Chapter 646 Vesiculobullous Disorders
Many diseases are characterized by vesiculobullous lesions; they vary considerably in cause, age of onset, and pattern. The morphology of the blister often provides a visual clue to the location of the lesion within the skin. Blisters localized to the epidermal layers are thin-walled, relatively flaccid, and easily ruptured. Subepidermal blisters are tense, thick-walled, and more durable. Biopsies of blisters can be diagnostic because the level of cleavage within the skin and associated findings, such as the nature of the inflammatory infiltrate, are characteristic for a particular disorder. Other diagnostic procedures, such as immunofluorescence and electron microscopy, can often help distinguish vesiculobullous disorders that have nearly identical histopathologic findings (Table 646-1).
Table 646-1 SITES OF BLISTER FORMATION AND DIAGNOSTIC STUDIES FOR THE VESICULOBULLOUS DISORDERS
EB, epidermolysis bullosa; GL, granular layer; IC, intracorneal; IE, intraepidermal; KOH, potassium hydroxide; SC, subcorneal; SE, subepidermal.
646.1 Erythema Multiforme
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.
Pathogenesis
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. HSV Pol1 gene expressed in HA-EM lesions upregulates/activates the transcription factor SP1 and inflammatory cytokines. These cytokines, released by activated mononuclear cells and keratinocytes, may contribute to epidermal cell death and constitutional symptoms.
Pathology
Microscopic findings in EM 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. In severe cases, the entire epidermis becomes necrotic.
Differential Diagnosis
The differential diagnosis of EM also includes bullous pemphigoid, pemphigus, linear immunoglobulin (Ig) A dermatosis, graft versus host disease, bullous drug eruption, urticaria, viral infections such as HSV, reactive arthritis syndromes, 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. Serum sickness-like reaction (SSLR) to cefaclor may also manifest as EM-like lesions; the lesions may develop a dusky to purple center, but in most cases, the eruption of cefaclor-induced SSLR is pruritic, transient, and migratory and is probably urticarial rather than true EM.
Treatment
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.
Gober MD, Laing JM, Burnett JW, et al. The Herpes simplex virus gene Pol expressed in herpes-associated erythema multiforme lesions upregulates/activates SP1 and inflammatory cytokines. Dermatology. 2007;215:97-106.
Lamoreux MR, Sternbach MR, Hsu WT. Erythema multiforme. Am Fam Physician. 2006;74:1883-1888.
Williams PM, Conklin RJ. Erythema multiforme: a review and contrast from Stevens-Johnson syndrome/toxic epidermal necrolysis. Dent Clin North Am. 2005;49:67-76.
646.2 Stevens-Johnson Syndrome
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.)
Pathogenesis
Pathogenesis is related to drug-specific CD8+ cytotoxic T cells, with perforin/granzyme B and granulysin triggering keratinocyte apoptosis. This process is followed by expanded enactment of apoptosis involving the interaction of soluble Fas ligand with Fas receptor.
Differential Diagnosis
The differential diagnosis of Stevens-Johnson syndrome includes toxic epidermal necrolysis, urticaria, DRESS (drug rash [or reaction] with eosinophilia and systemic symptoms) syndrome (Chapter 637.2) and other drug eruptions and viral exanthems, including Kawasaki disease.
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