Pediatric Dermatology Consult - January 2016
By Ellen S. Haddock and Lawrence F. Eichenfield, M.D.
Urticaria multiforme
Although not the most classic presentation, this patient’s migrating rash is most consistent with urticaria (hives). Urticaria is dermal edema which causes transient edematous and usually pruritic wheals.1,2 Each individual lesion lasts less than 24 hours and disappears without leaving a mark. Urticaria is caused by mast cell activation, which leads to release of antihistamines and other substances that increase capillary and venule permeability, allowing fluid to leak into the extravascular space.1 In children, mast cell activation is usually triggered by infections, drugs, or foods.1
Classic urticaria consists of large, pruritic plaques and may be associated with airway edema. However, urticaria also can present with annular and polycyclic lesions, which may be less pruritic and are not associated with airway edema.3 This “multiple redness” is distinct from erythema multiforme (EM), although often urticaria is confused with EM. Lesions of EM are annular and typically have purpuric or dusky centers, with each lesion lasting a minimum of 1 week.4 Annular lesions in urticaria usually do not have central duskiness or blisters. Often the centers of annular urticaria lesions are relatively normal and edges are raised. Some urticaria, especially in younger children as in this case, is sometimes called “urticaria multiforme” because the ecchymotic centers are reminiscent of, but distinct from, classic target lesions of EM. Urticaria multiforme is commonly misdiagnosed as EM, with 29% of patients originally misdiagnosed in one study.3
Urticaria multiforme occurs most commonly in infants and preschool-aged children,5 although it has been diagnosed in patients as old as 18 years.6 Patients often have had an antecedent bacterial or viral illness, recent treatment with antibiotics, or recent vaccination (67%, 44%, and 11% of patients, respectively, in one series).4 In contrast with classic urticaria, urticaria multiforme has not been associated with food allergy.4
In this case, urticaria multiforme was likely caused by a hypersensitivity reaction to amoxicillin. A reaction to nitrofurantoin was less likely because the patient had been taking it continuously for months without any complications.
Differential diagnosis
The differential diagnosis for urticaria multiforme includes EM and a serum sickness–like reaction. The main clue that this patient’s rash was a subtype of urticaria rather than EM was its transience, with individual lesions appearing and disappearing in less than a day.4 In contrast, the lesions of EM are fixed, persisting for a week or longer. While urticaria multiforme may have central ecchymosis (termed “hemorrhagic urticaria”) that looks similar to the dusky centers of EM lesions and persists longer than the transient edematous plaques,1 it resolves quickly with appropriate treatment.4 In contrast, the dusky centers of EM, which are caused by epidermal necrosis, take longer to resolve.4 Dermatographism, if present, would support a diagnosis of urticaria rather than EM. Similarly, facial or acral edema, if present, would support a diagnosis of urticaria multiforme; they are uncommon in EM. In contrast, any necrosis, blistering, or erosions in the centers of the annular lesions or on mucosal membranes would suggest EM, as necrosis, blistering, erosions, and mucosal involvement do not occur in urticaria multiforme.4 We stress that in EM, “the center of the lesion is the center of the action,” while in urticaria, wheals often have relatively normal centers.
Although both urticaria and EM lesions may be pruritic, any burning sensation is more suggestive of EM.4 Urticaria multiforme is often associated with antibiotics, vaccinations, and upper respiratory infections, while EM is most commonly associated with herpes simplex infection.4,7
Urticaria multiforme also may appear similar to a serum sickness–like reaction, which is another kind of hypersensitivity reaction triggered by the administration of antibiotics. It is most commonly associated with cefaclor, but also is associated with other antibiotics including amoxicillin.8 As with urticaria, hypersensitivity drug eruptions and serum sickness-like reactions may present with purpuric, polycyclic wheals with central clearing. However, as with EM, the lesions of serum sickness–like reactions are fixed, lasting for days to weeks.4 Facial or acral angioedema may occur in both urticaria multiforme and serum sickness–like reactions, but serum sickness–like reactions are not associated with dermatographism.4 Furthermore, serum sickness–like reactions are typically associated with high-grade fever, myalgia, arthralgia, and lymphadenopathy, which are not seen in urticaria multiforme.4,5
Diagnosis of urticaria multiforme usually can be made by history and physical exam, so lab testing and skin biopsy typically are not necessary.5 If performed, lab work may show modest elevation in erythrocyte sedimentation rate and C-reactive protein, but often these acute-phase reactants are within normal limits, and complete blood count and complete metabolic panel are unremarkable.3,5 Although urticaria multiforme often is associated with antecedent viral or bacterial infections, work-up for infectious etiology typically is not fruitful or helpful.4 If lesions are biopsied, the histology of urticaria multiforme is indistinguishable from other types of acute urticaria, showing dermal edema with perivascular lymphocytic infiltrate.9 In contrast, EM shows exocytosis, spongiosis, and epidermal necrosis.9
