What is the appropriate workup for a patient presenting with angioedema?

Workup for Angioedema

The workup for angioedema must immediately prioritize airway assessment, followed by rapid clinical differentiation between histamine-mediated and bradykinin-mediated subtypes, as this distinction fundamentally determines both diagnostic testing and treatment efficacy.

Immediate Clinical Assessment

Airway Evaluation (First Priority)

• Assess for signs of impending airway closure immediately: voice change, inability to swallow, dyspnea, stridor, or drooling signal life-threatening obstruction requiring urgent intervention 1, 2.
• Monitor continuously in a facility equipped for emergency intubation or tracheostomy if oropharyngeal or laryngeal involvement is present 1, 2.
• Avoid direct laryngoscopy unless absolutely necessary, as instrumentation can worsen edema 1, 3, 2.

Rapid Clinical Differentiation

Key distinguishing features between histamine-mediated and bradykinin-mediated angioedema:

Feature	Histamine-Mediated	Bradykinin-Mediated
Urticaria present	~50% of cases [4,5]	Absent [1,5]
Pruritus	Present [1]	Absent [1,5]
Onset speed	Rapid (minutes) [1]	Slower (hours) [1,5]
Response to antihistamines/epinephrine	Effective [1]	Ineffective [1,2,5]

Medication History (Critical for Diagnosis)

• Obtain ACE inhibitor history immediately, as these are the most common cause of bradykinin-mediated angioedema 1, 2, 6.
• ACE inhibitor-induced angioedema can occur years after initiating treatment and may recur for weeks to months after discontinuation 2, 6, 7.
• Document use of angiotensin II receptor blockers (ARBs), as 2-17% cross-reactivity exists 2.
• Ask about estrogen-containing medications, NSAIDs, and fibrinolytic agents 6, 7.

Family and Personal History

• Family history of recurrent non-urticarial swelling strongly suggests hereditary angioedema (HAE) 1, 5.
• Recurrent abdominal pain attacks or unexplained swelling episodes are characteristic of HAE 8, 1, 5.
• Previous episodes without urticaria point toward bradykinin-mediated etiology 1, 5.

Laboratory Workup

For Suspected Bradykinin-Mediated Angioedema

Step 1: Initial Screening

• Measure C4 level first as the primary screening test for C1-inhibitor deficiency 1, 5.
• Low C4 suggests hereditary or acquired C1-inhibitor deficiency 1.

Step 2: Confirmatory Testing (if C4 is low)

• C1-inhibitor antigen level 1, 5
• C1-inhibitor functional assay 1, 5
• C1q level to differentiate hereditary (normal C1q) from acquired (low C1q) forms 1.

Step 3: Advanced Testing (if strong clinical suspicion but normal C1-inhibitor)

• Targeted gene sequencing for HAE with normal C1-inhibitor (HAE-nl-C1INH), including SERPING1 and Factor XII mutations 1, 5.

For Suspected Histamine-Mediated Angioedema

• Serum tryptase level during acute episode if anaphylaxis is suspected 1.
• Specific IgE testing or skin prick testing for suspected allergens (foods, medications, insect venoms) after acute episode resolves 8, 4.
• Consider complete blood count and erythrocyte sedimentation rate if chronic spontaneous urticaria with angioedema is present 8.

For Idiopathic Angioedema

• Normal C4, C1-inhibitor antigen, C1-inhibitor function, and no family history establish idiopathic angioedema diagnosis 5.
• Further classify as histaminergic (responds to high-dose antihistamines) versus non-histaminergic 5.

Disease Activity and Control Assessment

• Use the Angioedema Activity Score to quantify disease activity in patients with chronic spontaneous urticaria and angioedema 8.
• Use the Angioedema Control Test (AECT) to assess disease control; a score ≥10 indicates well-controlled disease 8.
• Use the Angioedema Urticaria Quality of Life questionnaire to determine quality of life impairment 8.

Common Pitfalls to Avoid

• Do not assume angioedema is allergic simply because it involves facial swelling; absence of urticaria and pruritus strongly suggests bradykinin-mediated etiology 1, 5.
• Do not delay specific testing in bradykinin-mediated angioedema; historical mortality for untreated attacks is approximately 30% 1.
• Do not discharge patients with oropharyngeal or laryngeal involvement without extended observation (minimum several hours), as progression can occur over 24 hours 1, 2.
• Do not substitute an ARB in patients with ACE inhibitor-induced angioedema without specialist consultation, as cross-reactivity occurs 2.
• African American patients, smokers, older individuals, and females are at higher risk for ACE inhibitor-induced angioedema 1, 2.

Observation Duration

• Patients with oropharyngeal or laryngeal involvement require extended monitoring based on severity and anatomic location 1, 2.
• Histamine-mediated angioedema with minimal symptoms may be discharged after 2-4 hours if symptoms resolve 8, 3.
• Bradykinin-mediated angioedema requires facility-based observation for several hours even if symptoms appear mild, given potential for delayed progression 1.