Erythema multiforme (EM) is a self-limited acute hypersensitivity reaction to a variety of inciting agents including medications, viruses, bacteria, and fungi. The cutaneous lesions of EM have been described for centuries, the current name having been adopted in 1866 by von Hebra.¹ EM is characterized by an abrupt onset of red papules that progress to form target lesions.²

Erythema multiforme is often separated into two forms: EM minor and EM major.^4,5 EM minor is primarily the term used to describe the classic form described by von Hebra in 1866 and is most often associated with herpes simplex virus. EM major describes the more severe form with mucosal involvement, that is more often related to medications and Mycoplasma pneumoniae.^2,3 About 20% of cases of EM minor occur in children and adolescents,⁴ with a small male preponderance.² EM major is less common than its EM minor counterpart, but it has a higher predilection for the pediatric population, especially adolescents. There are a multitude of infections that are reported in association with erythema multiforme including Epstein Barr virus, herpes simplex virus (HSV), vaccinia, and certain bacterial and fungal infections. Many consider EM major a less severe form of Stevens–Johnson syndrome (SJS).³ SJS and toxic epidermal necrolysis are discussed in Chapter 161. In EM, a local cell-mediated response to an inciting antigen occurs at the site of lesion eruption and leads to local tissue damage.^2,4 Skin cells demonstrate a change in the histocompatibility antigens displayed that is thought to be induced by infiltration of T cells into dermal tissues.^2,4

Many patients with EM minor do not have prodromal symptoms; however, in those suffering from recurrent EM, a relationship with previous HSV eruption is well established.^1,2,4,5 Those with EM major often have a prodrome of symptoms such as headache, fever, and malaise that may occur from a few days to 2 weeks before onset of the eruption. The EM spectrum can be seen any time throughout the year; however, there is an increase in incidence during the spring and fall.

The classic skin finding in EM is a fixed target or iris lesion. This is usually preceded by a red papule or plaque. The target lesion is manifested as an area of central duskiness surrounded by a circular plaque of pallor and a peripheral rim of erythema yielding a ring-like shape.^2-5 The rash is symmetrical and may develop anywhere on the body, but often presents on the extensor surfaces of the extremities, gradually progressing proximally (Figure 64-1). Once lesions appear, they remain fixed in the affected areas for at least a week or longer.

These lesions may be pruritic or painful, or both. The lesions may uncommonly become vesicular or bullous but frequently retain the target shape. EM minor often involves a single mucous membrane, which is most commonly seen as localized mouth lesions.² The mucous membrane lesions are similar to those seen in HSV, with some appearing vesicular and others appearing ulcerated and even blood crusted, but they generally avoid the gingiva. Arthralgia may also be a symptom in patients with EM minor. Systemic symptoms are rare; however, mild fever and malaise may be present. Table 64-1 lists the commonly encountered potential triggers of EM in children.

In EM major, the nonspecific prodromal symptoms are followed by an abrupt and rapid onset of cutaneous and mucosal lesions.³ The skin may become red and tender and then rapidly progress to vesicles and ulcerations, with bullous lesions being much more common in EM major than EM minor. Large areas of skin may be left with tender ulcers exposed as the illness progresses. Unlike EM minor, EM major often has systemic symptoms, as well as involvement of other organ systems.^1,3 By definition, mucous membrane involvement in this circumstance is present in at least two sites.³ The eyes may present with signs and symptoms of injection, ulceration, and discharge. Dysuria may result from inflammation of the genitourinary mucosa and dyschezia from involvement of the gastrointestinal tract. Rarely, pulmonary mucosal involvement may also be encountered. Most cases of EM major result from exposure to medications, although a subset of cases have been linked to infection with Mycoplasma pneumoniae or enterovirus.^1,3,5

COURSE OF ILLNESS

EM minor is generally a self-limited illness that typically lasts about 4 weeks. The lesions develop over the first week and the symptoms often resolve over the next 1 to 2 weeks.³ Recurrent lesions may erupt as the first batch of lesions resolves; however, the total course still lasts about 4 weeks.

EM major, in contrast, tends to last somewhat longer,¹ and resolution often takes up to 6 weeks. Long-term sequelae are related to unresolved organ system involvement in EM major. If all organ systems recover without incident, there are no long-term associated risks. Mortality is very low in EM minor and estimated to be about 10% in EM major.³