Diana earned her PhD and PharmD with distinction in the field of Medicinal and Pharmaceutical Chemistry at the Universidade do Porto. She is an accomplished oncology scientist with 10+ years of experience in developing and managing R&D projects and research staff directed to the development of small proteins fit for medical use.
Hereditary angioedema (HAE) is a rare genetic condition in which patients experience recurrent attacks of skin and submucosal swelling, most commonly as a consequence of deficient or dysfunctional C1 inhibitor (C1-INH) protein.1,2
The World Allergy Organization (WAO) has joined efforts with the European Academy of Allergy and Clinical Immunology (EAACI) to envision an international guideline on the diagnosis and management of HAE.3 This guideline has now been revised, and the new revision provides updated information on the management of the disease following evaluation of the most recent available evidence by a global and diversified panel of experts (scientists, clinicians, patients, and patient advocates) who were involved in an online Delphi process. Twenty-eight recommendations on the diagnosis and management of HAE have now been published.2
The US Hereditary Angioedema Association (HAEA) Advisory Board has also established a set of recommendations concerning the management of HAE secondary to C1-INH deficiency.4 These recommendations have recently been updated and extended, with 11 members of the US HAEA Medical Advisory Board (US HAEA MAB) reviewing information on HAE treatment that has been made available in the literature.5 All recommendations provided in the current publication resulted from face-to-face discussions with and the unanimous approval of several US expert HAE physicians. These recommendations address the treatment of HAE attacks, prophylactic therapy, patient monitoring, and the development of management plans while also providing information for women and children with and without deficient C1-INH levels about the burden of the disease.5
The WAO/EAACI guidelines recommend that all patients with suspected type I or type II HAE undergo tests to measure blood levels of C4 and C1-INH as well as C1-INH function. Confirmation of diagnosis is recommended for patients testing positive in any of the previous assessments. Patients with normal C1-INH levels and activity should undergo further evaluation of genetic variations that may be responsible for the disease.2
On-demand treatment should be considered for all HAE attacks, and any episode affecting the upper airway must be treated. All attacks should be treated early with intravenous C1-INH, ecallantide, or icatibant. Procedures like endotracheal intubation, esophagogastroduodenoscopy, or bronchoscopy may precipitate angioedema near the site of intervention within 48 h. Rapid treatment with an effective HAE on-demand medication can lower the mortality associated with upper airway angioedema. Early intubation or tracheostomy are recommended in patients with progressive edema of the upper airway. It is recommended that patients with HAE always carry enough medication for on-demand treatment of at least 2 HAE episodes.2
Short-term prophylaxis with C1-INH as a first-line therapy is recommended before medical procedures such as dental surgery. For any situation to which the patient may be exposed that is considered a potential trigger of an episode, a prophylactic approach is also recommended.2 Long-term prophylaxis with C1-INH, berotralstat, or lanadelumab as a first-line therapy can be also considered for patients with HAE at every follow-up visit and after the evaluation of disease activity and control. Androgens are only recommended as a second-line therapy for long-term prophylaxis, while antifibrinolytics are not recommended in these situations. Monitoring patients undergoing long-term prophylaxis is also suggested.2
Screening for HAE is recommended for all family members of patients with HAE, and it should be carried as soon as possible in children.2 C1-INH or icatibant should be used to treat HAE episodes in children under 12 years of age. Plasma-derived C1-INH is also recommended for women who are pregnant or lactating.2
It is recommended that all patients consult specialists with expertise in HAE and follow an established action plan. Patients should be educated on potential triggers for HAE episodes, and they may self-administer on-demand therapy when properly taught.2
US HAEA Medical Advisory Board Recommendations
The US HAEA MAB recommends that serum levels of C4 and C1-INH and the functionality of C1-INH are determined for HAE diagnosis. To reach a diagnosis of HAE in the presence of normal C1-INH levels, additional genetic testing for mutations in genes encoding for factor XII, plasminogen, angiopoietin-1, and kininogen should be performed. Screening for HAE is recommended for all first-degree relatives of the patient. An early diagnosis in children is important for reducing morbidity and mortality.5
To address HAE attacks, patients must carry effective on-demand medication. All HAE attacks should be treated. C1-INH replacement therapy, ecallantide, or icatibant should be the first-line treatment in these episodes. When possible, on-demand therapy should be self-administered or administered by a caregiver.5
Short-term prophylaxis is recommended for patients who are at risk of experiencing an episode following exposure to a known trigger (including dental surgery). Long-term prophylaxis should be performed using C1-INH or lanadelumab as the first-line treatment; however, in cases of HAE with normal levels of C1-INH, initial treatment should include progestin-based medication or an antifibrinolytic. The use of C1-INH is recommended for pregnant or breastfeeding women, either as prophylactic or on-demand therapy. If first-line therapies are not available, HAE attacks can be treated with solvent detergent-treated plasma (SDP). Fresh frozen plasma (FFP) can also be used to treat HAE attacks, if SDP is not available.3,5
Patients with HAE must follow individualized management plans after consulting HAE specialists. These plans must detail the use of effective on-demand therapy, the potential use of prophylactic medication, and the prophylactic procedure before medical procedures or exposure to triggers.5
Regular follow-ups are important, and their frequency varies according to the status of the disease. Patients with well-controlled HAE may follow up every 6 to 12 months. Patients are to be encouraged to keep a registry of their symptoms, medications used, and adverse effects. This information should be shared and reviewed with the care team.5
1. Hereditary angioedema. Genetic and Rare Diseases Information Center (GARD). Updated November 8, 2021. Accessed June 23, 2022.
2. Maurer M, Magerl M, Betschel S, et al. The international WAO/EAACI guideline for the management of hereditary angioedema–the 2021 revision and update. Allergy. Published online January 10, 2022. doi:10.1111/all.15214
3. Maurer M, Magerl M, Ansotegui I, et al. The international WAO/EAACI guideline for the management of hereditary angioedema–the 2017 revision and update. Allergy. 2018;73(8):1575-1596. doi:10.1111/all.13384
4. Zuraw BL, Banerji A, Bernstein JA, et al; US Hereditary Angioedema Association Medical Advisory Board. US Hereditary Angioedema Association Medical Advisory Board 2013 recommendations for the management of hereditary angioedema due to C1 inhibitor deficiency. J Allergy Clin Immunol Pract. 2013;1(5):458-467. doi:10.1016/j.jaip.2013.07.002
5. Busse PJ, Christiansen SC, Riedl MA, et al. US HAEA Medical Advisory Board 2020 guidelines for the management of hereditary angioedema. J Allergy Clin Immunol Pract. 2021;9(1):132-150.e3. doi:10.1016/j.jaip.2020.08.046
Reviewed by Debjyoti Talukdar, MD, on 6/27/2022.