What is the differential diagnosis for blistering diseases on the feet?

Differential Diagnosis for Blistering Diseases of the Feet

The differential diagnosis for foot blistering includes autoimmune bullous diseases (bullous pemphigoid, pemphigus, epidermolysis bullosa acquisita), infectious causes (bullous tinea, bacterial infections), metabolic disorders (bullosis diabeticorum), drug reactions, friction blisters, and less commonly, inherited epidermolysis bullosa or Stevens-Johnson syndrome/toxic epidermal necrolysis. 1, 2

Primary Autoimmune Bullous Disorders

Bullous Pemphigoid

• Most common autoimmune blistering disease, typically affecting patients >70 years of age with tense bullae on erythematous or normal-appearing skin 1
• Feet involvement presents with symmetrical distribution of vesicles and bullae, often on flexural surfaces 1
• Diagnosis requires linear IgG and/or C3 deposits along the dermoepidermal junction on direct immunofluorescence (DIF) of perilesional skin 1
• Histopathology shows subepidermal bullae containing eosinophils and/or neutrophils with dermal eosinophilic infiltrate 1
• Confirm with ELISA for anti-BP180 and/or anti-BP230 IgG autoantibodies 1

Pemphigus Group

• Intraepidermal blistering with flaccid bullae that rupture easily, leaving erosions 3, 4
• Less common on feet compared to trunk and mucous membranes 4
• Requires DIF showing intercellular IgG deposits and histology demonstrating acantholysis 4

Epidermolysis Bullosa Acquisita

• Subepidermal blistering disorder with blisters at sites of trauma, particularly feet 3, 4
• Chronic course with scarring and milia formation 4
• DIF shows linear IgG at basement membrane zone; indirect immunofluorescence on salt-split skin shows dermal binding pattern 4

Inherited Blistering Disorders

Epidermolysis Bullosa (EB)

• Painful foot blistering exacerbated by walking or standing is the hallmark presentation 1
• Blisters triggered by friction, walking, heat, trauma, and hyperhidrosis, typically worse in summer 1
• All EB subtypes (EBS, JEB, RDEB, DDEB) can affect feet with varying severity 1
• Associated findings include hyperkeratosis (callus), nail loss, altered gait, and foot deformities 1
• Diagnosis based on clinical presentation, family history, and genetic testing 1

Infectious Causes

Bullous Tinea

• Fungal infection presenting as painful blisters on plantar aspect of feet 2
• Histopathologic examination of unroofed blister reveals fungal elements 2
• Confirm with KOH preparation and fungal culture 2

Bacterial Infections

• Necrotizing bacterial infections (Streptococcus, Pseudomonas) can cause bullae 1
• Associated with systemic signs of infection including fever, elevated white blood cell count 1
• Requires wound culture and immediate antibiotic therapy 1

Metabolic and Endocrine Disorders

Bullosis Diabeticorum

• Spontaneous, painless blisters on feet of patients with long-standing diabetes, typically on anterior foot or toes 2
• Blisters appear suddenly without preceding trauma 2
• Diagnosis of exclusion after ruling out infection and autoimmune causes 2
• Associated with diabetic neuropathy and poor glycemic control 5

Diabetic Foot Infection

• Must distinguish from simple blistering: requires ≥2 signs of inflammation (erythema >0.5 cm around wound, local swelling/induration, tenderness, warmth, purulent discharge) 1
• Elevated inflammatory markers (ESR >60 mm/hour or CRP >3.2 mg/dL) combined with ulcer depth >3 mm suggests osteomyelitis 6
• However, up to 50% of severe diabetic foot infections may have normal inflammatory markers 6

Drug-Related Blistering

Drug Reactions and Immune Checkpoint Inhibitor Toxicity

• Bullous drug eruptions can present with blisters covering <10% to >30% body surface area 1
• Symptomatic bullae or erosions on skin or mucosal surfaces indicate at least grade 2 severity 1
• Requires detailed medication history over preceding 1-6 months 5
• Management includes holding offending agent, dermatology consultation, and consideration of systemic steroids (prednisone 0.5-1 mg/kg/day) 1

Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN)

• Life-threatening drug reaction with painful rash, mucosal involvement, and epidermal detachment 1
• Presents with prodromal illness (fever, malaise), followed by painful rash initially on face and chest 1
• Histopathology shows variable epidermal damage ranging from individual cell apoptosis to confluent epidermal necrosis with subepidermal vesicle formation 1
• Requires immediate discontinuation of culprit drug and urgent dermatology consultation 1

Traumatic and Mechanical Causes

Friction Blisters

• Asymptomatic, noninflammatory blisters <10% body surface area at pressure points 1
• Do not require treatment cessation, only local wound care 1
• Common in patients with altered gait, ill-fitting footwear, or peripheral neuropathy 1, 5

Pressure-Related Blistering

• Occurs at weight-bearing zones in patients with loss of protective sensation (LOPS) 5
• Associated with hyperkeratosis surrounding the ulcer 1
• Risk factors include peripheral neuropathy (diabetic or non-diabetic), previous foot ulceration, and poor footwear 5

Diagnostic Algorithm

Initial Clinical Assessment

• Obtain detailed history: onset timing, progression, associated symptoms (pain, pruritus, drainage), medication history (1-6 months prior), diabetes duration and control, previous foot problems 5, 2
• Physical examination: assess blister characteristics (tense vs. flaccid, size, distribution), surrounding skin (erythema, warmth, induration), presence of scarring or milia, nail changes, signs of infection 1
• Evaluate for systemic involvement: fever, mucosal lesions (eyes, mouth, genitalia), lymphadenopathy 1

Laboratory Workup

• Skin biopsy for histopathology: obtain from early intact blister on erythematous skin, place in formalin 1
• Direct immunofluorescence (DIF): perilesional skin biopsy in Michel's medium or immunofluorescence transport medium—most critical test for autoimmune bullous diseases 1
• Wound culture: if infection suspected, obtain before antibiotic initiation 1
• Serological testing: ELISA for BP180/BP230 antibodies if bullous pemphigoid suspected; indirect immunofluorescence on salt-split skin 1
• Inflammatory markers: ESR and CRP if diabetic foot infection or osteomyelitis suspected 6

Key Diagnostic Pitfalls

• Friction blisters in diabetic patients with neuropathy can rapidly progress to infected ulcers—always assess for signs of infection even in seemingly benign blisters 1, 5
• Normal inflammatory markers do not exclude diabetic foot infection—up to 50% of severe infections present with normal ESR/CRP 6
• Bullous pemphigoid can present without typical tense bullae—nonbullous forms may show only excoriations, prurigo, or urticarial lesions 1
• Delay in seeking care significantly increases amputation risk—always document timing and any barriers to healthcare access 5
• Drug-induced blistering may occur weeks to months after medication initiation—obtain comprehensive medication history including recent changes 1, 5
• Mucosal involvement suggests more severe disease (pemphigus, SJS/TEN, mucous membrane pemphigoid) and requires urgent evaluation 1