Hereditary angioedema with C1 inhibitor deficiency: delay in diagnosis in Europe
© Zanichelli et al.; licensee BioMed Central Ltd. 2013
Received: 3 April 2013
Accepted: 30 June 2013
Published: 12 August 2013
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.
KeywordsBradykinin C1-inhibitor Diagnosis Hereditary angioedema Icatibant
Hereditary angioedema (HAE), due to C1-inhibitor (C1-INH) deficiency, is a rare disease with an estimated frequency of 1:50 000. HAE is caused by mutations in the C1-INH gene that results in reduced levels (type I) or function (type II) of C1-INH protein. The deficiency of C1-INH leads to increased activation of the contact system, which generates elevated levels of bradykinin (the mediator of the increased vascular permeability) and the resulting edema observed in HAE patients. The clinical features of HAE include recurrent episodes of edema, which usually last for 2–5 days. The skin, gastrointestinal tract, and upper airway are most commonly affected. Delayed treatment of laryngeal swelling can result in death[1, 4].
The rarity of HAE, the fact that its symptoms overlap with those of other forms of angioedema and, in cases of abdominal attack, can appear to be a surgical emergency, mean that it is frequently misdiagnosed. Consequently, HAE patients may experience considerable delays in diagnosis[5, 6]. 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. Without an accurate diagnosis, HAE patients may not receive treatment that can effectively treat their attacks. Inappropriate treatment could result in higher morbidity and mortality, adverse events, and unnecessary surgical interventions[8, 9].
Recently published studies and guidelines[10–18] have resulted in an increased awareness of HAE in the scientific community; however, HAE remains under-diagnosed. The Icatibant Outcome Survey (IOS) is an international, observational study that documents the clinical outcome of HAE patients eligible for treatment with icatibant. Here, we report the delay in diagnosis in adult patients with type I or II HAE.
Material and methods
IOS registry data from 171 HAE type I and II patients (female/male: 105/66; HAE type I/II: 158/13) from centers in Germany (N = 46), Spain (N = 45), Italy (N = 30), France (N = 18), the UK (N = 17), Denmark (N = 13), Israel (N = 1) and Sweden (N = 1) were analyzed.
HAE type I was diagnosed in symptomatic patients when both C1-INH concentration and function were below normal; HAE type II was diagnosed in symptomatic patients when C1-INH concentration was normal or above normal, and function was below normal. The normal ranges (according to local reference values) for C1-INH concentration and function were 15–50 mg/dL and 70–130%, respectively. Patients diagnosed prior to the onset of symptoms, i.e. on the basis of family history, were excluded from this analysis.
Study design and setting
IOS is an international, multicenter, observational patient registry for patients treated with icatibant (Firazyr®). This analysis is based on data collected between July 2009 and June 2012. IOS is conducted in accordance with the Declaration of Helsinki, and the International Conference on Harmonization Good Clinical Practice Guidelines. After approval from local Ethics Committees and/or Health Authorities (where applicable) had been obtained by the center, all patients provided written informed consent.
Demographic and diagnostic information were collected from the patient at enrollment. Patient ages at first symptoms and at diagnosis were recorded, and the delay between first symptoms and diagnosis was calculated.
In order to compare the age at diagnosis, the age at first symptoms, and the delay between first symptoms and diagnosis, the Wilcoxon–Mann–Whitney test was used. The one-way analysis of variance with multiple comparisons (‘least significant difference method’ from Fisher) was used for the comparison between countries (Sweden and Israel were excluded from this analysis due to low patient numbers). The level of statistical significance chosen was alpha = 0.05.
Age at first symptoms and diagnosis, and delay in diagnosis by patient type
Age at first symptoms (years)
HAE type I
HAE type II
Age at diagnosis (years)
HAE type I
HAE type II
Delay between first symptoms and diagnosis (years)
HAE type I
HAE type II
Delay in diagnosis by country
Nine (5.3%) of the 171 patients included in the IOS database were diagnosed with HAE type I or II based on their family history and prior to the onset of symptoms. These patients therefore have negative delay in diagnosis values and were excluded from the analyses above.
Our study demonstrates that, in a sizable population of HAE patients from eight countries, the median delay in diagnosis is 8.5 years [range 0.0–62.0]. Possible explanations for the difference in delay in diagnosis between countries (although not statistically significant; p = 0.1583) include awareness of HAE among physicians, patient selection bias during IOS enrolment, or demographic differences between national patient populations.
We found a considerable difference in delay in diagnosis between patients with HAE type I and II, although not significant (8.0 [0.0–62.0] versus 21.0 years [0.0–42.0]; p = 0.051). This difference might be due to the fact that patients are only tested for C1-INH levels, which are normal or elevated in HAE type II patients. To avoid further delay in diagnosis of type II patients, functional C1-INH analysis also needs to be performed.
Interestingly, patients with a positive HAE family history were not diagnosed earlier than those with a negative family history and, currently, only nine (5.3%) of the 171 patients enrolled in IOS were diagnosed prior to the onset of symptoms, i.e. on the basis of family history. This indicates that patients may not be adequately informed about the hereditary nature of their disease or, alternatively, may choose not to seek diagnosis. Undiagnosed patients are at a greatly increased risk of premature death from asphyxiation and of the social and economic consequences of untreated HAE[9, 18]. Active screening of family members for C1-INH deficiency, access to effective, well-tolerated treatment options, and education of patients and their families with regards to the benefit of diagnosis and treatment are necessary to improve this unsatisfactory situation.
Patients with HAE continue to have an unacceptable delay (median 8.5 years [0.0–62.0]) between the time they experience their first attack and are adequately diagnosed. This delay could be reduced by increasing awareness of HAE in the scientific community, as well as among patients. Since it might be difficult to differentiate HAE symptoms from those of more common angioedemas; when HAE is suspected, laboratory analysis for C1-INH levels and function can confirm the deficiency and guide physicians in making a correct diagnosis and initiating appropriate treatment.
Icatibant outcome survey.
Shire HGT Inc. sponsored and provided funding for the IOS study.
Medical writing support was provided by Claire Crouchley, PhD and Kerren Davenport, Prime Medica Ltd, Knutsford, Cheshire, UK, and funded by Shire HGT Inc. Responsibility for opinions, conclusions, and interpretation of data lies with the authors.
The authors would like to acknowledge the following colleagues for their efforts: The colleagues of Hilary Longhurst: Ms L Lorenzo and Mr J Dempster, and Dr M Buckland and Dr S Grigoriadou.
The colleagues of Andrea Zanichelli: Professor M Triggiani, Dr V Montinaro and Dr M Bova.
The authors would also like to thank the IOS investigators for their contributions:
Denmark: Bygum A; France: Blanchard Delauny C, Coppere B, Fain O, Gompel A, Guez S, Jeandel P, Launay D, Maillard H, Martin L, Masseau A, Ollivier Y; Germany: Baş M, Bauer M, Bork K, Greve J; Greece: Psarros F; Israel: Graif Y, Kivity S, Toubi E; Italy: Cillari E, Montinaro V, Triggiani M; Spain: Gala G, Guilarte L, Hernandez D, Hernando de Larramnedi C, Lleonart R, Lobera T, Baeza ML, Marques L; Sweden: Bjoerkander J; UK: Helbert M.
- Zuraw BL: Hereditary angioedema. N Engl J Med. 2008, 359: 1027-1036. 10.1056/NEJMcp0803977.View ArticlePubMedGoogle Scholar
- Agostoni A, Aygören-Pürsün E, Binkley KE, Blanch A, Bork K, Bouillet L, Bucher C, Castaldo AJ, Cicardi M, Davis AE, De Carolis C, Drouet C, Duponchel C, Farkas H, Fáy K, Fekete B, Fischer B, Fontana L, Füst G, Giacomelli R, Gröner A, Hack CE, Harmat G, Jakenfelds J, Juers M, Kalmár L, Kaposi PN, Karádi I, Kitzinger A, Kollár T: Hereditary and acquired angio-oedema: problems and progress: proceedings of the third C1 esterase inhibitor deficiency workshop and beyond. J Allergy Clin Immunol. 2004, 114 (Suppl 3): S51-131.View ArticlePubMedGoogle Scholar
- Cugno M, Zanichelli A, Foieni F, Caccia S, Cicardi M: C1-inhibitor deficiency and angioedema: molecular mechanisms and clinical progress. Trends Mol Med. 2009, 15: 69-78. 10.1016/j.molmed.2008.12.001.View ArticlePubMedGoogle Scholar
- Zilberberg M, 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: 511-519. 10.2500/aap.2010.31.3403.View ArticlePubMedGoogle Scholar
- Roche O, Blanch A, Caballero T, Sastre N, Callejo D, López-Trascasa M: Hereditary angio-oedema due to C1 inhibitor deficiency: patient registry and approach to the prevalence in Spain. Ann Allergy Asthma Immunol. 2005, 94: 498-503. 10.1016/S1081-1206(10)61121-0.View ArticlePubMedGoogle Scholar
- Bygum A: Hereditary angio-oedema in Denmark: a nationwide survey. Br J Dermatol. 2009, 161: 1153-1158. 10.1111/j.1365-2133.2009.09366.x.View ArticlePubMedGoogle Scholar
- 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: 211-214. 10.1016/j.anai.2009.12.004.View ArticlePubMedGoogle Scholar
- Zanichelli A, Vacchini R, Badini M, Penna V, Cicardi M: Standard care impact on angio-oedema because of hereditary C1 inhibitor deficiency: a 21-month prospective 2 study in a cohort of 103 patients. Allergy. 2010, 66: 192-196.View ArticlePubMedGoogle Scholar
- 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. 10.1016/j.jaci.2012.05.055.View ArticlePubMedGoogle Scholar
- Zuraw BL, Busse PJ, White M, Jacobs J, Lumry W, Baker J, Craig T, Grant JA, Hurewitz D, Bielory L, Cartwright WE, Koleilat M, Ryan W, Schaefer O, Manning M, Patel P, Bernstein JA, Friedman RA, Wilkinson R, Tanner D, Kohler G, Gunther G, Levy R, McClellan J, Redhead J, Guss D, Heyman E, Blumenstein BA, Kalfus I, Frank MM: Nanofiltered C1 inhibitor concentrate for treatment of hereditary angioedema. N Engl J Med. 2010, 363: 513-522. 10.1056/NEJMoa0805538.View ArticlePubMedGoogle Scholar
- Zuraw B, Cicardi M, Levy RJ, Nuijens JH, Relan A, Visscher S, Haase G, Kaufman L, Hack CE: Recombinant human C1-inhibitor for the treatment of acute angioedema attacks in patients with hereditary angioedema. J Allergy Clin Immunol. 2010, 126: 821-827. 10.1016/j.jaci.2010.07.021.View ArticlePubMedGoogle Scholar
- Cicardi M, Levy RJ, McNeil DL, Li HH, Sheffer AL, Campion M, Horn PT, Pullman WE: Ecallantide for the treatment of acute attacks in hereditary angioedema. N Engl J Med. 2010, 363: 523-531. 10.1056/NEJMoa0905079.View ArticlePubMedGoogle Scholar
- Cicardi M, Banerji A, Bracho F, Malbran A, Rosenkranz B, Riedl M, Bork K, Lumry W, Aberer W, Bier H, Bas M, Greve J, Hoffmann TK, Farkas H, Reshef A, Ritchie B, Yang W, Grabbe J, Kivity S, Kreuz W, Levy RJ, Luger T, Obtulowicz K, Schmid-Grendelmeier P, Bull C, Sitkauskiene B, Smith WB, Toubi E, Werner S, Anné S: Icatibant, a new bradykinin-receptor antagonist, in hereditary angioedema. N Engl J Med. 2010, 363: 532-541. 10.1056/NEJMoa0906393.View ArticlePubMedGoogle Scholar
- Levy RJ, Lumry WR, McNeil DL, Li HH, Campion M, Horn PT, Pullman WE: EDEMA4: a phase 3, double-blind study of subcutaneous ecallantide treatment for acute attacks of hereditary angioedema. Ann Allergy Asthma Immunol. 2010, 104: 523-529. 10.1016/j.anai.2010.04.012.View ArticlePubMedGoogle Scholar
- Craig TJ, Levy RJ, Wasserman RL, Bewtra AK, Hurewitz D, Obtulowicz K, Reshef A, Ritchie B, Moldovan D, Shirov T, Grivcheva-Panovska V, Kiessling PC, Keinecke HO, Bernstein JA: Efficacy of human C1 esterase inhibitor concentrate compared with placebo in acute hereditary angioedema attacks. J Allergy Clin Immunol. 2009, 124: 801-808. 10.1016/j.jaci.2009.07.017.View ArticlePubMedGoogle Scholar
- Cicardi M, Bork K, Caballero T, Craig T, Li HH, Longhurst H, Reshef A, Zuraw B, HAWK (Hereditary Angioedema International Working Group): Evidence-based recommendations for the therapeutic management of angioedema owing to hereditary C1 inhibitor deficiency: consensus report of an International Working Group. Allergy. 2012, 67: 147-157. 10.1111/j.1398-9995.2011.02751.x.View ArticlePubMedGoogle Scholar
- Craig T, Pursun EA, Bork K, Bowen T, Boysen H, Farkas H, Grumach A, Katelaris CH, Lockey R, Longhurst H, Lumry W, Magerl M, Martinez-Saguer I, Ritchie B, Nast A, Pawankar R, Zuraw B, Maurer M: WAO guideline for the management of hereditary angioedema. World Allergy Organ J. 2012, 5: 182-199. 10.1097/WOX.0b013e318279affa.PubMed CentralView ArticlePubMedGoogle Scholar
- Lumry WR, Castaldo AJ, Vernon MK, Blaustein MB, Willson DA, Horn PT: The humanistic burden of hereditary angioedema: Impact on health-related quality of life, productivity, and depression. Allergy Asthma Proc. 2010, 31: 407-414. 10.2500/aap.2010.31.3394.View ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.