Erythema Multiforme Workup

Updated: Feb 20, 2020
  • Author: Jose A Plaza, MD; Chief Editor: William D James, MD  more...
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Approach Considerations

No specific laboratory tests are indicated to make the diagnosis of erythema multiforme (EM), which should be arrived at clinically. The clinical picture can guide laboratory testing in severe cases.

Cultures are indicated in severe cases and should be obtained from blood, sputum, and mucosal lesions.

No specific imaging studies are necessary in most cases, although chest radiography may be useful in cases with respiratory symptoms or signs, particularly if an underlying pulmonary infection is suspected.


CBC Count

The complete blood cell (CBC) count with differential usually reveals moderate leukocytosis with atypical lymphocytes and lymphopenia, possibly secondary to the depletion of CD4 lymphocytes (90% of patients). An eosinophil count greater than 1000/mm3 may also be seen. Neutropenia (30% of patients) may occur and indicates a poor prognosis. A severely elevated total white blood cell (WBC) counts indicate infection. Mild anemia may be present, and thrombocytopenia is found in 15% of patients.


Chemistries and Other Laboratory Tests

Electrolytes values may be abnormal with severe skin and mucous membrane involvement due to fluid losses. These values are useful to guide volume and electrolyte replacement therapy.

Blood urea nitrogen (BUN) and creatinine tests are indicated to screen for renal involvement and dehydration in severe cases requiring hospitalization. Prerenal azotemia and elevated serum urea nitrogen levels may be found and indicate a poor prognosis.

Also in severe cases, the erythrocyte sedimentation (ESR) rate may be elevated, but this is a nonspecific finding. Mildly elevated liver transaminase levels may be found with hepatic involvement.


Immunofluorescence and PCR

Specific herpes simplex virus (HSV) antigens have been detected within keratinocytes by immunofluorescence study. The HSV DNA has been identified primarily within the keratinocytes by polymerase chain reaction (PCR) amplification.

Direct immunofluorescence staining and examination may also identify an alternative diagnosis (eg, pemphigoid, immunoglobulin A [IgA] linear dermatosis.


Biopsy and Histologic Features

Histopathologic examination of a cutaneous punch biopsy may be used to confirm the diagnosis of erythema multiforme (EM) and to rule out the differential diagnosis (see Differentials).A skin biopsy of the cutaneous lesions may also exclude the presence of other blistering disorders, such as in equivocal cases, particularly in absence of target lesions.

Erythema multiforme

Histologically, erythema multiforme is the prototypical vacuolar interface dermatitis showing a lymphocytic infiltrate along the dermoepidermal junction associated with hydropic changes and dyskeratosis of basal keratinocytes (see the following image). This vacuolar change represents individual or small groups of necrotic (apoptotic) keratinocytes. In addition, a characteristic sparse-to-moderate lymphocytic infiltrate is present around the superficial vascular plexuses.

Interface dermatitis with prominent dyskeratotic c Interface dermatitis with prominent dyskeratotic cells in epidermis.

As the lesions progress, partial-to-full-thickness epidermal necrosis, intraepidermal vesiculation, or subepidermal blisters may appear, owing to spongiosis and to the cellular damage of the basal layer of the epidermis. Occasionally, severe papillary edema is present. The dermal inflammatory infiltrate is characterized by high-density lichenoid infiltrate rich in T cells, composed of lymphocytes (CD4+ more abundant than CD8+ in the papillary dermis; in the epidermis, there is a predominance of CD8 T cells and macrophages) and macrophages, with a few neutrophils and occasional eosinophils (particularly in those cases associated with medications).

Erythema multiforme vs SJS/TEN and SSS

Histology and immunochemistry studies have shown that inflammatory infiltrates of erythema multiforme and Steven-Johnson syndrome / toxic epidermal necrolysis (SJS/TEN) are strikingly different in density and nature. Erythema multiforme has a high density of cell infiltrate rich in T-lymphocytes. By contrast, SJS/TEN is characterized by a cell-poor infiltrate of macrophages and dendrocytes with strong tumor necrosis factor (TNF)–alpha immunoreactivity. Immune complex deposition is variable and nonspecific. In severe cases, fibrinoid necrosis can occur in the stomach, spleen, trachea, and bronchi.

Histologic examination of skin biopsies in staphylococcal scalded skin syndrome (SSSS) reveals cleavage of cell layers within the epidermis.