Angioedema

Angioedema is localised, self-limited, non-pitting swelling of the deep dermis, subcutaneous or submucosal tissue from transient increased vascular permeability. It involves the face (lips, eyelids, tongue), larynx, extremities, genitalia and gastrointestinal tract. The mediators are mast cell (histamine) or bradykinin.

Histaminergic (mast cell-mediated) angioedema: with or without urticaria. Responds to antihistamines, corticosteroids and adrenaline.

• Allergic (IgE-mediated): foods, drugs, venoms, latex.
• Non-allergic: NSAIDs and aspirin, contrast media, opioids.
• Spontaneous or inducible chronic urticaria with angioedema (40% of chronic urticaria patients).
• Idiopathic histaminergic.

Bradykinin-mediated angioedema: no urticaria, no itch, does not respond to antihistamines, steroids or adrenaline.

• Hereditary angioedema (HAE):
  • HAE type I (85%): C1 inhibitor (C1-INH) deficiency (low antigen and function), SERPING1 mutations, autosomal dominant.
  • HAE type II (15%): normal or high C1-INH antigen with low function.
  • HAE with normal C1-INH (type III): FXII, plasminogen, angiopoietin-1, kininogen, myoferlin and heparan sulfate-glucosamine 3-O-sulfotransferase 6 mutations, mainly women with oestrogen sensitivity.
  • Prevalence about 1 in 50,000.
• Acquired angioedema (AAE): C1-INH deficiency caused by consumption (B-cell lymphoproliferative disease, autoimmune disease) or anti-C1-INH antibodies, onset after age 40, no family history.
• ACE inhibitor-induced angioedema: impaired bradykinin breakdown, 0.1 to 0.7% of users, 3 to 5 times higher in Black patients, can occur at any time (even years after starting). Also with sacubitril, DPP-4 inhibitors, mTOR inhibitors, and tissue plasminogen activators.
• Idiopathic non-histaminergic.

Pathophysiology of HAE: unregulated activation of the contact system and plasma kallikrein leads to excess bradykinin, which acts on B2 receptors to increase vascular permeability. Triggers: trauma (dental procedures, intubation), infection, stress, menstruation, oestrogen (contraceptives, pregnancy, HRT), and ACE inhibitors.

HAE morbidity: laryngeal attacks cause death by asphyxiation (historically 25-30% mortality in undiagnosed families), diagnostic delay averages 8 to 10 years, and abdominal attacks are often misdiagnosed as surgical emergencies.

• Histaminergic: onset within minutes to hours, swelling peaks in a few hours, lasts up to 24 to 48 hours, with associated urticaria, itch, flushing, bronchospasm or anaphylaxis. Responds quickly to treatment.
• Bradykinin-mediated: onset gradual over several hours, lasting 2 to 5 days (HAE) or 1 to 3 days (ACE inhibitor). No itch or urticaria, painless or tight sensation, and may involve:
  • Face, lips, tongue, extremities, genitalia.
  • Abdominal attacks: severe colicky pain, vomiting, diarrhoea, ascites, hypovolaemia, mimicking acute abdomen.
  • Upper airway: voice change, stridor, dysphagia, drooling, throat tightness, and potentially fatal asphyxia.
  • Prodrome: tingling, fatigue, erythema marginatum (non-itchy serpiginous rash) in up to 40-50%.
• HAE usually begins in childhood or adolescence, with attack frequency varying (weekly to once a year), and a family history in 75%.
• ACE inhibitor angioedema: face, lips, tongue, and larynx most commonly, and can recur after discontinuation for weeks to months.
• Acquired angioedema: later onset, no family history, associated with lymphoma, monoclonal gammopathy, or autoimmune disease.

Differential diagnosis: allergic reaction, anaphylaxis, urticaria, cellulitis or erysipelas, contact dermatitis, superior vena cava syndrome, dermatomyositis (periorbital), nephrotic syndrome and thyroid eye disease (periorbital swelling), Melkersson-Rosenthal syndrome (recurrent orofacial swelling), Quincke oedema, lymphoedema, and facial emphysema.

Red flags: tongue swelling, voice change, stridor, difficulty swallowing or breathing, hypotension, and abdominal pain with swelling elsewhere.

Initial approach

• Determine whether urticaria is present, timing and duration, triggers, medications (ACE inhibitors, ARBs, NSAIDs, oestrogens, DPP-4 inhibitors, sacubitril), family history, and response to antihistamines.
• Acute episodes in a patient without urticaria: consider bradykinin-mediated.

Laboratory evaluation for suspected bradykinin-mediated angioedema

• C4 level: low in nearly all HAE types I and II and AAE between attacks (screening test, sensitivity about 95-98%), normal in HAE with normal C1-INH, ACE inhibitor angioedema and histaminergic.
• C1-INH antigenic level and C1-INH functional activity: type I (low antigen, low function), type II (normal or high antigen, low function below 50%), AAE (low).
• C1q level: low in acquired angioedema (normal in HAE). Anti-C1-INH autoantibodies.
• Repeat testing if initial values are borderline, avoiding testing during pregnancy and in infants under 1 year (C1-INH may be low physiologically).
• Genetic testing: SERPING1 sequencing and deletion/duplication analysis, and for HAE with normal C1-INH, panels for F12, PLG, ANGPT1, KNG1, MYOF, and HS3ST6.
• Screening for lymphoproliferative disorders in acquired angioedema: serum protein electrophoresis, immunofixation, free light chains, CBC, LDH, imaging.
• Tryptase (baseline and during attack) and allergy testing for histaminergic angioedema. Chronic spontaneous urticaria work-up (CBC, CRP, thyroid autoantibodies).
• Abdominal imaging (ultrasound or CT) in attacks shows bowel wall oedema, free fluid.
• Family screening for HAE: C4, C1-INH level and function for relatives (including children).

Airway and acute management (any angioedema with laryngeal involvement)

• Assess airway immediately. Early senior anaesthetic or ENT involvement, with awake fibreoptic intubation or surgical airway if progressing. Sit upright, oxygen, monitoring.
• Undifferentiated or histaminergic: adrenaline 0.5 mg IM (0.5 mL of 1:1000) repeated in 5 minutes, antihistamine (chlorphenamine 10 mg IV, cetirizine 10 mg), hydrocortisone 200 mg IV, and anaphylaxis management.
• ACE inhibitor angioedema: stop the drug permanently (and avoid ARBs and sacubitril with caution, ARBs are used in selected patients only after a gap). Airway management is primary. Icatibant 30 mg SC (repeat after 6 hours, up to 3 doses in 24 hours) or C1-INH concentrate 20 units/kg, or fresh frozen plasma 2 units have case-based evidence. Tranexamic acid is of limited benefit.

Acute attacks in HAE (treat as early as possible, regardless of severity, and all laryngeal attacks)

• First-line on-demand therapy (any one):
  • Plasma-derived C1-INH (Berinert) 20 units/kg IV (or Cinryze 1000 units IV, may repeat once).
  • Recombinant C1-INH (conestat alfa, Ruconest) 50 units/kg IV (maximum 4200 units).
  • Icatibant (bradykinin B2 receptor antagonist) 30 mg SC into the abdomen, repeat after 6 hours if needed (maximum 3 doses in 24 hours). Self-administered at the onset of symptoms.
  • Ecallantide (plasma kallikrein inhibitor) 30 mg SC (three 10 mg injections), given under supervision because of anaphylaxis risk.
  • Sebetralstat 600 mg orally (first oral on-demand kallikrein inhibitor), taken at attack onset.
• If these are unavailable: solvent/detergent-treated plasma or fresh frozen plasma 2 units IV (may transiently worsen attacks).
• Adjuncts: IV fluids, antiemetics (ondansetron 4 mg IV), analgesia (opioids for abdominal pain), and airway monitoring. Antihistamines, steroids and adrenaline are not effective for bradykinin attacks (adrenaline only if anaphylaxis is possible).
• Patients should always carry at least two doses of on-demand therapy, and be trained for self-administration.

Short-term prophylaxis (before procedures, intubation, dental surgery, endoscopy)

• Plasma-derived C1-INH 1000 units IV (or 20 units/kg) within 6 hours before the procedure, with on-demand therapy available. Alternative: attenuated androgens (danazol 200 mg three times daily for 5 days before and 2 to 3 days after), or fresh frozen plasma 2 units 1 to 12 hours before.

Long-term prophylaxis (frequent or severe attacks, impaired quality of life)

• First line:
  • Lanadelumab (monoclonal antibody against plasma kallikrein) 300 mg SC every 2 weeks (every 4 weeks if attack-free for 6 months). Reduces attacks by 87%.
  • Berotralstat 150 mg orally once daily (oral plasma kallikrein inhibitor, reduces attacks by 44%).
  • Plasma-derived C1-INH SC (Haegarda) 60 units/kg twice weekly, or IV C1-INH (Cinryze) 1000 units every 3 to 4 days.
  • Garadacimab (anti-FXIIa antibody) 200 mg SC monthly (after loading), and donidalorsen (prekallikrein antisense) 80 mg SC every 4 to 8 weeks.
• Second line:
  • Attenuated androgens (danazol 50 to 200 mg daily, stanozolol, oxandrolone) are effective but cause virilisation, hepatotoxicity (peliosis hepatis, adenoma), dyslipidaemia, hypertension, and are contraindicated in children, pregnancy and breastfeeding. Monitor liver tests, lipids, and liver ultrasound.
  • Tranexamic acid 500 mg to 1 g two to three times daily (less effective, an option in children and women).
• Treatment goals: complete disease control and normalisation of life (assessed with AECT or AAS score).

Special populations

• Children: plasma-derived C1-INH is first choice for prophylaxis and on-demand therapy. Icatibant (from age 2), lanadelumab (from age 2), berotralstat (from age 12). Avoid androgens.
• Pregnancy and lactation: plasma-derived C1-INH is the treatment of choice (on-demand 20 units/kg and prophylaxis). Avoid androgens, ACE inhibitors, oestrogens. Plan delivery in a centre with HAE expertise, and have C1-INH available.
• Oestrogen-sensitive patients: stop oestrogen-containing contraceptives and HRT, use progestin-only methods (desogestrel 75 micrograms, levonorgestrel IUD), which can reduce attack frequency.
• Acquired angioedema: treat the underlying disease (rituximab 375 mg/m2 weekly for 4 doses for autoimmune cases, lymphoma therapy), and use C1-INH or icatibant for attacks. Antifibrinolytics and androgens are alternatives.
• HAE with normal C1-INH: icatibant, C1-INH, lanadelumab, progestins, and tranexamic acid.

Histaminergic angioedema

• Second-generation antihistamines at standard dose (cetirizine 10 mg, fexofenadine 180 mg, bilastine 20 mg), up-dosing to four times in chronic spontaneous urticaria, omalizumab 300 mg SC every 4 weeks, ciclosporin 3 to 5 mg/kg/day, and avoidance of NSAIDs if triggers. Short oral steroid course (prednisolone 0.5 mg/kg for 3 to 5 days) for severe attacks.
• Identify and avoid allergens, review drugs.

Education and follow-up

• Patient action plan, medical alert identification, written emergency letter, avoidance of triggers (trauma, infections), dental prophylaxis, vaccinations (hepatitis A and B if receiving plasma products), and family screening. Review every 6 months (attack diary, treatment response, adverse effects), annual liver tests and ultrasound if on androgens, and psychological support. Specialist HAE centre involvement.