Laboratory Evaluation for Unexplained Rash
For any patient presenting with an unexplained rash, begin with a complete blood count with differential, C-reactive protein, and erythrocyte sedimentation rate as your baseline inflammatory workup 1, 2, 3.
Essential First-Line Blood Tests
The initial laboratory evaluation should include:
Complete blood count (CBC) with differential to screen for infection, inflammation, eosinophilia (suggesting drug reaction or parasitic infection), atypical lymphocytes (viral infection), or hematologic disorders 1, 2, 3, 4
Inflammatory markers: CRP and ESR to assess systemic inflammation and guide further workup 1, 2, 3
Comprehensive metabolic panel including liver function tests and renal function (urea and electrolytes) to identify hepatic or renal causes and assess organ involvement 3, 4
Additional Testing Based on Rash Characteristics
For Urticarial or Inflammatory Rashes
If the rash is urticarial, recurrent, or suggests autoinflammatory disease:
Serum amyloid A (SAA) and S100 proteins if available, particularly when considering autoinflammatory syndromes 1
Complement C4 and C1-inhibitor levels if angioedema is present to rule out hereditary angioedema 1
For Suspected Autoimmune Etiology
When clinical features suggest connective tissue disease or vasculitis:
Antinuclear antibody (ANA), rheumatoid factor, and anti-double-stranded DNA antibodies if autoimmune or inflammatory conditions are suspected 2, 4, 5
These tests are particularly important if the rash is accompanied by joint pain, photosensitivity, or systemic symptoms 5
For Infectious Considerations
Blood cultures if fever is present or systemic infection is suspected 2
HIV and hepatitis serology (A, B, C) if risk factors are present or the clinical picture suggests viral etiology 2, 3
Viral studies if vesicular component or history suggests viral etiology 2
Critical Diagnostic Procedures Beyond Blood Work
Skin biopsy should be considered early, especially if diagnosis remains unclear after initial testing 2. This is particularly important for:
- Suspected vasculitis (look for vessel damage and fibrinoid deposits) 1
- Persistent or atypical rashes not responding to initial management 1
- Distinguishing between drug reactions and other inflammatory conditions 6
For specific rash types requiring direct examination rather than blood work:
Scabies: Light microscopy of mineral oil preparations from multiple skin scrapings (scrape 20 papules vigorously) to demonstrate mites, eggs, or feces 1, 7
Fungal infections: Potassium hydroxide 10% preparation of skin scrapings 1
Herpes simplex or zoster: Tzanck preparation for giant cells, or PCR/immunofluorescence for viral confirmation 1, 7
Tests NOT Routinely Recommended
Thyroid function tests should not be ordered reflexively; only obtain when additional clinical features suggest endocrinopathy 3
Extensive malignancy screening is not routinely recommended unless specific systemic symptoms are present 3
Surface swab cultures are not indicated for most bacterial skin infections (exception: conjunctivitis) 1
Common Pitfalls to Avoid
Do not skip ferritin testing if pruritus is prominent, as both iron deficiency and overload can cause itching 3
Scabies must be confirmed microscopically when possible; clinical diagnosis alone in institutional settings can lead to pseudo-outbreaks with widespread psychogenic symptoms 7
Eosinophilia with systemic symptoms (DRESS syndrome) requires immediate recognition as mortality approaches 10%; look for facial edema, lymphadenopathy, and organ involvement occurring within 2 months of drug initiation 6
Long-lasting individual wheals (>24 hours) suggest urticarial vasculitis rather than typical urticaria and warrant skin biopsy 1
Special Populations
For nursing home or long-term care facility residents with unexplained generalized rash: