What is the appropriate work‑up for chronic urticaria in an otherwise healthy adult?

Work-up of Chronic Urticaria

Initial Assessment: History and Physical Examination

For most patients with chronic urticaria responding to standard H1 antihistamines, no laboratory investigations are required. 1

The diagnostic work-up should focus on the "7 Cs" framework: confirm diagnosis, identify causes, assess cofactors, check comorbidities, evaluate consequences, predict course, and monitor control. 1

Key Historical Elements to Document

• Individual wheal duration: Wheals lasting >24 hours suggest urticarial vasculitis and mandate skin biopsy. 1
• Presence of angioedema: Significantly worsens prognosis; >50% of patients with combined wheals and angioedema have active disease beyond 5 years. 2
• Medication history: Specifically ask about ACE inhibitors, ARBs, NSAIDs, and aspirin—these can cause or exacerbate urticaria. 1
• Systemic symptoms: Fever, joint/bone pain, or malaise raise concern for autoinflammatory syndromes. 1
• Reproducible triggers: Ask "Can you make your wheals appear?"—this identifies chronic inducible urticaria requiring provocation testing. 1

Physical Examination Focus

• Review patient photo documentation of lesions. 1
• Assess for signs of systemic disease (thyroid abnormalities, lymphadenopathy). 1
• Perform dermographism testing at bedside. 1

Laboratory Testing Algorithm

Mild Disease (Controlled on Standard Antihistamines)

No testing required. 1

Moderate-to-Severe or Antihistamine-Refractory Disease

Obtain a focused screening panel: 1

• Complete blood count with differential: Detects eosinophilia (helminth infections) or leukopenia (systemic lupus erythematosus). 1
• ESR or CRP: Usually normal in chronic spontaneous urticaria; elevated in urticarial vasculitis and autoinflammatory syndromes. 1
• Total IgE level: Low or very low levels suggest autoimmune chronic urticaria. 1
• IgG anti-thyroid peroxidase (anti-TPO): Thyroid autoimmunity occurs in ~14% of chronic urticaria patients versus ~6% of controls. 1
• High anti-TPO/total IgE ratio: Currently the best surrogate marker for autoimmune chronic spontaneous urticaria. 1

Red-Flag Scenarios Requiring Additional Testing

If wheals persist >24 hours: 1

• Perform lesional skin biopsy to confirm or exclude urticarial vasculitis (look for leukocytoclasia, endothelial damage, perivascular fibrin, red cell extravasation). 1
• If vasculitis confirmed, obtain full vasculitis screen including C3 and C4 to distinguish normocomplementemic from hypocomplementemic disease. 1

If systemic symptoms present (fever, arthralgia, malaise): 1

• Measure CRP and ESR (always elevated in autoinflammatory syndromes). 1
• Screen for paraproteinemia in adults. 1
• Consider skin biopsy looking for neutrophil-rich infiltrates. 1
• Genetic testing for hereditary periodic fever syndromes if strongly suspected. 1

If angioedema without wheals: 1

• Measure serum C4 as initial screening (low C4 has very high sensitivity for C1-inhibitor deficiency). 1
• If C4 low, confirm with C1-inhibitor quantitative and functional assays. 1
• Test for C1q and C1-inhibitor antibodies if acquired angioedema suspected. 1
• Perform genetic analysis if laboratory results normal but clinical suspicion remains. 1
• Review ACE inhibitor use—remission should occur within days to 6 months of discontinuation. 1

Specialized Testing (Only in Experienced Centers)

• Autologous serum skin test (ASST): Reasonably sensitive and specific screening test for histamine-releasing autoantibodies in autoimmune chronic urticaria (~30% of cases). 1, 2
• Provocation testing: For suspected chronic inducible urticaria (cold, pressure, dermographism, heat, exercise) using standardized protocols. 1

What NOT to Test

Avoid extensive laboratory workups in typical cases: 1, 3

• Routine allergy testing (skin prick, specific IgE) is not indicated unless history suggests specific allergen triggers. 1
• Screening for occult infections (dental abscess, gastrointestinal candidiasis) has little supporting evidence. 1
• Routine cancer screening is not indicated—no statistical association exists between malignancy and urticaria. 1
• In acute urticaria, no investigations are required unless history suggests specific triggers. 1

Disease Activity Monitoring

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

• 7-Day Urticaria Activity Score (UAS7): Range 0–42, combining daily wheal count (0–3) and itch severity (0–3) over 7 days. 1
• Urticaria Control Test (UCT): Guides treatment escalation decisions. 1
• Base therapeutic decisions on disease control measurements, not merely symptom presence. 1

Common Pitfalls to Avoid

• Do not perform extensive testing for acute urticaria—it adds no clinical value and is not cost-effective. 1, 3
• Do not assume all angioedema is histamine-mediated—bradykinin-mediated forms (ACE inhibitor-induced, hereditary angioedema) require distinct management and will not respond to antihistamines. 1
• Do not delay skin biopsy when wheals last >24 hours—urticarial vasculitis requires different treatment and has worse prognosis. 1
• Recognize that 80–90% of chronic urticaria remains idiopathic—this reflects current knowledge limits, not diagnostic failure. 4, 5

Special Considerations

Helicobacter pylori testing: Meta-analysis shows higher likelihood of chronic urticaria remission after successful eradication; consider testing in refractory cases. 1, 2

Celiac disease screening: Significantly increased prevalence in children and adolescents with severe chronic urticaria. 1, 2