Hypersensitivity Syndromes and Vasculitis

Erythema multiforme is a relatively common, acute—often recurrent—inflammatory disease characterized by target-shaped skin lesions.

Commonly, erythema multiforme is associated with herpes simplex, Mycoplasma pneumoniae, and upper respiratory tract infections, although erythema multiforme may be associated with many conditions ( Table 11.1 ).

Rarely, erythema multiforme is associated with contact allergens, drugs, connective tissue diseases, physical agents, x-ray therapy, pregnancy, and internal malignancies.

The cause of erythema multiforme is unknown in at least half of the patients.

A minority of patients with reactivation of herpes simplex develop recurrent erythema multiforme.

Erythema multiforme is thought to be produced by a cytotoxic immune response directed against keratinocytes expressing foreign viral or drug antigens.

As its name suggests, erythema multiforme shows numerous lesion morphologies: target lesions, erythematous macules and papules, urticarial-like lesions, vesicles, and bullae.

Patients should only be diagnosed clinically with erythema multiforme if target lesions are seen.

Target lesions begin as dusky-red, round macules and papules that may burn and itch.

These early lesions appear suddenly in a symmetric pattern on the palms, soles, backs of the hands and feet, and the extensor aspect of the forearms and legs. The diagnosis of erythema multiforme may not be suspected until the nonspecific early lesions evolve into target lesions during a period of 24 to 48 hours.

The classic “iris” or target lesion results from centrifugal spread of the red maculopapule to a circumference of 1 to 3 cm. The center of the iris can appear dark red, purpuric, or vesicular and is due to acute epidermal injury. This central area is surrounded by a pale area of edematous skin, which is in turn surrounded by a sharp discrete ring of erythema.

Lesions appear in crops, resolving in 1 to 2 weeks without scarring.

Postinflammatory pigment changes are common (hypopigmentation and/or hyperpigmentation).

Bullae and erosions may be present in the oral cavity.

The urticarial plaques seen in erythema multiforme are distinguished from hives in that they are fixed and do not resolve in 24 hours.

Erythema multiforme lesions may occur in areas of trauma (Koebner's phenomenon).

Erythema multiforme may be preceded by cough, malaise, and fever and may be associated with pneumonia.

Laboratory testing is not necessary. Vesicles or erosions suggestive of herpes simplex confirmed by viral culture or direct immunofluorescence.

Skin biopsy shows an interface reaction with necrotic keratinocytes and can be helpful when the diagnosis is uncertain.

Usually, erythema multiforme resolves within 1 month.

Patients who develop erythema multiforme associated with reactivated herpes simplex may require suppressive therapy to prevent recurrences.

Most patients with erythema multiforme do not require treatment.

Ruptured blisters and eroded skin can be treated with local measures, such as topical antibiotics.

Widespread erythema multiforme responds rapidly to 1 to 3 weeks of systemic corticosteroids. Prednisone 40 to 80 mg/day should be administered until lesions resolve, and then tapered as appropriate.

Recurrent herpes-associated erythema multiforme can be prevented by administering oral acyclovir (200 mg two or three times a day or 400 mg twice a day), valacyclovir (Valtrex), 500 mg/day, or famciclovir (Famvir) 125 mg twice daily as continuous suppressive therapy.

Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are two conditions characterized by epidermal necrosis with varying degrees of body surface area (BSA) (SJS < 10% BSA, SJS/TEN overlap 10%–30% BSA, and TEN >30% BSA).

SJS is three times more common than TEN.

The mortality rate of SJS is 10% and more than 30% for TEN.

Drug reactions account for 80% to 95% of cases of TEN. The most frequently associated drugs are co-trimoxazole and other sulfonamides, lamotrigine, carbamazepine, phenytoin, phenobarbital, sulfasalazine, aminopenicillins, cephalosporins, quinolones, oxicam nonsteroidal anti-inflammatory drugs, allopurinol, and nevirapine.

On average, TEN occurs 2 weeks after initiation of the drug.

Those infected with HIV have a 1000-fold increased risk for TEN, which in part may be related to antiretroviral use.

Certain autoimmune conditions such as systemic lupus erythematosus appear to be at greater risk for drug-induced TEN.

TEN can be precipitated by a recent immunization (diphtheria–pertussis–tetanus, measles, poliomyelitis, influenza), viral infection (cytomegalovirus, Epstein–Barr virus, herpes simplex, varicella-zoster, hepatitis A, dengue), mycoplasmal infection, streptococcal infection, syphilis, histoplasmosis, coccidioidomycosis, and tuberculosis.

Acute graft-versus-host disease and contrast medium can be associated with TEN.

TEN is caused by CD8 T-cell−mediated cell death in susceptible hosts.

Most patients develop diffusely red “sunburn-like” tender skin with scattered target lesions and bullae. Bullae quickly coalesce, resulting in widespread skin sloughing.

Full-thickness epidermal necrosis and detachment (necrolysis) leave a tender glistening raw surface.

Gentle lateral pressure easily produces epidermal detachment.

Mucous membranes develop exquisitely painful erosions.

Cutaneous sequelae of TEN include dyspigmentation, eruptive melanocytic nevi, onychodystrophy, and hair thinning.

Findings include ocular (sicca syndrome, symblepharon, corneal scarring, blindness), pulmonary (chronic bronchitis and respiratory tract obstruction), oral (reduced salivary flow, periodontal disease), genitourinary system (dyspareunia, vaginal adhesions, balanitis and genitourinary strictures), and gastrointestinal system (esophageal strictures).

A skin biopsy can be helpful to distinguish between TEN and staphylococcal scalded skin syndrome. Sloughed skin can be “jelly-rolled” onto a round wooden applicator and sent for frozen section. This quick and simple test will show a superficial epidermal split in staphylococcal scalded skin syndrome and a full-thickness necrotic epidermis in TEN.

A skin biopsy sent for direct immunofluorescence can distinguish between TEN and autoimmune blistering conditions, such as paraneoplastic pemphigus.

Staphylococcal scalded skin syndrome

Graft-versus-host disease

Staphylococcal toxic shock syndrome

Kawasaki disease

Acute-onset paraneoplastic pemphigus

SJS/TEN can be preceded by fever, malaise, cough, and abdominal pain.

Predictors of poor outcome include old age, widespread blistering, immunodeficiency, neutropenia, impaired renal function, and multiple medications.

Overall, the mortality rate for TEN is 30% to 50%.

The mortality rate for acute graft-versus-host disease−associated TEN is nearly 100%.

Treatment regimens focus on controlling pain, identifying and treating sources of infection, withdrawing suspected offending medications, maintaining fluid and nutritional requirements, and providing meticulous local wound care. If possible, severely affected patients should be managed in a burn unit.

Erythema nodosum is a panniculitis characterized by tender pink nodules on the extensor surface of the lower legs.

In adults, erythema nodosum is five or six times more common in women, and the peak age of onset is 20 to 30 years of age. In children, boys and girls are affected equally.

Erythema nodosum is thought to be due to a hypersensitivity reaction to a variety of antigenic stimuli.

Many bacteria, viruses, fungi, parasites, drugs, malignancies, and connective tissue diseases have been associated with erythema nodosum ( Box 11.1 ). In the United States streptococcal infections and sarcoidosis are commonly associated with erythema nodosum.

Half of cases are idiopathic.

Erythema nodosum is characterized by pink to dusky-red firm nodules with indistinct edges, occurring symmetrically on the pretibial surfaces. Erythema nodosum can occur on the head, neck, torso, arms, and thighs.

Erythema nodosum fades over a period of 1 to 2 weeks, similar to a bruise, and does not leave residual scars.

Ankle edema and leg pain are common.

Erythema nodosum may be associated with fever, malaise, diarrhea, headache, conjunctivitis, and cough.

Laboratory evaluation should be guided by history and physical examination. Initial tests should include a throat culture or rapid test for Streptococcus, a complete blood count, and a chest radiograph.

A deep skin biopsy to include fat can be helpful in patients with atypical lesions.

Chest radiograph may show bilateral hilar adenopathy. This finding can be present in erythema nodosum due to sarcoidosis as well as other diseases.