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; Cetor-n^®, 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]).

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.

Indications for testing include clinical suspicion or positive family history [8,19,20,22,29-31]. Testing under one year of age may not be reliable and should be confirmed after age one (false negative and false positive tests may occur unless using genetic typing) [8,19,20,29-31]. If clinical suspicion of C1-INH deficiency, we recommend screening with C4, (C4 is normal between swelling events in only 2% of cases; [19,31]), C1 inhibitor antigenic protein and C1 inhibitor function, if available. However, a normal C4 particularly during an edema attack should make one question the diagnosis of HAE (there is no indication for screening CH50 nor C3) [6,8,10,19,22,29,31]. If serum C4 and C1-INH antigenic proteins are both low (below manufacturer's normal range) and AAE not suspected, then the diagnosis is compatible with HAE-C1INH-Type I (Type I HAE) (suggest repeat testing once to confirm). If AAE is possible such as with no family history and later onset of symptoms (age over 40), then serum C1q antigenic protein testing is suggested. If low C1q, the diagnosis is compatible with AAE (C1q antigenic protein is reduced in 75% of AAE but usually normal in HAE; [10]). If C4 is normal or low and C1-INH antigenic protein normal but clinical suspicion is strong, HAE is NOT ruled out and C1-INH functional assay should be obtained (in a laboratory skilled in functional C1-INH assay with careful sample drawing, handling, shipping, and interpreting results) [8,18,19,28,29,34]. If C1-INH functional activity is low with normal or elevated C1-INH antigenic protein and normal C1q, this is compatible with HAE-C1INH-Type II (Type II HAE) (tests should be repeated at least once to confirm the diagnosis; sample mishandling is common) [8,18,19,28,29,34]. If C4 antigenic protein and C1-INH functional assays are both normal, this rules out Types I and II HAE but does not rule out type III HAE (HAE-FXII and HAE-Unknown) (normal C1-INH protein and function occurring mainly in women; some with mutations in the coagulation factor XII gene or other unidentified defects; [11,13,19,25,35] nor medication-related angioedema (e.g. ACE-I-related Angioedema; [10,19,22]). If C4 and C1-INH protein are normal, we suggest repeating these during an acute attack [19,28]. Genetic testing is usually not necessary to confirm the diagnosis of HAE-C1INH types I and II particularly if positive family history (autosomal dominant with approximately 25% representing de novo mutations) [8,19,29,31]. However, genetic testing is occasionally helpful in confirming HAE-C1INH (particularly before one year of age and cord blood; [8]) and may contribute to investigation of type III HAE [8,11,13,19,25]. Although C4 and C1-INH protein antigen are routine laboratory tests, C1-INH functional assays are specialized laboratory tests and should only be done in reference laboratories with careful attention to sample handling for complement [8,11,13,17,19,28,29,34]. C1-INH functional assays may use chromogenic or C1s binding ELISA assays. Both distinguish between normal and abnormal but the C1s ELISA assay performance may be poor if manufacturer's normal range (> 67%) is used. The reference laboratory should determine normal range locally with receiver operator characteristic (ROC) analysis, since higher cutoff (84%) may give better discrimination [34].

Baseline blood borne pathogen surveillance (hemovigilance) samples should be collected and stored at baseline and annually including testing for hepatitis B, C, G; HIV; HTLV; parvovirus and future testing for possible emerging pathogens (serum and nucleic acid storage [19,29,31]. As pdC1INH may be required at any time on an emergency basis after diagnosis, hemovigilance and baseline chemistries and urinalysis are best done at diagnosis. Although production methods for pdC1INH may differ, safety of new generation pdC1INH has been excellent [19,28,29,31,36-38]. Since attenuated androgens may predispose to lipid abnormalities [39] and liver disorders including liver cancer, we suggest [1,7,11,12,17,19,37] serum lipid profile and liver function tests be obtained prior to androgen administration and abdominal liver and spleen ultrasound be performed prior to continuous androgen administration (repeated annually) [8,17,19,28,29,31,40]. Liver function studies (including alanine aminotransferase, ALT, total bilirubin, alkaline phosphatase, albumin, alk phos, and possibly PT/PTT and alpha fetoprotein); creatine kinase (CK), lactic dehydrogenase (LDH), blood urea nitrogen (BUN), creatinine (Cr), complete blood count (CBC) and differential; as well, urinalysis should be obtained at diagnosis [8,17,19,28,29,31,40,41].

We recommend that patients at risk for receiving blood products receive vaccination to hepatitis B (may be combination hepatitis A) [8,19,29,31].

Some medications may trigger or worsen angioedema events in patients with HAE and should be avoided including estrogen contraceptives, hormone replacement therapy, and ACE-Inhibitors [8,11,13,17,19,22,29,31,32]. Plasminogen activators are a theoretical risk but the benefit may outweigh the risk [19].

Most of the pediatric considerations of HAE are incorporated in the above algorithms (Figures ​(Figures1,1, ​,22 and ​and33 and Appendix 1) and have been reviewed elsewhere. Most treatment drugs have been licensed for adults with pediatric licensing pending [6,8,14,18,19,29-31,35].

Most of the pregnancy and lactation considerations of HAE are incorporated in the above algorithms (Figures ​(Figures1,1, ​,22 and ​and33 and Appendix 1) and have been reviewed elsewhere. Most treatment drugs have not been trialed in pregnancy and are not licensed for use in this setting although there is anecdotal use of pdC1INH use in pregnancy and lactation [6,15,19,29,32,33,52,53]. Tranexamic acid can be found in breast milk [44].

Since our first Canadian International Consensus meeting in 2003 when plasma-derived C1-inhibitor concentrates had been available for decades in Europe but not widely outside Europe, many new therapies have emerged in HAE management. Many phase III clinical trials have been completed and some reported on. Several products are now licensed for prophylaxis and therapy of HAE and hopefully are reducing the morbidity and mortality in this disorder. These therapies and home care concepts are providing freedom for work, travel, and every day activities including sports activities with more normalization of life style and improved quality of life for HAE patients. We must strive to elevate the standard of care for HAE patients through comprehensive care clinics and home care programs and institute safety, efficacy, and cost benefit monitoring. Data base registries may provide the health care systems, patients, and patient groups with the necessary data to choose the most appropriate individualized management of one's HAE. Consensus approaches are only interim guides to chronic and rare diseases such as HAE and should be replaced as soon as possible with more phase III studies, meta analyses, large phase IV post-marketing trials, and head-to-head studies using data base registry validation of consensus approaches including quality of life and cost-benefit analyses followed by guidelines and then standards for HAE disease management.

Many of the authors have either entered consultancy with or have been involved in educational programs and their organization, had direct funding from, have been speakers for, or have had consultation agreements with CSL Behring, Dyax, Jerini, Pharming, ViroPharma, Shire. The 2010 International Consensus Algorithm for the Diagnosis, Therapy and Management of Hereditary Angioedema was arrived at during the Canadian Hereditary Angioedema Network (CHAEN)/Réseau Canadien d'angioédème héréditaire (RCAH) second meeting held May 15^th/16^th, 2010, Toronto, Canada and was cosponsored by CHAEN/RCAH, the Canadian Society of Allergy and Clinical Immunology, and the University of Calgary and was funded through an unrestricted educational grant from CSL Behring. Publication of this manuscript is sponsored by University of Calgary.

TB prepared the manuscript. All authors have read, revised and approved the manuscript.