What is the appropriate outpatient management for a patient presenting with angioedema without anaphylaxis (no urticaria, wheezing, hypotension, or airway compromise)?

Outpatient Management of Angioedema Without Anaphylaxis

Immediate Clinical Differentiation

The single most critical first step is determining whether the angioedema is histamine-mediated or bradykinin-mediated, because standard allergy treatments (antihistamines, corticosteroids, epinephrine) are completely ineffective and potentially dangerous for bradykinin-mediated forms. 1

Key Clinical Features to Distinguish Mechanism

Bradykinin-mediated angioedema is suggested by:

• Absence of urticaria (hives) and pruritus 1, 2
• Slower progression over hours rather than minutes 1
• Current or recent ACE inhibitor use (most common cause, affecting 0.1-0.7% of patients) 3, 4
• Family history of recurrent angioedema 1, 4
• Recurrent abdominal pain attacks 1, 4

Histamine-mediated angioedema typically presents with:

• Concomitant urticaria in approximately 50% of cases 1
• Associated pruritus 1
• Rapid onset within minutes 1

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Management Based on Mechanism

For Histamine-Mediated Angioedema (Outpatient Setting)

Second-generation H1 antihistamines at 2-4 times the FDA-approved dose are the preferred first-line therapy (e.g., cetirizine 20-40 mg daily or loratadine 20-40 mg daily). 1

• Add an H2 blocker (famotidine 20 mg twice daily or ranitidine 50 mg twice daily) to enhance antihistaminic effect 1
• If insufficient response after adequate trial, add montelukast 10 mg daily 1
• Patients with significant symptoms or any airway involvement require immediate epinephrine 0.3 mL (0.1%) intramuscularly and should not be managed as outpatients 1
• Prescribe an epinephrine auto-injector for patients at risk of recurrence 5

For Bradykinin-Mediated Angioedema (Requires Urgent Referral)

Standard allergy medications have no effect on bradykinin-mediated angioedema and delay appropriate therapy. 1

If ACE inhibitor-induced:

• Discontinue the ACE inhibitor permanently and immediately 1
• Symptoms can recur for weeks to months after discontinuation 1
• Do NOT substitute an ARB, as cross-reactivity can occur (though most patients tolerate ARBs, a modest risk exists) 3, 1

Critical warning: Even mild-appearing bradykinin-mediated attacks can progress over 24 hours and may necessitate intubation; these patients require facility-based observation for several hours, not outpatient management. 1 Historical mortality for untreated bradykinin-mediated attacks is approximately 30%. 1

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Mandatory Diagnostic Work-Up

For Angioedema Without Urticaria

Order immediately:

• C4 level (screening test—low in 95% of C1-INH deficiency between attacks, nearly 100% during attacks) 1, 4
• C1 inhibitor antigen level 1, 4
• C1 inhibitor functional activity 1, 4

A normal C4 level during an attack essentially excludes C1 inhibitor deficiency. 4

If acquired C1-INH deficiency suspected (onset >40 years, no family history):

• C1q level (low in acquired, normal in hereditary) 1, 4
• Anti-C1-INH antibodies 1, 4
• Paraprotein screen to exclude lymphoproliferative disorders 4

For Angioedema With Urticaria

Order:

• Complete blood count 4
• C-reactive protein or ESR 4
• Total IgE level 4
• IgG-anti-thyroid peroxidase antibodies 4
• Specific IgE testing or skin-prick testing for suspected allergens (after acute episode resolves) 1

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Observation and Disposition Criteria

Safe for Outpatient Management

Patients with histamine-mediated angioedema may be discharged after 2-4 hours if:

• Minimal residual symptoms 1
• Complete resolution of swelling 1
• No oropharyngeal or laryngeal involvement 1
• Patient educated about warning signs 1

Requires Facility-Based Observation or Admission

Any patient with:

• Oropharyngeal or laryngeal involvement (voice change, dysphagia, dyspnea, stridor, drooling) 1
• Suspected or confirmed bradykinin-mediated angioedema 1
• Progression of symptoms despite treatment 1

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Critical Pitfalls to Avoid

• Do NOT assume ACE inhibitor-induced angioedema only occurs early in treatment—it can develop after many years of stable therapy 4
• Do NOT treat bradykinin-mediated angioedema with epinephrine, antihistamines, or corticosteroids—these are ineffective and waste critical time 1
• Do NOT discharge patients with oropharyngeal/laryngeal involvement without extended observation 1
• Do NOT assume normal C1-INH levels exclude hereditary angioedema—HAE with normal C1-INH exists and requires genetic testing 1, 4
• Do NOT order C1 inhibitor testing in patients with urticaria/wheals present—the presence of wheals suggests mast cell-mediated mechanism 4

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Follow-Up and Referral

All patients with suspected bradykinin-mediated angioedema require urgent referral to allergy/immunology for:

• Diagnostic confirmation 1
• Consideration of prophylactic therapy 1
• Education on self-administration of rescue medications (if hereditary angioedema confirmed) 1
• Genetic counseling (if hereditary angioedema confirmed) 1

Patients with histamine-mediated angioedema refractory to high-dose antihistamines and montelukast should be referred for consideration of omalizumab therapy. 1