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?

Division of Pulmonary, Allergy, and Critical Care Medicine, Penn State Milton S. Hershey Medical Center, Hershey, Pennsylvania 17033, USA.
Annals of allergy, asthma & immunology: official publication of the American College of Allergy, Asthma, & Immunology (Impact Factor: 2.6). 03/2010; 104(3):211-4. DOI: 10.1016/j.anai.2009.12.004
Source: PubMed


Hereditary angioedema (HAE) is an autosomal dominant disorder characterized by a deficiency of C1 esterase inhibitor (C1 INH) protein or function. Guidelines do not exist regarding diagnostic criteria or routine testing of family members of patients with HAE. Laboratory data for diagnosis include complement factor 4 level; C1 INH antigenic protein level, which is reduced in approximately 85% of patients with HAE; and C1 INH functional assay, which is considered an unreliable test in the United States secondary to inconsistent standardization of assays.
To assess the shortcomings of diagnosing HAE and to determine whether family members of patients with HAE are being adequately screened.
The top physician prescribers of danazol in the United States were screened via an Internet questionnaire focusing on the diagnosis and current management of HAE. To assess the patient perspective on HAE, affected individuals in the United States, the United Kingdom, France, Germany, and The Netherlands participated in the Web-based International Survey of Patient Experience of Hereditary Angioedema.
All 80 physicians who completed the survey were allergist or immunologists with a mean of 7 patients with C1 INH deficiency in their practices. Almost 84% of physician respondents used C1 INH level and function for diagnosis, and 63.8% used complement factor 4 levels. A total of 313 patients with HAE completed the survey. Respondents noted that only 48% of immediate family members and 26% of extended family members had been tested.
Guidelines could potentially alleviate delays in diagnosis and incorrect diagnoses and could lead to adequate screening of family members.

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    • "Previous nationwide surveys in Spain and Denmark have reported mean delays in diagnosis of 13.1 and 16.3 years, respectively [5,6]. In an international web-based survey, 313 patients with HAE reported visiting an average of 4.4 physicians over an average of 8.3 years before receiving an accurate HAE diagnosis [7]. Without an accurate diagnosis, HAE patients may not receive treatment that can effectively treat their attacks. "
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    ABSTRACT: Hereditary angioedema (HAE) is a rare, debilitating, and potentially life-threatening disease characterized by recurrent edema attacks. Important advances in HAE treatment have been made, including the development of new therapies for treating or preventing attacks. Nevertheless, the disease is still frequently misdiagnosed and inappropriately treated, potentially exposing patients with laryngeal attacks to the risk of asphyxiation. The Icatibant Outcome Survey (IOS) is an international, observational study that documents the clinical outcome of HAE patients eligible for treatment with icatibant. Patient ages at first symptoms and at diagnosis were recorded at enrolment, and the delay between first symptoms and diagnosis was calculated. The median [range] diagnostic delay in HAE type I and II patients across eight countries was 8.5 years [0--62.0]. The median delay in diagnosis was longer for HAE type II versus type I (21 versus 8 years, respectively), although this did not quite reach statistical significance. Although it can be difficult to differentiate HAE symptoms from those of more common angioedema sub-types (e.g. idiopathic or acquired angioedema), our results show that HAE type I and II patients have an unacceptable delay in diagnosis, even those with a family history of the disease. Raising physician awareness of this disabling and potentially fatal disease may lead to a more accurate diagnosis and timely treatment.
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    • "Although the initial symptoms of HAE can occur at any age, symptoms usually first appear in childhood, worsen during puberty, and persist throughout life, with attack frequency and severity varying from patient to patient. HAE is not generally diagnosed at initial presentation, and the time of diagnosis has been shown to range from 8 to 22 years from the first attack[6,21,22]. Attacks often occur without a trigger; however, precipitating factors that have been shown to contribute to the frequency of attacks include stress, trauma, infection, menstruation, and pregnancy[3,4,9,21,23]. "
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    ABSTRACT: Hereditary angioedema (HAE) caused by C1-esterase inhibitor deficiency is an autosomal-dominant disease resulting from a mutation in the C1-inhibitor gene. HAE is characterized by recurrent attacks of intense, massive, localized subcutaneous edema involving the extremities, genitalia, face, or trunk, or submucosal edema of upper airway or bowels. These symptoms may be disabling, have a dramatic impact on quality of life, and can be life-threatening when affecting the upper airways. Because the manifestations and severity of HAE are highly variable and unpredictable, patients need individualized care to reduce the burden of HAE on daily life. Although effective therapy for the treatment of HAE attacks has been available in many countries for more than 30 years, until recently, there were no agents approved in the United States to treat HAE acutely. Therefore, prophylactic therapy is an integral part of HAE treatment in the United States and for selected patients worldwide. Routine long-term prophylaxis with either attenuated androgens or C1-esterase inhibitor has been shown to reduce the frequency and severity of HAE attacks. Therapy with attenuated androgens, a mainstay of treatment in the past, has been marked by concern about potential adverse effects. C1-esterase inhibitor works directly on the complement and contact plasma cascades to reduce bradykinin release, which is the primary pathologic mechanism in HAE. Different approaches to long-term prophylactic therapy can be used to successfully manage HAE when tailored to meet the needs of the individual patient.
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