2026 International‑Canadian Guideline for Hereditary Angioedema (HAE)

Full‑text source: Allergy, Asthma & Clinical Immunology, 2026; 22(Suppl 1) Working group: Canadian Hereditary Angioedema Network (CHAEN‑RCAH), international multidisciplinary expert panel. Disclaimer: This is structured expert‑summary excerpt for medical‑professional education only, cannot replace original guideline or clinical‑physician decision‑making.

1 Definition & Pathogenesis

Hereditary angioedema (HAE) is an autosomal‑dominant, bradykinin‑mediated rare disease. Dysregulated plasma‑kallikrein‑kinin cascade generates excessive bradykinin, producing transient, non‑pruritic, non‑urticarial subcutaneous/mucosal swellingPMC.

• Key clinical features: swelling of extremities, face, gastrointestinal tract, genitals, larynx. No wheals / no pruritus. Laryngeal oedema may cause fatal asphyxiation.
• 20‑25 % of patients have de‑novo pathogenic variants; negative family history does not rule‑out diagnosis.

2 Classification

1. HAE‑C1‑INH‑Deficient (HAE‑1 / HAE‑2, SERPING1‑related)
   • Type 1 (~85 %): Low C1‑INH antigen + low C1‑INH function; low‑C4 complement levelPMC.
   • Type 2 (~15 %): Normal / elevated C1‑INH antigen, impaired C1‑INH function; low‑C4 complement level.
2. HAE‑nC1‑INH (normal C1‑INH, formerly type 3)
   • C1‑INH antigen & function, C4 are within normal laboratory ranges.
   • Predominantly female‑affected; most common driver: F12 gain‑of‑function variant; multiple other gene loci reported; many cases remain genetically‑unexplainedPMC.

Distinction: HAE ≠ ACE‑inhibitor‑induced angioedema, acquired angioedema (AAE), histamine‑mediated urticaria‑associated angioedema.

3 Diagnostic Work‑up

3.1 Clinical red‑flags prompting HAE testing

‑ Recurrent pain‑predominant swelling without wheals/itch; laryngeal oedema; recurrent unexplained abdominal pain‑attacks; positive family‑history; poor/no‑response to antihistamines, corticosteroids, adrenaline for swelling episodes云南省卫生....

3.2 Laboratory algorithm for suspected HAE‑1/2

1. First‑line panel: plasma C4, C1‑INH antigen, C1‑INH functional activity (test outside acute‑attack whenever possible). Repeat testing on separate blood‑draw to confirm abnormal resultsPMC.
2. Low‑C4 + reduced‑C1‑INH function → diagnosis of HAE‑1/2.
3. Normal‑C4 + normal‑C1‑INH function → cannot diagnose HAE‑1/2; consider HAE‑nC1‑INH; refer to HAE‑specialist for genetic testing (F12, PLG etc.).
4. SERPING1‑gene sequencing: diagnostic alternative when complement‑assays ambiguous or unavailable; large‑deletion variants may escape standard sequencing panels.
5. Family‑screening: all first‑degree relatives of confirmed HAE‑patients require early screening (complement testing / causal‑variant targeted‑genetic testing)Wiley Onli....

Biopsy is not routine for HAE diagnosis.

3.3 Differential diagnosis

Acquired angioedema (AAE), drug‑induced angioedema (ACE‑i), idiopathic angioedema, urticaria, intestinal‑obstruction, anaphylaxis, soft‑tissue infection.

4 Therapeutic Framework

Three treatment pillars: on‑demand acute‑attack therapy; short‑term prophylaxis (STP); long‑term prophylaxis (LTP).

Critical safety note: Antihistamines, systemic corticosteroids, adrenaline are ineffective for HAE bradykinin‑mediated swelling. Adrenaline is only used for concomitant true anaphylaxis.

4.1 On‑demand (acute‑attack) treatment

• Recommendation: Treat as early as possible. All laryngeal, facial, pharyngeal, severe abdominal / limb attacks require on‑demand therapy. Patient self‑administration training is strongly encouragedNational C....
• First‑line agents for HAE‑1/2:
  1. Plasma‑derived C1‑INH concentrate (iv / sc)
  2. Recombinant C1‑INH (conestat‑alfa, iv)
  3. Icatibant (bradykinin‑B2‑receptor antagonist, subcutaneous)
• Backup: solvent‑detergent‑treated plasma if above agents unavailable; fresh‑frozen‑plasma as last‑resort optionPubMed.
• Laryngeal‑attack management: immediate on‑demand medication + emergency‑hospital admission; secure‑airway preparedness (intubation / tracheostomy). All patients should carry emergency‑medication + medical‑alert identification bracelet/card云南省卫生....

4.2 Short‑term prophylaxis (STP)

‑ Indicated before dental‑surgery, invasive‑procedures, major‑trauma (high‑trigger events). ‑ Preferred: pdC1‑INH concentrate given pre‑procedure. Avoid androgens for STP whenever possible.

4.3 Long‑term prophylaxis (LTP)

Indications for initiating LTP

≥1 attack/month; history of laryngeal oedema; poor quality‑of‑life from attacks; limited access to urgent‑on‑demand‑therapy.

Even on LTP, patients must retain access to on‑demand rescue‑medication, breakthrough‑attacks still occur.

First‑line LTP agents (HAE‑1/2)

1. Lanadelumab: anti‑kallikrein mAb 300 mg sc q2‑4 weeks. 2. Subcutaneous plasma‑derived C1‑INH. 3. Berotralstat: oral kallikrein‑inhibitor 150 mg once‑daily; monitor CYP3A‑mediated drug‑interactions, gastrointestinal adverse events. 4. Garadacimab: new‑approved anti‑FXII‑antibody for patients ≥12 years old (Canadian label 2026)Drug and H....

Second‑line / conditional‑options

Attenuated androgens (danazol): lowest effective dose; significant adverse‑effect profile; avoid in children, pregnancy, breastfeeding. Antifibrinolytics (tranexamic‑acid): limited‑efficacy, select‑patient‑use only.

For HAE‑nC1‑INH: evidence‑base is limited; specialist‑driven individualized‑approach.

5 Special‑populations

5.1 Paediatrics

‑ Family‑at‑risk children: screening; complement testing may need repetition after age 1 year (immature infant complement‑system)Wiley Onli.... ‑ On‑demand therapy: age‑approved C1‑INH / icatibant. ‑ LTP: lanadelumab, berotralstat per licensed age‑cut‑offs. Androgens are not preferred in paediatric population; if mandatory, use lowest‑dose in Tanner‑V adolescents only. ‑ Oestrogen‑containing contraceptives are discouraged; may trigger‑worsen‑attacksWiley Onli....

5.2 Pregnancy & Lactation

‑ Only pd‑C1‑INH is recommended for acute‑attack and prophylaxis during pregnancy/lactation. ‑ Androgens are contraindicated. Icatibant may be considered when benefit outweighs risk under specialist supervision. Oestrogen‑containing medications should be avoided.

5.3 Peri‑operative

‑ Multidisciplinary planning; STP before intervention; ensure on‑demand rescue‑medication available intra‑and‑post‑operatively.

6 Trigger avoidance & patient‑centred‑care

‑ Common triggers: oestrogen‑containing drugs, trauma/surgery, dental‑procedures, stress, infections, menses. ACE‑inhibitors should be avoided entirely. ‑ Do not impose excessive‑unnecessary‑activity‑restrictions. ‑ Patient education, self‑administration training, medical‑alert‑card, attack‑diary for monitoring attack‑frequency/severity. Referral to HAE‑patient‑support‑organisations.

7 Core take‑home recommendations

1. HAE is bradykinin‑mediated; antihistamines, steroids are ineffective for acute swelling.
2. Suspected HAE‑1/2: test C4, C1‑INH antigen & C1‑INH function; repeat abnormal results; screen first‑degree‑relatives.
3. Acute‑attacks: early‑on‑demand‑treatment with C1‑INH‑preparations or icatibant; laryngeal‑attacks are medical‑emergency.
4. LTP is indicated for frequent‑attacks / laryngeal‑history; lanadelumab, sc‑pdC1‑INH, berotralstat are first‑line; rescue‑medication must always remain available.
5. Pregnancy: only pd‑C1‑INH preferred; androgens contraindicated.
6. HAE‑nC1‑INH diagnosis is challenging; always refer to HAE‑specialist centre