Toxic Epidermal Necrolysis: Overview of a Serious Skin Condition

Abstract: Toxic epidermal necrolysis (TEN), a life-threatening skin condition, is characterized by sudden-onset epidermal erythema, superficial necrosis, and skin erosions that progress to widespread blistering and full-thickness epidermal necrosis. TEN can result from toxic or hypersensitive reactions, an immune response, or severe physiologic stress. Infections and drugs are the most common triggers. This review describes the pathogenesis, etiology, epidemiology, presentation, diagnosis, supportive management, and prognosis of this serious condition that, while rare in children, carries significant morbidity and mortality.

Toxic epidermal necrolysis (TEN) is a rare, life-threatening dermatologic condition characterized by epidermal erythema, superficial necrosis, and skin erosions. It has a sudden onset and generalization within 1 to 2 days and progresses to include widespread blister formation and morbilliform or confluent erythema, along with skin tenderness, an absence of target lesions, full-thickness epidermal necrosis, and a minimal to absent dermal infiltrate.¹ TEN can result from toxic or hypersensitive reactions, an immune response, or severe physiologic stress.

Pathogenesis

The epidermolysis and blistering of TEN result from keratinocyte apoptosis. There is evidence supporting several immunopathologic pathways leading to keratinocyte apoptosis in TEN^3,4: 

• Fas ligand activation on keratinocyte membranes leading to apoptosis

• Release of destructive proteins (perforin and granzyme B) from cytotoxic T lymphocytes (CTLs) generated from an interaction with major histocompatibility complex class I–expressing cells

• Overproduction of T cell and/or macrophage-derived cytokines (interferon-γ, tumor necrosis factor α, and various interleukins)

• Secretion of granulysin from CTLs, natural killer cells, and natural killer T cells leading to cell death.

Epidemiology

Worldwide, TEN is estimated to occur at the frequency of 0.4 to 1.3 cases per million per year.² The HLA-B*1502 and HLA-B*5801 alleles have been implicated in the development of TEN in Han Chinese patients receiving carbamazepine and in Japanese patients receiving allopurinol, respectively.⁵ Women are more frequently affected than are men, with a ratio of 1.5 to 1. TEN occurs in all age groups but is less common in children. Infection is more commonly implicated in children, whereas medication exposure is a more common etiology in adults.

Clinical Manifestations

The disease begins with low-grade fever, malaise, localized skin tenderness, and diffuse erythema. Inflammatory changes in the oral cavity, eyes, and genitals may appear before the involvement of skin.¹ The rash usually begins as centrally distributed, flat, atypical targets or purpuric macules. Skin lesions typically involve greater than 30% of the skin surface. The skin lesions coalesce and fill with fluid, thus producing large and flaccid blisters. These lesions may wrinkle, slide laterally, and separate with slight pressure (the Nikolsky sign). Separation of skin layers characteristically occurs at the basement membrane.² Thus, full-thickness epidermis is lost in large sheets. The underlying denuded skin is erythematous and tender.

Inflammation, blistering, and erosion of oral mucosa are early and common findings in TEN. Pain and breaking in the oral mucosa may interfere with oral intake, requiring nasogastric or nasoduodenal feeding. Ocular involvement varies in severity and can include mild inflammation, conjunctival erosion, purulent exudates, fibrous adhesions, corneal ulceration, and blindness. Involvement of respiratory epithelium indicates a poor prognosis and may result in bronchial hypersecretion, hypoxemia, interstitial infiltrates, pulmonary edema, and bronchopneumonia. Many patients with respiratory involvement require intubation and ventilator support.^1-3 

Etiology 

Infections and medications are common causes of TEN.^2,4 Among infectious agents, Mycoplasma pneumoniae, herpesvirus, and hepatitis A virus are most common. Sulfonamide antibiotics, anticonvulsants (eg, phenobarbital, phenytoin, carbamazepine, valproic acid), nonsteroidal anti-inflammatory drugs, allopurinol, and antiretroviral medications (eg, nevirapine, abacavir, lamotrigine) are the most common drugs associated with TEN. In addition, vaccines and bone marrow or solid organ transplantation also have been associated with the development of TEN.

Differential Diagnosis

The differential diagnosis of TEN includes autoimmune bullous diseases (eg, pemphigus, pemphigoid and paraneoplastic pemphigus), staphylococcal scalded skin syndrome (SSSS), bullous lupus, Kawasaki disease, acute generalized exanthematous pustulosis, and acute graft-versus-host disease.^1,2 The lesions in SSSS are high in the epidermis, just below the stratum corneum. The diagnosis of either TEN or SSSS can be made rapidly by examination of a skin biopsy by frozen section technique. Histologic examination of a biopsy sample, including direct immunofluorescence analysis, differentiates TEN from autoimmune bullous disease.

Management

Early identification and withdrawal of the offending agent improves the prognosis. Management is similar to that of severe burns and may best be accomplished in a hospital burn unit.^3-5

Patients with TEN are prone to hypothermia, since they have lost a significant amount of skin; therefore, warming devices and blankets should be used to prevent hypothermia. Fluid status and pulmonary status should be carefully monitored. Areas of skin erosion should be covered with nonadherent protective dressings such as petroleum gauze.

Respiratory distress may result from mucosal sloughing and edema and may necessitate endotracheal intubation and ventilation. Silver compounds (not utilizing sulfa medications) should be used, because they assist in wound healing and prevent infection and bacterial growth. Antibiotic prophylaxis is not indicated unless sepsis is suspected.^2,3,5 Patients with mucosal vulnerability may have severe bleeding complications. Coagulation profile and blood cell counts should be strictly monitored, and transfusion of red blood cells, platelets, and plasma products should be considered when necessary.

If the lesions are extensive or rapidly progressing, immunosuppressive therapy should be considered (weighing the risks and benefits) and should be started earlier in the illness. Intravenous immunoglobulin (IVIG) has been reported to be effective in treatment of TEN in some case series.^3,5,6 However, other studies have reported that IVIG is not effective.^3,4,7 A number of therapeutic interventions—including the use of corticosteroids,^2,3 plasmapheresis,⁸ tumor necrosis factor α inhibitors,^9,11 cyclophosphamide,^2,10 and cyclosporin^2,5—have not been found to be effective, and many studies using these therapies yielded inconclusive results. Therefore, a need exists for randomized, controlled studies to further evaluate potential treatment modalities for TEN.

Management of TEN requires a multidisciplinary team approach.^2,3 Patients with suspected TEN should be admitted to a burn unit as quickly as possible. Dermatologists may assist with diagnosis, biopsy, and inpatient treatment. Ophthalmology consultation is required for assisting in the treatment of ocular manifestations and preventing long-term sequelae. Otorhinolaryngology and urology consultation may be helpful in patients with significant mucous membrane involvement.

Short-Term Complications

Breaks in skin predispose patients with TEN to septicemia with organisms such as Pseudomonas aeruginosa, Staphylococcus aureus, Gram-negative species, and Candida albicans. Ulceration of certain mucosal membranes may result in pain, scarring, and stricture formation. Ocular complications may include lid edema, persistent dry eyes, chronic photosensitivity, conjunctivitis, keratitis, conjunctival fornix foreshortening, symblepharon, corneal ulceration and scarring, and blindness. Inflammation of respiratory epithelium may result in bronchial hypersecretion, hypoxemia, interstitial infiltrates, pulmonary edema, bacterial pneumonia, or bronchiolitis obliterans, pulmonary embolism and acute respiratory distress syndrome. Gastrointestinal hemorrhage may result from intestinal inflammation. Hypovolemia may result from poor oral intake or increased fluid loss. Renal hypoperfusion, acute tubular necrosis, and renal insufficiency may develop subsequent to septic shock.

Long-Term Complications

Scarring of skin in areas of infection or over pressure points, postinflammatory hyperpigmentation, and nail growth abnormalities are frequently associated with TEN.

Long-term ocular sequelae may include a Sjögren-like syndrome, corneal abrasions, corneal scarring with neovascularization, palpebral synechiae, entropion, or symblepharon and blindness. Strictures of the throat and esophagus, vulvovaginal synechiae, and phimosis have been reported in the literature.

Prognosis

The prognosis for TEN is guarded. More recent studies cite overall mortality rates of 25% to 35%.^2,5

TEN is uncommon condition in children that carries significant morbidity and mortality. Infections and drugs are the most common triggers. Supportive care is the only management modality. Some experimental therapies have been tried with inconclusive results. The development of multicenter, randomized, controlled trials is required to assess the efficacy of different therapies for TEN.

References: 

1.Morelli JG. Vesiculobullous disorders. In: Kliegman RM, Stanton BF, St. Geme JW III, Schor NF, Behrman RE, eds. Nelson Textbook of Pediatrics. 19th ed. Philadelphia, PA: Elsevier Saunders; 2011:2241-2249.

2.Hypersensitivity syndromes and vasculitis. In: Habif TP. Clinical Dermatology: A Color Guide to Diagnosis and Therapy. 5th ed. Philadelphia, PA: Mosby Elsevier; 2010:710-740.

3.Vanness E. Erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. In: Bope ET, Kellerman RD, eds. Conn’s Current Therapy 2012. Philadelphia, PA: Elsevier Saunders; 2012:227-228.

4.Khalili B, Bahna SL. Pathogenesis and recent therapeutic trends in Stevens-Johnson syndrome and toxic epidermal necrolysis. Ann Allergy Asthma Immunol. 2006:97(3):272-280.

5.Downey A, Jackson C, Harun N, Cooper A. Toxic epidermal necrolysis: review of pathogenesis and management. J Am Acad Dermatol. 2012;66(6): 995-1003.

6.Metry DW, Jung P, Levy ML. Use of intravenous immunoglobulin in children with Stevens-Johnson syndrome and toxic epidermal necrolysis: seven cases and review of the literature. Pediatrics. 2003:112(6 pt 1):1430-1436.

7.Shortt R, Gomez M, Mittmann N, Cartotto R. Intravenous immunoglobulin does not improve outcome in toxic epidermal necrolysis. J Burn Care Rehabil. 2004:25(3):246-255.

8.Chaidemenos GC, Chrysomallis F, Sombolos K, Mourellou O, Ioannides D, Papakonstantinou M. Plasmapheresis in toxic epidermal necrolysis. Int J Dermatol. 1997:36(3):218-221.

9.Hunger RE, Hunziker T, Buettiker U, Braathen LR, Yawalkar N. Rapid resolution of toxic epidermal necrolysis with anti-TNF-α treatment. J Allergy Clin Immunol. 2005:116(4):923-924.

10.Frangiogiannis NG, Boridy I, Mazhar M, Mathews R, Gangopadhyay S, Cate T. Cyclophosphamide in the treatment of toxic epidermal necrolysis. South Med J. 1996: 89(10):1001-1003.

11.Fischer M, Fiedler E, Marsch WC, Wohlrab J. Antitumor necrosis factor-α antibodies (infliximab) in the treatment of a patient with toxic epidermal necrolysis. Br J Dermatol. 2002:146(4):707-709.