(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 30 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. 653-1 and 653-2 [1] [2]).
Figure 653-1 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, 3rd ed, St. Louis, Mosby, 2002, p 156.)
Figure 653-2 “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, 3rd ed, St. Louis, Mosby, 2002, 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.
Although EM may present initially with urticarial lesions, unlike urticaria, a given lesion of EM does not fade within 24 hr. Serum sickness–like reaction (SSLR) to cefaclor may also present with EM-like lesions. Although the lesions may develop a dusky to purple center, in most cases, the eruption of cefaclor-induced SSLR is pruritic, transient, and migratory and is probably urticarial rather than true EM.
The differential diagnosis of EM also includes bullous pemphigoid, pemphigus, linear IgA dermatosis, graft vs host disease, bullous drug eruption, urticaria, viral infections such as herpes simplex, Reiter disease, Kawasaki disease, Behçet disease, allergic vasculitis, erythema annulare centrifugum, and periarteritis nodosa. EM that primarily involves the oral mucosa may be confused with bullous pemphigoid, pemphigus vulgaris, vesiculobullous or erosive lichen planus, Behçet syndrome, recurrent aphthous stomatitis, and primary herpetic gingivostomatitis.
Among the numerous factors implicated in the etiology of 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 ( Fig. 653-3 ). HSV antigens and DNA are present in skin lesions of EM but are absent in nonlesional skin. Presence of the human leukocyte antigens B62, B35, 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 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.
Figure 653-3 Recurrent labial herpes simplex virus (HSV).
The pathogenesis of EM is unclear, but it may be a host-specific cell-mediated immune response to an antigenic stimulus, resulting in damage to keratinocytes. Cytokines released by activated mononuclear cells and keratinocytes may contribute to epidermal cell death and constitutional symptoms.
Microscopic findings of EM, as with the gross appearance of the cutaneous eruption, are variable but may aid in diagnosis. Early lesions typically show slight intercellular edema, rare dyskeratotic keratinocytes, and basal vacuolation in the epidermis and a perivascular lymphohistiocytic infiltrate with edema in the upper dermis. More mature lesions show an accentuation of these characteristics and the development of lymphocytic exocytosis and an intense, perivascular, and interstitial mononuclear infiltrate in the upper third of the dermis. The entire epidermis becomes necrotic in severe cases.
Treatment of EM is supportive. Topical emollients, systemic antihistamines, and nonsteroidal anti-inflammatory agents do not alter the course of the disease but may provide symptomatic relief. No controlled, prospective studies support the use of corticosteroids in the management of EM. Rather, glucocorticoid therapy may be permissive of HSV replication and make EM episodes more frequent or continuous. Prophylactic oral acyclovir given for 6 mo may be effective in controlling recurrent episodes of HSV-associated EM. On discontinuation of acyclovir, both HSV and EM may recur, although episodes may be less frequent and milder.
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. 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 contrast to 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.
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 agents most commonly precipitating Stevens-Johnson syndrome and toxic epidermal necrolysis.
Treatment.
Management of Stevens-Johnson syndrome is supportive and symptomatic. Potentially offending drugs must be discontinued as soon as possible. Ophthalmologic consultation is mandatory because ocular sequelae such as corneal scarring can lead to vision loss. Topical steroids may reduce ocular morbidity. Oral lesions should be managed with mouthwashes and glycerin swabs. Vaginal lesions should be observed closely and treated to prevent vaginal stricture or fusion. Topical anesthetics (diphenhydramine, dyclonine, and viscous lidocaine) may provide relief from pain, particularly when applied before eating. Denuded skin lesions can be cleansed with saline or Burow solution compresses. Antibiotic therapy is appropriate for documented secondary bacterial infection. Treatment may require admission to an intensive care unit; intravenous fluids; nutritional support; sheepskin or air-fluid bedding; daily saline or Burow solution compresses; paraffin gauze or hydrogel dressing of denuded areas; saline compresses on the eyelids, lips, or nose; analgesics; and urinary catheterization (when needed). A daily examination for infection and ocular lesions, which constitute the major cause of long-term morbidity, is essential. Systemic antibiotics are indicated for urinary or cutaneous infections and for suspected bacteremia because infection is the leading cause of death. Prophylactic systemic antibiotics, however, are not necessary. Although corticosteroids are sometimes advocated in early, severe cases of Stevens-Johnson syndrome, no prospective double-blind studies evaluating their efficacy have been reported. Most authorities discourage their use because of reports of increased morbidity and mortality (sepsis) with their administration. Intravenous immunoglobulin (1.5–2.0 g/kg/day × 3 days) has also been used and believed by many to be effective.
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 Fas-mediated keratinocyte apoptosis. 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; however, some contend that toxic epidermal necrolysis represents the most severe form of the spectrum of 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. Nikolsky sign (denudation of the skin with gentle tangential pressure) is present but only in the areas of erythema. 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 [drug rash, eosinophilia, systemic symptoms] syndrome) is a multisystem reaction that appears ≈4 wk to 3 mo after starting phenytoin, carbamazepine, phenobarbitone, or primidone. Although initially described with anticonvulsant therapy, other drugs, most commonly, antibiotics, have been implicated. 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, 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 (see Chapter 74 ). 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 hydrogel dressings alleviate pain and reduce fluid loss. Narcotics are often required for pain relief. Mouth and eye care may be necessary, such as for EM major. Because of an immune mechanism, systemic glucocorticosteroids and IV immunoglobulin have been used with apparent success. Nonetheless, this treatment remains controversial.
(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 30 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. 653-1 and 653-2 [1] [2]).
Figure 653-1 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, 3rd ed, St. Louis, Mosby, 2002, p 156.)
Figure 653-2 “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, 3rd ed, St. Louis, Mosby, 2002, 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.
Although EM may present initially with urticarial lesions, unlike urticaria, a given lesion of EM does not fade within 24 hr. Serum sickness–like reaction (SSLR) to cefaclor may also present with EM-like lesions. Although the lesions may develop a dusky to purple center, in most cases, the eruption of cefaclor-induced SSLR is pruritic, transient, and migratory and is probably urticarial rather than true EM.
The differential diagnosis of EM also includes bullous pemphigoid, pemphigus, linear IgA dermatosis, graft vs host disease, bullous drug eruption, urticaria, viral infections such as herpes simplex, Reiter disease, Kawasaki disease, Behçet disease, allergic vasculitis, erythema annulare centrifugum, and periarteritis nodosa. EM that primarily involves the oral mucosa may be confused with bullous pemphigoid, pemphigus vulgaris, vesiculobullous or erosive lichen planus, Behçet syndrome, recurrent aphthous stomatitis, and primary herpetic gingivostomatitis.
Among the numerous factors implicated in the etiology of 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 ( Fig. 653-3 ). HSV antigens and DNA are present in skin lesions of EM but are absent in nonlesional skin. Presence of the human leukocyte antigens B62, B35, 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 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.
Figure 653-3 Recurrent labial herpes simplex virus (HSV).
The pathogenesis of EM is unclear, but it may be a host-specific cell-mediated immune response to an antigenic stimulus, resulting in damage to keratinocytes. Cytokines released by activated mononuclear cells and keratinocytes may contribute to epidermal cell death and constitutional symptoms.
Microscopic findings of EM, as with the gross appearance of the cutaneous eruption, are variable but may aid in diagnosis. Early lesions typically show slight intercellular edema, rare dyskeratotic keratinocytes, and basal vacuolation in the epidermis and a perivascular lymphohistiocytic infiltrate with edema in the upper dermis. More mature lesions show an accentuation of these characteristics and the development of lymphocytic exocytosis and an intense, perivascular, and interstitial mononuclear infiltrate in the upper third of the dermis. The entire epidermis becomes necrotic in severe cases.
Treatment of EM is supportive. Topical emollients, systemic antihistamines, and nonsteroidal anti-inflammatory agents do not alter the course of the disease but may provide symptomatic relief. No controlled, prospective studies support the use of corticosteroids in the management of EM. Rather, glucocorticoid therapy may be permissive of HSV replication and make EM episodes more frequent or continuous. Prophylactic oral acyclovir given for 6 mo may be effective in controlling recurrent episodes of HSV-associated EM. On discontinuation of acyclovir, both HSV and EM may recur, although episodes may be less frequent and milder.
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. 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 contrast to 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.
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 agents most commonly precipitating Stevens-Johnson syndrome and toxic epidermal necrolysis.
Treatment.
Management of Stevens-Johnson syndrome is supportive and symptomatic. Potentially offending drugs must be discontinued as soon as possible. Ophthalmologic consultation is mandatory because ocular sequelae such as corneal scarring can lead to vision loss. Topical steroids may reduce ocular morbidity. Oral lesions should be managed with mouthwashes and glycerin swabs. Vaginal lesions should be observed closely and treated to prevent vaginal stricture or fusion. Topical anesthetics (diphenhydramine, dyclonine, and viscous lidocaine) may provide relief from pain, particularly when applied before eating. Denuded skin lesions can be cleansed with saline or Burow solution compresses. Antibiotic therapy is appropriate for documented secondary bacterial infection. Treatment may require admission to an intensive care unit; intravenous fluids; nutritional support; sheepskin or air-fluid bedding; daily saline or Burow solution compresses; paraffin gauze or hydrogel dressing of denuded areas; saline compresses on the eyelids, lips, or nose; analgesics; and urinary catheterization (when needed). A daily examination for infection and ocular lesions, which constitute the major cause of long-term morbidity, is essential. Systemic antibiotics are indicated for urinary or cutaneous infections and for suspected bacteremia because infection is the leading cause of death. Prophylactic systemic antibiotics, however, are not necessary. Although corticosteroids are sometimes advocated in early, severe cases of Stevens-Johnson syndrome, no prospective double-blind studies evaluating their efficacy have been reported. Most authorities discourage their use because of reports of increased morbidity and mortality (sepsis) with their administration. Intravenous immunoglobulin (1.5–2.0 g/kg/day × 3 days) has also been used and believed by many to be effective.
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 Fas-mediated keratinocyte apoptosis. 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; however, some contend that toxic epidermal necrolysis represents the most severe form of the spectrum of 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. Nikolsky sign (denudation of the skin with gentle tangential pressure) is present but only in the areas of erythema. 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 [drug rash, eosinophilia, systemic symptoms] syndrome) is a multisystem reaction that appears ≈4 wk to 3 mo after starting phenytoin, carbamazepine, phenobarbitone, or primidone. Although initially described with anticonvulsant therapy, other drugs, most commonly, antibiotics, have been implicated. 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, 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 (see Chapter 74 ). 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 hydrogel dressings alleviate pain and reduce fluid loss. Narcotics are often required for pain relief. Mouth and eye care may be necessary, such as for EM major. Because of an immune mechanism, systemic glucocorticosteroids and IV immunoglobulin have been used with apparent success. Nonetheless, this treatment remains controversial.