What are the possible causes of blistering rashes if it's not Hand, Foot, and Mouth Disease (HFMD)?

Differential Diagnosis of Blistering Rashes When HFMD is Excluded

If HFMD is ruled out, consider viral infections (chickenpox, herpes simplex), autoimmune bullous diseases (bullous pemphigoid), bacterial infections (impetigo), contact dermatitis, drug reactions, and insect bites as the primary alternative causes of blistering rashes. 1, 2

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; 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

Viral Causes of Blistering

Chickenpox (Varicella)

• Unlike HFMD, chickenpox vesicles are widely distributed across the trunk and face rather than concentrated on hands, feet, and mouth 1
• Lesions appear in crops with different stages present simultaneously 1

Herpes Simplex Virus

• Can cause vesicular eruptions, particularly in children with atopic dermatitis (eczema herpeticum) 4
• "Eczema coxsackium" mimics herpetic superinfection in eczematous skin but is caused by coxsackievirus rather than herpes 4

Autoimmune Bullous Diseases

Bullous Pemphigoid

• Tense blisters on erythematous or normal-looking skin of limbs and trunk, most common in elderly patients 5
• Pruritus alone or with urticarial plaques may precede bullae by weeks or months 5
• Diagnosis confirmed by direct immunofluorescence showing linear IgG and C3 deposition at the basement membrane zone 5
• Incidence of 43 per million per year in the U.K., making it the most common immunobullous disease 5

Linear IgA Disease

• Subepidermal blistering disease that requires differentiation from bullous pemphigoid using direct immunofluorescence and salt-split skin studies 5

Drug-Induced Blistering

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 5

Chemotherapy-Induced Hand-Foot Syndrome

• Presents with dysesthesia, burning pain, and hyperkeratosis rather than discrete vesicles 1
• Occurs in 6-60% of patients on capecitabine, 5-FU, or doxorubicin 3
• Well-defined painful hyperkeratosis distinguishes this from viral vesicular eruptions 3

Bacterial and Inflammatory Causes

Impetigo

• Bacterial skin infection causing vesicles and bullae that rupture to form honey-colored crusts 5
• Must be recognized and treated before initiating immunosuppressant therapy 5

Contact Dermatitis

• Can cause blistering, particularly with irritant exposure 5
• Frequent hand washing (especially water >40°C) increases risk of irritant contact dermatitis 3

Other Important Differentials

Insect Bites

• Can cause localized blistering reactions 5

Erythema Multiforme

• Target lesions with central blistering, often triggered by infections or medications 5

Syphilis (Secondary)

• Treponema pallidum can present with rash on palms and soles, though typically maculopapular rather than vesicular 1

Critical Diagnostic Pitfalls

• Do not wait for the classic triad (fever, rash, tick bite) before treating suspected Rocky Mountain spotted fever—only a minority present with all three initially, and delayed treatment increases mortality 3
• Viral and bacterial skin infections should be recognized and treated before initiating immunosuppressant therapy for suspected autoimmune conditions 5
• In immunocompromised patients, maintain a low threshold for investigation as clinical presentations can be particularly non-specific and severe 5

Diagnostic Approach

• 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 5
• 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 5, 3