Guideline sources The following summarized guidelines for the evaluation and management of hereditary angioedema (HAE) are prepared by our editorial team based on guidelines from the European Academy of Allergy and Clinical Immunology (EAACI/WAO 2022) and the European Academy of Allergy and Clinical Immunology (EAACI/AAAAI 2013). 1 2 Guidelines 1. Screening and diagnosis Pathogenesis: Recognize that: HAE is an autosomal dominant disease, and most patients with HAE have a positive family history of angioedema A HAE is caused by mutations in the serine protease inhibitor C1 resulting in a serine protease inhibitor C1 functional deficiency B most cases of HAE result from a deficiency of the serine protease inhibitor C1 inhibitor B primary mediator of swelling in patients with HAE is bradykinin. A Clinical presentation: Recognize that: https://web.pathway.md/diseases/reckKNwfgTDOxd7L6 1/4 6/24/23, 12:41 PM Hereditary angioedema Pathway disease severity is highly variable, as characterized by episodic rather than continuous swelling B a precipitating cause for most attacks is unknown stress and trauma are recognized as precipitants B HAE is characterized by relatively prolonged attacks B attacks of swelling generally involve the extremities, abdomen, genitourinary tract, face, oropharynx, or larynx and follow a stereotypical pattern in which the swelling worsens over 24 hours, peaks, and then slowly resolves over the following 48-72 hours A attacks can be preceded by a prodrome B onset of swelling in patients with HAE most often begins during childhood and frequently worsens around puberty B HAE attacks are associated with significant potential morbidity and potential mortality. A Diagnosis: Recognize that two forms of HAE are indistinguishable clinically and require laboratory testing for diagnostic confirmation: type I HAE presents with low serine protease inhibitor C1 antigenic and functional levels type II HAE presents with normal serine protease inhibitor C1 antigenic levels but decreased serine protease inhibitor C1 inhibitor functional levels. A Diagnose type I or type II HAE based on low serine protease inhibitor C1 antigenic or functional levels, decreased C4 levels and generally normal C1q levels. A Screening of family relatives: screen family members of patients for HAE. B 2. Diagnostic investigations Blood tests: Assess blood C1 inhibitor function, C1 inhibitor protein, and C4 levels in all patients with suspected HAE. B Consider repeating testing for C1 inhibitor function, C1 inhibitor protein, and C4 in patients tested positive, to confirm the diagnosis of HAE-1/2. C Genetic tests: assess for known mutations underlying HAE with normal C1 inhibitor levels in patients with suspected HAE having normal C1 inhibitor levels. B 3. Medical management General principles: ensure that all patients have an action plan. B Show 3 more Management of acute attacks: As per WAO 2022 guidelines, offer on-demand treatment in all patients presenting with an acute attack. B https://web.pathway.md/diseases/reckKNwfgTDOxd7L6 2/4 6/24/23, 12:41 PM Hereditary angioedema Pathway Show 4 more As per AAAAI 2013 guidelines, do not use epinephrine, corticosteroids and antihistamines for the treatment of patients with HAE. D Show 4 more Prophylactic treatment: As per WAO 2022 guidelines, ensure that all patients have sufficient medication for on-demand treatment of at least 2 attacks and carry on-demand medication at all times. B Show 8 more As per AAAAI 2013 guidelines, consider administering FFP, serine protease inhibitor C1 inhibitor replacement or short-term, high-dose anabolic androgen therapy as short-term prophylaxis in patients with HAE. C Show 5 more 4. Nonpharmacologic interventions Avoidance of triggers: As per WAO 2022 guidelines, educate all patients about triggers likely to induce attacks. B As per AAAAI 2013 guidelines, offer adjunctive strategies, such as avoidance of ACEIs and estrogen therapy as feasible, and stress reduction to decrease the frequency and severity of HAE attacks. B 5. Specific circumstances Pregnant patients: As per WAO 2022 guidelines, prefer plasma-derived C1 inhibitors during pregnancy and lactation. B As per AAAAI 2013 guidelines: Recognize that pregnancy may be associated with an increase in the frequency and severity of HAE episodes. B Prefer plasma-derived C1 inhibitor for long-term prophylaxis recognizing that androgens are contraindicated in pregnancy. B Pediatric patients: Test children from HAE-affected families and all offspring of an affected parent as soon as possible. B Administer C1 inhibitor or icatibant for the treatment of attacks in < 12 years old pediatric patients with HAE. A Patients with normal C1 inhibitor levels: Recognize that: https://web.pathway.md/diseases/reckKNwfgTDOxd7L6 3/4 6/24/23, 12:41 PM Hereditary angioedema Pathway familial recurrent angioedema characterized by normal C1 inhibitor function might represent HAE with normal C1 inhibitor levels, but there are no agreed upon criteria for diagnosing HAE with normal C1 inhibitor levels at this time some kindreds with HAE with normal C1 inhibitor levels appear to require high estrogen levels for the angioedema to manifest HAE with normal C1 inhibitor levels can be caused by increased bradykinin signaling. B Consider offering drugs developed for patients with HAE with reduced C1 inhibitor function in patients with HAE with normal C1 inhibitor levels. C Patients with acquired angioedema: Recognize that acquired C1 inhibitor deficiency: results from enhanced catabolism of C1 inhibitor B might be associated with C1 inhibitor autoantibodies with or without an underlying condition such as lymphoma B has clinical characteristics similar to those in HAE attacks. B Show 2 more Patients with ACEI-associated angioedema: recognize that ACEIs are associated with angioedema in approximately 0.1-0.7% of patients and ARBs have been associated with angioedema less commonly. A Show 3 more References 1. Bruce L Zuraw, Jonathan A Bernstein, David M Lang et al. A focused parameter update: hereditary angioedema, acquired C1 inhibitor deficiency, and angiotensin-converting enzyme inhibitor-associated angioedema. J Allergy Clin Immunol. 2013 Jun;131 6 1491 3. Open 2. Marcus Maurer, Markus Magerl, Stephen Betschel et al. The international WAO/EAACI guideline for the management of hereditary angioedema-The 2021 revision and update. Allergy. 2022 Jul;77 7 1961 1990. Open https://web.pathway.md/diseases/reckKNwfgTDOxd7L6 4/4