Hereditary angioedema

General paediatrics, Immunology

=C1 esterase inhibitor deficiency.  Acquired angioedema seen, esp ACE inhibitor associated acquired AE, more common in blacks and transplant patients.

Sense of smell is impaired in HAE, correlates with complement levels!

Angioedema is bradykinin mediated, hence why different from urticaria and not responsive to anithistamines, steroids etc.

Prothrombin fragment F1 and 2 plus D-dimer levels have diagnostic value in acute attacks.

Consensus algorithm in 2010 (more recent American viewpoints).

Clinical

Recurrent circumscribed, non-pruritic, non-pitting oedema. Not usually painful unless a pressure area. Can affect virtually anywhere but typically extremities.   Upper respiratory tract involvement eg tongue, pharynx and larynx accounts for the reported 15–33% mortality. Abdominal pain with vomiting are dominant symptoms in approximately 25% (intestinal wall and mesenteric oedema).

Urticaria is not a feature of C1 INH deficiency. However, prodromal “serpiginous” erythema has been reported in up to 25% of patients which may be mistaken for urticaria or even cellulitis.

Classically, oedema develops gradually over several hours, continues to progress slowly for 12–36 hr, and then subsides after 2–5 days. Sudden onset abdo pain without visible oedema can occur, with or without diarrhoea.

Attacks can be once a year in some, weekly in others.  Triggers are trauma including dental work, surgery; infection; emotional stress; drugs eg OCP, ACE inhibitors (which can cause oedema without HAE, of course).  Can present under 1yr of age.  Laryngeal attacks tend to come later in life (rarely under age 3).  Gets worse with puberty.

Good dental hygiene important in prevention!

Diagnosis

Testing under age 1 unreliable so always repeat.  Baseline C4 is low in 98% of cases so good screening test – if normal during attack then review diagnosis!  No need for CH50.

Low C1 inhibitor suggests type 1 HAE.  Acquired is possible in people over 40 without family history, C1q low in these cases.

If normal C1 inhibitor but strong clinical suspicion, do C1 inhibitor functional assay to look for type 2 HAE.  If still normal, repeat testing during attack.

Type 3 HAE has normal C1 inhibitor and function – mainly women.  Due to Factor XII gene mutations and others.

Genetic testing (SERPING1) may be useful where these tests not conclusive.

Acute attacks

Human pdC1-INH (Berniert, Cinryze else Conestat-alpha which comes from transgenic rabbits) is recommended for all attacks (for adults and children). Not licensed for acquired? Beware rabbit allergy!?

  • “Wait and see” is only an option for attacks not involving the face, neck, or abdomen and intestine.
  • Attenuated androgens no longer available – stanozolol (up to 16 mg/day) or danazol (up to 1 g/day) given early (may shorten its duration).
  • Tranexamic acid weak – needs to be taken immediately – most don’t bother now
  • Upper airway esp voice alteration and dysphagia – give C1 INH promptly. How easily can family find veins?? Else family bring to emergency department! Dose depends on weight and seriousness of reaction. In a life-threatening situation we recommend 1000–1500 U. In other situations 500–1000 U is often sufficient. Administering C1 INH concentrate shortens the duration of attacks by about a third and also halves the time to the beginning of the relief of symptoms.
  • For acute attacks of abdominal oedema, pain relief should be given at an appropriate level. Non-steroidal anti-inflammatory drugs are useful.
  • If the attack is severe, C1 INH concentrate should be infused at the same dose as above. Early intervention prevents avoidable pain and reduces disruption to the patient’s life. The patient should be observed closely until symptoms start to improve. The median time to the beginning of the relief of symptoms after concentrate infusion is 0.5–1.5 h, with complete resolution of symptoms after 24 hr. If symptoms persist at a high intensity 2 h after infusion, additional C1 INH concentrate should be given and alternative diagnoses should be considered.
  • No benefit from steroids or antihistamines!  Adrenaline has only a transient and modest effect.
  • Home therapy is recommended for children with frequent and debilitating attacks, under the condition of medically supervised training.
  • Recombinant C1-INH concentrate (Ruconest) similar.
  • Subcut bradykinin B2 receptor antagonist Icatibant safe, effective and convenient (subcut) for acute attacks. Less rapid onset but then you can do it yourself. Similar price. Theoretical risk of thrombosis

Short-term prophylaxis

Children don’t need prophylaxis as much as adults, but is recommended for surgery in the head and neck area. pdC1-INH is recommended, if not available, use danazol. Tranexamic acid can also be used.

Give C1-INH up to 24hrs before procedure (with/without further dose post-procedure), or else 48hr steroids/TA before and after.

Long-term prophylaxis

The only treatment option for long-term prophylaxis in children is pdC1-INH. Question is not just frequency of attacks but severity (laryngeal vs hand, for example).

Attenuated androgens worked but not available. Side effects not great, include weight gain, virilization, muslce cramps, jaundice. In children, stunts growth.

C1 inhibitor has short half life so needed every 2-3 days. Subcut works for prophylaxis! Costs £140K per year.

Berotralstat – oral kallikrein inhibitor – some GI upset, long QT. NICE/SMC approved. £10 000 per month so similar.

Lanadelumab – subcut monoclonal kallikrein inhibitor. 2-4 weekly. Similar cost.

At the current pediatric consensus meeting for German-speaking countries, several concerns were raised about these international consensus recommendations:

  • Experts strongly advocated taking body weight into account in treatment in pediatrics. Discomfort emerged as to whether appropriate dosing is possible for patients between 12 and 18 years of age with fixed doses established in adults.
  • For attenuated androgens, sufficient data are lacking on the long-term safety over decades of use Should there be a reason for its use in isolated cases, the initial dose (see above) should only be administered for a short period (e.g., for short-term prophylaxis prior to elective procedures).
  • Tranexamic acid (less effective than attenuated androgens) is recommended for long-term prophylaxis in patients for whom pdC1-INH is not available or in whom attenuated androgens are deemed unacceptable.  Side effects are nausea, vomiting, diarrhoea, muscle cramps. Thrombosis is theoretical risk, not seen in practice, in US restricted as evidence in animals of tumours, regular eye examination and LFTs recommended in BNF..

Autoimmune HAE can be treated with C1-INH but some are resistant due to rapid catabolism so icatibant seems a good option. HAE with normal C1-INH function do not respond to antihistamines or steroids but do respond to C1-INH, tranexamic acid, danazol.

[ Eur J Pediatr (2012) 171:1339–1348]

[Bowen et al. Allergy, Asthma & Clinical Immunology 2010, 6:24]