Review
The burden of illness in patients with hereditary angioedema

https://doi.org/10.1016/j.anai.2013.08.019Get rights and content

Abstract

Objective

Hereditary angioedema (HAE) is a rare genetic disease characterized by long-term recurrent attacks of subcutaneous or submucosal edema in different parts of the body. A comprehensive review of the literature on burden of illness for patients with HAE is presented.

Data Sources

A Boolean search was performed using MEDLINE and EMBASE databases and the Internet.

Study Selection

Articles discussing aspects of the burden of illness in HAE were selected. Topics focused on the course of the disease, nature of attacks, treatment, quality of life, and costs.

Results

Hereditary angioedema is associated with a significant and multifaceted disease burden. Diagnosis is often delayed for years, with patients receiving ineffective treatment and unnecessary medical procedures before diagnosis. HAE attacks are painful, unpredictable, and debilitating and often require emergency medical attention. Attacks can affect a patient's daily activities, including work or schooling. Depression and anxiety are prevalent in patients with HAE. Recent advances in treatment provide patients with effective and well-tolerated prophylactic and on-demand therapeutic options. However, end points specific to HAE that better measure the impact of treatment on disease burden are lacking. Furthermore, there is a notable paucity of literature directed toward physicians who are instrumental in diagnosing and treating patients with HAE (eg, emergency department).

Conclusion

More publications are broadening the understanding of HAE. However, important gaps remain. Effective management of HAE requires a more comprehensive understanding of the disease burden so that disease management can be individualized to meet specific patient needs.

Introduction

Hereditary angioedema (HAE) is a rare autosomal dominant disease characterized by recurrent attacks of subcutaneous or submucosal edema that can affect the face, respiratory tract, extremities, gastrointestinal (GI) tract, genitalia, or other areas of the body. HAE involves all ethnic groups equally, but its global prevalence is not well defined, with estimates ranging from 1 in 10,000 to 1 in 100,000.[1], [2], [3], [4] There are thought to be approximately 6,000 patients living with HAE in the United States.5

Three types of HAE have been defined based on levels and activity of plasma complement-1 esterase inhibitor (C1INH). Type I HAE, the most prevalent form (85%), is characterized by the lack of plasma C1INH.6 In type II (15%), C1INH is secreted into the plasma but is nonfunctional. These 2 types are caused by mutations in the SERPING1 gene, which codes for C1INH. Although autosomally dominant, de novo mutations are thought to occur in approximately 25% of cases.7

The third and rarest type, HAE with normal C1INH (previously referred to as type III HAE), remains poorly understood.[8], [9], [10], [11] Although attacks are similar to those of types I and II, it is characterized by normal plasma levels of functional C1INH. Symptoms frequently emerge or are worsened by estrogen therapy, and mutations in factor XII are believed to play a role in 20% to 30% of patients.8 Although the incidence does not differ between men and women for types I and II, HAE with normal C1INH predominantly affects women.8

Symptoms of types I and II usually present during childhood, with approximately 50% of patients presenting by 10 years of age and nearly all by 20 years of age,[12], [13], [14] but diagnosis is often delayed by approximately 8 years on average.[2], [15], [16] Patients with HAE with normal C1INH present at a slightly older age compared with those with types I and II. Attacks in all types of HAE are often unpredictable, painful, and potentially life threatening and significantly affect a patient's quality of life (QOL).[17], [18], [19] Depression and anxiety are prevalent.19

In the past, treatments for HAE in the United States were lacking or associated with significant side effects. Since 2008, some effective and well-tolerated prophylactic and on-demand treatments have become available in the United States, including plasma-derived C1INH concentrates (Cinryze, ViroPharma Inc, Exton, Pennsylvania; Berinert, CSL Behring LLC, Kankakee, Illinois), a recombinant plasma kallikrein inhibitor, ecallantide (Kalbitor, Dyax Corp, Burlington, Massachusetts), and a small-molecule selective bradykinin B2 receptor antagonist, icatibant (Firazyr, Shire Orphan Technologies, Lexington, Massachusetts). However, these treatments can be expensive, and their availability may be limited at some medical facilities.[20], [21]

Because of the rarity of HAE, it has been difficult to systematically assess its humanistic and economic burden to better understand the challenges facing patients, caregivers, and health care systems, to identify knowledge gaps, and to improve disease management. Recently, some retrospective and prospective studies and patient and physician surveys have begun to establish a portrait of its multifaceted burden of illness (Fig 1). The present report presents a comprehensive review of the burden of illness of HAE with respect to its diagnosis, symptoms, treatment, QOL, and costs.

Section snippets

Literature Search Methods

A Boolean search was constructed to find articles on the burden of HAE listed on MEDLINE and EMBASE. Search terms included HAE (with thesaurus terms) cross-referenced with searches on topics of interest, including patient-reported outcomes, QOL, disability, productivity, depression, questionnaires, surveys, hospitalizations, and economics. Nonhuman and non–English-language publications were excluded, as were conference and meeting abstracts. Relevant publications were selected and supplemental

Diagnosis

Hereditary angioedema is under-recognized and frequently misdiagnosed, resulting in significant morbidity and mortality. Episodes of swelling involving the skin are frequently mistaken as allergic reactions and abdominal attacks as appendicitis or irritable bowel syndrome. Misdiagnosis can lead to unnecessary treatments and surgical procedures (eg, appendectomy) and premature death.[15], [28] Some patients are misdiagnosed with psychosomatic symptoms and referred for psychiatric evaluation.4 In

Treatment

Historically, acute treatment of HAE in the United States involved supportive care with narcotic analgesics, antiemetics, and fluid replacement.17 Corticosteroids, antihistamines, and epinephrine are ineffective for HAE, but are frequently administered nonetheless.25 Fresh frozen plasma has been used for acute attacks and short-term prophylaxis, with some success, but there is concern that angioedema could worsen because of the presence of contact-system proteins, which could increase

Changing the Landscape of HAE

Unfortunately, as a rare disease, it has been difficult to systematically characterize the burden of illness associated with HAE. Nonetheless, some studies are establishing a landscape. The burden of illness is multifaceted and complex, but the tools specific to HAE to more fully understand its impact on patients, caregivers, and health care systems have not been developed. More epidemiologic data are needed to better understand the scale of the burden and how it might vary across subgroups.

Conclusions

Hereditary angioedema is a disease with a great burden of illness that can significantly affect all aspects of a patient's life. As clinical and observational data of this rare disease continue to increase, there is a better understanding of its burden, the knowledge gaps, and potential steps to improve the lives of patients. Barriers to early diagnosis and intervention clearly need to be addressed in the short term. The introduction of novel treatments is a significant advancement, but without

Acknowledgments

Medical writing and editing services were provided by Michael Raffin from PHOCUS (North Wales, PA) and were supported by Shire (Eysins, Switzerland).

References (70)

  • T. Caballero et al.

    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)
  • N. Javaud et al.

    Bradykinin-mediated angioedema: factors prompting ED visits

    Am J Emerg Med

    (2013)
  • K. Bork et al.

    Asphyxiation by laryngeal edema in patients with hereditary angioedema

    Mayo Clin Proc

    (2000)
  • R.G. Gower et al.

    Hereditary angioedema caused by C1-esterase inhibitor deficiency: A literature-based analysis and clinical commentary on prophylaxis treatment strategies

    World Allergy Organ J

    (2011)
  • M. Prematta et al.

    Fresh frozen plasma for the treatment of hereditary angioedema

    Ann Allergy Asthma Immunol

    (2007)
  • R.J. Levy et al.

    EDEMA4: a phase 3, double-blind study of subcutaneous ecallantide treatment for acute attacks of hereditary angioedema

    Ann Allergy Asthma Immunol

    (2010)
  • K. Bork et al.

    Benefits and risks of danazol in hereditary angioedema: a long-term survey of 118 patients

    Ann Allergy Asthma Immunol

    (2008)
  • T.J. Craig et al.

    Efficacy of human C1 esterase inhibitor concentrate compared with placebo in acute hereditary angioedema attacks

    J Allergy Clin Immunol

    (2009)
  • M. Levi et al.

    Self-administration of C1-inhibitor concentrate in patients with hereditary or acquired angioedema caused by C1-inhibitor deficiency

    J Allergy Clin Immunol

    (2006)
  • Orphanet. Hereditary angioedema. Available at: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=91378....
  • A. Bygum

    Hereditary angio-oedema in Denmark: a nationwide survey

    Br J Dermatol

    (2009)
  • A. Agostoni 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)
  • U.C. Nzeako et al.

    Hereditary angioedema: a broad review for clinicians

    Arch Intern Med

    (2001)
  • M.D. Zilberberg et al.

    Descriptive epidemiology of hereditary angioedema hospitalizations in the United States, 2004–2007

    Allergy Asthma Proc

    (2011)
  • B.L. Zuraw et al.

    Hereditary angioedema with normal C1 inhibitor function: Consensus of an international expert panel

    Allergy Asthma Proc

    (2012)
  • K. Bork

    Diagnosis and treatment of hereditary angioedema with normal C1 inhibitor

    Allergy Asthma Clin Immunol

    (2010)
  • L. Bouillet

    Hereditary angioedema in women

    Allergy Asthma Clin Immunol

    (2010)
  • K. Bork et al.

    Clinical studies of sudden upper airway obstruction in patients with hereditary angioedema due to C1 esterase inhibitor deficiency

    Arch Intern Med

    (2003)
  • A.K. Bewtra et al.

    C1-inhibitor therapy for hereditary angioedema attacks: Prospective patient assessments of health-related quality of life

    Allergy Asthma Proc

    (2012)
  • B.L. Zuraw

    Clinical practice. Hereditary angioedema

    N Engl J Med

    (2008)
  • W.R. Lumry et al.

    The humanistic burden of hereditary angioedema: Impact on health-related quality of life, productivity, and depression

    Allergy Asthma Proc

    (2010)
  • Shands at the University of Florida. Formulary update. Available at:...
  • Three new drugs for hereditary angioedema

    Med Lett Drugs Ther

    (2010)
  • K. Bork et al.

    Symptoms, course, and complications of abdominal attacks in hereditary angioedema due to C1 inhibitor deficiency

    Am J Gastroenterol

    (2006)
  • S.W. Huang

    Results of an on-line survey of patients with hereditary angioedema

    Allergy Asthma Proc

    (2004)
  • Cited by (83)

    • Optimization of care for patients with hereditary angioedema living in rural areas

      2022, Annals of Allergy, Asthma and Immunology
      Citation Excerpt :

      There are several barriers to diagnosis in patients with HAE. For example, there may be limited recognition of HAE by hospitalists and ED physicians, and HAE may not be considered in a differential diagnosis.15 Misdiagnosis is frequent, with approximately 50% of patients (n = 185) diagnosed as having HAE type 1 or 2 reporting that they had previously been misdiagnosed, most frequently with allergic angioedema, appendicitis, or other gastrointestinal disorders.16

    • Preventive Treatment of Hereditary Angioedema: A Review of Phase III Clinical Trial Data for Subcutaneous C1 Inhibitor and Relevance for Patient Management

      2021, Clinical Therapeutics
      Citation Excerpt :

      The course of the disease can be more severe in women compared with men. HAE significantly impairs health-related quality of life (HRQoL), not just during an attack but also between attacks,23–27 and is associated with elevated rates of anxiety and depression.26–29 Attacks can lead to missed work, school, and daily activities, as well as decreased productivity, hindered career advancement, and lost income,26,28,30–33 which can affect caregivers in addition to the patient.

    View all citing articles on Scopus

    Disclosures: Dr. Banerji has served on the advisory board and received clinical research funding from Dyax, Shire, CSL, and Virpharma.

    Disclaimer: All opinions expressed in this manuscript are those of the author.

    View full text