What is the next step in managing a 50-year-old woman with recurrent episodes of sudden onset facial swelling, particularly lip swelling, without pruritus, lasting less than a week, and increasing in frequency over the past three months?

Recurrent Facial Angioedema Without Urticaria: Diagnostic Workup

The next step is to obtain complement C4, C1-INH antigen level, and C1-INH functional activity testing to rule out hereditary or acquired angioedema, while simultaneously taking a detailed medication history focusing on ACE inhibitors, NSAIDs, and other potential drug culprits. 1, 2

Initial Critical Assessment

The clinical presentation—recurrent facial and lip swelling without pruritus, lasting less than a week, and increasing in frequency—strongly suggests non-histaminergic (bradykinin-mediated) angioedema rather than allergic angioedema. 1, 3 The absence of urticaria is a key distinguishing feature that narrows the differential significantly. 1

Step 1: Medication History Review

Immediately review all medications, particularly:

• ACE inhibitors (most common drug cause, accounting for 30-40% of emergency department angioedema cases) 4, 5
• Angiotensin receptor blockers (ARBs)
• Dipeptidyl peptidase inhibitors
• Neprilysin inhibitors
• NSAIDs
• Tissue plasminogen activators 1

Critical pitfall: ACE inhibitor-induced angioedema can occur even after years of stable use, not just in the first month. 6 If the patient is on an ACE inhibitor, discontinue it immediately and observe for 1-3 months, as symptoms can persist for weeks to months after stopping. 1, 6

Step 2: Laboratory Testing for C1-INH Deficiency

Order the following tests simultaneously:

• Complement C4 level (screening test—will be low in HAE types 1 and 2) 1, 2
• C1-INH antigen level 2
• C1-INH functional activity (essential—do not skip this, as it's needed to diagnose HAE type 2 where antigen may be normal but function is impaired) 2

If acquired angioedema is suspected (adult onset without family history, age >40):

• Add C1q level (low in acquired, normal in hereditary) 1
• Add C1-INH autoantibodies 1, 2

Step 3: Family History Assessment

Ask specifically about:

• Family members with recurrent unexplained swelling 1
• Age of symptom onset in the patient (HAE typically begins in adolescence/early adulthood, though HAE with normal C1-INH often presents later, around age 20-55 years) 1
• Estrogen exposure as a trigger (oral contraceptives, pregnancy, hormone replacement therapy—particularly important in women with HAE-FXII) 1

Step 4: Clinical Feature Documentation

Document attack characteristics that distinguish bradykinin-mediated from histaminergic angioedema:

• Duration: Bradykinin-mediated attacks progress more slowly and last longer (often 2-5 days) 1
• Response to treatment: Lack of response to antihistamines, corticosteroids, or epinephrine strongly suggests bradykinin-mediated angioedema 1, 2, 6
• Abdominal involvement: Ask about unexplained abdominal pain episodes (may indicate visceral angioedema) 1
• Laryngeal involvement: Any history of throat swelling or voice changes (life-threatening risk) 1, 6

Diagnostic Algorithm Based on Test Results

If C1-INH testing is abnormal:

• Low C4 + Low C1-INH antigen = HAE Type 1 1, 2
• Low C4 + Normal C1-INH antigen but low function = HAE Type 2 1, 2
• Low C1q = Acquired C1-INH deficiency (evaluate for lymphoproliferative disorders, autoimmune disease) 1

If C1-INH testing is normal but clinical suspicion remains high:

• Consider HAE with normal C1-INH (HAE-nC1INH) 1
• Proceed to targeted gene sequencing for known mutations (Factor XII, Plasminogen, Angiopoietin-1, Kininogen, Myoferlin, HS3ST6) 1, 2
• Strong family history makes genetic testing more urgent 1

If all testing is normal and no medication cause identified:

• Trial of high-dose H1 antihistamines (up to 4x standard dose) for sufficient period 1
• If responsive: likely histaminergic idiopathic angioedema 1
• If non-responsive: consider trial of bradykinin B2 receptor antagonist (icatibant) during an attack to confirm bradykinin-mediated mechanism 1

Critical Safety Considerations

Life-threatening airway risk: Laryngeal involvement can cause asphyxiation and death, particularly with plasminogen gene mutations (HAE-PLG). 1 Patients should be counseled on emergency airway management and may need emergency tracheotomy if severe laryngeal edema develops. 7, 5

Common diagnostic pitfall: Misdiagnosing bradykinin-mediated angioedema as allergic angioedema leads to inappropriate treatment with antihistamines and steroids, which are ineffective. 2 The absence of pruritus and urticaria in this case strongly argues against histaminergic mechanisms. 1, 3

Referral Consideration

Refer to allergist-immunologist for comprehensive evaluation, as they have specific expertise in differentiating angioedema subtypes, performing appropriate testing, and managing both hereditary and acquired forms. 1 This is particularly important given the increasing frequency of attacks, which suggests progressive disease requiring specialized management. 1, 3