What is the most likely cause of a rash on the hands and feet with targetoid lesions, sharply demarcated on the palmar aspect of the hands and symmetric on the dorsal and plantar aspects of the feet?

Erythema Multiforme

Most Likely Diagnosis

The clinical presentation of sharply demarcated targetoid lesions with red centers on the palmar aspect of the hands and symmetric involvement of the dorsal and plantar aspects of the feet over 5 days is most consistent with erythema multiforme (EM). 1, 2

Key Diagnostic Features Supporting This Diagnosis

The constellation of findings strongly points to EM based on:

• Targetoid morphology: The "target" or "iris" lesions with red centers are the hallmark of EM, classically described as having three zones of color 1, 2
• Acral distribution: EM characteristically presents symmetrically on the extremities, especially on extensor surfaces, and spreads centripetally - the palmar and plantar involvement described is typical 2, 3
• Sharp demarcation: EM lesions are well-defined and fixed for a minimum of 7 days, distinguishing them from urticaria which resolves within 24 hours 2
• Duration: The 5-day timeline fits with EM's acute, self-limited course 1, 3

Critical Differential Diagnoses to Exclude

While EM is most likely, you must actively rule out more serious conditions:

Hand-Foot-Mouth Disease (HFMD)

• HFMD presents with vesicular lesions on palms and soles but typically includes oral lesions and occurs predominantly in children 4, 5
• The vesicles in HFMD evolve from pink macules, whereas EM presents with targetoid lesions from onset 4
• HFMD is caused by enteroviruses (CV-A6, CV-A16, enterovirus 71) and usually includes fever as the first symptom 4, 5

Rocky Mountain Spotted Fever (RMSF)

• This is life-threatening and requires immediate empiric doxycycline if suspected - do not wait for confirmatory testing 6
• RMSF presents with blanching pink macules that evolve to petechiae on palms and soles 2-4 days after fever onset 6, 5
• Key distinguishing features: recent tick exposure, high fever, headache, and progression to petechiae rather than targetoid lesions 6
• Mortality increases from 5% to potentially fatal if treatment is delayed 6

Stevens-Johnson Syndrome (SJS)

• SJS presents with widespread erythematous or purpuric macules with blisters, not discrete targetoid lesions 2
• SJS involves extensive mucosal involvement and systemic toxicity 1
• EM and SJS are now classified as separate disorders based on clinical research 1

Erysipeloid

• Caused by Erysipelothrix rhusiopathiae from handling fish, marine animals, or poultry 7
• Presents as red maculopapular lesion on fingers/hands with centrifugal spread and central clearing 7
• Can develop a blue ring with peripheral red halo giving target appearance, but typically unilateral and associated with occupational exposure 7

Identifying the Underlying Trigger

Once EM is confirmed, investigate the etiology systematically:

Most Common Causes (in order of frequency):

Infections (most common):

• Herpes simplex virus (HSV) is the leading cause of EM 1, 2, 3
• Mycoplasma pneumoniae, especially in children 2, 3
• Other viral infections: hepatitis C, Coxsackie virus, Epstein-Barr virus 3

Medications (second most common):

• Allopurinol, phenobarbital, phenytoin, valproic acid 3
• Antibiotics: sulfonamides, penicillins, erythromycin, nitrofurantoin, tetracyclines 3
• NSAIDs: acetylsalicylic acid 3
• TNF-α inhibitors: adalimumab, infliximab, etanercept 3

Recent triggers reported:

• Vaccinations (including HPV vaccine) 8, 3
• Contact allergens (formaldehyde, colophonium, disinfectants) 9
• Immunotherapy for melanoma 3
• Topical medications like imiquimod 3

Management Algorithm

Acute EM Treatment:

For isolated cutaneous EM without mucosal involvement:

• Topical high-potency corticosteroids to affected areas 1, 2
• Oral antihistamines for symptomatic relief 1, 8, 2
• Identify and eliminate the trigger if known (stop offending medication, treat underlying infection) 1, 2

For mucosal involvement:

• Antiseptic or anesthetic solutions for oral lesions 1
• Severe cases may require hospitalization for IV fluids and electrolyte repletion 2

Recurrent EM Management:

First-line for HSV-associated recurrent EM:

• Prophylactic antiviral therapy is the most successful approach 1, 2
• Note: Topical acyclovir prophylaxis does not prevent recurrences 3
• If resistant to one antiviral, switch to an alternative agent 3

Second-line for antiviral-resistant cases:

• Dapsone 3
• JAK inhibitors 3
• Apremilast 3
• Other immunosuppressive agents, antibiotics, anthelmintics, or antimalarials 1

Critical Pitfalls to Avoid

• Do not confuse EM with SJS - this leads to inappropriate aggressive treatment; EM is self-limited while SJS requires different management 1, 2
• Do not delay treatment for RMSF if fever and tick exposure are present - empiric doxycycline must be started immediately as mortality increases dramatically with delay 6
• Do not assume all targetoid lesions are EM - erysipeloid can mimic this appearance but requires penicillin treatment 7
• Do not use topical acyclovir for prophylaxis in recurrent HSV-associated EM - it is ineffective; systemic antivirals are required 3
• Individual EM lesions remain fixed for ≥7 days - if lesions resolve within 24 hours, consider urticaria instead 2