What are the common causes of erythema multiforme (EM) in young adults?

Common Causes of Erythema Multiforme in Young Adults

Herpes simplex virus (HSV) infection is the most common cause of erythema multiforme in young adults, followed by Mycoplasma pneumoniae and drug reactions. 1, 2

Primary Infectious Triggers

Herpes Simplex Virus

• HSV is the predominant infectious cause of EM, particularly in recurrent cases where HSV association is nearly universal. 1, 3, 4
• The mechanism involves a hypersensitivity reaction with cytotoxic T lymphocytes inducing keratinocyte apoptosis, typically appearing 10 days after viral infection. 5, 4
• Recurrent EM is almost always HSV-associated, making this the key etiology to investigate in patients with multiple episodes. 6, 7

Mycoplasma pneumoniae

• M. pneumoniae represents another significant infectious trigger, particularly common in children and young adults. 1, 8
• This pathogen is associated with better prognosis compared to other causes. 1
• Mycoplasma-induced EM may present with predominantly mucous membrane involvement with minimal cutaneous lesions, termed "Mycoplasma pneumoniae-associated mucositis." 1, 9

Other Infectious Agents

• Additional viral triggers include hepatitis C virus, Coxsackie virus, and Epstein-Barr virus, though these are less common than HSV. 8
• These alternative infectious causes should be considered when HSV testing is negative and clinical suspicion remains high. 8

Drug-Induced Erythema Multiforme

Medications constitute the second most frequently identified cause of EM in young adults. 4, 8

Commonly Implicated Medications

• Allopurinol, anticonvulsants (phenobarbital, phenytoin, valproic acid), and antibiotics (sulfonamides, penicillins, erythromycin, nitrofurantoin, tetracyclines) are frequently reported triggers. 8
• NSAIDs (acetylsalicylic acid), statins, and TNF-α inhibitors (adalimumab, infliximab, etanercept) have also been documented as causative agents. 8
• Anticancer agents can cause toxic erythema resembling EM, requiring careful differentiation in oncology patients. 1

Critical Diagnostic Approach for Drug-Induced EM

• Document all medications taken in the preceding 2 months, as drug-induced reactions may have delayed onset. 2
• Immediate discontinuation of the culprit drug is essential when identified. 9

Distinguishing EM from More Serious Conditions

Key Differentiating Features from Stevens-Johnson Syndrome/TEN

• EM presents with typical target lesions or raised atypical targets, predominantly on limbs and extremities, whereas SJS/TEN features flat atypical targets or purpuric macules with epidermal detachment. 1, 2
• EM is mostly HSV-related with lower mortality and better prognosis, while SJS/TEN is usually drug-triggered with significantly worse outcomes. 1, 9
• The Nikolsky sign is positive in SJS/TEN but negative in EM. 2

Differentiation from Urticaria

• Individual urticarial lesions typically resolve within 24 hours, whereas EM lesions remain fixed for a minimum of 7 days. 1, 7
• This temporal distinction is critical for accurate diagnosis in young adults presenting with acute rash. 1

Diagnostic Workup Priorities

Essential Investigations

• HSV PCR or serology should be obtained to identify the most common trigger. 2
• Skin biopsy from lesional skin showing variable epidermal damage, basal cell vacuolar degeneration, and perivascular lymphocytic infiltrate confirms the diagnosis when clinical presentation is uncertain. 1, 9
• Direct immunofluorescence on perilesional biopsy excludes immunobullous disorders that can mimic EM. 2, 9

Clinical Assessment Components

• Document lesion morphology precisely, looking for the characteristic three-zone target configuration with central dark papule/vesicle, pale zone, and erythematous halo. 5, 2
• Map distribution pattern, as EM characteristically affects extremities with centripetal spread. 7
• Examine all mucosal surfaces for erosions and hemorrhagic crusting to determine disease severity. 2

Common Pitfalls to Avoid

• Repeatedly elevated Mycoplasma titers can lead to delayed diagnosis of HSV-induced EM, as prior M. pneumoniae infection may confound serologic interpretation. 6
• Biopsy timing is crucial—early lesions may not show characteristic histopathological features, leading to diagnostic uncertainty. 9
• Inadequate clinical information provided to pathologists may result in misdiagnosis, as histopathology alone is not definitively diagnostic without clinical correlation. 9