Bradykinin-mediated angioedema

Angioedema without urticaria usually has the same pathogenesis as angioedema with urticaria (ie mast cell activation with histamine release); however, angioedema without urticaria can also be caused by a raised concentration of bradykinin rather than histamine. The two main forms of angioedema without urticaria are angiotensin converting enzyme inhibitor (ACEI)–induced angioedema, and hereditary angioedema. These are caused by a raised concentration of bradykinin rather than histamine.

ACEI-induced angioedema usually occurs during the first week of therapy (often within hours of the first dose). However, angioedema can present after a month or even several years of therapy. ACEIs are contraindicated in patients with a history of idiopathic angioedema—do not rechallenge patients because subsequent episodes are often more severe. Angiotensin II receptor blockers are sometimes prescribed as an alternative to ACEIs for patients with a history of ACEI-induced angioedema. Continue to monitor these patients closely because the angioedema can still recur even for an extended period of time after stopping the ACEI, and angioedema may also be triggered by angiotensin II receptor blockers. Sacubitril+valsartan treatment (for heart failure) is contraindicated in patients with a history of angioedema caused by ACEIs or angiotensin II receptor blockers because it can increase the risk of angioedema (compared to angiotensin II receptor blocker or ACEI therapy alone).

Hereditary angioedema is rare. It is caused by an inherited deficiency of a complement inhibitor (C₁ esterase inhibitor). Symptoms usually begin in childhood with painful lesions that often occur after trauma (eg after surgery or dentistry). Refer the patient to an immunologist for advice. Estrogen-containing contraceptives should be avoided in patients with hereditary angioedema because these can lead to exacerbation of the conditionAustralasian society of clinical immunology and allergy (ASCIA) HAE working party, 2022. Sacubitril+valsartan treatment (for heart failure) is contraindicated in patients with a history of hereditary angioedema because it can increase the risk of angioedema (compared to angiotensin II receptor blocker or ACEI therapy alone).

Bradykinin-mediated angioedema can be difficult to differentiate from mast cell–mediated angioedema. It is usually unintentionally initially treated as a mast cell–mediated angioedema (see Assessment and initial treatment of angioedema; however, there will typically be no response because bradykinin-mediated angioedema is not histamine driven. If there is no response to treatment for mast cell–mediated angioedema, refer for specialist assessment and confirmation of bradykinin-mediated angioedema diagnosis. Specialist treatments are available for bradykinin-mediated angioedema (eg tranexamic acid, icatibant, purified C₁ esterase inhibitor, lanadelumab).

Tranexamic acid (an antifibrinolytic agent) is generally well tolerated and is used for the prophylaxis of hereditary angioedema and idiopathic angioedemaHoriuchi, 2018van den Elzen, 2018. Evidence for its use in treatment of acute angioedema is lacking.

Icatibant, a bradykinin B₂ receptor antagonist, is used for the acute treatment of hereditary angioedema. There is also some evidence to support its use in the treatment of ACEI-induced angioedema.

Purified C₁ esterase inhibitor is used for both acute and prophylactic treatment of hereditary angioedema.

Lanadelumab is a human monoclonal plasma kallikrein inhibitor used for the prevention of recurrent attacks of hereditary angioedema.

In the absence of other options, fresh frozen plasma (FFP) may be considered, especially in urgent care settings.