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 morbilliform) drug 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).¹² NLE 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.

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