Rudolph's Pediatrics, 22nd Ed.

CHAPTER 362. Immunologic Diseases

Julie Prendiville

DRUG ERUPTIONS

Cutaneous adverse reactions to drugs are common in pediatric practice and often present a diagnostic challenge.1 The pathogenesis of most drug eruptions is not well understood. With the exception of fixed drug eruption (discussed shortly), a diagnosis of drug causation cannot be based solely on the morphology of the skin lesions.2 A high index of suspicion is important so that the offending drug is discontinued and avoided in the future, particularly in the case of life-threatening reactions such as anaphylaxis, the drug hypersensitivity syndrome (DHS), and Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN). Conversely, it is important not to erroneously label a child as “allergic” to a widely used medication such as penicillin. There are no standardized laboratory investigations that confirm drug causation, and the value of allergy testing is largely restricted to cases of immunoglobulin E (IgE)-mediated penicillin hypersensitivity. Therefore, a detailed history, evaluation of the morphology of the eruption, consideration of a differential diagnosis, and careful clinical judgment are essential.

The timing of the reaction may be helpful. Medications begun recently, particularly within the past weeks, are more likely to be culpable than drugs taken for many months. Urticaria usually occurs within hours to 1 day after beginning a medication, whereas exanthems develop 7 to 10 days into treatment unless there has been previous exposure. Life-threatening reactions to sulfonamides and anticonvulsants such as drug hypersensitivity syndrome and SJS/TEN characteristically occur 1 to 3 weeks after initiating therapy. Although these serious reactions are rare, the parents of children prescribed these medications should be advised to seek medical attention if a rash or fever develops during the first weeks of treatment.

Exanthematous (or morbilliformdrug eruptions, although often extremely pruritic, are usually benign and self-limited. They may be difficult to distinguish from a viral exanthem. Some are the result of a drug-virus interaction such as occurs when ampicillin is administered to patients with an Epstein-Barr virus infection; human herpes virus-6 and cytomegalovirus have also been implicated.

Drug hypersensitivity syndrome or drug reaction with eosinophilia and systemic symptoms (DRESS) should be considered in all patients presenting with an exanthematous drug eruption. This is characterized by a generalized exanthem, facial edema, fever, hepatitis, lymphadenopathy, eosinophilia, and variable multiorgan disease. Because it is accompanied by fever and signs of systemic toxicity, this serious and sometimes life-threatening disorder may be mistaken for a viral or other infectious illness.

Generalized erythroderma with widespread superficial pustules is seen as a drug reaction to erythromycin, penicillins, and other medications and is known as acute generalized exanthematous pustulosis(AGEP).

Acute urticarial drug eruptions may be associated with airway angioedema and anaphylaxis. These life-threatening complications usually develop shortly after administration of the medication. Urticaria in childhood is often precipitated by a viral or upper respiratory tract illness for which the child may have been administered an antibiotic, and it can be difficult to ascertain whether the cause of the urticaria is the infection, the drug, or perhaps a drug-virus interaction. It is wise to discontinue the medication and consult an allergist before considering oral rechallenge if further use of the medication is anticipated. Cefaclor causes a serum sickness-like urticarial eruption, often associated with arthralgia, in up to 3% of children who take this antibiotic. Serum sickness-like reaction has been reported in association with several other antibiotics as well.

The fixed drug eruption is characterized by 1 or more discrete plaques of dusky erythema that develop hours to days after drug exposure. Central blistering is often present. The mucous membranes of the lips or penis are commonly affected, but lesions may appear at any location. They typically resolve to leave an area of postinflammatory hyperpigmentation. If the offending drug is readministered, lesions reappear in precisely the same anatomic locations. A nonpigmenting fixed drug eruption that presents with localized erythema and subsequently desquamates may be caused by pseudoephedrine, contained in over-the-counter remedies for upper respiratory tract symptoms.

Drug eruptions are managed by discontinuing the offending medication and providing supportive and symptomatic treatment. Specific therapy is required for urticaria and anaphylaxis. Immune modulating agents such as systemic corticosteroids, intravenous immunoglobulin, or cyclosporine are often utilized in the management of life-threatening reactions such as drug hypersensitivity syndrome and severe SJS/TEN; there is no consensus about the optimal regimen.3

HYPERSENSITIVITY REACTIONS

Urticaria (hives) is common in children. The primary wheal is an erythematous, edematous papule or plaque produced by a sudden increase in interstitial fluid within the upper dermis. Most cases of acute urticaria result from type 1, IgE-mediated hypersensitivity, but chronic urticaria may be precipitated by other pathogenetic mechanisms. The mast cell plays a central role as the effector cell in all forms of urticaria.

In acute urticaria, red or pink wheals appear suddenly, persist for 2 to 12 hours, then resolve or shift to new sites. The wheals can be pale or dusky blue in the center, producing a targetlike appearance that may be confused with erythema multiforme or vasculitis. Intense pruritus is usually present but may be absent. Lesions vary in size from a few millimeters to several centimeters and are often annular or geographic in configuration.4 They may be associated with deep cutaneous edema (angioedema) or, less frequently, with respiratory tract involvement producing laryngospasm or bronchospasm. Acute urticaria can be distinguished from other conditions, such as erythema multiforme, vasculitis, exanthems, and papular urticaria (due to insect bites) by the evanescent nature of the lesions.5 Urticaria and angioedema are discussed in detail in Chapter 193.

Erythema multiforme, sometimes called erythema multiforme minor, is a hypersensitivity reaction confined to the skin and/or mouth, without systemic toxicity. Infection with the herpes simplex virus is the most common cause of erythema multiforme minor, although the herpetic infection may have resolved by the time the erythema multiforme develops. The skin lesions of erythema multiforme usually have an abrupt onset but may develop over several days as crops of new lesions appear.8 Typical lesions begin as erythematous macules, which rapidly evolve into erythematous edematous plaques. The central portion of the lesions may become dusky, necrotic, or blistered, with variable rings of concentric color change, including an intensification of redness at the periphery of the lesions (“target” lesions). Multiple symmetric lesions occur on the extremities, including the palms and soles. The face, groin, and neck are often affected as well. Lesions on the trunk are less prominent than those on the extremities (centrifugal distribution). Mucosal involvement is variable and may appear at the same time as the skin eruption, or precede or follow it by several days. Multiple erosions, with or without overlying pseudomembranes, may develop on the lips, tongue, and palate (Fig. 362-1).9

In Stevens-Johnson syndrome, sometimes called erythema multiforme major, mucosal lesions predominate, occur at more than 1 site, and usually appear before the cutaneous lesions in association with fever and signs of systemic toxicity. Severe, painful erosions occur on the lips and mucous membranes and may also involve the ocular, genital, and anal mucosae. An extensive eruption of erythematous macules and papules, often with superimposed blisters and erosions, on the face, trunk, extremities, and genitalia, is associated with the mucosal lesions. Atypical target lesions and blue macules may be seen.

Toxic epidermolysis necrolysis is defined as full-thickness epidermal necrosis of more than 30% of the body surface.9 Many consider TEN and SJS to be related disorders with a similar pathogenetic mechanism; overlapping cases with manifestations that resemble both SJS and TEN may occur with blistering and epidermal detachment of more than 10% of the body surface area. In bullous SJS and TEN, stroking of the skin at the edge of a blister may extend it (positive Nikolsky sign). Systemic toxicity in patients with SJS and TEN is often severe, particularly with fever, dysphagia from oral and esophageal erosions, tracheal and bronchial erosions, respiratory abnormalities, noninfectious hepatitis, urinary tract obstruction, and sometimes sepsis. Long-term sequelae can include dyspigmentation, dry eyes, nail dystrophy, and mucosal scarring, particularly of the eyes with resultant symblepharon, synechiae, entropion and ectropion, trichiasis, corneal opacities, and pannus formation. Strictures of the bronchus, urethra, vagina, or anus may occasionally occur. The mortality rate is particularly high (25%) in patients with TEN.

FIGURE 362-1. Erythema multiforme minor associated with preceding herpes simplex infection. Note target lesions on hands and blistering of lips and oral mucosa.

Most cases of either SJS or TEN are precipitated by drugs, particularly sulfonamides, the aromatic anticonvulsants (phenobarbital, phenytoin, and carbamazepine), and allopurinol. Other drugs have been implicated and idiopathic cases occur. SJS is often also triggered by infections, and an association with Mycoplasma pneumoniae is well recognized. TEN may develop as a manifestation of severe, acute graft-versus-host disease.

Erythema multiforme minor is a self-limited process and requires no specific treatment.

Patients with TEN and severe SJS should be hospitalized for supportive care until the skin and mucosae reepithelialize. If skin loss is extensive, management in a specialized burn unit or intensive care unit is required. Patients with respiratory distress also require intensive care.

The use of specific treatments such as systemic corticosteroids, intravenous immunoglobulin, or cyclosporine in the management of severe SJS and TEN is controversial because no studies have clearly demonstrated their efficacy. Nevertheless, they are often used in the treatment of these life-threatening disorders.10

DERMATOLOGIC MANIFESTATIONS OF COLLAGEN VASCULAR DISEASES

LUPUS ERYTHEMATOSUS

In lupus erythematosus (LE), the skin may be the sole organ system affected, or it may be involved as a manifestation of systemic LE. Cutaneous LE may be classified as (1) acute cutaneous LE, (2) subacute cutaneous LE, or (3) chronic cutaneous LE, of which the most common variant is discoid LE. Transient skin involvement resembling subacute cutaneous LE is characteristic of neonatal LE. Sunlight is an important stimulus in the initiation of cutaneous LE.

Systemic Lupus Erythematosus

The most common skin manifestation of systemic lupus erythematosus (SLE) is acute cutaneous lupus erythematosus, characterized by an erythematous eruption that may be localized to the malar area of the face, the “butterfly rash,” or may be more generalized (Fig. 204-1). SLE is discussed in further detail in Chapter 204. The rash is photosensitive and may present as macular erythema or as erythematous, edematous, scaly plaques on the malar area and nasal bridge. Similar lesions may occur elsewhere on the body, especially in areas exposed to sunlight. Patients with SLE may also develop cheilitis and scarring plaques identical to those seen in discoid lupus erythematosus (DLE).11

Subacute cutaneous lupus erythematosus is characterized by a photosensitive, papulosquamous, or annular-polycyclic erythema associated with positive serology for anti-Ro (SSA) or anti-La (SSB) antibodies. Although usually a benign disorder with mild systemic symptoms, subacute cutaneous lupus erythematosus may sometimes occur in patients with systemic lupus erythematosus.

Nonspecific cutaneous findings are common in SLE. These include a nonscarring alopecia, mucosal ulceration (most commonly on the hard palate), and capillary loop telangiectasia of the proximal nail folds. Raynaud phenomenon, cold-induced distal acrocyanosis, or chilblain-like lesions (chilblain LE) may be associated with digital ulcerations. Cutaneous leukocytoclastic vasculitis manifested by palpable purpura or livedo reticularis with ulceration may also be seen. Rare cutaneous manifestations of SLE include urticarial vasculitis, bullous LE, and lupus panniculitis.

Sun avoidance and the use of broad-spectrum sunscreens are extremely important. Some cutaneous manifestations of SLE may respond to topical or intralesional corticosteroids. Antimalarials such as hydroxychloroquine or chloroquine may also be helpful. The use of systemic steroids or cytotoxic agents is determined by the activity of extracutaneous disease.

Discoid Lupus Erythematosus

Discoid lupus erythematosus (DLE) is a chronic, disfiguring dermatosis that not uncommonly begins in late adolescence. The characteristic lesion is an erythematous scaly plaque that shows a triad of atrophy, telangiectasia, and follicular plugging. Hypopigmentation, depigmentation, or hyperpigmentation and scarring commonly develop with time. The scalp, face, and the pinna of the ear are the sites of predilection, but lesions may be found on other sun-exposed sites. Histo-pathology is usually diagnostic in DLE.  Only a small number of patients with DLE progress to SLE. However, lesions that are characteristic of DLE are seen in about 20% of patients with systemic LE during the course of their disease.

Treatment of DLE includes careful avoidance of sun exposure and the regular use of broad-spectrum (UVB and UVA) sunscreens with SPF 30 or higher. Potent topical (eg, fluocinonide ointment) or intralesional corticosteroids are the most commonly employed forms of therapy. Patients with disfiguring disease may benefit from antimalarials (eg, hydroxychloroquine).

Neonatal Lupus Erythematosus

Neonatal lupus erythematosus (NLE) is associated with transplacental passage of maternal anti-Ro (SSA), anti-La (SSB), or anti-U1RNP antibodies from mother to fetus. It is characterized most commonly by a transient skin eruption and/or permanent congenital heart block. A minority of infants have both skin and heart disease. Other manifestations of NLE include thrombocytopenia, leukopenia, hemolytic anemia, hepatitis, pulmonary disease, and central nervous system involvement. The skin lesions of NLE are characteristically annular, erythematous patches or plaques over the head and neck (Fig. 362-2).12NLE may also present with diffuse facial erythema, particularly in a periorbital distribution referred to as “raccoon eyes,” or telangiectatic lesions. Annular or macular lesions occur on the trunk and limbs and can be widespread. The skin eruption may be present at birth or become apparent during the first few months of life.

A diagnosis of NLE is confirmed by positive serology for anti-Ro (SSA) antibodies in the mother and infant. Anti-La (SSB) antibodies are found less commonly, and NLE associated with anti-U1RNP antibodies is rare. The mother may have systemic or acute cutaneous lupus erythematosus or Sjögren syndrome, but many are asymptomatic or have only minor symptoms and signs of connective tissue disease. Mothers of affected infants should be carefully evaluated and followed and advised about the risk of NLE in future pregnancies.

Passively transferred antibodies in the infant are lost during the first 6 months of life. Congenital heart block, caused by maldevelopment and scarring of the conduction system, may require the implantation of a permanent pacemaker. No treatment of the cutaneous lesions other than sun protection is usually required. These lesions usually resolve spontaneously by 6 months with little or no scarring. Hematologic abnormalities, hepatitis, and other systemic manifestations of NLE are also transient.

CHILDHOOD DERMATOMYOSITIS

Dermatomyositis is a chronic inflammatory disease involving skeletal muscle and skin. It usually presentswith proximal muscle weakness and a rash, but the rash may precede the onset of muscle disease. There are occasionally children who develop the typical rash of dermatomyositis with little or no muscle disease. A purplish discoloration of the periorbital skin (heliotrope sign) is typical but may be subtle or absent. A diffuse macular erythema or violaceous discoloration commonly affects the malar areas of the face and may be confused with acute cutaneous LE (Fig. 205-1).13 Erythema or erythematous scaly plaques are seen on the elbows, knees, upper back, chest, and buttocks. These lesions may resemble psoriasis but are less scaly and have ill-defined margins. Flesh-colored or erythematous papules over the metacarpophalangeal joints (Gottron sign) are highly characteristic (Fig. 362-3), as are capillary loop telangiectases of the periungual skin and gum margins. Dermatomyositis is discussed further in Chapter 205.

FIGURE 362-2. Neonatal lupus erythematosus.

SCLERODERMA

Scleroderma may be localized to the skin (morphea or linear scleroderma) or may involve the skin and internal organs (systemic scleroderma).13 These are discussed in detail in Chapter 206.

In systemic sclerosis, hardening of the skin of the fingers and hands is accompanied by ulceration of the fingertips, telangiectasia, and atrophy. Raynaud phenomenon is almost always present. Facial involvement results in a taut appearance, with furrowing of the skin around the lips and restricted opening of the mouth (Fig. 206-1).

Morphea is characterized by discrete areas of skin hardening. The indurated plaques often have a distinct violaceous border; atrophy, hypopigmentation, or hyperpigmentation may be present.

Linear scleroderma may occur in one or more linear bands on the face (en coup de sabre) or over the length of an extremity (Fig. 206-2 and eFig. 362.1 ). The prognosis for linear scleroderma is less favorable than for morphea, because underlying musculoskeletal structures are often involved. Hemiatrophy of affected areas can occur and may be severely disfiguring and/or impair function of the limb. The disease remits after 3 to 5 years. Physiotherapy is important to limit joint contractures, and massage may be of benefit. Treatment with prednisone in combination with methotrexate may halt progress of the disease in some cases.14

FIGURE 362-3. Dermatomyositis: Gottron papules on dorsum of hands.

Parry-Romberg syndrome is characterized by progressive linear or hemifacial atrophy that develops in the presence of normal or atrophic skin. Some children show mixed morphologies of linear scleroderma and facial hemiatrophy; thus, Parry-Romberg syndrome may be a variant of linear scleroderma. These patients may have underlying intracerebral malformations or calcifications that result in seizures or hemiparesis.

Atrophoderma is characterized by depressed areas of skin that can be circumscribed (atrophoderma of Pasini and Pierini) or linear (linear atrophoderma of Moulin). The lesions have a hyperpigmented, bluish or violaceous color that resembles morphea, but there is no sclerosis or induration. Large, circumscribed areas on the trunk may be difficult to distinguish from morphea, and occasionally, the 2 conditions coexist. Linear atrophoderma on the limbs can be mistaken for linear scleroderma. The pathogenesis of this disorder is unknown.

Lichen sclerosus is an inflammatory disorder of unknown etiology that not uncommonly affects the anogenital area of prepubertal girls. In boys, the prepuce and glans penis are the sites of predilection and may lead to phimosis or meatal obstruction (balanitis xerotica obliterans). Affected females most often present with chronic vulvar pruritus. They may also complain of dysuria or painful defecation and constipation that result from perianal fissuring. The typical clinical appearance is a white discoloration with atrophy of the vulva and perianal area in a “figure-of-8” pattern. The presence of purpura, telangiectasia, or erosions of the vulva or perianal skin may lead to a mistaken diagnosis of sexual abuse. Small hemorrhagic blisters may be misdiagnosed as hemangiomas (Fig. 362-4). Chronic lichen sclerosus may cause adhesions and effacement of the labia minora and sometimes scarring. Extragenital lichen sclerosus is very rare in childhood. The diagnosis of genital lichen sclerosus is usually made clinically and rarely requires a skin biopsy.  The course of the disease is variable; in the majority of children it appears to remit at or around puberty. Topical steroids are the most effective treatment for vulvar and perianal disease. A midpotency topical steroid or application of a high-potency preparation for short periods is usually required.15 Surgical intervention may be necessary for boys with phimosis or meatal narrowing. There is no effective treatment for extragenital lichen sclerosus.

CUTANEOUS VASCULITIS

Vasculitis, the inflammatory destruction of blood vessels, occurs in a variety of pediatric disorders and is classified by the size of the affected vessels. When present, skin lesions may provide an important clinical sign for diagnosis. Vasculitides are discussed in more detail in Chapter 203.

FIGURE 362-4. Lichen sclerosus.

Henoch-Schönlein purpura (HSP) is a systemic leukocytoclastic vasculitis involving small vessels of the skin, joints, gastrointestinal tract, and kidneys. Skin involvement is usually the presenting sign with the development of “palpable purpura” predominantly over the lower extremities and buttocks (Fig. 203-1 and eFig. 362.2 ). Early lesions may present as urticarial papules or plaques. The histopathology of HSP shows perivascular neutrophils and their debris (leukocytoclasis), fibrin deposition in vessel walls, and variable extravasation of erythrocytes. The immunopathologic demonstration of IgA deposits within vessel walls is diagnostic and may be found on nonlesional skin. HSP in most children is self-limited and requires no treatment. Because the onset of nephritis may follow that of the skin lesions by several weeks, blood pressure and urinalysis should be monitored for at least 1 month in all patients.

A variant of leukocytoclastic vasculitis seen in infants and toddlers that resembles HSP is termed hemorrhagic edema of infancy and is characterized clinically by annular erythematous and purpuric plaques.16Unlike HSP, it commonly affects the face as well as the limbs and genitalia. Multiorgan disease is less common than in older children with HSP. Nevertheless, these infants should be evaluated for systemic involvement.

Small-vessel leukocytoclastic vasculitis, characterized clinically by palpable purpura, is seen in a number of conditions other than HSP and requires exclusion of collagen vascular diseases, infections, and a drug reaction.

Polyarteritis nodosa (PAN) is a necrotizing vasculitis of small and medium-sized arteries. Childhood PAN is characterized by multisystem organ disease and the presence of painful subcutaneous nodules. Livedo reticularis is a frequent association. Cutaneous PAN, a milder variant predominantly affecting the skin, is often preceded by streptococcal infection. Infantile PAN tends to involve more selectively the coronary arteries and is sometimes accompanied by a morbilliform eruption. This variant shares common features with Kawasaki disease.

THE SKIN IN ACQUIRED IMMUNODEFICIENCY DISEASES

GRAFT-VERSUS-HOST DISEASE

Graft-versus-host disease (GVHD) is a multisystem illness caused by the reaction of exogenous, immunocompetent cells against the tissues of a histoincompatible, immunosup-pressed patient. Cutaneous disease is often the earliest sign of GVHD and contributes significantly to its morbidity and mortality.17 The clinical manifestations of GVHD are divided into acute and chronic phases. Acute GVHD develops 7 to 30 days after grafting. The rash is usually an erythematous macular eruption resembling a viral exanthem or drug eruption. Erythema of the palms and soles as well as on the earlobes and the proximal nail folds is often seen. Mucosal involvement is common. In severe disease, a scar-latiniform rash begins acrally, spreads to involve the entire skin, and is rapidly followed by the development of toxic epidermal necrolysis (TEN). Most patients with TEN caused by GVHD do not survive. The characteristic cutaneous histo-pathology in GVHD is a sparse inflammatory infiltrate at the dermal-epidermal junction and clustering of lymphocytes around individual necrotic keratinocytes (satellite cell necrosis). In many early or mild cases, histopathology is not diagnostic, and differentiation from a viral exan-them or drug reaction is particularly difficult. In chronic GVHD, mucosal and cutaneous lesions develop that mimic those seen in lichen planus. Over time, involved areas may become atrophic and show reticulate hyperpigmentation. Sclerodermatous changes develop in some patients with chronic GVHD.

HUMAN IMMUNODEFICIENCY VIRUS

Human immunodeficiency virus (HIV) infection in children is most commonly transmitted from an infected mother before or during birth.18 Pediatric HIV infection can also be transmitted by breast milk, by transfusion of contaminated blood or blood products, or, rarely, by sexual abuse. A wide variety of cutaneous manifestations of HIV infection are now recognized, although they have become less common and less severe with the advent of effective antiretroviral therapy. Most are common childhood dermatoses and infections that tend to be unusually severe, poorly responsive to therapy, and recurrent.19 Skin disease may sometimes provide the first evidence of HIV-related illness.

Mucocutaneous infection is the most common type of skin disease associated with HIV. Persistent oral candidiasis and/or candidal diaper dermatitis occur in more than 65% of children with HIV infection. Candidal paronychia may result in destruction of the nail plate. Other fungal infections include unusual and severe patterns of tinea corporis, tinea capitis, and onychomycosis. Several cutaneous viral infections occur, especially herpes simplex, which often takes the form of chronic or recurrent gingivostomatitis or herpetic whitlow. Herpes zoster also occurs with increased frequency; lesions are often accompanied by severe discomfort and may result in scarring. A chronic form of varicella-zoster infection, characterized by multiple scattered nodules, has been recognized in children with HIV infection. Molluscum contagiosum and warts are especially severe in untreated HIV-infected children. There may be unusually extensive flat warts or large and persistent genital warts. Bacterial infections include cellulitis, impetigo, folliculitis, and ecthyma.

Cutaneous inflammatory disorders such as seborrheic dermatitis, eczema, and psoriasis are exacerbated by HIV infection. Drug eruptions, in many cases attributable to trimethoprimsulfamethoxazole, may also occur. Kaposi sarcoma, a low-grade vascular neoplasm presenting with violaceous papules and nodules in adults, is rare in pediatric HIV infection.

AUTOIMMUNE BLISTERING DISEASES

Autoimmune blistering diseases are mediated by circulating immunoglobulins that are deposited in the skin, resulting in inflammation and blister formation.20 They are not common in children. The clinical features of these disorders overlap so that diagnosis requires skin biopsy specimens for histopathologic and direct immunofluorescence examinations to determine the site and type of autoantibody deposition. Indirect immunofluorescence using the patient’s serum and immunoelectronmicroscopy may also be required to localize the autoantibody binding site within the epidermis or dermal-epidermal junction.

LINEAR IGA BULLOUS DERMATOSIS OF CHILDHOOD

Linear IgA bullous dermatosis (LABD), also known as chronic bullous dermatosis of childhood, usually has its onset during the first decade of life after 1 year of age. Typically, there is a sudden eruption of tense bullae and vesicles with clustering into annular or rosetted arrays. The scalp, face, perineum, abdomen, buttocks, and thighs are the most commonly affected sites, but the distal extremities are also be involved. Some patients have mucous membrane involvement. Scarring does not occur, but postinflammatory pigmentary changes may be pronounced. Pruritus is a variable symptom.

LABD is often initially misdiagnosed as bullous impetigo or bullous erythema multiforme. The diagnosis is established by demonstration of linear deposition of IgA and C3 at the dermal-epidermal junction on direct immunofluorescence of perilesional skin. LABD usually responds to treatment with either dapsone (1.5–2.0 mg/kg/day) or sulfapyridine (60–200 mg/kg/day in divided doses). Glucose-6-phosphate dehydrogenase (G6PD) deficiency must be excluded before initiating therapy with either drug, and regular blood counts must be obtained during treatment. The addition of prednisone (1–2 mg/kg/day) may be necessary in severe cases. Episodes of remissions and exacerbations are usually followed by complete resolution within several months to a few years.

DERMATITIS HERPETIFORMIS

Dermatitis herpetiformis is a chronic blistering disease that is rare in childhood. It is characterized by intensely pruritic papules, vesicles, and occasional bullae, usually located on the elbows, knees, shoulders, neck, and sacral area. Direct immunofluorescence of perilesional skin demonstrates a granular deposition of IgA within the dermal papillae. Gluten-sensitive enteropathy can be demonstrated in 85% to 90% of cases. Although overt gastrointestinal symptoms are usually absent, jejunal villus atrophy is evident on intestinal biopsy (see Chapter 408).

PEMPHIGUS

In pemphigus, IgG autoantibodies directed against components of desmosomes (desmogleins) on the surface of the keratinocytes disrupt cell-cell adhesion within the epidermis. In pemphigus vulgaris, these antibodies result in a middle to lower intraepidermal separation. In pemphigus foliaceus, the plane of cleavage is more superficial within the granular cell layer. Both diseases are rare in childhood, although a variant of pemphigus foliaceus (fogo selvagem) is endemic in certain parts of Brazil.

In pemphigus vulgaris, painful oral mucous membrane erosions often precede the onset of skin lesions. Generalized, flaccid bullae and erosions measuring 5 to 20 mm are found in the scalp or intertriginous areas. Paraneoplastic pemphigus in children is associated with an underlying tumor, most commonly Castleman tumor; mortality is high when there is pulmonary involvement.21 Treatment with high doses of systemic corticosteroids often in conjunction with azathioprine or other steroid-sparing agent, is usually necessary to control the disease. Intravenous immunoglobulin and rituximab are also reported to be of benefit.

Pemphigus foliaceus presents with eczematous and crusted lesions, frequently on the upper torso, and intact blisters may not be apparent.  With early diagnosis and adequate treatment, the prognosis for pemphigus in children is good.