TEN was observed for allopurinol and HLA-B*5801. Although the strength of the relationship continued to vary between ethnicities, the correlation persisted in Han Chinese, Japanese, Thai, and Europeans, unlike for HLA-B*1502 and carbamazepine.

In summary, for many of these markers, prevalence patterns make the marker too rare to function as a screening tool outside the context of specific ethnicities. Beyond issues of prevalence, some markers are associated with a TEN reaction in one population, but not in another: a phenomenon that likely traces to interactions between the “maker” allele and other genetic variables.

Multiple lines of evidence point to T cells as critical effectors of the TEN process. T cells are the predominant cell type found in the blister fluid and exudate of patients with acute TEN.

Suppression or cytotoxic T-cell infiltrates are observed in the epidermis in TEN. ^, The observation of blebbing of the keratinocyte plasma membrane in TEN is considered a reliable morphologic finding of cytotoxic T-lymphocyte cytolysis. Serum and exudate levels of markers of T-cell activation have been shown to correlate with disease activity and resolution.

TEN is perhaps best understood as an immunologically mediated burn. For the most part, TEN resembles a classic type IV (delayed) hypersensitivity disorder. The delay between exposure and reaction, the critical role of T cells, and the accelerated reaction reported in cases of reexposure to an initial trigger all favor this characterization. ^, Although some have pointed to immunofluorescence microscopy findings of IgM and C3 deposited along the dermoepidermal junction and dermal vessels in cases of postherpetic SJS and EM as evidence of an associated type II hypersensitivity reaction, others attribute this to simple nonspecific exudation. ^, The exact antigen that activates the T-cell receptor varies depending on the specific trigger agent: the recognized moiety could be a molecule within the medication, a by-product of agent metabolism, or a complex formed between an endogenous peptide and either of the preceding. Keratinocyte apoptosis is central to the pathogenesis of TEN. This event is thought to be mediated by ligand/receptor interaction of the tumor necrosis factor (TNF) superfamily (as TNF-α/TNF receptor or FasL/Fas interaction). ^, Through a series of experiments, Viard et al. observed, in vitro, that TEN patients expressed lytically active Fas ligand and that the action of this ligand could be blocked by both a monoclonal antibody and human immunoglobins. In SJS, keratinocyte DNA fragmentation has been found in about 90% of cases associated with dermal perforin-positive lymphocytes. ^,

An early skin biopsy is essential for diagnosis. Skin manifestations vary from patient to patient and with the age of the lesion ( Fig. 36.2 ). Advancing edges of the target lesions show scattered necrotic keratinocytes in the epidermis and only mild dermal inflammation. In older lesions and central zones of target lesions, the dusky appearance corresponds to areas of extensive keratinocyte necrosis, often with the formation of subepidermal bullae and dermoepidermal separation. The surrounding erythematous zone shows papillary dermal edema, vascular dilation with endothelial cell swelling, and perivascular mononuclear cell infiltrate. Extravasated erythrocytes may be seen in the surrounding papillary dermis. The reticular dermis is normal. ^,

Toxic epidermal necrolysisis characterized by massive sloughing of the epidermal tissue.

Epidermal and dermoepidermal suppressor or cytotoxic T lymphocytes, in addition to dermal infiltrates of helper T lymphocytes, have been demonstrated. ^{, ,} Hertl has confirmed that these epidermal cells are cytotoxic T cells. Langerhans cells appear to be reduced in the epidermis, although numerous dermal macrophages are observed. A more intense dermal cell infiltrate is present in SJS, especially in postherpetic cases. Dendritic lymphoid cells are observed, opposed to damaged dermal macrophages and necrotic keratinocytes. Furthermore, at the point where the cytoplasmic processes contact the keratinocyte, the plasma membrane of the keratinocyte is absent. Aberrant expression of HLA-DR on keratinocytes has been observed, a phenomenon that has been present in many other inflammatory skin disorders. ^,

Although mucocutaneous erosions are the most common features of TEN/SJS, the disease may present with multisystem involvement. Renal manifestations like glomerulonephritis and acute tubular necrosis, as well as hepatitis and hepatocellular necrosis, have been described. ^{, ,} Hypoalbuminemia, asymptomatic hyperamylasemia, increased erythrocyte sedimentation rate, leukocytosis, thrombocytopenia, and normochromic and normocytic anemia are not uncommon. ^, Leukopenia is a frequent and poor prognostic sign. ^{, ,} This is due in part to depletion of the T helper/inducer lymphocyte population (CD4 ⁺ ). The white blood cell count generally returns to normal levels after 2 to 5 days. The cause of this immunosuppression is unclear.

Drugs suspected of having initiated the disease should be discontinued immediately. Administration of pain medication is of high priority, and antipyretic agents may be required. The use of broad-spectrum antibiotics should be carefully considered: neutropenia is the only complication in which “prophylactic” antibiotics are indicated. Otherwise, systemic antibiotics only should be used for documented infections or suspected sepsis.

Intravenous replacement of fluid losses through the exposed body surface is required. However, because patients do not develop the massive edema and fluid losses evident in burn patients, fluid resuscitation formulas commonly employed in the management of thermal injuries overestimate the actual need. ^, Lactated Ringer’s solution is given at a rate determined by close monitoring of the patient’s condition, resuscitation indexes, and urine output. Once wound coverage is accomplished, fluid requirements usually decrease.

Central line placement should be avoided if possible to reduce the risk of infection and sepsis. To further minimize this risk, lines should be placed in areas of uninvolved skin. Invasive devices are removed as soon as possible, and oral and nasogastric routes are used at earliest convenience. The environmental temperature should be raised to between 30°C and 32°C to reduce metabolic energy expenditure. Heat shields and infrared lamps are beneficial in patients’ rooms, bathrooms, and operating rooms.

Stress ulceration prophylaxis is advisable.

Because the pathophysiology of TEN appears to be initially immunologic, it is logical to consider immunosuppressive therapy as an early treatment modality. The following sections will briefly review the literature with regard to the use of corticosteroids, cyclosporine A, intravenous immunoglobins, and thalidomide.

Surgical approach.

Debridement of necrotic epidermis and coverage of the large wound surface with biologic or synthetic dressings have been advocated by several authors. ^{, ,} Sloughed epidermis should be removed to reduce bacterial growth and the risk for infection. The exposed and tender dermis should be covered. Debridement is best undertaken under general anesthesia as soon as diagnosis by histology is established. Blood loss associated with debridement is minimal, so overresuscitation must be avoided.

Synthetic dressings, such as Biobrane, Suprathel, and biologic dressings, such as homograft (cadaver allograft) and porcine xenograft skin, greatly reduce the pain, decrease fluid loss, and promote healing. Biobrane and similar products should be used with caution when covering wound areas greater than 40% TBSA secondary to the increasing incidence of local infections. Porcine xenograft adheres well to the skin and is commercially available in large quantities. ^, Homograft is more likely to become vascularized and therefore reduces the number of graft changes. However this must be weighed against the potentially poor cosmetic results of vascularized homograft ( Fig. 36.5 ). Grafted areas must be immobilized and protected from shear forces. In both adults and children, continuous rotation or air fluidized (Clinitron) beds frequently are used.

Homograft vascularization occurring over a second-degree thermal injury, resulting in a poor cosmetic result.

Enteral nutrition should be initiated immediately once the patient is resuscitated. Because of the frequent presence of oral mucosal ulcerations, patients may be reluctant to take nutrition orally and thus require a nasogastric tube placement. Unlike burned patients who have significantly elevated metabolic rates, these patients appear to have metabolic rates only slightly above basal requirements. Weight stabilization and a positive nitrogen balance have been achieved in adults with 2500 kcal/day. ^,

Two distinct epidermolytic toxins (ETA and ETB) are responsible for the blistering in staphylococcal scalded skin syndrome. ETA is heat stable, whereas ETB is heat labile and encoded by a bacterial plasmid. Most toxigenic strains of S. aureus are identified as group 2 phage. The exfoliative toxin is metabolized and excreted by the kidneys, leading to a predisposition of patients with renal immaturity (children) or renal compromise. The exfoliative toxins produce blistering by disrupting the epidermal granular cell layers through interdesmosomal splittings but without epidermal necrosis and with very few inflammatory cells. The exact mechanism of action of the toxins has not been determined, although it is felt that the toxins directly affect desmosomes. One might be proteolytic disruption of desmosomes with the toxin or part of its sequence act acting as a serine protease. ^{, ,}

Onset may be marked by fever, malaise, and irritability. Scarlatiniform erythema is often accentuated in flexural and periorificial areas. The skin is generally tender to touch, and sheets of skin may peel away in response to minor trauma (Nikolsky’s sign). Blisters appear within 24 to 48 hours of rupture, leaving a characteristic moist erythematous epidermal base. Severe mucosal involvement is not a typical feature.

Diagnosis of staphylococcal scalded skin syndrome can be made rapidly with a skin biopsy. The characteristic intraepidermal level of splitting is seen, with the split occurring at the granular layer level (stratum granulosum) with no epidermal necrosis or inflammatory cells in the corium. Immunofluorescent studies of the skin are negative. A Tzanck preparation from a scraping of the base of a freshly denuded area will reveal the affected cell population (i.e., acanthocytic keratinocytes). Bullae, denuded skin, and blood are usually sterile, however, and staphylococci can usually be cultured from nares, conjunctiva, or pharynx.

With diagnosis, antibiotics should be started, and semisynthetic penicillinase-resistant penicillin analogs are indicated (e.g., methicillin or oxacillin) because the majority of group 2 staphylococci show resistance to penicillin. Administration of steroids to these patients is contraindicated. After screening for colonization, decontamination of colonized areas, especially the nasopharyngeal region in patients and nursing staff, may be advisable to prevent further spread. Fluid resuscitation is usually required at a lesser volume compared with a burn patient with a similarly involved BSA. Fluid substitution should be guided by urine output, hemodynamic parameters, and electrolyte and colloid status.

Until skin barrier function is restored, patients should receive appropriate wound dressings to prevent secondary wound infection. Topical agents are soothing and bacteriostatic. It needs to be pointed out that the wound initially is not colonized or infected, so alternatively, large areas can be more effectively managed with biologic or synthetic dressings. They have the advantage of eliminating the need for frequent dressing changes, which can be particularly traumatic for young children. Mortality usually is low but may occur in very young and adult patients, usually from sepsis or electrolyte imbalance on the basis of underlying disease. Complete wound healing is usually observed within 7 days, and scarring and altered pigmentation are not common.

Early diagnosis is of extreme importance and consequence. Initial presentation is deceptive because the findings may be localized pain and edema without discoloration of the skin. Later, induration and erythema may be evident. Paresthesia of overlying skin and eventual dusky discoloration and local blistering may occur in the later course. Severe toxemia may develop, usually out of proportion to the local signs. Severe systemic alterations are characteristic of myonecrosis. Gas inclusion may be evident in subcutaneous tissues on x-ray. Computed tomography and magnetic resonance imaging may help in the diagnosis and provide information on the nature and extent of the infection. Frozen section biopsies may provide early histologic evidence of infection. Gram stains and microbiologic testing are very important diagnostic tools and guide antibiotic treatment. However, a definite distinction between necrotizing fasciitis, myonecrosis, and other soft tissue infections often can only be established during surgery.

The key to successful management of necrotizing infections is early diagnosis and radical surgical intervention. Surgical exploration involves complete excision of all necrotic tissues. If more than one operation for debridement of infected necrotic tissue is needed, mortality increases from 43% to 71%; this outcome drastically highlights the importance of adequate initial necrosectomy. In patients with many risk factors, early amputation of the extremity, especially in cases of myonecrosis, should be considered. Broad-spectrum antibiotics are started preoperatively, although high-dose penicillin is appropriate for clostridial infections. However, antibiotic treatment is no substitution for surgical intervention. Adequate fluid resuscitation and nutritional support are also required. Wounds are packed open with antiseptic-soaked dressings, which need to be changed frequently. Kaiser and Cerra have reported unsatisfactory results with either early application of porcine xenografts or burn wound topical antimicrobials. Complete control of local and systemic infection is required before wound closure is addressed.

As in burns, secondary infections must be prevented by proper wound management. Biologic or synthetic dressings offer the advantages of decreased pain, decreased fluid loss, and prevention of secondary infection. Frequently large areas of skin and soft tissue loss result from this disease and will eventually require extensive surgery to achieve adequate closure.

Some authors advocate the use of hyperbaric oxygen and claim that it results in decreased mortality and reduced need for debridement; however, most of these reports are case reports or uncontrolled trials, and adequate prospective controlled trials in patients are still lacking. ^, In animals, hyperbaric oxygen therapy alone did not improve survival or bacterial colonization but did show adjuvant effects to antibiotic treatment. In summary, hyperbaric oxygen therapy, if available, should not delay radical surgical debridement and should be used as an adjunct to radical surgery and antibiotic therapy. ^,