Differential Diagnosis of Blistering Rashes

Life-Threatening Causes to Exclude First

Rocky Mountain spotted fever presents with fever and maculopapular rash spreading to palms and soles 2-4 days after fever onset, with 5-10% mortality if untreated, and requires urgent doxycycline treatment 2, 3
Meningococcal infection can present with vesicular or petechial rash on palms and soles and requires immediate recognition 1
Ehrlichiosis presents with fever, headache, and rash involving palms/soles in 30% of adults and 60% of children, with 3% case-fatality rate 3

Chickenpox vesicles are widely distributed across the trunk and face rather than concentrated on hands, feet, and mouth, and lesions appear in crops with different stages present simultaneously 1

Bullous pemphigoid is characterized by tense blisters on erythematous or normal-looking skin of limbs and trunk, most common in elderly patients, with an incidence of 43 per million per year in the U.K. 4
Diagnosis of bullous pemphigoid is confirmed by direct immunofluorescence showing linear IgG and C3 deposition at the basement membrane zone 4

Drug hypersensitivity reactions can cause palmoplantar involvement but lack the characteristic vesicular morphology of HFMD 2
Spironolactone, neuroleptics, and furosemide have been associated with bullous pemphigoid in epidemiological studies 4

Impetigo is a bacterial skin infection causing vesicles and bullae that rupture to form honey-colored crusts, and must be recognized and treated before initiating immunosuppressant therapy 4
Contact dermatitis can cause blistering, particularly with irritant exposure, and frequent hand washing increases risk of irritant contact dermatitis 3, 4

Insect bites can cause localized blistering reactions 4
Erythema multiforme is characterized by target lesions with central blistering, often triggered by infections or medications 4
Syphilis (secondary) can present with rash on palms and soles, though typically maculopapular rather than vesicular 1

Do not wait for the classic triad (fever, rash, tick bite) before treating suspected Rocky Mountain spotted fever, as delayed treatment increases mortality 3
Viral and bacterial skin infections should be recognized and treated before initiating immunosuppressant therapy for suspected autoimmune conditions 4

Obtain vesicle fluid for viral PCR if viral etiology suspected (enterovirus, herpes simplex, varicella) 5
Perform skin biopsy with direct immunofluorescence from perilesional skin if autoimmune bullous disease suspected 4
Consider serologic testing for Rocky Mountain spotted fever, ehrlichiosis, or syphilis based on exposure history and clinical presentation 1, 3
Review medication history for potential drug-induced causes, particularly in elderly patients or those on chemotherapy 3, 4