Currently Viewing:
Supplements New Horizons in the Diagnosis and Treatment of Hereditary Angioedema: Overcoming Barriers to Management and Improving Patient Outcomes
Currently Reading
Severity of Hereditary Angioedema, Prevalence, and Diagnostic Considerations
Jonathan A. Bernstein, MD
Economic Burden Limiting Proper Healthcare Delivery, Management, and Improvement of Patient Outcomes
William J. Cardarelli, PharmD
Participating Faculty

Severity of Hereditary Angioedema, Prevalence, and Diagnostic Considerations

Jonathan A. Bernstein, MD
Another physician survey conducted by Lunn and colleagues found that patients with HAE in the United States visited an average of 4.4 physicians before receiving a diagnosis of HAE; 65% of patients initially received a misdiagnosis; and the average time to diagnosis was 8.3 years. Also, just 63.8% of physicians used C4 levels to aid in their diagnosis.34 Similarly, a patient-based survey in the United States found that although one-third of patients received a diagnosis of HAE within 1 year of their initial attack, another one-third experienced a delay to diagnosis of more than 10 years.21 Patients with abdominal symptoms associated with HAE are especially likely to be susceptible to the consequences of misdiagnosis and to undergo unnecessary surgical procedures, such as an appendectomy or exploratory diagnostic procedure.35,36

Zanichelli and colleagues found that 44.3% of patients with HAE reported receiving 1 or more prior misdiagnoses, with the most common misdiagnoses being allergic angioedema and appendicitis. It is important to note that patients who had a history of prior misdiagnosis experienced a median delay of 13.3 years to achieve a correct diagnosis versus 1.7 years to diagnosis for patients who did not experience a previous misdiagnosis.37 

Therefore, in patients with HAE, achieving the correct diagnosis early in the course of symptoms is critical to optimize patient outcomes. Most cases of HAE are still undiagnosed for several years after the initial attack, leading to significant morbidity, frequent emergency department visits, and potential mortality. Improved healthcare provider awareness and understanding of the condition and its differential diagnosis will assist in improving outcomes in patients with HAE.


Hereditary angioedema is a lifelong disorder that is often misdiagnosed or unrecognized when patients initially present with symptoms of angioedema. It is critical to understand the framework for the diagnosis of HAE, including a deficiency in functional C1-INH, and to recognize the variability in frequency and severity of attacks that may occur among patients. Early and accurate diagnosis will assist in developing an individual plan to effectively manage, treat, and prevent future attacks. 

Author affiliation: Professor of Clinical Medicine, University of Cincinnati College of Medicine, Department of Internal Medicine; Division of Immunology, Allergy Section, Cincinnati, OH.
Funding source: This activity is supported by educational grants from CSL Behring and Shire.
Author disclosure: Dr Bernstein has the following relevant financial relationships with commercial interests to disclose: GRANT/RESEARCH SUPPORT: BioCryst, CSL Behring, Genentech, Novartis, Pharming, Shire. CONSULTANT: AstraZeneca, BioCryst, CSL Behring, Merck, Sanofi, Shire. SPEAKERS BUREAU: AstraZeneca, CSL Behring, Pharming, Shire.
Authorship information: Concept and design; critical revision of the manuscript for important intellectual content; drafting of the manuscript; supervision.
Address correspondence to:
Dr Bernstein gratefully acknowledges Mona Shah, PharmD, for her contributions to the development of this article.
  1. Zuraw BL. Clinical practice. Hereditary angioedema. N Engl J Med. 2008;359(10):1027-1036. doi: 10.1056/NEJMcp0803977.
  2. Nzeako UC, Frigas E, Tremaine WJ. Hereditary angioedema: a broad review for clinicians. Arch Intern Med. 2001;161(20):2417-2429.
  3. Epstein TG, Bernstein JA. Current and emerging management options for hereditary angioedema in the US. Drugs. 2008;68(18):2561-257 doi: 10.2165/0003495-200868180-00003.
  4. Bernstein JA. Update on angioedema: evaluation, diagnosis, and treatment. Allergy Asthma Proc. 2011;32(6):408-412. doi: 10.2500/aap.2011.32.3469.
  5. Bernstein JA, Riedl M, Zacek L, Shapiro RS. Facilitating home-based treatment of hereditary angioedema. Allergy Asthma Proc. 2015;36(2):92-99. doi: 10.2500/aap.20136.3820.
  6. Bork K, Meng G, Staubach P, Hardt J. Hereditary angioedema: new findings concerning symptoms, affected organs, and course. Am J Med. 2006;119(3):267-274. doi: 10.1016/j.amjmed.2005.09.064.
  7. Tse K, Zuraw BL. Recognizing and managing hereditary angioedema. Cleve Clin J Med. 2013;80(5):297-308. doi: 10.3949/ccjm.80a.12073.
  8. Bernstein JA, Moellman J. Emerging concepts in the diagnosis and treatment of patients with undifferentiated angioedema. Int J Emerg Med. 2012;5(1):39. doi: 10.1186/1865-1380-5-39.
  9. Bork K. Diagnosis and treatment of hereditary angioedema with normal C1 inhibitor. Allergy Asthma Clin Immunol. 2010;6(1):15. doi: 10.1186/1710-1492-6-15.
  10. Agostoni A, Cicardi M. Hereditary and acquired C1-inhibitor deficiency: biological and clinical characteristics in 235 patients. Medicine (Baltimore). 1992;71(4):206-215.
  11. Lumry WR. Overview of epidemiology, pathophysiology, and disease progression in hereditary angioedema. Am J Manag Care. 2013;19(suppl 7):S103-S110.
  12. Longhurst H, Cicardi M. Hereditary angio-oedema. Lancet. 2012;379(9814):474-481. doi: 10.1016/S0140-6736(11)60935-5.
  13. Farkas H, Varga L, Széplaki G, Visy B, Harmat G, Bowen T. Management of hereditary angioedema in pediatric patients. Pediatrics. 2007;120(3):e713-e722. doi: 10.1542/peds.2006-3303.
  14. Ebo DG, Bridts CH. Images in clinical medicine. Disfiguring angioedema. N Engl J Med. 2012;367(16):1539. doi: 10.1056/NEJMicm1200960.
  15. Farkas H. Pediatric hereditary angioedema due to C1-inhibitor deficiency. Allergy Asthma Clin Immunol. 2010;6(1):18. doi: 10.1186/1710-1492-6-18.
  16. Bork K, Staubach P, Eckardt AJ, Hardt J. Symptoms, course, and complications of abdominal attacks in hereditary angioedema due to C1 inhibitor deficiency. Am J Gastroenterol. 2006;101(3):619-627. doi: 10.1111/j.1572-0241.2006.00492.x.
  17. Agostoni A, Aygören-Pürsün E, Binkley KE, et al. Hereditary and acquired angioedema: problems and progress: proceedings of the third C1 esterase inhibitor deficiency workshop and beyond. J Allergy Clin Immunol. 2004;114(suppl 3):S51-S131. doi: 10.1016/j.jaci.2004.06.047.
  18. Bork K, Hardt J, Schicketanz KH, Ressel N. Clinical studies of sudden upper airway obstruction in patients with hereditary angioedema due to C1 esterase inhibitor deficiency. Arch Intern Med. 2003;163(10):1229-1235.
  19. Caballero T, Maurer M, Longhurst HJ, Aberer W, Bouillet L, Fabien V; IOS Study Group. Triggers and prodromal symptoms of angioedema attacks in patients with hereditary angioedema. J Investig Allergol Clin Immunol. 2016;26(6):383-386. doi: 10.18176/jiaci.0102.
  20. Wilson DA, Bork K, Shea EP, Rentz AM, Blaustein MB, Pullman WE. Economic costs associated with acute attacks and long-term management of hereditary angioedema. Ann Allergy Asthma Immunol. 2010;104(4):314-3 doi: 10.1016/j.anai.2010.01.024.
  21. Banerji A, Busse P, Christiansen SC, et al. Current state of hereditary angioedema management: a patient survey. Allergy Asthma Proc. 2015;36(3):213-217. doi: 10.2500/aap.2015.36.3824.
  22. Fouche AS, Saunders EF, Craig T. Depression and anxiety in patients with hereditary angioedema. Ann Allergy Asthma Immunol. 2014;112(4):371-375. doi: 10.1016/j.anai.2013.05.028.
  23. Bernstein JA, Cremonesi P, Hoffmann TK, Hollingsworth J. Angioedema in the emergency department: a practical guide to differential diagnosis and management. Int J Emerg Med. 2017;10(1):15. doi: 10.1186/s12245-017-0141-z.
  24. Cicardi M, Suffritti C, Perego F, Caccia S. Novelties in the diagnosis and treatment of angioedema. J Investig Allergol Clin Immunol. 2016;26(4):212-221. doi: 10.18176/jiaci.0087.
  25. Bowen T, Cicardi M, Farkas H, et al. 2010 International consensus algorithm for the diagnosis, therapy and management of hereditary angioedema. Allergy Asthma Clin Immunol. 2010;6(1):24. doi: 10.1186/1710-1492-6-24.
  26. Tarzi MD, Hickey A, Förster T, Mohammadi M, Longhurst HJ. An evaluation of tests used for the diagnosis and monitoring of C1 inhibitor deficiency: normal serum C4 does not exclude hereditary angio-oedema. Clin Exp Immunol. 2007;149(3):513-516.
  27. Moellman JJ, Bernstein JA, Lindsell C, et al; American College of Allergy, Asthma & Immunology; Society for Academic Emergency Medicine. A consensus parameter for the evaluation and management of angioedema in the emergency department. Acad Emerg Med. 2014;21(4):469-484. doi: 10.1111/acem.12341.
  28. Zuraw BL, Bernstein JA, Lang DM, et al; American Academy of Allergy, Asthma & Immunology; American College of Allergy, Asthma & Immunology. A focused parameter update: hereditary angioedema, acquired C1 inhibitor deficiency, and angiotensin-converting enzyme inhibitor-associated angioedema. J Allergy Clin Immunol. 2013;131(6):1491-1493. doi: 10.1016/j.jaci.2013.03.034.
  29. Pedrosa M, Phillips-Angles E, López-Lera A, López-Trascasa M, Caballero T. Complement study versus CINH gene testing for the diagnosis of type I hereditary angioedema in children. J Clin Immunol. 2016;36(1):16-18. doi: 10.1007/s10875-015-0222-9.
  30. Caballero T, Farkas H, Bouillet L, et al; C-1-INH Deficiency Working Group. International consensus and practical guidelines on the gynecologic and obstetric management of female patients with
    hereditary angioedema caused by C1 inhibitor deficiency. J Allergy Clin Immunol. 2012;129(2):308-320. doi: 10.1016/j.jaci.2011.11.025.
  31. Sánchez-Borges M, González-Aveledo LA. Angiotensin-converting enzyme inhibitors and angioedema. Allergy Asthma Immunol Res. 2010;2(3):195-198. doi: 10.4168/aair.2010.2.3.195.
  32. Riedl M, Gower RG, Chrvala CA. Current medical management of hereditary angioedema:
    results from a large survey of US physicians. Ann Allergy Asthma Immunol. 2011;106(4):316-322.e4. doi: 10.1016/j.anai.2010.12.012.
  33. 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(3):692-697. doi: 10.1016/j.jaci.2012.05.055.
  34. Lunn ML, Santos CB, Craig TJ. Is there a need for clinical guidelines in the United States for the diagnosis of hereditary angioedema and the screening of family members of affected patients? Ann Allergy Asthma Immunol. 2010;104(3):211-214. doi: 10.1016/j.anai.2009.12.004.
  35. Banerji A, Baş M, Bernstein JA, et al. Expert perspectives on hereditary angioedema: key areas for advancements in care across the patient journey. Allergy Rhinol (Providence). 2016;7(3):172-181. doi: 10.2500/ar.2016.7.0165.
  36. Bowie KJ, Scarupa MD, Li HH. Unnecessary abdominal surgeries secondary to undiagnosed hereditary angioedema. J Allergy Clin Immunol. 2007;119(1):S276. Abstract 1082. doi: 10.1016/j.jaci.2006.12.452.
  37. Zanichelli A, Longhurst HJ, Maurer M, et al; IOS Study Group. Misdiagnosis trends in patients with hereditary angioedema from the real-world clinical setting. Ann Allergy Asthma Immunol. 2016;117(4):394-398. doi: 10.1016/j.anai.2016.08.014.
Copyright AJMC 2006-2019 Clinical Care Targeted Communications Group, LLC. All Rights Reserved.
Welcome the the new and improved, the premier managed market network. Tell us about yourself so that we can serve you better.
Sign Up