What is the diagnostic workup for a 49-year-old female with a pruritic (itchy) rash on the left abdomen under the breast and hip and the right side of the back, unresponsive to Benadryl (diphenhydramine)?

Diagnostic Workup for Pruritic Rash Unresponsive to Benadryl

Begin with a thorough history focusing on medication use (including over-the-counter drugs and herbal remedies), travel history, sexual history, and potential intravenous drug use, followed by complete physical examination to characterize the rash distribution and morphology. 1

Initial Clinical Assessment

History Taking - Key Elements

• Medication review: Document all current and recent medications, as drug-induced pruritus can occur with or without visible rash 1
• Travel history: Assess exposure to parasitic infections (schistosomes, helminths) that can cause intense pruritus 1
• Sexual history and IV drug use: Important for evaluating HIV and hepatitis risk, which are associated with pruritic conditions 1
• Timing and triggers: Note if pruritus worsens with water contact (aquagenic pruritus suggests polycythemia vera) or occurs primarily at night (suggests lymphoma) 1

Physical Examination Focus

• Rash morphology and distribution: The localized, asymmetric distribution (left abdomen under breast/hip, right back) suggests a dermatomal or contact pattern rather than generalized pruritus 2
• Lymph node examination: Enlarged nodes may indicate lymphoma 1
• Skin inspection: Look for excoriations, xerosis, or subtle signs of dermatosis 1

Laboratory Investigations

First-Line Testing

Order the following initial workup to identify systemic causes: 1

• Complete blood count with differential: Screen for polycythemia vera, lymphoma, eosinophilia (HIV-associated) 1
• Blood film examination: Essential for identifying hematologic abnormalities 1
• Ferritin level: Iron deficiency is associated with pruritus in 25% of patients with systemic disease; note that ferritin is an acute-phase protein and may be falsely normal 1
• Liver function tests: Screen for cholestatic causes (hepatitis A, B, C, E) 1
• Renal function tests: Evaluate for uremic pruritus 1
• Lactate dehydrogenase and ESR: Helpful in lymphoma screening 1

Additional Testing Based on Initial Results

• If ferritin is low-normal with anemia/microcytosis: Check serum iron and total iron binding capacity; test for tissue transglutaminase antibodies (celiac disease) 1
• If polycythemia suspected: Test for JAK2 V617F mutation (present in 97% of polycythemia vera cases) 1
• If lymphoma suspected: Consider imaging and lymph node biopsy 1

Differential Diagnosis Considerations

Given the Localized Distribution

The asymmetric, localized pattern suggests:

• Contact dermatitis: Including paradoxical reaction to diphenhydramine itself (documented cause of contact dermatitis and urticaria) 3, 4
• Herpes zoster: Dermatomal distribution, may present with pruritus before vesicles appear 1
• Localized dermatosis: Eczematous eruption, early bullous pemphigoid (can present with pruritus alone in elderly) 1, 5

Systemic Causes to Exclude

• Drug-induced pruritus: 12.5% of cutaneous drug reactions present as pruritus without rash 1
• Hematologic disorders: Polycythemia vera, lymphoma (though typically more generalized) 1
• Infectious causes: Scabies (can present with severe pruritus and minimal skin signs), HIV-related conditions 1

Diagnostic Procedures

Skin Biopsy

Consider skin biopsy if diagnosis remains unclear after initial workup, particularly to rule out:

• Early bullous pemphigoid (with direct immunofluorescence) 1
• Cutaneous lymphoma (rarely presents with normal-appearing skin) 1
• Eczematous drug eruption 5

When to Refer

Refer to dermatology if: 1

• Diagnosis remains uncertain after initial evaluation
• Patient is significantly distressed despite initial management
• Skin biopsy is needed for definitive diagnosis
• Symptoms persist despite appropriate treatment for 2 weeks

Initial Management While Awaiting Results

Symptomatic Treatment

• Emollients: High lipid content moisturizers applied liberally 1
• Topical corticosteroids: Moderate-to-high potency (triamcinolone 0.1%, mometasone 0.1%, or betamethasone 0.1%) for inflammatory component 1, 6
• Non-sedating antihistamines: Loratadine 10 mg daily (preferred over diphenhydramine given lack of response) 1
• Alternative antipruritic: Hydroxyzine 10-25 mg as needed for refractory itching 1, 7

Second-Line Options if Initial Treatment Fails

• Gabapentin or pregabalin: Particularly useful in neuropathic or refractory pruritus (gabapentin 900-3600 mg daily or pregabalin 25-150 mg daily) 1
• Topical menthol 0.5% or urea-containing lotions for additional symptomatic relief 1

Critical Pitfalls to Avoid

• Do not assume antihistamine failure rules out allergic etiology: Diphenhydramine itself can cause contact dermatitis or urticaria in sensitized individuals 3, 4
• Do not overlook medication history: Drug-induced pruritus is common and may occur without visible rash 1
• Do not delay workup in patients over 65 years: Pruritus can be the sole presenting feature of bullous pemphigoid in elderly patients 1
• Avoid sedating antihistamines in elderly patients: Associated with increased fall risk and cognitive impairment 1

Follow-Up Strategy

Reassess after 2 weeks of treatment: 1

• If symptoms worsen or fail to improve, proceed with skin biopsy and specialist referral
• If partial improvement, continue current regimen and complete laboratory workup
• Maintain regular follow-up as underlying systemic causes may not be evident initially 1