What is the diagnosis and treatment for angioedema (angioneurotic edema)?

Diagnosis and Treatment of Angioedema (Angioneurotic Edema)

Begin by confirming recurrent angioedema without hives through photographic, laryngoscopic, or imaging evidence to exclude factitious cases, then systematically exclude C1-INH deficiency, medication-induced causes, and mast cell-mediated disease before considering hereditary forms. 1

Initial Clinical Assessment

Step 1: Confirm True Angioedema

• Document recurrent episodes of non-pitting edema affecting skin, mucous membranes, face, or upper aerodigestive tract without urticaria 1, 2
• Obtain photographic evidence, laryngoscopic findings, or imaging during attacks to differentiate from angioedema mimics (lymphedema, myxedema, superior vena cava syndrome, factitious angioedema) 1
• For abdominal presentations, obtain CT or ultrasound showing bowel wall edema and intraperitoneal fluid to confirm true angioedema 1
• Collect detailed medication history (especially ACE inhibitors, ARBs, NSAIDs, DPP-4 inhibitors) and family history of similar episodes 1

Diagnostic Algorithm

Step 2: Exclude C1-INH Deficiency (HAE-C1INH)

• Measure C4 level (screening test with high sensitivity), C1-INH antigen, and C1-INH functional activity 1, 3
• If acquired C1-INH deficiency suspected (onset after age 40), add C1q level and anti-C1-INH antibodies 1
• Low C4 with low C1-INH confirms hereditary or acquired C1-INH deficiency 3
• Normal C1q suggests hereditary form; low C1q indicates acquired deficiency 3

Step 3: Exclude Medication-Associated Angioedema

• Discontinue all suspected medications (ACE inhibitors, DPP-4 inhibitors, neprilysin inhibitors, tissue plasminogen activators, NSAIDs) 1, 2
• Observe for 1-3 months depending on attack frequency, as medication effects may persist 1
• ACE inhibitor-induced angioedema can occur months to years after drug initiation 2, 4

Step 4: Assess Family History

• Document family history of recurrent angioedema or diagnosed HAE in relatives 1
• If strong family history exists, proceed directly to targeted gene sequencing for known HAE-nC1INH variants (F12, ANGPT1, PLG, KNG1, MYOF, HS3ST6) 1
• Note that absence of family history does not exclude HAE due to de novo mutations, variable penetrance, or recall bias 1

Step 5: Exclude Mast Cell-Mediated Angioedema

• Evaluate for accompanying urticaria, pruritus, or response to allergen exposure 1, 3
• Trial high-dose second-generation H1-antihistamine (4× standard dose) for sufficient duration to assess response 1
• If inadequate response, add daily montelukast unless contraindicated 1
• If still unresponsive, trial omalizumab for 4-6 months 1
• Response to any of these medications confirms mast cell-mediated angioedema 1

Step 6: Genetic Testing (If Available)

• Perform targeted next-generation sequencing or Sanger sequencing for known HAE pathogenic variants 1
• Identified pathogenic variant confirms HAE-nC1INH diagnosis 1
• Novel variants are considered variants of unknown significance until confirmed by research 1
• Most common: F12 gene variant (p.Thr328Lys) accounts for 83.4% of HAE-nC1INH families 1

Step 7: Therapeutic Trial

• In absence of identified pathogenic variant, trial bradykinin B2 receptor antagonist (icatibant) or other approved HAE on-demand treatment 1
• Prompt and durable response supports bradykinin-mediated angioedema diagnosis 1
• Lack of response does not exclude HAE; consider alternative HAE medications or tranexamic acid 1

Step 8: Screen Family Members

• When HAE diagnosed, screen all related family members by clinical history 1
• Perform targeted genetic screening on all family members (symptomatic and asymptomatic) when pathogenic variant identified 1

Treatment Based on Type

Acute Attack Management

For Hereditary Angioedema (HAE):

• First-line treatments: plasma-derived C1-inhibitor (1000-2000 U IV), icatibant (30 mg subcutaneously), or ecallantide 5, 6
• Administer as early as possible in attack for maximum efficacy 5
• Icatibant may be repeated at 6-hour intervals if inadequate response; maximum 3 injections per 24 hours 6
• Patients should self-administer upon attack recognition to minimize time to treatment 5, 6
• Critical: Standard allergy treatments (epinephrine, corticosteroids, antihistamines) are NOT effective for HAE 5, 3

For ACE Inhibitor-Induced Angioedema:

• Immediately and permanently discontinue ACE inhibitor 5, 2, 4
• Consider icatibant (30 mg subcutaneously) or fresh frozen plasma if bradykinin-targeted therapies unavailable 5, 4
• Never restart ACE inhibitor; switching to ARB carries 2-17% recurrence risk 5

For Mast Cell-Mediated (Allergic) Angioedema:

• Administer intramuscular epinephrine immediately for significant symptoms or airway involvement 3, 4
• Give IV diphenhydramine and IV methylprednisolone as adjunctive therapy 3, 4

For Laryngeal Involvement (Any Type):

• Treat as medical emergency requiring immediate intervention 5, 3
• Monitor in facility capable of emergency intubation or tracheostomy 5, 3, 7
• Consider elective intubation early if signs of impending airway closure (voice changes, dysphagia, respiratory distress) 5, 3
• Historical mortality approaches 30% without treatment 3, 7

Supportive Care:

• Aggressive IV hydration for abdominal attacks 5, 3
• Antiemetics for nausea/vomiting 5, 3
• Appropriate analgesia while avoiding narcotic dependence in frequent attackers 5, 3

Prophylaxis for HAE

Short-Term Prophylaxis (Before Procedures):

• Plasma-derived C1-inhibitor (1000-2000 U IV) before dental or surgical procedures 5, 3
• Alternative: Danazol 2.5-10 mg/kg if C1-INH unavailable 5

Long-Term Prophylaxis (Frequent Attacks):

• Tranexamic acid 30-50 mg/kg/day (preferred in children where C1-INH unavailable) 5, 3
• Attenuated androgens: Danazol 100 mg on alternate days (monitor for side effects) 5, 3

Resource-Limited Settings

When First-Line Treatments Unavailable:

• Fresh frozen plasma (FFP) 10-15 mL/kg (approximately 2-4 units) may be effective for acute HAE attacks 1, 5
• First improvement typically noted at 90 minutes 1
• FFP contains approximately 1 unit/mL of C1-INH 1
• Use only when bradykinin-targeted therapies unavailable and symptoms severe 5

Critical Pitfalls to Avoid

• Never delay epinephrine in histamine-mediated angioedema with airway involvement 3
• Never use standard allergy treatments for confirmed or suspected HAE—they waste critical time 5, 3
• Never discharge patients with oropharyngeal or laryngeal involvement without adequate observation 3
• Never prescribe ACE inhibitors to patients with any form of angioedema 5, 3
• Never rely solely on family history to diagnose or exclude HAE due to variable penetrance and de novo mutations 1
• Never assume angioedema without urticaria is HAE without excluding medication causes first 1

Special Considerations

Female patients with HAE-FXII:

• Estrogen is major trigger in majority of cases 1
• Symptoms often first appear during pregnancy or with estrogen-containing contraceptives 1
• Average age of onset: 20 years (range 1-65 years) 1

Abdominal attacks:

• May mimic surgical abdomen with severe pain, hypotension, hemoconcentration, and leukocytosis 8
• Risk of hypovolemic shock from fluid sequestration in peritoneal cavity and intestinal wall 8
• Imaging showing bowel wall edema critical for diagnosis 1