Angiodema
1. Definition & Key Clinical Features
- Anatomical depth Swelling of the reticular dermis, subcutaneous fat or sub-mucosa
- lips
- tongue
- uvula
- larynx
- bowel wall
- genitalia
- Consistency
- “Brawny” – tends to feel thick and firm
- non-pitting
- may be painful or warm.
- Onset/Duration
- Minutes–hours
- histaminergic episodes usually resolve <24 h
- bradykinin-mediated episodes 24–72 h
- Red-flags
- Voice change, stridor, dysphagia, abdominal colic → treat as airway emergency. Allergy Australia
2. Pathophysiological Classification
| Mechanism | Mediator | Typical context | Response to adrenaline/antihistamine |
|---|---|---|---|
| Mast-cell / histamine | Histamine, PGD₂ | • Allergy • Anaphylaxis • urticaria • NSAID or opiate reactions | Yes (rapid) |
| Bradykinin excess | Bradykinin | • ACE-inhibitor • Hereditary (C1-INH deficiency/dysfunction) • Acquired C1-INH deficiency | Poor (requires specific therapy) |
3. Aetiology
Hereditary angio-oedema (HAE)
- Definition & genetics
Autosomal-dominant, bradykinin-mediated angioedema caused by deficiency or dysfunction of C1 esterase inhibitor (C1-INH). The unchecked kallikrein–kinin cascade generates excess bradykinin, resulting in recurrent, non-pruritic swelling of skin and mucosa. Australian Prescriber - Epidemiology
- Prevalence ≈ 1 in 50 000 people worldwide.
- About 50 % of gene carriers experience their first attack before 10 years of age. Allergy Australia
- Clinical phenotypes
| Type | C1-INH antigen | C1-INH functional activity | Proportion of cases | Typical mutation |
|---|---|---|---|---|
| Type I | ↓ (low) | ↓ (low) | ~85 % | SERPING1 loss-of-function |
| Type II | ↔/↑ (normal or elevated) | ↓ (dysfunctional) | ~15 % | SERPING1 missense (dysfunctional protein) |
| HAE with normal C1-INH* | Normal | Normal | < 5 % | Gain-of-function variants in F12, PLG, ANGPT1, KNG1, MYOF, HS3ST6, etc. |
* Previously called “type III”; generally shows oestrogen sensitivity and later onset.
- Pathophysiological hallmark
Quantitative or qualitative C1-INH impairment → uncontrolled plasma kallikrein activity → over-production of bradykinin → increased vascular permeability → episodic angioedema.
Acquired bradykinin-mediated
| Trigger | Mechanism | Incidence / risk profile | Salient clinical clues |
|---|---|---|---|
| ACE-inhibitors (eg ramipril, perindopril) | ↓ Bradykinin breakdown → excess bradykinin | 0.1 – 0.7 % of users; risk ↑ 4- to 5-fold in people of African ancestry, females, smokers, age > 65 y JA Clinical OnlineUpToDate | May occur anytime from first dose to years later; no urticaria; does not respond to antihistamines or adrenaline. Icatibant or C1-INH concentrate is required in severe cases. |
| ARBs (eg irbesartan) | Unclear; minimal effect on bradykinin but occasional cross-reactivity | Incidence ≈ one-third that of ACEIs; true cross-reaction is rare but possible NP Journaluspharmacist.com | Consider in patients who switch from an ACEI and relapse. |
| Oestrogen exposure (combined OCP, HRT, pregnancy, tamoxifen) | Up-regulates kallikrein–kinin cascade; may unmask HAE with normal C1-INH (FXII, PLG, etc.) | Predominantly affects women; attacks often coincide with high-oestrogen states BioMed CentralBioMed Central | Laryngeal episodes more common; avoid exogenous oestrogen, consider lanadelumab / berotralstat for prophylaxis. |
| Acquired C1-INH deficiency — lymphoproliferative or autoimmune anti-C1-INH antibody | Auto-antibody neutralises C1-INH or consumes it | Very rare (< 1 : 500 000); median age > 40 y; 50–70 % have an underlying B-cell malignancy immunology.orgThe Australian National University | Low C1-INH and low C4 with no family history; treat flares with C1-INH or icatibant and address the underlying dyscrasia (eg rituximab). |
Histaminergic – Histamine (mast-cell)–mediated angioedema
| Sub-category | Underlying pathway | Typical precipitants | Key management points |
|---|---|---|---|
| IgE-mediated allergy / anaphylaxis | Antigen cross-links IgE on mast cells → histamine & tryptase release | Foods (nuts, shellfish), β-lactams, latex, insect venom, contrast media (in true IgE-positive cases) | IM adrenaline first-line; add high-dose second-generation H1 antihistamine and corticosteroid. Allergy Australia |
| Non-IgE mast-cell activation | Direct receptor-dependent degranulation | Opioids (morphine, codeine), radiocontrast, vancomycin (“red-man”), neuromuscular blockers | May occur on first exposure; treat as for anaphylaxis but adrenaline requirements often lower; pre-medicate with H1/H2 ± glucocorticoid if contrast unavoidable. Walsh Medical MediaAAAAI |
| Cyclo-oxygenase-1 inhibition | COX-1 blockade → arachidonic acid shunted to leukotriene pathway | Aspirin, non-selective NSAIDs | Cross-reactive; typically urticaria + angioedema within 30–120 min. Stop culprit; consider montelukast for prevention. JA Clinical OnlineSpringerLink |
| Idiopathic chronic / recurrent angioedema | Unknown; mast-cell or kinin pathways variably implicated | No identifiable trigger | Trial high-dose non-sedating H1 antihistamine → a |
Practical differentiation at the bedside
| Feature | Bradykinin-driven | Histamine-driven |
|---|---|---|
| Speed of onset | Slower (hours) | Rapid (minutes–hours) |
| Itch / urticaria | Absent | Common |
| Response to adrenaline / antihistamine | Poor | Good |
| C4 level (between attacks) | Often low | Normal |
4. Initial Assessment (ED / GP)
- Airway, Breathing, Circulation – anticipate rapid laryngeal progression; early anaesthetics/ENT call-out.
- Focused history
- drug list (ACE-I?)
- C1-INH deficiency FHx
- urticaria presence
- prior similar episodes
- trigger exposure.
- Targeted tests (after stabilisation)
- C4 + quantitative/functional C1-INH if bradykinin AE suspected.
- Consider naso-laryngoscopy for voice change/dysphagia. AAEM
5. Acute Treatment Algorithm
| Step | Histamine-mediated | Bradykinin-mediated (HAE or ACEI) |
|---|---|---|
| A. First-line | Adrenaline 0.5 mg IM (0.01 mg/kg child) ± repeat q5 min until improved | Not effective – skip |
| B. Adjuncts | Non-sedating H1 antihistamine (e.g. cetirizine 10 mg PO/IV) ± H2 blocker ± corticosteroid (e.g. hydrocortisone 200 mg IV) | Specific therapies: • Icatibant 30 mg SC × 1 (may repeat at 6 h) (PBS Authority for acute HAE; off-label ACEI-AE) PBS Australian Prescriber • C1-INH concentrate (Berinert® 20 IU/kg IV) or recombinant (Conestat alfa 50 IU/kg IV, max 4200 IU) (HAE only) Allergy Australia • Fresh frozen plasma 2 units IV if above unavailable (HAE or ACEI) FFP contains ACE (kininase II), which degrades bradykinin ⚠️ risk viral transmission/volume overload AAEM |
| C. Airway control | Early intubation/otracheal tube if tongue or laryngeal swelling progresses | Same; oedema may be refractory—consider surgical airway early |
| D. Observe | ≥4 h post-resolution | ≥24 h; biphasic rarity but delayed oedema possible |
Note: Epinephrine, antihistamines and steroids have no proven benefit in isolated ACE-I angio-oedema, but give empirically if mechanism unclear while arranging definitive therapy. AAEM AAEM
6. Disposition & Secondary Prevention
| Context | Key actions |
|---|---|
| ACE-I angio-oedema | • Cease ACE-I permanently (class effect). • Substitute dihydropyridine CCB, thiazide or β-blocker; ARB only with specialist advice. • Provide written “ACEI-angio-oedema” alert. |
| HAE | • Supply patient-held ASCIA HAE Management Plan + self-injectable icatibant or C1-INH. • Consider long-term prophylaxis when ≥2 attacks/month or QoL impaired: – Lanadelumab 300 mg SC q2–4 weeks (PBS 2024). – Berotralstat 150 mg PO daily. – Attenuated androgens (danazol) or tranexamic acid if modern biologics unavailable. Allergy Australia |
| Histaminergic | • Identify triggers provide ASCIA Action Plan for Anaphylaxis Training in adrenaline autoinjector if systemic allergy suspected. Allergy Australia |
Follow-up with clinical immunologist is recommended for all recurrent or idiopathic angio-oedema. Allergy Australia
7. Practical Doses
| Drug | Dose | Notes |
|---|---|---|
| Adrenaline IM | 0.5 mg (0.3 mg ≥ 6 y; 0.15 mg < 6 y) lateral thigh | Repeat q5 min PRN; give lying flat |
| Icatibant | 30 mg SC (abdomen) | May repeat ×2 at ≥6 h; PBS Authority (HAE acute attacks) |
| C1-INH (Berinert®) | 20 IU/kg IV push over 5 min | Weight-based; e.g. 1500 IU for 75 kg patient |
| Hydrocortisone | 200 mg IV (child 4 mg/kg max 100 mg) | Slow onset (4–6 h) |
| Cetirizine IV/PO | 10 mg | First-line antihistamine |
