International consensus algorithm for the diagnosis, therapy and management of hereditary angioedema

Background: We published the Canadian 2003 International Consensus Algorithm for the Diagnosis, Therapy, and Management of Hereditary Angioedema (HAE; C1 inhibitor [C1-INH] deficiency) and updated this as Hereditary angioedema: a current state-of-the-art review: Canadian Hungarian 2007 International Consensus Algorithm for the Diagnosis, Therapy, and Management of Hereditary Angioedema. Objective: To update the International Consensus Algorithm for the Diagnosis, Therapy and Management of Hereditary Angioedema (circa 2010). Methods: The Canadian Hereditary Angioedema Network (CHAEN)/Réseau Canadien d’angioédème héréditaire (RCAH) http://www.haecanada.com and cosponsors University of Calgary and the Canadian Society of Allergy and Clinical Immunology (with an unrestricted educational grant from CSL Behring) held our third Conference May 15th to 16th, 2010 in Toronto Canada to update our consensus approach. The Consensus document was reviewed at the meeting and then circulated for review. Results: This manuscript is the 2010 International Consensus Algorithm for the Diagnosis, Therapy and Management of Hereditary Angioedema that resulted from that conference. Conclusions: Consensus approach is only an interim guide to a complex disorder such as HAE and should be replaced as soon as possible with large phase III and IV clinical trials, meta analyses, and using data base registry validation of approaches including quality of life and cost benefit analyses, followed by large head-to-head clinical trials and then evidence-based guidelines and standards for HAE disease management. * Correspondence: [email protected] Departments of Medicine and Paediatrics, University of Calgary, Calgary, Alberta, Canada Bowen et al. Allergy, Asthma & Clinical Immunology 2010, 6:24 http://www.aacijournal.com/content/6/1/24 ALLERGY, ASTHMA & CLINICAL IMMUNOLOGY © 2010 Bowen et al; licensee 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. Introduction When our first consensus meeting took place in Toronto, Canada in October 2003, there were no licensed drugs in North America for the treatment of HAE attacks and only two randomized clinical trials with plasma-derived C1 inhibitor replacement therapy (pdC1INH;[1,2]) and a few clinical trials using androgens and antifibrinolytics [3-5]. C1-esterase inhibitor concentrates (Berinert P® and Cetor®) were available mostly in Europe at the time [Henkel G. CSL Behring Personal communication: Berinert approved for HAE acute swelling therapy by Country and year of approval: Argentina 2003; Australia January 2010; Austria 1990; Belgium 2009; Bulgaria 2008; Canada 2010; Cyprus 2009; Czech Republic 2009; Denmark 2009; Finland 2009; France 2009; Germany 1979 (predecessor product, pasteurized product since 1985); Great Britain 2009; Greece 2009; Hungary 1997; Italy 2010; Japan 1990; Luxembourg 2010; Netherlands 2009; Norway 2009; Poland 2009; Portugal 2009; Romania 2009; Slovakia 2009; Slovenia 2009; Spain 2009; Sweden 2009; Switzerland 1993; USA 2009]. There are now several phase III clinical trials underway or reported in HAE therapy and these have led to the licensing of pdC1INH in many parts of the world including Europe and the United States, bradykinin receptor antagonist Icatibant in Europe, and kallikrein inhibitor Ecallantide in the United States. More phase III clinical trials are currently underway or pending reporting including pdC1INH (Berinert®, CSL Behring; Cinryze®, ViroPharma; Cetorn®, Sanquin), recombinant C1-INH replacement therapy (conestat alfa; Rhucin®, Pharming), kallikrein inhibitor (Ecallantide, Kalbitor®, Dyax), and bradykinin-2-receptor antagonist (Icatibant, Firazyr®, Jerini/Shire) (reviewed in [6]). Consensus approaches require timely updating and validation and hopefully with the establishment of data base registries for HAE such as the European HAE Register http://www.haeregister.org, the US Hereditary Angioedema Association registry: http://www.hereditaryangioedema.com/, and the European Society for Immunedeficiencies registry http://www.esid.org/esid_registry. php such validation will occur including quality of life (QOL) and cost benefit analyses and drug-drug comparisons. Consensus documents need replacing with evidence-based recommendations based on large phase III and IV trials, head-to-head drug comparisons, meta analyses, guidelines and then standards and we look forward to the improved care of HAE patients as these roll out. To update our previous consensus approach, the Canadian Hereditary Angioedema Network (CHAEN)/ Réseau Canadien d’angioédème héréditaire (RCAH) http://www.haecanada.com and cosponsors University of Calgary and the Canadian Society of Allergy and Clinical Immunology (with an unrestricted educational grant from CSL Behring) held our third Consensus Conference May 15th to 16th, 2010 in Toronto Canada. This manuscript is the 2010 International Consensus Algorithm for the Diagnosis, Therapy and Management of Hereditary Angioedema that was agreed to at that conference and this was further circulated for review and comment to previous consensus participants. Speakers at the Conference were encouraged to submit their views for publication and these manuscripts are published together as a thematic publication grouping on HAE in the official journal of the Canadian Society of Allergy and Clinical Immunology: Allergy Asthma Clinical Immunology; 2010 (in press [6-16]). Patient Group Perspective Similar to the six Hungarian-sponsored HAE Workshops as indicated in their publication [17], it is appropriate that Patient Groups participate in HAE management consensus discussions to share the patient perspective of HAE management and to help reflect on the development of comprehensive care clinics, home therapy programs, and overall management of HAE. The Canadian and Canadian Hungarian consensus document processes [18,19] included Patient Group participation in discussion, approval, and co-authoring. Patient groups should participate in and coauthor consensus treatment documents affecting their care. The Patient Advisory Committee of the Canadian Hereditary Angioedema Network (CHAEN)/Réseau Canadien d’angioédème héréditaire (RCAH) http://www.haecanada. com and HAE International Patient Organization for C1 Inhibitor Deficiencies (HAEi) http://www.haei.org participated in the Conference. HAE Diagnosis Algorithm: See Figure 1 Clinical Characteristics Clinical characteristics are reviewed in previous documents [1,6-20]. Patients with HAE may experience recurrent nonpruritic edema of skin and submucosal tissues associated with pain syndromes, nausea, vomiting, diarrhea, and life-threatening airway swellings. Risk of dying from airway obstruction if left untreated is significant [9,17,21]. A prodromal serpiginous erythematous rash is sometimes seen but pruritic urticaria usually makes the diagnosis of HAE unlikely [17,20,22]. HAE genetics are autosomal dominant with 25% spontaneous mutation; the HAE-C1INH gene mapping to chromosome 11q12-q13.1 [17-19]; and the protein defect described by Donaldson in 1963 [23]. An acquired form (acquired angioedema, AAE) was described in 1972 (reviewed in [10]) and is not the focus of this article. AAE differs from HAE having absent family history, late Bowen et al. Allergy, Asthma & Clinical Immunology 2010, 6:24 http://www.aacijournal.com/content/6/1/24 Page 2 of 13