How do I approach a case of chronic spontaneous urticaria, from taking a medical history to clinical examination and investigations?

Approach to Chronic Spontaneous Urticaria: A Step-by-Step Clinical Algorithm

Initial Patient Complaint and History Taking

Begin by establishing the diagnosis through specific questioning about wheal characteristics and duration. 1

Present History - Key Questions to Ask:

• "For how long does each individual wheal last?" - Individual wheals lasting >24 hours suggest urticarial vasculitis, not CSU 1
• "Can you make your wheals appear? Can you bring out your wheals?" - A positive response indicates chronic inducible urticaria rather than CSU 1
• Duration of symptoms: CSU is defined as spontaneous wheals, angioedema, or both occurring for ≥6 weeks 2, 3
• Frequency and timing: Document daily wheal occurrence and pruritus severity 1
• Presence of angioedema: Determine if swelling occurs with or without wheals 1

Past Medical History - Critical Elements:

• ACE inhibitor use: These medications can cause angioedema and must be identified immediately; remission should occur within days to 6 months of discontinuation 1
• Other medications: NSAIDs, aspirin, codeine - all can exacerbate CSU 4
• Recurrent unexplained fever, joint/bone pain, or malaise: Suggests autoinflammatory disease 1
• Thyroid disease: Approximately 20% of CSU patients have autoimmune thyroiditis 2
• Psychiatric history: 10-31% have anxiety, 7-29% have depression 2

Family History:

• Detailed family history of angioedema without wheals: Suggests hereditary angioedema (HAE) 1
• Age of disease onset in family members with similar symptoms 1
• History of autoinflammatory syndromes (cryopyrin-associated periodic syndromes, familial cold autoinflammatory syndrome) 1

Clinical Examination

Skin Examination:

• Document wheal characteristics: Size, distribution, color, and whether they are confluent 1
• Photograph lesions: Visual documentation is essential for diagnosis confirmation 1
• Dermatographism testing: Stroke the skin firmly to assess for physical urticaria 1
• Duration observation: Ideally observe individual wheals to confirm they resolve within 24 hours 1

Angioedema Assessment:

• Location: Lips, eyes, tongue, hands, feet most commonly affected 1
• Ask about abdominal angioedema: Often not visible but painful 1
• Absence of wheals with angioedema: Raises concern for bradykinin-mediated angioedema (HAE or ACE-inhibitor induced) rather than mast cell-mediated 1

Systemic Examination:

• Signs of thyroid disease 2
• Evidence of metabolic syndrome (present in 6-20% of CSU patients) 2
• Signs of systemic inflammation or autoinflammatory disease 1

Disease Activity and Control Assessment

Implement validated scoring tools immediately to establish baseline severity and guide treatment decisions. 1

7-Day Urticaria Activity Score (UAS7):

• Score wheals daily: 0 (none), 1 (<20/24h), 2 (20-50/24h), 3 (>50/24h or large confluent areas) 1
• Score pruritus daily: 0 (none), 1 (mild), 2 (moderate/troublesome), 3 (severe/interferes with daily activity or sleep) 1
• Sum scores over 7 days (maximum 42 points) 1
• Use for patients with CSU presenting with wheals 1

Urticaria Control Test (UCT):

• Four questions assessing the past 4 weeks 1
• Score ≥12 indicates well-controlled disease 5
• Use to guide treatment escalation decisions 4

Angioedema Control Test (AECT):

• Use for patients with angioedema (with or without wheals) 1
• Cutoff for well-controlled disease is 10 points 1
• Available in 4-week and 3-month recall versions 1

Quality of Life Assessment:

• Chronic Urticaria Quality of Life (CU-Q2oL) questionnaire 1
• Dermatology Life Quality Index: Approximately 40% of CSU patients score >10, indicating very large or extremely large negative effect 2

Investigations: The 7 Cs Approach

The diagnostic workup serves seven specific purposes (the 7 Cs), not just to confirm diagnosis. 1

Basic Laboratory Tests (Required for All Patients):

• Complete blood count with differential 1
• C-reactive protein (CRP) and/or erythrocyte sedimentation rate (ESR) 1
• Total IgE level 1
• IgG anti-thyroid peroxidase (anti-TPO) 1

Rationale: Low or very low total IgE with elevated IgG anti-TPO suggests autoimmune CSU; a high ratio of IgG anti-TPO to total IgE is the best surrogate marker for autoimmune CSU 1

Additional Testing for Angioedema Without Wheals:

• Serum C4 level immediately: Low C4 has high sensitivity for C1 inhibitor deficiency 4
• If C4 is low: Quantitative and functional C1 inhibitor assays 4
• C1q level and C1-INH antibodies if acquired angioedema (AAE) suspected 1
• Gene mutation analysis if above tests unremarkable but history suggests HAE 1

Testing for Specific Scenarios:

• Elevated inflammatory markers (CRP/ESR): Test for paraproteinemia in adults, consider skin biopsy for neutrophil-rich infiltrates, gene mutation analysis for hereditary periodic fever syndromes if strongly suspected 1
• Average wheal duration >24 hours: Skin biopsy to assess for urticarial vasculitis (look for small vessel damage in papillary/reticular dermis, fibrinoid deposits) 1
• History suggestive of inducible urticaria: Standardized provocation testing according to international consensus recommendations 1
• Antihistamine-refractory patients: CU index to determine presence of antibodies against IgE, FcεRI, or anti-FcεRII 1

Tests NOT Routinely Recommended:

• No routine testing in acute urticaria unless history suggests specific underlying cause 1
• Extensive allergy testing is not indicated for CSU 1

Differential Diagnosis Exclusion

Key Conditions to Rule Out:

• Urticarial vasculitis: Wheals lasting >24 hours, skin biopsy showing vasculitis 1
• Hereditary or acquired angioedema: Low C4, abnormal C1-INH levels/function 1, 4
• ACE inhibitor-induced angioedema: History of ACE inhibitor use 1, 4
• Autoinflammatory diseases: Schnitzler syndrome, systemic-onset juvenile idiopathic arthritis, adult-onset Still disease, cryopyrin-associated periodic syndromes 1
• Chronic inducible urticaria: Positive provocation testing 1, 5

Treatment Algorithm Based on Assessment

First-Line Treatment:

• Second-generation H1 antihistamines at standard doses 2, 6
• Approximately 40% achieve partial or complete response (>50% symptom reduction) 2

Second-Line Treatment (Inadequate Response After 2-4 Weeks):

• Updose second-generation H1 antihistamines up to 4 times standard daily dose 4, 6
• Continue for 2-4 weeks before determining inadequate response 4

Third-Line Treatment (Inadequate Response to High-Dose Antihistamines):

• Omalizumab 300mg subcutaneously every 4 weeks 4, 2, 6
• Allow up to 6 months for response demonstration before considering failure 4
• At least 30% have insufficient response, especially those with IgG-mediated autoimmune urticaria 2

Fourth-Line Treatment (Omalizumab Failure):

• Cyclosporine (up to 5mg/kg body weight) 5, 2
• Improves symptoms in 54-73% of patients, especially those with autoimmune CSU 2
• Monitor blood pressure and renal function 5

Critical Pitfalls to Avoid

• Never use prolonged corticosteroids as maintenance therapy: Restrict to short courses only for severe acute urticaria or life-threatening angioedema affecting the mouth 4
• Do not continue ACE inhibitors in patients with angioedema: Must be discontinued immediately 4
• Avoid NSAIDs, aspirin, codeine, and alcohol: These exacerbate CSU 4
• Do not assume all angioedema is mast cell-mediated: Always check C4 to rule out HAE, which requires completely different treatment 4
• Do not stop effective treatment prematurely: Maintain complete symptom control for at least 3 consecutive months before attempting step-down 4