What workup should be ordered for non-painful facial swelling with negative infection and autoimmune workup?

Diagnostic Workup for Non-Painful Facial Swelling

For non-painful facial swelling with negative infection and autoimmune workup, a comprehensive evaluation should include testing for bullous pemphigoid, angioedema, and neoplastic causes, with skin biopsy being the most definitive diagnostic test.

Initial Evaluation

When faced with non-painful facial swelling where initial infection and autoimmune workups have been negative, consider the following diagnostic approach:

Laboratory Tests

• Complete blood count with differential to assess for eosinophilia, neutrophilia, anemia, or thrombocytopenia 1
• Complete metabolic profile including liver function tests, renal function, and electrolytes 1
• Inflammatory markers: C-reactive protein (CRP) and Erythrocyte Sedimentation Rate (ESR) 1
• Serum tryptase, Complement C4, and C1-INH levels and function to evaluate for angioedema 1
• Autoantibody testing:
  • Anti-Desmoglein 1 and 3 (for pemphigus) 2
  • Anti-Bullous Pemphigoid Antigen 1 and 2 (BP180 and BP230) 2
  • Antinuclear antibody (ANA) panel, rheumatoid factor, anti-double-stranded DNA, and ANCA 1

Imaging Studies

• MRI of face and neck with contrast to evaluate for:
  • Deep tissue involvement
  • Vascular malformations
  • Neoplastic processes 3
• Consider CT scan if abscess is suspected despite negative infection workup 3

Definitive Diagnostic Procedures

• Skin biopsy for histopathology and direct immunofluorescence - critical for diagnosis of bullous pemphigoid and other autoimmune blistering diseases 2, 4
• Consider patch testing if allergic contact dermatitis is suspected 1

Specific Diagnostic Considerations

Bullous Pemphigoid

Bullous pemphigoid should be high on the differential diagnosis list as it can present with facial swelling and may have been missed in the initial autoimmune workup. The British Journal of Dermatology recommends:

• Testing for Anti-Bullous Pemphigoid Antigen 1 and 2 2
• Skin biopsy from an area with active inflammation 2
• Direct immunofluorescence testing of the biopsy specimen 2

Angioedema

Consider acquired C1-inhibitor deficiency or bradykinin-mediated angioedema, which can be missed on routine testing:

• C1-INH functional assay (not just quantitative levels) 5
• C1q levels (decreased in acquired C1-INH deficiency) 5
• Anti-C1-INH autoantibodies 5
• Review of medications that may cause angioedema (particularly ACE inhibitors) 6

Neoplastic Causes

If swelling is progressive:

• Consider lymphoma, particularly if there is associated lymphadenopathy
• Evaluate for rhabdomyosarcoma, Langerhans cell histiocytosis, or metastatic disease if rapidly progressive 3

Other Considerations

• Vascular malformations (hemangioma, lymphangioma) 3
• Granulomatous conditions (sarcoidosis) 6
• Paraneoplastic syndromes 6

Diagnostic Pitfalls to Avoid

1. Don't assume all facial swelling is infectious or allergic - when these have been ruled out, consider rarer causes 6

2. Don't miss bullous pemphigoid - early disease may present with non-specific swelling before blisters appear 2

3. Don't overlook medication-induced angioedema - particularly ACE inhibitors which can unmask underlying C1-INH deficiency 5

4. Don't stop at negative blood tests - skin biopsy with direct immunofluorescence is often necessary for definitive diagnosis 2, 4

5. Don't forget to document progression - serial photography can help track changes over time 1

By following this structured diagnostic approach, you can identify the underlying cause of non-painful facial swelling even when initial infection and autoimmune workups are negative.