How to manage a patient with blistering lesions of unknown cause?

Management of Blistering Lesions of Unknown Cause in a Non-Diabetic, Afebrile Patient Without Trauma or New Medications

Begin with immediate wound care—gently cleanse with antimicrobial solution, leave the blister roof intact as a biological dressing, apply bland emollient, and obtain skin biopsies for histopathology and direct immunofluorescence to establish the diagnosis while ruling out autoimmune bullous disease, occult infection, or atypical malignancy. 1, 2

Initial Assessment and Documentation

Perform a systematic physical examination focusing on:

• Vital signs and oxygen saturation to identify systemic involvement or early sepsis 1, 2
• All mucosal surfaces (eyes, mouth, nose, genitalia) for erosions or blistering that would suggest Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) or autoimmune disease 1
• Skin examination for target lesions, atypical targets, purpuric macules, areas of epidermal detachment, and Nikolsky sign 1
• Body surface area (BSA) involvement using body maps: <10% BSA (Grade 1), 10-30% BSA (Grade 2), >30% BSA (Grades 3-4) 2
• Serial photographs to document progression 2

Obtain a detailed medication history covering the previous 2 months, including over-the-counter medications, complementary therapies, and any brand switches, even though the patient reports no new medications—occult drug exposure remains a critical differential 1

Immediate Laboratory Investigations

Order within 24 hours:

• Complete blood count, erythrocyte sedimentation rate, C-reactive protein 1, 2
• Renal function (urea, electrolytes, magnesium, phosphate, bicarbonate) 1, 2
• Liver function tests, glucose, coagulation studies 1, 2
• Mycoplasma serology 1
• Chest X-ray 1
• Bacterial and viral cultures from any erosions or blister fluid 2, 3

Diagnostic Biopsies (Critical Step)

Obtain two skin biopsies immediately:

1. Lesional skin biopsy (just adjacent to a blister) for routine histopathology 1
2. Perilesional skin biopsy from uninvolved skin approximately 1 cm from a fresh blister, sent unfixed (snap-frozen in liquid nitrogen or in Michel's transport medium) for direct immunofluorescence 1

Direct immunofluorescence is the gold standard for diagnosing autoimmune bullous diseases—it will show IgG deposition in intercellular spaces for pemphigus vulgaris or linear IgG/C3 at the basement membrane zone for bullous pemphigoid 1. The British Association of Dermatologists emphasizes that this step cannot be delayed, as it distinguishes life-threatening autoimmune disease from infectious or traumatic causes 1, 2, 3.

Immediate Blister Management

For intact blisters:

• Gently cleanse with antimicrobial solution without rupturing 1, 2, 4
• Leave completely alone if asymptomatic and observe 2, 4
• If drainage is necessary, pierce at the base with a sterile needle and apply gentle pressure with sterile gauze 1, 2, 4
• Never deroof the blister—the roof serves as a natural biological dressing that reduces infection risk and promotes re-epithelialization 1, 2, 3, 4

For all affected areas:

• Apply bland emollient (white petrolatum 50% with liquid paraffin 50%) to support barrier function, reduce water loss, and encourage healing 2, 3, 4
• Cover with non-adherent dressing if needed for protection or exudate absorption 2, 3, 4
• Change dressings using aseptic technique 3, 4

Differential Diagnosis to Actively Consider

Given the absence of fever, trauma, diabetes, and new medications, the British Journal of Dermatology guidelines emphasize considering 1:

• Autoimmune bullous diseases: Bullous pemphigoid (most common in elderly), pemphigus vulgaris, mucous membrane pemphigoid, linear IgA bullous dermatosis 1
• Occult drug reaction: Generalized bullous fixed drug eruption, despite negative medication history 1
• Infection: Staphylococcal scalded skin syndrome (even without fever initially), secondary bacterial infection 1
• Atypical presentations: Bullous malignant melanoma (particularly if acral location), paraneoplastic pemphigus 1, 5

Treatment Based on Extent and Severity

For <10% BSA (Grade 1):

• Observation with local wound care only 2
• No systemic treatment required initially 2
• Reassess within 24-48 hours 2, 3

For 10-30% BSA (Grade 2):

• Consult dermatology urgently 2
• Initiate high-potency topical corticosteroid (clobetasol 0.05% or betamethasone dipropionate) if autoimmune disease suspected 2, 3
• Re-evaluate every 3 days for progression 2

For >30% BSA (Grades 3-4):

• Immediate hospitalization under dermatology or multidisciplinary team 2
• Intravenous methylprednisolone 1-2 mg/kg if autoimmune bullous disease confirmed, converting to oral steroids when appropriate with gradual taper over at least 4 weeks 2
• Establish IV access through non-lesional skin, initiate fluid resuscitation if indicated 1
• Insert nasogastric tube if oral intake inadequate 1
• Insert urinary catheter if urogenital involvement present 1

Infection Monitoring and Management

Daily monitoring for:

• Erythema, purulent discharge, fever, increased pain 2, 3
• Daily washing with antibacterial products to reduce colonization 2

If infection suspected:

• Obtain Gram stain and bacterial/viral cultures before initiating antibiotics 3
• Apply topical antimicrobials (silver-based products) only to clinically infected areas, not prophylactically 2, 3, 4
• For mild infection without systemic symptoms: semi-synthetic penicillin, first-generation cephalosporin, or clindamycin 3

Ophthalmological Evaluation

Urgent ophthalmology consultation if any mucosal involvement is present, as ocular complications can lead to permanent vision loss in SJS/TEN or cicatricial pemphigoid 1, 2

Critical Pitfalls to Avoid

• Do not assume a simple friction blister when there is rapid progression within 24 hours—this suggests severe underlying pathology 2, 3
• Do not delay skin biopsy with direct immunofluorescence—this is essential for definitive diagnosis and cannot be substituted with clinical assessment alone 1, 2, 3
• Do not apply topical antimicrobials prophylactically to all blisters—reserve for clinically infected areas only, as prophylactic use provides no benefit and may delay healing 2, 3, 4
• Do not routinely deroof blisters—the roof is protective and promotes healing 1, 2, 3, 4
• Do not underestimate the need for ophthalmology evaluation with any mucosal involvement 1, 2
• Do not miss hemorrhagic blistering as a rare presentation of acral malignant melanoma, particularly on acral sites 5

Follow-Up and Monitoring

• Document daily the number, size, and location of blisters on body charts 2, 3, 4
• Reassess within 24-48 hours if managed as outpatient 2, 3, 4
• Offer analgesia prior to dressing changes, as patients commonly report pain or burning 4

The British Journal of Dermatology emphasizes that while bullous pemphigoid is the most common autoimmune blistering disease in the elderly (incidence 43 per million per year in the UK), pemphigus vulgaris carries higher mortality (34-42% in mucocutaneous disease) and requires more aggressive immunosuppression 1. Therefore, establishing the correct diagnosis through biopsy with direct immunofluorescence is the single most important step in management 1.