Recurrent Blisters and Weeping to Bilateral Lower Extremities
Most Likely Diagnosis
Bullous pemphigoid is the most likely diagnosis in an elderly patient presenting with recurrent tense bullae and weeping on bilateral lower extremities, particularly if preceded by weeks to months of severe pruritus. 1, 2 However, cellulitis with bullous formation must be urgently excluded, as it requires immediate hospitalization and parenteral antibiotics rather than immunosuppression. 3
Critical Initial Assessment: Rule Out Life-Threatening Conditions First
Red Flags Requiring Immediate Hospitalization
- Pain disproportionate to physical findings is the hallmark of necrotizing fasciitis and mandates emergent surgical consultation. 1
- Systemic toxicity (fever, tachycardia, hypotension, confusion) indicates infectious cellulitis or necrotizing fasciitis requiring immediate hospitalization and parenteral antibiotics. 3, 1
- Rapidly spreading erythema, warmth, and edema with bullae suggest cellulitis, which can present with vesicles and bullae filled with clear fluid. 3
Key Distinguishing Features
- Cellulitis typically presents unilaterally or asymmetrically with acute onset, whereas bullous pemphigoid presents with symmetric distribution on flexural surfaces and inner thighs. 3, 1
- Tense bullae on erythematous or normal-appearing skin without systemic toxicity favor bullous pemphigoid over infection. 1, 2
Diagnostic Workup for Bullous Pemphigoid
Essential Diagnostic Tests
Direct immunofluorescence (DIF) from perilesional skin is the single most critical and mandatory test, showing linear IgG and/or C3 deposits along the dermoepidermal junction. 1, 2, 4 This test must be performed even when histopathology is obtained, as relying on histopathology alone leads to misdiagnosis. 1
Histopathology from an early intact bulla reveals subepidermal cleft with eosinophilic infiltrate. 3, 2, 4
Serum ELISA for anti-BP180 and anti-BP230 antibodies supports diagnosis, with anti-BP180 >27 U/mL indicating increased relapse risk. 1, 2
Clinical Diagnostic Criteria
High specificity (95%) for bullous pemphigoid when three of four criteria are present with positive DIF: 4
- Age >70 years
- Absence of atrophic scarring after healing
- Absence or minimal mucosal involvement
- Absence of predominant bullous lesions on neck and head
A history of pruritus preceding blisters by weeks to months is highly suggestive of bullous pemphigoid. 1, 4
Differential Diagnoses to Consider
Infectious Causes
- Cellulitis with bullous formation presents with acute onset, unilateral or asymmetric distribution, systemic symptoms, and positive blood cultures in 5% of cases. 3
- Streptococci (groups A, B, C, G) are the most common pathogens, often originating from macerated or fissured interdigital toe spaces with tinea pedis. 3
Other Autoimmune Blistering Diseases
- Pemphigus vulgaris presents with flaccid (not tense) bullae, positive Nikolsky sign, and prominent mucosal involvement. 1, 4
- Linear IgA disease shows only IgA (not IgG) on DIF. 4
Venous Insufficiency-Related
- Stasis dermatitis can present with poorly demarcated erythematous plaques on bilateral lower legs, classically involving the medial malleolus, and may initially mimic solitary neoplastic lesions. 5, 6
Treatment Algorithm for Bullous Pemphigoid
First-Line Treatment: Superpotent Topical Corticosteroids
Superpotent topical corticosteroids are first-line for all disease severities, providing superior disease control with significantly lower mortality compared to systemic corticosteroids. 2
Treatment regimen: 2
- Localized disease (<10% body surface area): Apply clobetasol propionate directly to lesions only
- Mild widespread disease: Apply to whole body except face
- Generalized disease: Apply to entire body except face, standard dose 20g/day
Begin tapering after 15 days once disease control is achieved; reduce to maintenance therapy of 10g once weekly after 4 months. 2
Second-Line: Systemic Corticosteroids (Use Cautiously in Elderly)
When systemic corticosteroids are necessary, use the lowest effective dose: 0.3 mg/kg/day for moderate disease or up to 0.5 mg/kg/day for severe disease. 2
Doses exceeding 0.75 mg/kg/day (52.5 mg daily for a 70-kg patient) do not confer additional benefit and are associated with significantly higher mortality in elderly patients. 3, 2
Steroid-Sparing Alternative
Doxycycline 200 mg/day combined with nicotinamide represents a safer alternative for patients at high risk for steroid complications, with a 73.8% response rate and reduced mortality. 2
Azathioprine combined with prednisone allows reduction of steroid dose by approximately 45%, but requires TPMT activity assessment before initiation to prevent severe myelosuppression. 3, 2
Management of Predisposing Factors for Recurrent Cellulitis
If cellulitis is diagnosed, identify and treat predisposing conditions including edema, obesity, venous insufficiency, and toe web abnormalities (especially tinea pedis). 3
For patients with 3-4 episodes of cellulitis per year despite treating predisposing factors, prophylactic antibiotics should be considered: 3
- Oral penicillin or erythromycin twice daily for 4-52 weeks, OR
- Intramuscular benzathine penicillin every 2-4 weeks
Elevation of the affected area hastens improvement by promoting gravity drainage of edema and inflammatory substances. 3
Critical Pitfalls to Avoid
Never delay hospitalization if necrotizing fasciitis is suspected based on pain disproportionate to findings, as rapid deterioration can occur. 1
Never assume infection based on culture alone; obtain fungal stain to distinguish true infection from colonization. 1
Never use oral prednisone >0.75 mg/kg/day in elderly patients with bullous pemphigoid, as this leads to significant mortality. 1, 2
Never rely on histopathology alone; always obtain DIF from perilesional skin when bullous pemphigoid is suspected. 1, 2
Never escalate therapy in response to an occasional blister during maintenance phase, as this leads to overtreatment and unnecessary toxicity. 3, 2
Monitoring and Follow-Up
Regular monitoring is essential: 2
- Every 2 weeks for the first 3 months
- Monthly for months 4-6
- Every 2 months after 6 months
Laboratory monitoring should include disease activity assessment at each visit, with anti-BP180 IgG ELISA at days 0,60, and 150. 2
Positive DIF or elevated BP180 ELISA >27 U/mL indicates higher relapse risk. 2