Hereditary angioedema (HAE) is a rare genetic disease that has gone through a revolution in the past decade with numerous medications now available to treat people with HAE. Unfortunately, identifying those people remains a challenge for those unfamiliar with the condition.
HAE is characterized by repeated edema attacks that can affect any cutaneous or mucosal surface. The most common areas of swelling are the face, larynx, tongue, extremities, stomach, bowels, and genitals. The attacks can last several days. They can also be extremely debilitating, and possibly fatal, if not managed quickly and properly. The personal and societal costs for HAE are not clear but surveys have shown that people with HAE lose an average of 9 to 20 days of work/school due to their illness each year [Jolles, 2014; Aygören-Pürsün, 2014] and that the disease has interfered dramatically with patients’ability to succeed at work or school. [Lumry, 2010; 2018].
As noted by Timothy Craig, DO of the University of Penn, Hershey, HAE is easy to diagnose but only if the rare disease is suspected. Many of the symptoms can be misinterpreted as being due to more common allergic reactions.
HAE is due to reduced levels of C1-inhibitor, a protein involved in a number of physiological processes in plasma, most notably in the complement system. C1-inhibitor also binds and inhibits plasma kallikrein and factor XIa, thereby affecting bradykinin production. It is believed that disruptions of these processes lead to fluid leaking from the blood to connective tissue in people with HAE. (Levy, 2019)
There are three subtypes of HAE depending on the level of C1-inhibitor present:
- HAE with deficient C1-inhibitor (type 1)
- HAE with dysfunctional C1-inhibitor (type 2)
- HAE with normal C1-inhibitor
The first two subtypes are due to mutations in the SERPING1 gene while the third subtype remains poorly understood but the angioedema that develops appears to be bradykinin related [Abdulkarim 2019].
Regardless of the HAE subtype that a person may have, the symptoms tend to be similar for all people who have this condition. And the symptoms can be extremely debilitating.
Fortunately, treatment options are available for this condition to help manage the number and severity of the acute HAE attacks.
Currently there are seven FDA approved treatments for HAE. Four medications are focused on the C1 inhibitor:
- Bertinert
- Cinryze
- Heagarda
- Ruconest
Three medications alter the bradykinin/kallikrein system
- Firazyr
- Kalbitor
- Takhzyro
Medical professionals most likely to be involved in the long-term care of people with HAE tend to practice in the allergy, immunology, pulmonology, and internal medicine settings. For those healthcare professionals, they may understand the pathophysiology of HAE and how to treat the attacks if they are familiar with this rare condition. Others who may encounter these patients, most notably emergency care physicians and general practitioners, are likely less familiar with HAE and may inappropriately treat the swelling with antihistamines, corticosteroids, or epinephrine, which are not effective for HAE attacks.
HAE in the Emergency Department
Every year in the United States, over 1 million visits to the Emergency Department (ED) are due to angioedema or allergic reactions [Kelly 2013]. However, a very small portion of those visits are due to HAE – which account for 2280 and 5000 visits [ Zilberberg 2010, 2011]. So while a HAE visitation is rare, it is not so rare that an ED clinician will not see a case in their career. Therefore, it is important that they be able to diagnose a HAE attack as quickly as possible. [Bernstein 2017]
There are two reasons for this. First, a HAE attack that necessitates an ED visit may mean that the swelling is affecting the person’s breathing. Death by asphyxiation, while rare, is very much a concern for persons with HAE. If not diagnosed properly, the risk of death is three- to nine-fold higher in persons with HAE who have not received a confirmed diagnosis. [Borg 2012]
Second, the treatment for HAE is different from that of more common angioedemas and allergic reactions. Giving a person with HAE an antihistamine or a corticosteroid will provide no relief of symptoms and simply prolong the discomfort. [Bernstein 2017]
Therefore, it is important that members of the ED care team be able to distinguish between histamine-, angiotensin-converting enzyme inhibitor (ACEi)-, and bradykinin-mediated angioedema.
Patient Education
According to the World Allergy Organization (WAO) and the European Academy of Allergy and Clinical Immunology (EAACI) guidelines, it is recommended that all patients with HAE should be educated about possible triggers which may induce HAE attacks (e.g., stress, fatigue, menstrual cycle) or take short term prophylactic medication, which is recommended if the person is going to undergo a dental or other procedure that often leads to an HAE attack. The guidelines also state that most attacks are unpredictable and health care professionals should NOT support the concept of having the person with HAE excessively avoid suspected triggers and prevent them from living a normal life. [Maurier, 2018]
To that end, individuals with HAE should have the following:
- An action plan
- Comprehensive integrated care
- Knowledge and training to self-administer on-demand treatment if necessary
- Knowledge of possible triggers that may induce HAE attacks
References
- Abdulkarim A, Craig TJ. Hereditary angioedema. StatPearls. 2019 Jun 3. Available at http://www.ncbi.nlm.nih.gov/books/NBK482266/
- Jolles S, Williams P, Carne E, Mian H, Huissoon A, Wong G, et al. A UK national audit of hereditary and acquired angioedema. Clin Exp Immunol (2014) 175(1):59–67.
- Aygören-Pürsün E, Bygum A, Beusterien K, Hautamaki E, Sisic Z, Wait S, et al. Socioeconomic burden of hereditaangioedema: results from the hereditary angioedema burden of illness study in Europe. Orphanet J Rare Dis (2014) 9:99–108. doi:10.1186/1750-1172-9-99
- Lumry WR, Castaldo AJ, Vernon MK, Blaustein MB, Wilson DA, Horn PT. The humanistic burden of hereditary angioedema: impact on health-related quality of life, productivity, and depression. Allergy Asthma Proc (2010) 31(5):407–14.
- Lumry WR. Hereditary Angioedema: the economics of treatment of an orphan disease. Front Med. 2018;5:22.
- Levi M, Cohn DM, Zeerleder S. Hereditary angioedema: linking complement regulation to the coagulation system. Res Pract Thromb Haemost. 2019;3:38-43.
- Kelly M, Donnelly JP, McAnnally JR, Wang HE. National estimates of emergency department visits for angioedema and allergic reactions in the United States. Allergy Asthma Proc. 2013;34:150–4.
- Zilberberg MD, Jacobsen T, Tillotson G. The burden of hospitalizations and emergency department visits with hereditary angioedema and angioedema in the United States, 2007. Allergy Asthma Proc. 2010;31:511–9.
- Zilberberg MD, Nathanson BH, Jacobsen T, Tillotson G. Descriptive epidemiology of hereditary angioedema emergency department visits in the United States, 2006–2007. Allergy Asthma Proc. 2011;32:390–394.
- Bork K, Hardt J, Witzke G. Fatal laryngeal attacks and mortality in hereditary angioedema due to C1-INH deficiency. J Allergy Clin Immunol. 2012;130:692–697.
- Bernstein JA, Cremonesi P, Hoffman T, Hollingworth J. Angioedemia in the emergency department: a practical guide to differential diagnosis and management. Int J Emerg Med. 2017;10:15.
- 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;73:1575-1596.
