What is the diagnosis and recommended management for a patient presenting with generalized wheals (raised erythematous pruritic plaques) with surrounding flare?

Generalized Wheals and Flare: Diagnosis and Management

The diagnosis is urticaria (hives), defined by pruritic, raised, erythematous wheals with surrounding flare that resolve within 24 hours, and first-line treatment is non-sedating second-generation H1 antihistamines such as fexofenadine 180 mg daily or loratadine 10 mg daily. 1, 2, 3

Clinical Definition and Classification

Urticaria presents with three cardinal features 1, 4:

• Central swelling of various sizes with surrounding erythema (the "flare")
• Intense pruritus or occasional burning sensation
• Individual wheals resolving within 24 hours, though new lesions may continue to appear

Classification depends on duration 1, 5:

• Acute urticaria: Symptoms lasting less than 6 weeks 1, 3
• Chronic urticaria: Symptoms persisting beyond 6 weeks 1, 5

The condition may present with wheals alone, angioedema alone, or both together (occurring in 40% of cases) 1, 3.

Immediate Management Approach

First-Line Pharmacotherapy

Prescribe non-sedating second-generation H1 antihistamines immediately 1, 2:

• Fexofenadine 180 mg once daily (take with water, not fruit juice) 2
• Loratadine 10 mg once daily as an alternative 6
• These agents can be titrated up to 4 times the standard dose if symptoms persist after 2-4 weeks 1, 7

Critical administration guidance for fexofenadine 2:

• Take with water only—fruit juices (grapefruit, orange, apple) reduce bioavailability by 36%
• Avoid aluminum/magnesium-containing antacids within 2 hours (reduces absorption by 41%)

Adjunctive Symptomatic Measures

Apply emollients liberally at least twice daily to all affected areas using oil-in-water formulations 6, 8. This addresses xerosis that lowers the threshold for pruritus.

Reserve sedating antihistamines (hydroxyzine 25-50 mg) strictly for bedtime use when sleep is disrupted, and avoid long-term use in elderly patients due to dementia risk 6, 8.

Diagnostic Workup Based on Duration

For Acute Urticaria (<6 weeks)

Focus history on recent exposures 3, 4:

• New medications (antibiotics, NSAIDs, aspirin, ACE inhibitors)
• Food ingestion within 2 hours of symptom onset
• Insect stings or bites
• Recent infections (viral upper respiratory infections are common triggers)

Minimal laboratory testing is needed for acute urticaria unless systemic symptoms suggest anaphylaxis or the clinical picture is atypical 4, 7.

For Chronic Urticaria (>6 weeks)

Obtain the following initial laboratory panel 1, 6:

• Complete blood count with differential (screen for polycythemia vera, lymphoma, eosinophilia)
• Comprehensive iron studies including ferritin (iron deficiency causes 25% of generalized pruritus cases)
• Liver function tests, total bilirubin, serum bile acids
• Renal panel (urea, creatinine, electrolytes)
• Thyroid-stimulating hormone (40-60% of chronic urticaria patients have antithyroid antibodies)

Additional targeted testing based on clinical features 1, 6:

• JAK2 V617F mutation if aquagenic pruritus (triggered by water contact) suggests polycythemia vera
• HIV and hepatitis A, B, C serologies with appropriate risk factors or travel history
• Skin biopsy if individual wheals last longer than 24 hours (suggests urticarial vasculitis) or diagnosis remains unclear after 6 weeks

Escalation Algorithm for Refractory Cases

If symptoms persist after 2-4 weeks on standard-dose antihistamines 1, 7:

1. Increase antihistamine dose up to 4-fold (e.g., fexofenadine 180 mg twice daily) 1

2. Add H2 antihistamine (e.g., ranitidine or famotidine) as adjunctive therapy 1, 9

3. Add leukotriene receptor antagonist (montelukast 10 mg daily) 1, 7

4. Short corticosteroid burst (prednisone 40-60 mg daily for 3-7 days maximum) for severe exacerbations only—avoid long-term use 1, 7

For chronic spontaneous urticaria unresponsive to the above 1:

• Omalizumab (anti-IgE monoclonal antibody) is the next-line biologic therapy
• Cyclosporine or other immunosuppressants for truly refractory cases

Critical Diagnostic Pitfalls to Avoid

Do not assume all generalized wheals are simple urticaria 1:

• Wheals lasting >24 hours require skin biopsy to exclude urticarial vasculitis (look for vessel damage and fibrinoid deposits)
• Angioedema without wheals mandates exclusion of bradykinin-mediated angioedema (hereditary or ACE inhibitor-induced) before diagnosing urticaria
• Recurrent fever, joint pain, or malaise with wheals suggests autoinflammatory syndromes (Schnitzler syndrome, adult-onset Still disease) requiring inflammatory markers and paraprotein screening

Do not delay medication review 6, 10:

• Drug-induced urticaria accounts for 12.5% of cutaneous drug reactions
• ACE inhibitors, sartans, NSAIDs, and antibiotics are common culprits
• Symptoms may appear days to weeks after drug initiation

Do not perform extensive allergy testing routinely 9, 7:

• Allergic causes account for fewer than 10-20% of chronic urticaria cases
• IgE-mediated food allergy rarely causes isolated chronic urticaria without other systemic symptoms
• Specific IgE testing or skin prick tests should be reserved for cases with clear temporal relationship to specific exposures

When to Refer

Refer to dermatology or allergy/immunology if 6, 8:

• Symptoms persist beyond 2-4 weeks despite optimized antihistamine therapy
• Diagnosis remains uncertain after initial workup
• Individual wheals last longer than 24 hours
• Systemic symptoms (fever, arthralgias, weight loss) accompany urticaria

Refer to emergency department immediately if 6:

• Angioedema involves tongue, throat, or larynx with respiratory compromise
• Hypotension, tachycardia, or signs of anaphylaxis develop
• Severe abdominal pain with urticaria suggests systemic vasculitis

Assessment of Disease Control

Use validated patient-reported outcome measures at every visit 1:

• The 7-Day Urticaria Activity Score (UAS7) tracks daily wheal count and pruritus intensity
• Management decisions should be based on disease control measurements, not just symptom presence

More than 50% of patients with chronic urticaria experience resolution or significant improvement within one year 7, making regular reassessment essential to avoid overtreatment.