Immunology and AllergyTier 1Disease (DEADMAN)

Angioedema

Description

Deep dermal / submucosal swelling - non-pitting, asymmetric, non-pruritic
- Lips, periorbital, tongue, larynx, extremities, genitalia, bowel wall
The single question that classifies it: are there weals?

	Mast cell (histaminergic)	Bradykinin-mediated
Urticaria/weals	Present	Absent
Itch	Yes	No
Onset -> peak	Minutes	Hours (2-6h)
Duration	<24h	2-5 days
Prodrome	-	Tingling, erythema marginatum
Responds to adrenaline/antihistamine/steroid	Yes	No
Abdominal attacks	Uncommon	Common - mimics acute abdomen

Bradykinin-mediated causes

ACE inhibitor angioedema - commonest cause of bradykinin angioedema overall
Hereditary angioedema (HAE)
- Type I (85%) - low C1-INH antigenic level
- Type II (15%) - normal/high level, reduced function
- HAE with normal C1-INH - FXII, plasminogen, angiopoietin-1, kininogen-1 mutations
Acquired C1-INH deficiency - lymphoproliferative disease, monoclonal gammopathy, anti-C1-INH autoantibody

HAE ~1:50,000, autosomal dominant, no sex or ethnic predilection
- ~25% de novo mutations - absent family history does not exclude it
- Onset in childhood/adolescence; attacks worsen at puberty
ACE inhibitor angioedema: 0.1-0.7% of users
- ~4-5x higher in patients of African ancestry
- Onset at any time - median ~1 month but up to years into therapy
Acquired C1-INH deficiency: onset >40, no family history

Final common mediator is bradykinin acting on the B2 receptor -> endothelial gap formation -> plasma extravasation
C1 inhibitor is a serpin regulating three systems
- Classical complement (C1r, C1s) and lectin pathway (MASP)
- Contact system - factor XIIa and plasma kallikrein
- Fibrinolysis (plasmin)
C1-INH deficiency -> unopposed kallikrein -> high-molecular-weight kininogen cleaved -> bradykinin excess
Ongoing classical pathway consumption -> persistently low C4 even between attacks
ACE (kininase II) degrades bradykinin -> ACE inhibition -> bradykinin accumulation
Attack triggers: trauma (dental work, intubation), infection, stress, oestrogen (COCP, pregnancy), ACE inhibitors

Step 1 - are there weals?

Step 2 - complement screen

	C4	C1-INH level	C1-INH function	C1q
HAE type I	Low	Low	Low	Normal
HAE type II	Low	Normal/high	Low	Normal
Acquired C1-INH deficiency	Low	Low	Low	LOW
ACE inhibitor angioedema	Normal	Normal	Normal	Normal
HAE with normal C1-INH	Normal	Normal	Normal	Normal

Low C1q is the discriminator for acquired disease -> hunt for a lymphoproliferative disorder or paraprotein
Confirm with a repeat sample; genetic testing (SERPING1) if biochemistry equivocal
Normal C4 during an acute attack essentially excludes C1-INH deficiency
Screen first-degree relatives (age >1 year)

Imaging

Abdominal attack -> CT shows bowel wall oedema and ascites; many patients undergo needless laparotomy before diagnosis

A. Mast-cell mediated

B. ACE inhibitor angioedema

Cease the ACE inhibitor permanently - the whole class
Airway assessment; supportive care - adrenaline, steroids and antihistamines are usually ineffective but are given because the diagnosis is rarely certain at presentation
Icatibant has been used in severe cases; trial evidence is mixed
ARB usually tolerated (recurrence ~2-10%); sacubitril/valsartan contraindicated after ACEi angioedema

C. Hereditary angioedema

### Acute attack - treat early, treat any laryngeal or abdominal attack

Plasma-derived C1-INH concentrate IV (Berinert), or
Icatibant SC - bradykinin B2 receptor antagonist, self-administered
Fresh frozen plasma only if nothing else available (may worsen the attack - contains substrate)
Adrenaline, antihistamines and corticosteroids do not work - the commonest and most dangerous error
Airway: early intubation or surgical airway; do not wait

### Short-term prophylaxis

Before dental procedures, surgery, intubation - C1-INH concentrate 1-6h beforehand; tranexamic acid or danazol if unavailable

### Long-term prophylaxis

C1-INH concentrate (IV or SC), lanadelumab (anti-kallikrein mAb SC q2wk), berotralstat (oral kallikrein inhibitor)
Attenuated androgens (danazol) - effective but hepatic adenoma, dyslipidaemia, virilisation; avoid in children and pregnancy
Tranexamic acid - weak, mostly paediatric

### Every HAE patient needs

Written emergency plan, home supply of on-demand therapy with self-administration training, MedicAlert
Avoid ACE inhibitors and oestrogen-containing contraception
Family screening, specialist immunology follow-up

D. Acquired C1-INH deficiency

Lymphoproliferative disease and monoclonal gammopathy (acquired C1-INH deficiency)
Oestrogen exposure - COCP, HRT, pregnancy (HAE)
ACE inhibitors, sacubitril/valsartan, sirolimus, alteplase
SLE (acquired complement consumption)
Anxiety and psychological morbidity from unpredictable attacks

HAE: lifelong, unpredictable; attack frequency ranges from weekly to yearly
Untreated laryngeal attacks carry ~30% mortality - historically the main cause of death, now rare with on-demand therapy
Abdominal attacks -> repeated hospital admission, opioid exposure, unnecessary surgery
Attacks increase at puberty and with oestrogen; often improve in later adulthood
ACE inhibitor angioedema: resolves over days-weeks after cessation; recurrence for up to 3 months afterwards is expected and does not mean the diagnosis is wrong

Monitor

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