Etiology

Among the numerous factors implicated in the etiology of erythema multiforme (EM), infection with herpes simplex virus (HSV) is the most common. HSV labialis and, less commonly, HSV genitalis have been implicated in 60% of episodes of EM and are believed to trigger nearly all episodes of recurrent EM, frequently in association with sun exposure. HSV antigens and DNA are present in skin lesions of EM but are absent in nonlesional skin. Presence of the human leukocyte antigens A33, B62, B35, DQB1*0301, and DR53 is associated with an increased risk of HSV-induced EM, particularly the recurrent form. Most patients experience a single self-limited episode of EM. Lesions of HSV-induced recurrent EM (HA-EM) typically develop 10-14 days after onset of recurrent HSV eruptions, have a similar appearance from episode to episode, but may vary in frequency and duration in a given patient. Not all episodes of recurrent HSV evolve into EM in susceptible patients.

Clinical Manifestations

EM has numerous morphologic manifestations on the skin, varying from erythematous macules, papules, vesicles, bullae, or urticaria-appearing plaques to patches of confluent erythema. The eruption appears most commonly in patients between the ages of 10 and 40 yr and usually is asymptomatic, although a burning sensation or pruritus may be present. The diagnosis of EM is established by finding the classic lesion: doughnut-shaped, target-like (iris or bull’s-eye) papules with an erythematous outer border, an inner pale ring, and a dusky purple to necrotic center (Figs. 646-1 and 646-2).

Figure 646-1 Early fixed papules with a central dusky zone on the dorsum of the hand of a child with erythema multiforme due to herpes simplex virus.

(From Weston WL, Lane AT, Morelli J: Color textbook of pediatric dermatology, ed 3, St Louis, 2002, Mosby, p 156.)

Figure 646-2 “Target” or “iris” lesions with characteristic central dusky zone on palms of a child with erythema multiforme due to herpes simplex virus.

(From Weston WL, Lane AT, Morelli J: Color textbook of pediatric dermatology, ed 3, St Louis, 2002, Mosby, p 156.)

EM is characterized by an abrupt, symmetric cutaneous eruption, most commonly on the extensor upper extremities; lesions are relatively sparse on the face, trunk, and legs. The eruption often appears initially as red macules or urticarial plaques that expand centrifugally to form lesions up to 2 cm in diameter with a dusky to necrotic center. Lesions of a particular episode typically appear within 72 hr and remain fixed in place. Oral lesions may occur with a predilection for the vermilion border of the lips and the buccal mucosa, but other mucosal surfaces are spared. Prodromal symptoms are generally absent. Lesions typically resolve without sequelae in about 2 wk; progression to Stevens-Johnson syndrome does not occur. EM may manifest initially as urticarial lesions, but unlike urticaria, a given lesion of EM does not fade within 24 hr.

Etiology

Mycoplasma pneumoniae is the most convincingly demonstrated infectious cause of Stevens-Johnson syndrome. Drugs, particularly sulfonamides, nonsteroidal anti-inflammatory agents, antibiotics, and anticonvulsants, are the most common precipitants of Stevens-Johnson syndrome and toxic epidermal necrolysis. HLA-B*1502 and HLA-B*5801 have been implicated in the development of these two disorders in Han Chinese patients receiving carbamazepine and in Japanese patients receiving allopurinol, respectively.

Clinical Manifestations

Cutaneous lesions in Stevens-Johnson syndrome generally consist initially of erythematous macules that rapidly and variably develop central necrosis to form vesicles, bullae, and areas of denudation on the face, trunk, and extremities. The skin lesions are typically more widespread than in EM and are accompanied by involvement of two or more mucosal surfaces, namely the eyes, oral cavity, upper airway or esophagus, gastrointestinal tract, or anogenital mucosa (Fig. 646-3). A burning sensation, edema, and erythema of the lips and buccal mucosa are often the presenting signs, followed by development of bullae, ulceration, and hemorrhagic crusting. Lesions may be preceded by a flu-like upper respiratory illness. Pain from mucosal ulceration is often severe, but skin tenderness is minimal to absent in Stevens-Johnson syndrome, in contrast to pain in toxic epidermal necrolysis. Corneal ulceration, anterior uveitis, panophthalmitis, bronchitis, pneumonitis, myocarditis, hepatitis, enterocolitis, polyarthritis, hematuria, and acute tubular necrosis leading to renal failure may occur. Disseminated cutaneous bullae and erosions may result in increased insensible fluid loss and a high risk of bacterial superinfection and sepsis. New lesions occur in crops, and complete healing may take 4-6 wk; ocular scarring, visual impairment, and strictures of the esophagus, bronchi, vagina, urethra, or anus may remain. Nonspecific laboratory abnormalities in Stevens-Johnson syndrome include leukocytosis, elevated erythrocyte sedimentation rate, and, occasionally, increased liver transaminase levels and decreased serum albumin values. Toxic epidermal necrolysis is the most severe disorder in the clinical spectrum of the disease, involving considerable constitutional toxicity and extensive necrolysis of the mucous membranes and > 30% of the body surface area (Fig. 646-4).

Figure 646-3 Bullae are present on the conjunctivae (A) and in the mouth (B) with Stevens-Johnson syndrome. Sloughing, ulceration, and necrosis in the oral cavity interfere with eating (C). Genital lesions cause dysuria and interfere with voiding.

(From Habif TP, editor: Clinical dermatology, ed 4, Philadelphia, 2004, Mosby, p 631.)

Figure 646-4 A, Large sheets of full-thickness epidermis are shed. B, Toxic epidermal necrolysis begins with diffuse, hot erythema. In hours the skin becomes painful, and with slight thumb pressure, the skin wrinkles, slides laterally, and separates from the dermis (Nikolsky sign).

(From Habif TP, editor: Clinical dermatology, ed 4, Philadelphia, 2004, Mosby, p 633.)

Epidemiology and Etiology

The pathogenesis of toxic epidermal necrolysis is not proved but may involve a hypersensitivity phenomenon that results in damage primarily to the basal cell layer of the epidermis. Epidermal damage appears to result from keratinocyte apoptosis (Chapter 646.2). This condition is triggered by many of the same factors that are thought to be responsible for Stevens-Johnson syndrome, principally drugs such as the sulfonamides, amoxicillin, phenobarbital, hydantoin, butazones, and allopurinol. Toxic epidermal necrolysis is defined by (1) widespread blister formation and morbilliform or confluent erythema, associated with skin tenderness; (2) absence of target lesions; (3) sudden onset and generalization within 24-48 hr; (4) histologic findings of full-thickness epidermal necrosis and a minimal to absent dermal infiltrate. These criteria categorize toxic epidermal necrolysis as a separate entity from EM.

Clinical Manifestations

The prodrome consists of fever, malaise, localized skin tenderness, and diffuse erythema. Inflammation of the eyelids, conjunctivae, mouth, and genitals may precede skin lesions. Flaccid bullae may develop, although this is not a prominent feature. Characteristically, full-thickness epidermis is lost in large sheets (see Fig. 646-4). Nikolsky sign (denudation of the skin with gentle tangential pressure) is present but only in the areas of erythema (see Fig. 646-4). Healing takes place over 14 or more days. Scarring, particularly of the eyes, may result in corneal opacity. The course may be relentlessly progressive, complicated by severe dehydration, electrolyte imbalance, shock, and secondary localized infection and septicemia. Loss of nails and hair may also occur. Long-term morbidity includes alterations in skin pigmentation, eye problems (lack of tears, conjunctival scarring, loss of lashes), and strictures of mucosal surfaces. The differential diagnosis includes staphylococcal scalded skin syndrome, in which the blister cleavage plane is intraepidermal; graft versus host disease; chemical burns; drug eruptions; toxic shock syndrome; and pemphigus.

Anticonvulsant hypersensitivity syndrome (DRESS syndrome; Chapter 637.2) is a multisystem reaction that appears approximately 4 wk to 3 mo after the start of therapy with phenytoin, carbamazepine, phenobarbitone, primidone, or other drugs, most commonly antibiotics. The mucocutaneous eruption may be identical to that of EM, Stevens-Johnson syndrome, or toxic epidermal necrolysis, but the reaction also typically includes lymphadenopathy as well as fever, hepatic, renal and pulmonary disease, eosinophilia, atypical lymphocytosis, and leukocytosis.

Treatment

Appreciation of the specific etiologic factor is crucial. When the disorder is drug induced, administration of the drug must be discontinued as soon as possible. Management is similar to that for severe burns and may be best accomplished in a burn unit (Chapter 68). It may include strict reverse isolation, meticulous fluid and electrolyte therapy, use of an air-fluid bed, and daily cultures. Systemic antibiotic therapy is indicated when secondary infection is evident or suspected. Skin care consists of cleansing with isotonic saline or Burow solution. Biologic or colloid gel (Hydrogel) dressings alleviate pain and reduce fluid loss. Narcotics are often required for pain relief. Mouth and eye care, as for EM major, may be necessary. Because of an immune mechanism, systemic glucocorticosteroids and IVIG have been used with apparent success. Nonetheless, this treatment remains controversial.

Epidermolysis Bullosa

Diseases categorized under the general term epidermolysis bullosa (EB) are a heterogeneous group of congenital, hereditary blistering disorders. They differ in severity and prognosis, clinical and histologic features, and inheritance patterns, but are all characterized by induction of blisters by trauma and exacerbation of blistering in warm weather. The disorders can be categorized under 3 major headings with multiple subgroupings: epidermolysis bullosa simplex (EBS), junctional epidermolysis bullosa (JEB), and dystrophic epidermolysis bullosa (DEB) (Table 646-2). Kindler syndrome (Kindlin-1 gene), which includes poikiloderma and photosensitivity as well as easy blistering, is also considered a separate form of EB.

Table 646-2 CLINICAL PRESENTATION AND DIAGNOSIS OF SELECTED EPIDERMOLYSIS BULLOSA SUBTYPES IN THE NEONATAL PERIOD

Epidermolysis Bullosa Simplex

EBS is a nonscarring, autosomal dominant disorder. The defect in most common types of EBS is in keratin 5 or 14, which makes up intermediate filaments of the basal keratinocytes. The intraepidermal bullae result from cytolysis of the basal cells. There are multiple other rare variants with defects that also result in intraepidermal blistering.

In EBS—generalized other (formerly Koebner), blisters are usually present at birth or during the neonatal period. Sites of predilection are the hands, feet, elbows, knees, legs, and scalp. Intraoral lesions are minimal, nails rarely become dystrophic and usually regrow even when they are shed, and dentition is normal. Bullae heal with minimal to no scar or milia formation. Secondary infection is the primary complication. The propensity to blister decreases with age, and the long-term prognosis is good. Blisters should be drained by puncturing, but the blister top should be left intact to protect the underlying skin. Erosions may be covered with a semipermeable dressing.

EBS—localized (formerly Weber-Cockayne) predominantly affects the hands and feet and often manifests when a child begins to walk; onset may be delayed until puberty or early adulthood, when heavy shoes are worn or the feet are subjected to increased trauma. Bullae are usually restricted to the hands and feet (Fig. 646-5); rarely, they occur elsewhere, such as the dorsal aspect of the arms and the shins. The disorder ranges from mildly incapacitating to crippling at times of severe exacerbations.

Figure 646-5 Bullae of the feet in epidermolysis bullosa simplex—localized (Weber-Cockayne).

EBS—Dowling-Meara (herpetiformis) is characterized by grouped blisters resembling those of herpes simplex (Fig. 646-6). During infancy, blistering may be severe and extensive, may involve mucous membranes, and may result in shedding of nails, formation of milia, and mild pigmentary changes, without scarring. After the first few months of life, warm temperatures do not appear to exacerbate blistering. Hyperkeratosis and hyperhidrosis of the palms and soles may develop, but generally, the condition improves with age.

Figure 646-6 Grouped vesicle on an erythematous base in epidermolysis bullosa simplex—Dowling-Meara.

Junctional Epidermolysis Bullosa

JEB—Herlitz is an autosomal recessive condition that is life threatening. Blisters appear at birth or develop during the neonatal period, particularly on the perioral area, scalp, legs, diaper area, and thorax. Nails eventually become dystrophic and then often permanently lost. Mucous membrane involvement may be severe, and ulceration of the respiratory, gastrointestinal, and genitourinary epithelium has been documented in many affected children, although less frequently than in severe recessive dystrophic epidermolysis bullosa (RDEB). Healing is delayed, and vegetating granulomas may persist for a long time. Large, moist, erosive plaques (Fig. 646-7) may provide a portal of entry for bacteria, and septicemia is a frequent cause of death. Mild atrophy may be seen in areas of recurrent blistering. Defective dentition with early loss of teeth as a result of rampant caries is characteristic. Growth retardation and recalcitrant anemia are almost invariable. In addition to infection, cachexia and circulatory failure are common causes of death. Most patients die within the first 3 yr of life.

Figure 646-7 Nonhealing granulation tissue in junctional epidermolysis bullosa.

JEB—non-Herlitz is a heterogeneous group of disorders. Blistering may be severe in the neonatal period, making differentiation from the Herlitz type difficult. All conditions associated with the Herlitz type may be seen but are usually milder. JEB—non-Herlitz generalized (formerly generalized atrophic benign epidermolysis bullosa) is included as a variant of non-Herlitz JEB. Another variant of non-Herlitz JEB is associated with pyloric atresia.

In all types of JEB, a subepidermal blister is found on light microscopic examination, and electron microscopy demonstrates a cleavage plane in the lamina lucida, between the plasma membranes of the basal cells and the basal lamina. Absence or a great reduction of hemidesmosomes is seen on electron micrographs in JEB—Herlitz and some cases of JEB—non-Herlitz. The defect is in laminin 332 (formerly laminin 5), a glycoprotein associated with anchoring filaments beneath the hemidesmosomes. In JEB—non-Herlitz, defects have also been described in other hemidesmosomal components, such as Col17A1. In JEB—pyloric atresia, the defect is in the α6β4 integrin.

Treatment for junctional epidermolysis bullosa is supportive. The diet should provide adequate calories and supplemental iron. Infections should be treated promptly. Transfusions of packed red blood cells may be required if the patient shows no response to iron and erythropoietin therapy. Tissue-engineered skin grafts (artificial skin derived from human keratinocytes and fibroblasts) may be beneficial.

Dystrophic Epidermolysis Bullosa

All forms of DEB result from mutations in collagen VII, a major component of anchoring fibrils that tether the basement membrane and overlying epidermis to its dermal foundation. The blister is subepidermal in all types of DEB. The type and location of the mutation dictate the severity of the phenotype.

Dominant dystrophic epidermolysis bullosa (DDEB) is the most common type of DEB. The spectrum of DDEB is varied. Blisters may be manifest at birth and are often limited and characteristically form over acral bony prominences. The lesions heal promptly, with the formation of soft, wrinkled scars, milia, and alterations in pigmentation (Fig. 646-8). Abnormal nails and nail loss are common. In many cases, the blistering process is mild, causing little restriction of activity and not impairing growth and development. Mucous membrane involvement tends to be minimal.

Figure 646-8 Scarring with milia formation over the knee in dominant dystrophic epidermolysis bullosa.

RDEB—severe generalized (formerly RDEB—Hallopeau-Siemens) is the most incapacitating form of epidermolysis bullosa, although the clinical spectrum is wide. Some patients have blisters, scarring, and milia formation primarily on the hands, feet, elbows, and knees (Fig. 646-9). Others have extensive erosions and blister formation at birth that seriously impedes their care and feeding. Mucous membrane lesions are common and may cause severe nutritional deprivation, even in older children, whose growth may be retarded. During childhood, esophageal erosions and strictures, scarring of the buccal mucosa, flexion contractures of joints secondary to scarring of the integument, development of cutaneous carcinomas, and the development of digital fusion may significantly limit the quality of life (Fig. 646-10).

Figure 646-9 Severe scarring of the hands and knees in recessive dystrophic epidermolysis bullosa.

Figure 646-10 Mitten-hand deformity of recessive dystrophic epidermolysis bullosa.

Although the skin becomes less sensitive to trauma with aging in patients with RDEB, the progressive and permanent deformities complicate management, and the overall prognosis is poor. Foods that traumatize the buccal or esophageal mucosa should be avoided. If esophageal scarring develops, a semiliquid diet and esophageal dilatations may be required. Stricture excision or colonic interposition may be needed to relieve esophageal obstruction. In infants, severe oropharyngeal involvement may necessitate the use of special feeding devices such as a gastrostomy tube. Iron therapy for anemia, intermittent antibiotic therapy for secondary infections, which are a common cause of death, and periodic surgery for release of digits may reduce morbidity. Tissue-engineered skin grafts containing keratinocytes and fibroblasts are of some benefit. Allogeneic bone marrow transplantation may also be beneficial.

Pemphigus Vulgaris

Pemphigus Foliaceus

Clinical Manifestations

The superficial blisters rupture quickly, leaving erosions surrounded by erythema that heal with crusting and scaling (Fig. 646-11). Nikolsky sign is present. Focal lesions are usually localized to the scalp, face, neck, and upper trunk. Mucous membrane lesions are minimal or absent. Pruritus, pain, and a burning sensation are frequent complaints. The clinical course varies but is generally more benign than that of PV. Fogo selvagem, which is endemic in certain areas of Brazil, is identical clinically, histopathologically, and immunologically to pemphigus foliaceus.

Figure 646-11 Superficial erosions in pemphigus foliaceus.

Bullous Pemphigoid

Etiology/Pathogenesis

In dermatitis herpetiformis (DH), IgA antibodies are directed at epidermal transglutaminase. Gluten-sensitive enteropathy is found in all patients with DH, although the majority are asymptomatic or have minimal gastrointestinal symptoms (Chapter 330.2). The severity of the skin disease and the responsiveness to gluten restriction do not correlate with the severity of the intestinal inflammation. An antibody to smooth muscle endomysium is found in 70-90% of patients with DH. Ninety percent of patients with the disease express HLA DQ2. HLA DQ2–negative patients with DH usually express HLA DQ8.

Clinical Manifestations

DH is characterized by symmetric, grouped, small, tense, erythematous, stinging, intensely pruritic papules and vesicles. The eruption is pleomorphic, including erythematous, urticarial, papular, vesicular, and bullous lesions. Sites of predilection are the knees, elbows, shoulders, buttocks, and scalp; mucous membranes are usually spared. Hemorrhagic lesions may develop on the palms and soles. When pruritus is severe, excoriations may be the only visible sign (Fig. 646-12).

Figure 646-12 Multiple excoriations around the elbows in dermatitis herpetiformis.

Pathology

Subepidermal blisters composed predominantly of neutrophils are found in dermal papillae. The presence of granular IgA in the dermal papillary tips is diagnostic.

Differential Diagnosis

DH may mimic other chronic blistering diseases and may also resemble scabies, papular urticaria, insect bites, contact dermatitis, and papular eczema.

Treatment

Patients with DH show response within weeks to months to a gluten-free diet. Alternatively, oral administration of dapsone (0.5-2.0 mg/kg/day divided qd or bid) provides immediate relief from the intense pruritus but must be used with caution because of possible serious side effects (methemoglobinemia, hemolysis, and hypersensitivity syndrome [sulfone syndrome]). Local antipruritic measures may also be useful. Jejunal biopsy is indicated to diagnose gluten-sensitive enteropathy, because cutaneous manifestations may precede malabsorption. The disease is chronic and either a gluten-free diet or dapsone must be continued indefinitely to prevent relapse.

Etiology/Pathogenesis

Linear IgA dermatosis is a heterogeneous autoimmune disorder with antibodies targeting multiple antigens. It is caused by circulating IgA antibodies, most commonly to LABD97 and LAD-1, which are degradation proteins of BP180 (type 17 collagen). Linear IgA dermatosis may also be seen as a drug eruption. Most cases of drug-induced linear IgA dermatosis are related to vancomycin, although anticonvulsants, ampicillin, cyclosporine, and captopril have been implicated.

Clinical Manifestations

This rare dermatosis is most common in the 1st decade of life, with a peak incidence during the preschool years. The eruption consists of many large, tense bullae filled with clear or hemorrhagic fluid that develop on a normal or erythematous, urticarial base. Areas of predilection are the genitals and buttocks (Fig. 646-13), the perioral region, and the scalp. Sausage-shaped bullae may be arranged in an annular or rosette-like fashion around a central crust (Fig. 646-14). Erythematous plaques with gyrate margins bordered by intact bullae may develop over larger areas. Pruritus may be absent or very intense, and systemic signs or symptoms are absent.

Figure 646-13 Erosion on an erythematous base post loss of blister roof in linear IgA dermatosis.

Figure 646-14 Rosette-like blisters around a central crust typical of linear IgA dermatosis (chronic bullous dermatosis of childhood).

Pathology

The subepidermal bullae are infiltrated with a mixture of inflammatory cells. Neutrophilic abscesses may be noted in the dermal papillary tips, indistinguishable from those of dermatitis herpetiformis. The infiltrate may also be largely eosinophilic, resembling that in BP. Therefore, direct immunofluorescence studies are required for a definitive diagnosis of linear IgA dermatosis; perilesional skin demonstrates linear deposition of IgA and sometimes IgG and C3 at the dermal-epidermal junction. Immunoelectron microscopy has localized the immunoreactants to the sublamina densa, although a combined sublamina densa and lamina lucida pattern has also been seen.

Differential Diagnosis

The eruption can be distinguished by histopathologic and immunofluorescence studies from pemphigus, BP, DH, and EM. Gram stain and culture preclude the diagnosis of bullous impetigo.

Treatment

Many cases of linear IgA dermatosis respond favorably to oral dapsone (see treatment of DH). Children who show no response to dapsone may benefit from oral therapy with a methylprednisolone (1 mg/kg/day) or a combination of these drugs. The usual course is 2-4 yr, although some children have persistent or recurrent disease; there are no long-term sequelae.