1. Epidemiology and Incidence

Erythema multiforme (EM) is a rare condition in the general population but is likely under-recognized in the intensive care unit (ICU). Accurate estimation of its incidence is limited by nonstandardized reporting and significant clinical overlap with more severe mucocutaneous syndromes like Stevens-Johnson syndrome (SJS).

Population and ICU Context

• General Population Incidence: Estimated at 1–3 cases per million people per year, with a peak onset in the second to fourth decades of life and a slight male predominance.
• Critically Ill Cohorts: The true rates are unknown. However, single-center case series suggest that up to 5% of all drug eruptions observed in the ICU may be classified as EM.
• ICU-Specific Risk Modifiers: Factors that increase risk in critically ill patients include profound immunosuppression, prolonged exposure to broad-spectrum antibiotics or antivirals, and advanced age associated with immune senescence.

Challenges in Surveillance

Systematic tracking of EM is hampered by several factors:

• Diagnostic Variability: Inconsistent rates of skin biopsy and use of direct immunofluorescence lead to diagnostic uncertainty.
• Coding Limitations: Electronic health record (EHR) adverse-event modules often lack discrete codes for EM, lumping it with other rashes.

Key Points for Clinical Practice

• Maintain a high index of suspicion for atypical or amelanotic targetoid lesions, especially in immunosuppressed ICU patients.
• Advocate for early dermatology consultation and adherence to standardized case definitions to improve diagnostic and reporting accuracy.

2. Pathophysiology

EM is understood as a type III hypersensitivity reaction characterized by immune complex deposition and cytotoxic T-cell–mediated keratinocyte apoptosis, with pathology typically confined to the dermoepidermal junction.

Common Triggers

3. Impact of Pre-existing Chronic Diseases

In ICU patients, chronic comorbidities and their associated therapies can profoundly alter the risk, presentation, and clinical course of EM.

• HIV/AIDS: CD4+ lymphopenia impairs viral control (e.g., of HSV), yet the dysregulated immune system may exhibit heightened, aberrant T-cell activation in response to triggers. Presentations can be atypical and progress rapidly.
• Autoimmune Disorders (e.g., SLE): Underlying immune dysregulation, epitope spreading during flares, and immune complex formation can predispose patients to EM. Lesions may be difficult to distinguish from cutaneous vasculitis.
• Organ Dysfunction: Renal failure and hepatic impairment delay the clearance of drugs and their active metabolites, prolonging tissue exposure and increasing the risk of a reaction. Dose adjustments for organ function are critical.
• Immunosuppressive Therapies: While corticosteroids may attenuate the inflammation of EM, they also increase the risk of secondary infections and can delay wound healing.

A 52-year-old woman with lupus nephritis on prednisone and mycophenolate develops classic target lesions on her extremities after starting trimethoprim-sulfamethoxazole for a UTI. Her underlying renal impairment, which necessitated dose reduction, still allowed for drug accumulation in tissue, prompting a florid EM flare.

4. Social Determinants of Health

Nonclinical factors, including access to care, health literacy, and socioeconomic status, significantly influence the recognition, management, and outcomes of EM, particularly in high-acuity settings and during the transition of care.

Barriers to Optimal Care

• Medication Access: Insurance gaps and “pharmacy deserts” can delay the withdrawal of an offending drug or the initiation of essential therapies like antivirals for HSV-triggered EM.
• Health Literacy: Limited understanding of the condition can lead to poor adherence with supportive skin care, failure to recognize early signs of recurrence, and confusion about which medications to avoid.
• Socioeconomic Factors: Housing instability, lack of transportation, and food insecurity create major barriers to attending necessary outpatient follow-up appointments and maintaining proper wound care.

Mitigation Strategies

• Implement pharmacist-led medication access programs to expedite drug discontinuation and secure antiviral prophylaxis.
• Utilize “teach-back” models and provide multilingual educational materials to improve patient understanding and adherence.
• Develop standardized ICU-to-outpatient EM care pathways that include automatic triggers for dermatology and social work consultation, with teledermatology for follow-up.