What are the diagnostic tests and treatment options for patients presenting with angioedema and hives, including blood tests such as Complete Blood Count (CBC) and Erythrocyte Sedimentation Rate (ESR)?

Diagnostic Blood Tests for Angioedema and Hives

Initial Blood Work

For patients presenting with angioedema and hives, obtain a differential blood count, C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR), total IgE level, and IgG-anti-thyroid peroxidase (anti-TPO) antibodies as your basic laboratory panel. 1

These tests serve multiple diagnostic purposes:

• Differential blood count helps identify underlying inflammatory or infectious processes that may trigger or accompany urticaria 1
• CRP/ESR assesses for inflammatory conditions and can help distinguish inflammatory/autoinflammatory causes of angioedema 2
• Total IgE levels help identify autoallergic chronic spontaneous urticaria (CSU), where elevated IgE suggests IgE autoantibodies to self-antigens 1
• IgG-anti-TPO antibodies identify autoimmune CSU, as patients with autoimmune forms are more likely to have elevated anti-TPO levels 1

A critical diagnostic pearl: patients with autoimmune CSU typically have low or very low total IgE levels combined with elevated IgG-anti-TPO, and a high ratio of IgG-anti-TPO to total IgE is currently the best surrogate marker for autoimmune CSU 1

When Angioedema Occurs WITHOUT Hives

If angioedema presents without urticaria, immediately measure C4 level, C1 inhibitor (C1-INH) antigen, and C1-INH functional activity to screen for hereditary or acquired C1 inhibitor deficiency. 1, 2

The diagnostic algorithm proceeds as follows:

• C4 level is an excellent screening test, as it is low in 95% of patients with C1-INH deficiency between attacks and nearly 100% during attacks 2
• Normal C4 during an attack strongly suggests hereditary angioedema is unlikely 2
• If C4 is low, proceed with C1-INH testing to distinguish between HAE types 2

Interpreting C1 Inhibitor Results

The pattern of laboratory abnormalities distinguishes different forms:

• HAE Type I (85% of cases): Low C4, low C1-INH antigen, low C1-INH function, normal C1q 2
• HAE Type II: Low C4, normal/elevated C1-INH antigen, low C1-INH function, normal C1q 2
• Acquired C1-INH deficiency: Low C4, low C1-INH antigen/function, low C1q (this is the critical distinguishing feature) 2

A common diagnostic pitfall is failing to test C1-INH function, which is essential to diagnose HAE type 2 where antigen levels may be normal or elevated. 3

Additional Testing for Suspected Acquired C1-INH Deficiency

If acquired C1-INH deficiency is suspected based on age of symptom onset (typically >40 years), measure C1q level and anti-C1INH antibodies. 1

• C1q must be specifically requested when ordering, as it is critical to differentiate acquired from hereditary forms 2
• Consider paraprotein screening to rule out associated lymphoproliferative disorders 2

Genetic Testing Considerations

For patients with recurrent angioedema without hives who have normal C1-INH levels but fail to respond to antihistamines and omalizumab, perform targeted gene sequencing for known HAE pathogenic variants. 1, 3

Test for mutations in:

• Factor XII (F12)
• Plasminogen (PLG)
• Angiopoietin-1 (ANGPT1)
• Kininogen (KNG1)
• Myoferlin (MYOF)
• Heparan sulfate-glucosamine 3-O-sulfotransferase 6 (HS3ST6)
• Carboxypeptidase N1 (CPN1)
• DAB2 interacting protein (DAB2IP) 1, 2, 3

Critical Clinical Distinctions

The presence or absence of urticaria (hives) is the single most important clinical feature for determining the mechanism and appropriate testing strategy. 4

• Angioedema WITH hives suggests mast cell-mediated mechanisms (histaminergic) 1, 4
• Angioedema WITHOUT hives suggests bradykinin-mediated mechanisms or hereditary forms 1, 4

Approximately 10% of chronic urticaria patients present with angioedema alone without visible wheals, which can complicate the diagnostic picture. 1, 4

Medication-Induced Angioedema

Obtain a detailed medication history, particularly for ACE inhibitors, ARBs, NSAIDs, neprilysin inhibitors, and DPP-IV inhibitors, as these are common causes of non-histaminergic angioedema. 1, 2

Important considerations:

• No specific diagnostic blood test exists for ACE inhibitor-induced angioedema 2
• Diagnosis is confirmed by symptom resolution after drug discontinuation, which may take up to 6 weeks 2
• ACE inhibitors cause angioedema in 0.1-0.7% of patients, with higher risk in African Americans, smokers, older patients, and females 4, 2

Common Diagnostic Pitfalls to Avoid

Do not assume angioedema is allergic without proper testing—chronic urticaria and recurrent angioedema are rarely due to allergy. 5

• Failing to distinguish histaminergic from non-histaminergic forms leads to inappropriate treatment 6
• Misdiagnosing HAE as allergic angioedema results in ineffective use of antihistamines, corticosteroids, or epinephrine 3
• Not obtaining photographic or imaging documentation can lead to misdiagnosis of factitious angioedema 1, 3