Angioedema

Related clinical tool - Anaphylaxis

Angioedema is a self limited localised subcutaneous (or submucosal) swelling which results from extravasation of fluid into interstitial tissue.

Angioedema may be benign or life-threatening, depending on the body site involved.

Causes

  • Allergic or hypersensitivity reaction is the most common cause of angioedema, triggers include:
    • Medications - e.g. NSAIDs, penicillins and other antibiotics
    • Food – peanuts, shellfish, strawberries
    • Envenomation - wasps, bees or other insects
    • Latex

    This is IgE-mediated and histamine induced - it will usually respond to adrenaline, anti-histamines and corticosteroids. In this case, angioedema may present as a component of anaphylaxis.

  • Non-allergic angioedema is less common. It is usually bradykinin mediated and does not have associated allergic features, such as urticaria or bronchospasm. Causes include:
    • Hereditary angioedema – due to hereditary C1 esterase inhibitor deficiency or dysfunction.
    • Acquired angioedema - due to acquired C1 esterase inhibitor deficiency.
    • ACE-inhibitor induced angioedema.

    In non-allergic angioedema, bradykinin is produced in large amounts, which leads to increased vascular permeability and vasodilation that induces angioedema. This will not respond to the above treatments used for allergic reactions.

  • In hereditary angioedema, there is often no identifiable cause for an episode – triggers can include infection and minor trauma, such as dental work.
  • Acquired angioedema may be found in patients with lymphoproliferative disorders.
  • ACE-inhibitors block the action of ACE enzyme so that it can no longer degrade bradykinin – this results in an accumulation which can then trigger angioedema. Patients may have been taking ACE inhibitors for days, months or even years before this occurs.
  • NSAID-induced angioedema may be due to multiple mechanisms including hypersensitivity and COX-1 inhibition and the clinical presentation can have elements of both allergic and non-allergic presentations.

Clinical Features

Abrupt onset of swelling that is non-pitting and non-pruritic.

Sites that may be involved include the face, lips, mouth, throat, larynx, uvula, extremities and genitalia. Bowel wall angioedema may present as colicky abdominal pain.

Angioedema can be distinguished clinically from other causes of oedema by:

  • Onset in minutes to hours, with spontaneous resolution in hours to days.
  • Asymmetric distribution.
  • Tendency to not involve gravity dependent areas.
  • Involvement of face, lips, larynx and bowels.
  • Presence of other symptoms and signs of allergic reactions or anaphylaxis.

There may be features of significant airway involvement such as dyspnoea, dysphagia, stridor, vocal changes, hoarseness or drooling – this requires urgent management.

Features of GIT involvement (abdominal pain, nausea, vomiting, changes in bowel habit) may mimic an acute surgical abdomen.

Investigations

Appropriate investigations will depend upon the body site involved and suspected underlying cause - such as complement levels. Tryptase may be relevant if considering anaphylaxis as a differential.

Imaging may be indicated in some circumstances, e.g. CT abdomen in abdominal pain.

Management

Depends upon the site, severity and suspected mechanism – i.e. allergic or non allergic.

  • In all cases, the airway must be assessed for potential airway compromise.

The first goal is to secure the patient’s airway. This can be difficult – seek help early!

  • Angioedema with anaphylaxis - should be treated as per anaphylaxis guidelines.
  • Acute allergic angioedema without anaphylaxis - should be treated with antihistamines and corticosteroids – if the airway is involved, nebulised (5mLs 1:1000) or IM adrenaline (500mcgs adult) should be considered.
  • Non-allergic angioedema – will depend upon the site and severity of the reaction.
    • Episodes of peripheral or truncal angioedema that only cause mild to moderate discomfort may not require any specific treatment.
    • Abdominal attacks may require treatment depending upon the severity.
    • Attacks involving the face or genitalia usually require treatment.
    • Laryngeal/airway oedema will always require treatment.
  • Hereditary angioedema (C1 esterase inhibitor deficiency) - several treatment options exist.
    • Icatibant (Firazyr) - (30mg subcut injection)
      • Icatibant is a bradykinin 2 receptor antagonist and is indicated for emergency treatment of acute angioedema in patients >18 years with known HAE.
      • HAE patients may be prescribed pre-filled syringes that they can self-administer prior to presenting to ED.
    • Purified C1-INH concentrate (Berinert or Cinryze)
      • Berinert (20U/kg IV infusion) is indicated for acute attacks as well as pre-procedure prophylaxis and can be used in all age groups.
      • Cinryze is also registered (but not funded) for use in Australia.
    • FFP can be tried in this group if Icatibant or Berinert are not available. FFP has been used historically – however it may worsen the severity of the attack due to the inclusion of other biologically active molecules.
    • Icatibant and Berinert usually take at least 30 minutes to work – if there has been insufficient response after 60 minutes, a repeat dose may be given.
  • ACE inhibitor-induced angioedema - discontinue the drug and monitor for resolution
    • If treatment is required - icatibant, C1-INH concentrates and FFP have all been used for ACE inhibitor-induced angioedema with variable results.
    • FFP contains the ACE enzyme, which breaks down bradykinin – however, it may theoretically worsen the angioedema as above. There are case series of rapid improvement following 2-4 units of FFP.
    • Studies using icatibant have shown potential benefit, however it may not be widely available.
  • NSAID-induced angioedema is generally treated as allergic angioedema, where the airway is threatened and the diagnosis not clear then consider Icatibant. Consultation with Immunologists in complex cases is advised.

Recent article

This recent Medscape article Fresh Frozen Plasma for Progressive and Refractory Angiotensin-converting Enzyme Inhibitor-induced Angioedema1 has value in that it presents some background and cases. There is no great evidence here as over the last two decades there has been minimal work and scattered cases saying the same thing.

Conclusion

The risk benefit profile of using FFP for airway threatening angioedema needs to be assessed by the treating physician but evidence would appear to fall on the side of using it in most airway threatening cases.

This is an uncommon condition and confusion with anaphylaxis and allergy is a risk, therefore more work is required.

Non–allergy mediated angioedema should be distinguished on clinical grounds early in the presentation.

Further References and Resources

1 Hassen GW, Kalantari H, Parraga M et al. Fresh Frozen Plasma for Progressive and Refractory Angiotensin-converting Enzyme Inhibitor-induced Angioedema . J Emerg Med. 2013; 44(4):764-772

EP Monthly New Treatments for Angioedema, printed 12 September 2016

ASCIA – Angioedema Information for parents, consumers and carers

ASCIA – Position Paper on Hereditary Angioedema 2017

ASCIA – Hereditary Angioedema (HAE) Action Plan 2013

Up to Date – An overview of angioedema: Pathogenesis and causes - Bruce Zuraw, Clifton O’Bingham (2016)

UptoDate – An overview of angioedema: Clinical features, diagnosis and management – Bruce Zuraw, Clifton O’Bingham (2016)

EMCrit / PulmCrit - Treatment of ACEi-induced angioedema – Josh Farkas

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