Laboratory Testing for Erythema Multiforme
The diagnosis of erythema multiforme is primarily clinical, based on characteristic target lesions and history; routine laboratory testing is generally not required or recommended for diagnosis, but specific tests may be indicated to identify the underlying trigger or exclude alternative diagnoses. 1, 2, 3
Core Diagnostic Approach
Erythema multiforme is diagnosed clinically through recognition of typical targetoid lesions with acral distribution and histopathologic confirmation when needed—not through laboratory panels. 1, 2 The key is identifying the underlying cause rather than confirming the diagnosis itself through labs. 4
Trigger Identification Testing
When HSV is Suspected (Most Common Cause)
- HSV serology or PCR from active lesions if herpes simplex virus-associated EM is suspected, particularly in recurrent cases 1, 2
- This is the single most important test since HSV is the most common identifiable trigger 1, 4
When Mycoplasma pneumoniae is Suspected (Especially in Children)
- Mycoplasma pneumoniae serology if respiratory symptoms are present or in pediatric cases 1, 2
- Consider chest X-ray if pulmonary symptoms exist 1
When Other Infectious Triggers are Suspected
- Hepatitis C serology in appropriate clinical context 1
- Epstein-Barr virus serology if mononucleosis-like symptoms present 1
- Coxsackie virus testing in pediatric cases with appropriate clinical features 1
Exclusion of Alternative Diagnoses
When Immunobullous Disease is in the Differential
- Skin biopsy for routine histopathology from lesional skin adjacent to a blister 5, 3
- Direct immunofluorescence from perilesional skin to exclude pemphigus vulgaris, bullous pemphigoid, mucous membrane pemphigoid, linear IgA disease, and paraneoplastic pemphigus 5, 3, 6
When Stevens-Johnson Syndrome/TEN is Considered
- Complete blood count to assess for cytopenias 5
- Comprehensive metabolic panel including liver function tests, renal function, and electrolytes 5
- Erythrocyte sedimentation rate and C-reactive protein 5
- Chest X-ray 5
- Coagulation studies if severe disease 5
Critical distinction: SJS/TEN presents with widespread erythematous or purpuric macules with blisters and epidermal detachment, whereas EM shows fixed target lesions for minimum 7 days. 5, 2
Baseline Assessment for Severe Mucosal Involvement
When hospitalization is required for severe mucosal disease:
- Electrolytes and renal function to assess hydration status and guide fluid replacement 2, 3
- Complete blood count as baseline 5
- Bacterial cultures from erosions if secondary infection suspected 5
Tests NOT Routinely Indicated
- Autoimmune panels (ANA, complement levels, anti-dsDNA) are not indicated for EM diagnosis unless systemic lupus erythematosus or other autoimmune disease is specifically suspected 5, 7
- Routine inflammatory markers without specific indication 2
- Extensive infectious disease workup without clinical suspicion of specific pathogens 1
Common Pitfalls
Do not confuse EM with urticaria: Individual EM lesions remain fixed for ≥7 days, while urticarial lesions resolve within 24 hours—this is a clinical distinction, not a laboratory one. 2
Do not order extensive autoimmune panels reflexively: The evidence provided on SLE monitoring 5, 7, 8, 9 and eosinophilia workup 5 is not applicable to EM, which is an immune-mediated reaction pattern, not an autoimmune disease. 1, 4
Biopsy is confirmatory, not diagnostic: Histopathology shows interface dermatitis with keratinocyte necrosis, but the diagnosis remains primarily clinical based on the characteristic target lesions. 3, 6