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2010 International consensus algorithm for the diagnosis, therapy and management of hereditary angioedema Bowen, Tom; Cicardi, Marco; Farkas, Henriette; Bork, Konrad; Longhurst, Hilary J; Zuraw, Bruce; Aygoeren-Pürsün, Emel; Craig, Timothy; Binkley, Karen; Hebert, Jacques; Ritchie, Bruce; Bouillet, Laurence; Betschel, Stephen; Cogar, Della; Dean, John; Devaraj, Ramachand; Hamed, Azza; Kamra, Palinder; Keith, Paul K; Lacuesta, Gina; Leith, Eric; Lyons, Harriet; Mace, Sean; Mako, Barbara; Neurath, Doris; Poon, Man-Chiu; Rivard, Georges-Etienne; Schellenberg, Robert; Rowan, Dereth; Rowe, Anne; Stark, Donald; Sur, Smeeksha; Tsai, Ellie; Warrington, Richard; Waserman, Susan; Ameratunga, Rohan; Bernstein, Jonathan; Björkander, Janne; Brosz, Kristylea; Brosz, John; Bygum, Anette; Caballero, Teresa; Frank, Mike; Fust, George; Harmat, George; Kanani, Amin; Kreuz, Wolfhart; Levi, Marcel; Li, Henry; Martinez-Saguer, Inmaculada; Moldovan, Dumitru; Nagy, Istvan; Nielsen, Erik W; Nordenfelt, Patrik; Reshef, Avner; Rusicke, Eva; Smith-Foltz, Sarah; Späth, Peter; Varga, Lilian; Yu Xiang, Zhi Jul 28, 2010

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REVIEW Open Access2010 International consensus algorithm for thediagnosis, therapy and management ofhereditary angioedemaTom Bowen1*, Marco Cicardi2, Henriette Farkas3, Konrad Bork4, Hilary J Longhurst5, Bruce Zuraw6,Emel Aygoeren-Pürsün7, Timothy Craig8, Karen Binkley9, Jacques Hebert10, Bruce Ritchie11, Laurence Bouillet12,Stephen Betschel9, Della Cogar13,14, John Dean15, Ramachand Devaraj16, Azza Hamed17, Palinder Kamra17,Paul K Keith18, Gina Lacuesta19, Eric Leith20, Harriet Lyons13,21, Sean Mace9, Barbara Mako13,22, Doris Neurath23,Man-Chiu Poon24, Georges-Etienne Rivard25, Robert Schellenberg26, Dereth Rowan13,21, Anne Rowe13,27,Donald Stark26, Smeeksha Sur28, Ellie Tsai29, Richard Warrington30, Susan Waserman18, Rohan Ameratunga31,Jonathan Bernstein32, Janne Björkander33, Kristylea Brosz13,34, John Brosz13,34, Anette Bygum35, Teresa Caballero36,Mike Frank37, George Fust3, George Harmat38, Amin Kanani26, Wolfhart Kreuz7, Marcel Levi39, Henry Li40,Inmaculada Martinez-Saguer7, Dumitru Moldovan41, Istvan Nagy42, Erik W Nielsen43, Patrik Nordenfelt44,Avner Reshef45, Eva Rusicke7, Sarah Smith-Foltz46, Peter Späth47, Lilian Varga3, Zhi Yu Xiang48AbstractBackground: We published the Canadian 2003 International Consensus Algorithm for the Diagnosis, Therapy, andManagement of Hereditary Angioedema (HAE; C1 inhibitor [C1-INH] deficiency) and updated this as Hereditaryangioedema: a current state-of-the-art review: Canadian Hungarian 2007 International Consensus Algorithm for theDiagnosis, Therapy, and Management of Hereditary Angioedema.Objective: To update the International Consensus Algorithm for the Diagnosis, Therapy and Management ofHereditary 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 andClinical Immunology (with an unrestricted educational grant from CSL Behring) held our third Conference May15th to 16th, 2010 in Toronto Canada to update our consensus approach. The Consensus document was reviewedat the meeting and then circulated for review.Results: This manuscript is the 2010 International Consensus Algorithm for the Diagnosis, Therapy andManagement 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 bereplaced as soon as possible with large phase III and IV clinical trials, meta analyses, and using data base registryvalidation of approaches including quality of life and cost benefit analyses, followed by large head-to-head clinicaltrials and then evidence-based guidelines and standards for HAE disease management.* Correspondence: tbowen@pol.net1Departments of Medicine and Paediatrics, University of Calgary, Calgary,Alberta, CanadaBowen et al. Allergy, Asthma & Clinical Immunology 2010, 6:24http://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 CommonsAttribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction inany medium, provided the original work is properly cited.IntroductionWhen our first consensus meeting took place in Tor-onto, Canada in October 2003, there were no licenseddrugs in North America for the treatment of HAEattacks and only two randomized clinical trials withplasma-derived C1 inhibitor replacement therapy(pdC1INH;[1,2]) and a few clinical trials using andro-gens and antifibrinolytics [3-5]. C1-esterase inhibitorconcentrates (Berinert P® and Cetor®) were availablemostly in Europe at the time [Henkel G. CSL Behring -Personal communication: Berinert approved for HAEacute swelling therapy by Country and year of approval:Argentina 2003; Australia January 2010; Austria 1990;Belgium 2009; Bulgaria 2008; Canada 2010; Cyprus2009; Czech Republic 2009; Denmark 2009; Finland2009; France 2009; Germany - 1979 (predecessor pro-duct, pasteurized product since 1985); Great Britain2009; Greece 2009; Hungary 1997; Italy 2010; Japan1990; Luxembourg 2010; Netherlands 2009; Norway2009; Poland 2009; Portugal 2009; Romania 2009; Slova-kia 2009; Slovenia 2009; Spain 2009; Sweden 2009; Swit-zerland 1993; USA 2009]. There are now several phaseIII clinical trials underway or reported in HAE therapyand these have led to the licensing of pdC1INH inmany parts of the world including Europe and the Uni-ted States, bradykinin receptor antagonist Icatibant inEurope, and kallikrein inhibitor Ecallantide in the Uni-ted States. More phase III clinical trials are currentlyunderway 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-receptorantagonist (Icatibant, Firazyr®, Jerini/Shire) (reviewed in[6]). Consensus approaches require timely updating andvalidation and hopefully with the establishment of database registries for HAE such as the European HAE Reg-ister http://www.haeregister.org, the US HereditaryAngioedema Association registry: http://www.hereditar-yangioedema.com/, and the European Society for Immu-nedeficiencies registry http://www.esid.org/esid_registry.php such validation will occur including quality of life(QOL) and cost benefit analyses and drug-drug compar-isons. Consensus documents need replacing with evi-dence-based recommendations based on large phase IIIand IV trials, head-to-head drug comparisons, meta ana-lyses, guidelines and then standards and we look for-ward to the improved care of HAE patients as these rollout. To update our previous consensus approach, theCanadian Hereditary Angioedema Network (CHAEN)/Réseau Canadien d’angioédème héréditaire (RCAH)http://www.haecanada.com and cosponsors University ofCalgary and the Canadian Society of Allergy and ClinicalImmunology (with an unrestricted educational grantfrom CSL Behring) held our third Consensus Confer-ence May 15th to 16th, 2010 in Toronto Canada. Thismanuscript is the 2010 International Consensus Algo-rithm for the Diagnosis, Therapy and Management ofHereditary Angioedema that was agreed to at that con-ference and this was further circulated for review andcomment to previous consensus participants. Speakersat the Conference were encouraged to submit theirviews for publication and these manuscripts are pub-lished together as a thematic publication grouping onHAE in the official journal of the Canadian Society ofAllergy and Clinical Immunology: Allergy Asthma Clini-cal Immunology; 2010 (in press [6-16]).Patient Group PerspectiveSimilar to the six Hungarian-sponsored HAE Work-shops as indicated in their publication [17], it is appro-priate that Patient Groups participate in HAEmanagement consensus discussions to share the patientperspective of HAE management and to help reflect onthe development of comprehensive care clinics, hometherapy programs, and overall management of HAE.The Canadian and Canadian Hungarian consensusdocument processes [18,19] included Patient Group par-ticipation in discussion, approval, and co-authoring.Patient groups should participate in and coauthor con-sensus treatment documents affecting their care. ThePatient Advisory Committee of the Canadian HereditaryAngioedema Network (CHAEN)/Réseau Canadien d’an-gioédème héréditaire (RCAH) http://www.haecanada.com and HAE - International Patient Organization forC1 Inhibitor Deficiencies (HAEi) http://www.haei.orgparticipated in the Conference.HAE Diagnosis Algorithm: See Figure 1Clinical CharacteristicsClinical characteristics are reviewed in previous docu-ments [1,6-20]. Patients with HAE may experiencerecurrent nonpruritic edema of skin and submucosal tis-sues associated with pain syndromes, nausea, vomiting,diarrhea, and life-threatening airway swellings. Risk ofdying from airway obstruction if left untreated is signifi-cant [9,17,21]. A prodromal serpiginous erythematousrash is sometimes seen but pruritic urticaria usuallymakes the diagnosis of HAE unlikely [17,20,22]. HAEgenetics are autosomal dominant with 25% spontaneousmutation; the HAE-C1INH gene mapping to chromo-some 11q12-q13.1 [17-19]; and the protein defectdescribed 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, lateBowen et al. Allergy, Asthma & Clinical Immunology 2010, 6:24http://www.aacijournal.com/content/6/1/24Page 2 of 13onset of symptoms, usually low C1q antigen levels, pro-phylactic response to antifibrinolytics often better thanto androgens, and sometimes requiring markedly higherdoses of pdC1INH with rapid C1-INH catabolism andmay respond to Icatibant or Ecallantide [10,24]. Drug-induced angioedema (e.g. angiotensin-convertingenzyme inhibitors, ACE-I) is also not included in thisdiscussion [22]. The incidence of HAE is approximately1:50,000 with no ethnic group differences [17,19]. Thereseems to be little or no genotype phenotype correlationFigure 1 Hereditary Angioedema - HAE - Diagnostic Algorithm.Bowen et al. Allergy, Asthma & Clinical Immunology 2010, 6:24http://www.aacijournal.com/content/6/1/24Page 3 of 13[17]. Two forms of HAE have been described: type IHAE with low C1-INH antigenic protein and functionalactivity (85% of cases) and type II HAE with normal orelevated protein but low C1-INH function (15% ofcases); and HAE with normal C1-INH often referred toas type III HAE. HAE with normal C1-INH occursmainly in women and includes HAE associated withmutations in the coagulation factor XII gene and otherdefects yet to be identified [11,13,18,19,25]. The patho-physiology of types I and II HAE has been elucidatedwith the candidate molecule resulting in angioedemabeing bradykinin [17,18,23,25-28]. Age of onset is vari-able and may present under one year of age[1,6,7,18,19,25] with laryngeal attacks uncommon beforeage three and tend to occur later than other symptoms[8,18-20,29-31]. Angioedema events often worsen withpuberty, estrogen-containing birth control pills, or hor-mone replacement therapy [8,11,13,15,17,19,20,31,32].Untreated attacks typically last over 48 to 96 hours[17,20]. Attack triggers may include stress, infections,ACE-inhibitors, minor trauma, menstruation, pregnancy,oral contraceptives but are often unidentified withattacks varying from periodic, clustering, periods ofremission [17-20,26,29,31]. Angioedema attacks do notrespond to treatment with glucocorticoids or antihista-mines, and epinephrine has only a transient and modestbenefit [18,19,26,33].Diagnostic Algorithm: See Figure 1Indications for testing include clinical suspicion or posi-tive family history [8,19,20,22,29-31]. Testing under oneyear of age may not be reliable and should be confirmedafter age one (false negative and false positive tests mayoccur unless using genetic typing) [8,19,20,29-31]. Ifclinical suspicion of C1-INH deficiency, we recommendscreening with C4, (C4 is normal between swellingevents in only 2% of cases; [19,31]), C1 inhibitor anti-genic protein and C1 inhibitor function, if available.However, a normal C4 particularly during an edemaattack should make one question the diagnosis ofHAE (there is no indication for screening CH50 norC3) [6,8,10,19,22,29,31]. If serum C4 and C1-INH anti-genic proteins are both low (below manufacturer’s nor-mal range) and AAE not suspected, then the diagnosisis compatible with HAE-C1INH-Type I (Type I HAE)(suggest repeat testing once to confirm). If AAE is possi-ble such as with no family history and later onset ofsymptoms (age over 40), then serum C1q antigenic pro-tein testing is suggested. If low C1q, the diagnosis iscompatible with AAE (C1q antigenic protein is reducedin 75% of AAE but usually normal in HAE; [10]). If C4is normal or low and C1-INH antigenic protein normalbut clinical suspicion is strong, HAE is NOT ruled outand C1-INH functional assay should be obtained (in alaboratory skilled in functional C1-INH assay with care-ful sample drawing, handling, shipping, and interpretingresults) [8,18,19,28,29,34]. If C1-INH functional activityis low with normal or elevated C1-INH antigenic pro-tein and normal C1q, this is compatible with HAE-C1INH-Type II (Type II HAE) (tests should berepeated at least once to confirm the diagnosis; samplemishandling is common) [8,18,19,28,29,34]. If C4 anti-genic protein and C1-INH functional assays are bothnormal, this rules out Types I and II HAE but does notrule out type III HAE (HAE-FXII and HAE-Unknown) (normal C1-INH protein and functionoccurring mainly in women; some with mutations in thecoagulation 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 andC1-INH protein are normal, we suggest repeating theseduring an acute attack [19,28]. Genetic testing is usuallynot necessary to confirm the diagnosis of HAE-C1INHtypes I and II particularly if positive family history (auto-somal dominant with approximately 25% representingde novo mutations) [8,19,29,31]. However, genetic test-ing 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 anti-gen are routine laboratory tests, C1-INH functionalassays are specialized laboratory tests and shouldonly be done in reference laboratories with carefulattention to sample handling for complement[8,11,13,17,19,28,29,34]. C1-INH functional assays mayuse chromogenic or C1s binding ELISA assays. Both dis-tinguish between normal and abnormal but the C1sELISA assay performance may be poor if manufacturer’snormal range (> 67%) is used. The reference laboratoryshould determine normal range locally with receiveroperator characteristic (ROC) analysis, since higher cut-off (84%) may give better discrimination [34].Baseline laboratory testing at diagnosis at anyage and follow upBaseline blood borne pathogen surveillance (hemovigi-lance) samples should be collected and stored at base-line and annually including testing for hepatitis B, C, G;HIV; HTLV; parvovirus and future testing for possibleemerging pathogens (serum and nucleic acid storage[19,29,31]. As pdC1INH may be required at any time onan emergency basis after diagnosis, hemovigilance andbaseline chemistries and urinalysis are best done at diag-nosis. Although production methods for pdC1INH maydiffer, safety of new generation pdC1INH has beenexcellent [19,28,29,31,36-38]. Since attenuated andro-gens may predispose to lipid abnormalities [39] andliver disorders including liver cancer, we suggestBowen et al. Allergy, Asthma & Clinical Immunology 2010, 6:24http://www.aacijournal.com/content/6/1/24Page 4 of 13[1,7,11,12,17,19,37] serum lipid profile and liver functiontests be obtained prior to androgen administration andabdominal liver and spleen ultrasound be performedprior to continuous androgen administration (repeatedannually) [8,17,19,28,29,31,40]. Liver function studies(including alanine aminotransferase, ALT, total bilirubin,alkaline phosphatase, albumin, alk phos, and possiblyPT/PTT and alpha fetoprotein); creatine kinase (CK),lactic dehydrogenase (LDH), blood urea nitrogen (BUN),creatinine (Cr), complete blood count (CBC) and differ-ential; as well, urinalysis should be obtained at diagnosis[8,17,19,28,29,31,40,41].Vaccination recommendationsWe recommend that patients at risk for receiving bloodproducts receive vaccination to hepatitis B (may becombination hepatitis A) [8,19,29,31].Medications to avoid in patients with HAESome medications may trigger or worsen angioedemaevents in patients with HAE and should be avoidedincluding estrogen contraceptives, hormone replacementtherapy, and ACE-Inhibitors [8,11,13,17,19,22,29,31,32].Plasminogen activators are a theoretical risk but thebenefit may outweigh the risk [19].Short-Term Prophylaxis - see Figure 2Minor Manipulation - such as mild dental work(injection of local anaesthetic may precipitate anattack): if pdC1INH is immediately available, then noprophylaxis (unless such manipulations have previouslyprecipitated an attack in that patient in which caseprophylaxis with pdC1INH should be considered). IfpdC1INH is not available, then 17-alpha-alkylated ana-bolic androgen (Danazol most widely used but also sta-nozolol and oxandralone) or antifibrinolyticprophylaxis (if available, tranexamic acid is preferredto epsilon aminocaproic acid) (see Figure 2). Tranexa-mic acid as a 5% mouthwash may decrease bleedingfrom dental procedures and may prevent bradykininformation in plasminogen rich saliva [42-44]. If consid-ering more than mild manipulation, pdC1INH prophy-laxis should be considered. If pdC1INH not available,then short term Danazol is recommended (even inchildren and last trimester of pregnancy - avoid in thefirst two trimesters of pregnancy; [8,15,19,29,31,32].The recommended dose is 2.5 to 10 mg/kg/day, maxi-mum 600 mg daily, for five days before and two to fivedays after the event [8,19,29,31]; Stanozolol 4-6 mg/day is an alternative [29]. Whenever possible,PdC1INH should be immediately available[8,19,29,31]. Since anabolic androgens such as Danazolare more efficacious in the short term compared toantifibrinolytics such as Tranexamic acid (TA;Cyklokapron®) or epsilon aminocaproic acid (EACA;Amicar®), anabolic steroids are more often used forshort term prophylaxis in the setting where pdC1INHis not available [8,19,29,31]. The recommended dosefor oral TA (not fully established) is 25 mg/kg two tothree times daily with maximum 3 to 6 g daily; IVdose 10 mg/kg two to three times daily adjusting thedose for renal impairment [19,29,31,33,45-48].Intubation or major procedures - pdC1INH onehour pre surgery - as close to procedure as feasible -less than six hours before the procedure (should alwaysbe given if endotracheal intubation or manipulation;[8,9,12,14,19,29,31,45]. The optimal dose for prophylaxisfor procedures has not yet been established - we recom-mend 10 to 20 units per kg [8,9,12,14,19,29,31,45]. Asecond dose of equal amount should be immediatelyavailable at time of surgery. Repeat daily as needed untilthere is no further risk of angioedema. If pdC1INH isnot available, then Danazol or Stanozolol are recom-mended as in V.1 (see figure 2; androgens preferred toTA; TA in doses as above; [19,29,31,33,45,47].) Solvent/detergent treated plasma (SDP; 10 ml/kg; 2 to 4 units,400 to 800 ml per adult infusion) is an option one to sixhours presurgery (fresh frozen plasma or frozen plasmais less safe than SDP; [8,9,19,28,29,31,33,48]; Dr. MikeFrank’s group has reported using two units fresh frozenplasma the night before, [49-51]).PregnancypdC1INH prophylaxis is the safest prophylactic agentduring pregnancy [12,15,19,29,31,32]; discussed at the6th International HAE Conference held in Budapest inJune 2009; dose as in V.2).Pediatricsexcept when undergoing surgical or diagnostic interven-tions in the head and neck region, short-term prophy-laxis is less often required in children than adults(dosing as in V.1 and V.2; [8,31]).Long-Term Prophylaxis: See Figure 2Prophylaxis indications have been reviewed[12,17,19,52]. Consider prophylaxis with antifibrinolytics,attenuated androgens, or pdC1INH if more than onesevere event per month occurs and if a treatment foracute attacks is not sufficiently effective or is not avail-able [8,12,19,28,37,52-54]. It should be noted that: thenumber of events per year does not predict severityof the next event nor whether the first or next eventwill be an airway event.17-alpha-alkylated anabolic androgensAttenuated androgens such as Danazol and Stanozololare the usual agents with methyltestosterone andBowen et al. Allergy, Asthma & Clinical Immunology 2010, 6:24http://www.aacijournal.com/content/6/1/24Page 5 of 13oxandrolone as alternatives. Androgens are generallymore effective than antifibrinolytic agents [8,17-19,40].Androgen contraindications usually include pregnancy,lactation, cancer, hepatitis, and childhood (until finishedgrowing) [8,15,17-19,29,31,32]. Side effects may includevirilization, weight gain, acne, hair growth, altered libido,voice deepening, decreased breast size, menstrual irregu-larities, vasomotor symptoms, hypertension, atherogen-esis, altered lipid metabolism, altered liver enzymes,cholestasis, hepatic necrosis, liver neoplasms (hepatocel-lular adenomas or carcinomas), erythrocytosis, hemor-rhagic cystitis, and ambiguous genitalia in newborns ifmothers treated with androgens during pregnancy[8,17,19,28,37,40,41,55,56]. Androgen induction can bewith high dose and reduce or low dose and escalateaiming to achieve the lowest effective dose (maximumlong term doses recommended are 200 mg daily forDanazol and 2 mg daily for Stanozolol) [17-19,28,29,31,35,37,40,55]. Androgen therapy is not recommended forchildren but has been used in the prepubertal setting[8,17,19,29,31,35]. If patients are exposed to a precipitat-ing factor such as infection or if the sensation of pro-dromal attack symptoms or mild clinical manifestationsdeveloping, then doubling the dose for several days hasbeen tried. The lowest effective maintenance doseincluding trying alternate day or twice weekly should betried [19,28,29]. Danazol has been used in children[8,31,35] but pdC1INH may be the safest long termFigure 2 Hereditary Angioedema - HAE - Prophylaxis Algorithm.Bowen et al. Allergy, Asthma & Clinical Immunology 2010, 6:24http://www.aacijournal.com/content/6/1/24Page 6 of 13approach [8,31,35]. Danazol has been used for prophylaxis inHAE type III as have progesterone and tranexamic acid [11].Androgen Monitoringevery six months: liver enzymes (ALT, AST, alk phos),lipid profile, complete blood cell count, and urinalysis.For adults with a dose of 200 mg or less per day Dana-zol: suggest an annual liver spleen ultrasound. In prepu-bertal patients or in adults with doses higher than 200mg Danazol daily: suggest six monthly liver spleen ultra-sound for the detection of focal lesions and annual alphafetoprotein [8,19,29,31,35,57-60].Antifibrinolytic Agents (AFs;[45])Tranexamic acid (TA; Cyklokapron®) is more effectivethan epsilon aminocaproic acid (EACA; Amicar®;[3])and has mostly replaced EACA outside the USA. AFsmay not be as effective as androgen therapy in HAE butmay be useful in AAE [10,17,19,28]. TA is mostly usedfor prophylaxis in children before Tanner V pubertystage or if not wanting to risk androgen prophylaxis[8,17,19,29,31,35]. Dyspepsia is common and can bereduced by taking the drug with food. Other side effectsmay include myalgia, muscle weakness, elevated serumcreatine phosphokinase or aldolase, rhabdomyolysis(EACA particularly), hypotension, fatigue, and retinalchanges (seen in animals) [19,35,44,45]. TA dosage isnot well established [4,8,17,19,29,31,35,45] aiming forthe lowest effective maintenance with recommendedstarting dose of 20 to 50 mg/kg/day (split 2 to 3 timesdaily, taken with food, with daily maximum of 4 to 6 g;[4,8,17,19,35,44,45]. The dose may be able to be reducedto 0.5 g once or twice daily or even alternate-day ortwice weekly regimens [29]. TA Monitoring: sixmonthly CK, urinalysis, liver and renal function; annualophthalmology check for eye pressure (risk of glaucoma)[8,19,29,31,35]. AFs have not been associated withexcess thrombosis or myocardial infarction in controlledtrials [61-64], but there are case reports of thrombosisin patients with hypercoagulable states treated with AFs[65,66], so it is prudent to use it cautiously if there is afamily history of thrombophilia or active thromboem-bolic disease [35,45,65,66]. TA was reported effectivelong-term prophylaxis in HAE type III [67].Plasma-derived C1 inhibitor - pdC1INHHome pdC1INH self-infusion programs should beoffered to patients (created similar to hemophilia self-infusion programs which have existed for 35 years;[8,12,17,19,29,31,36,37,52,68,69]. The dose includingdose per kg for prophylaxis has not been fully estab-lished [12,14,36,37,70]. We recommend 500 units (if lessthan 50 kg, 110 lb) or 1000 units (if greater than 50 kg,110 lb) [1,12,14,19].Cinryze® from ViroPharma is FDA approved for ado-lescent and adult prophylaxis at a dose of 1000 unitsevery three or four days (see FDA approved packageinsert:http://www.fda.gov/BiologicsBloodVaccines/Blood-BloodProducts/ApprovedProducts/LicensedProducts-BLAs/FractionatedPlasmaProducts/ucm150480.htm)[12].Prophylaxis with pdC1INH is not 100% effective http://www.cinryze.com/documents/cinryze-prescribing-infor-mation.pdf. Cetor® from Sanquin is licensed in theNetherlands http://www.sanquinreagents.com/sanquin-eng/sqn_products_plasma.nsf/8551110e498bd2c8c12572110034decf/11343072be4286d2c125702a004a4e50/$FILE/Cetor%20SPC.pdf.Berinert® from CSL Behring is approved for therapyin many countries around the world including Europeand by USA FDA (see FDA approved package insert:http://www.fda.gov/BiologicsBloodVaccines/Blood-BloodProducts/ApprovedProducts/LicensedProducts-BLAs/FractionatedPlasmaProducts/ucm186264.htm).Reconstitution and administration of PdC1INH as perpackage inserts (see above web links; [18,19,35]). DONOT SHAKE as this will denature the protein. Admin-istration should be via peripheral vein (usually over tenminutes) (see product package insert references abovefor administration details) [8,18,19,29,31,35].Treatment of Acute HAE Attacks - see Figure 3We recommend treating attacks as early as possible.Plasma-derived C1-INH - PdC1INHPdC1INH has been the first line therapy for several dec-ades in Europe and elsewhere and used for many yearsin Canada under Special Access Program[8,12,17-19,29,31,35,37,38,48,52-54]. Berinert® from CSLBehring was licensed by USA FDA October 9th, 2009for therapy of HAE events and licensed in many othercountries for many years. Cetor® from Sanquin has beenavailable in The Netherlands for some time [35,53]. Ber-inert®, CSL Behring, has been shown to be more effec-tive than placebo for therapy of acute angioedemaattacks at a dose of 20 units/kg (see package insertreference above; [12,35,71]). However, use in othercountries is 500 to 1500 units [8,14,19,29,31,37,53,54,72]; Cetor dose recommendation is 1000 units -http://www.sanquin.nl/sanquin-eng/sqn_products_-plasma.nsf/8551110e498bd2c8c12572110034decf/11343072be4286d2c125702a004a4e50/$FILE/Cetor%20SPC.pdf). PdC1INH has been well tolerated and viraltransmission attributed to new generation pdC1INH hasnot been reported [33,36-38,73]. As pdC1INH is a bloodproduct, annual recipient hemovigilance and vein-to-vein tracking are essential (tracking and hemovigilancesimilar to home therapy programs for Hemophilia Com-prehensive Clinics). PdC1INH has been used to treatHAE attacks in HAE Type III [11,67].Bowen et al. Allergy, Asthma & Clinical Immunology 2010, 6:24http://www.aacijournal.com/content/6/1/24Page 7 of 13IcatibantIcatibant (Firazyr® from Jerini/Shire) is a small peptide,bradykinin receptor blocker approved for use in treat-ment of HAE in the European Union. Dose is 30 mgsubcutaneously in adults. Pediatric experience is pend-ing. Although not usually needed, the dose can berepeated six hourly twice more if needed (see packageinsert for Firazyr®). Local reactions are common withinjection [6,28]. Icatibant may be beneficial in type IIIHAE [11,74].EcallantideEcallantide, DX-88, Dyax, Kalbitor® is a small peptide,kallikrein inhibitor approved for treatment of HAE inthe USA since December 2009. Dose is 30 mg subcuta-neously (adults). It is not recommended for self infusionat this time because of a small risk of anaphylaxis and isbeing further studied in phase IV clinical trial [6].Emerging TherapiesRecombinant C1-INH, conestat alfa, Rhucin® is recom-binant human C1-INH produced in transgenic rabbitmilk [6,28]. Currently under FDA review, in June 2010it received a positive opinion from the European Medi-cines Agency’s (EMA) Committee for MedicinalProducts for Human Use (CHMP) for the treatment ofacute angioedema attacks in patients with HAE. Withthis positive opinion, the CHMP recommends the Eur-opean Commission to grant the European MarketingAuthorization. The product will be marketed in the EUunder the name Ruconest®.As new therapies become available, it will be veryimportant to conduct rigorous phase IV clinical trials(utilizing data base registries such as HAEA and HAEIand ESID provide) so that long term safety efficacy dataon these therapies can be closely monitored and toallow comparison of cost benefit studies including qual-ity of life issues between the various therapies. This willprovide funding organizations and patients better infor-mation on which to base their choices of products pro-vided under pharmaceutical plans and the most costeffective product for patient choice. It is exciting tofinally have licensed therapeutic and prophylactic medi-cations for treatment of this disorder.Other treatmentsIf the above currently available therapies such aspdC1INH, Icatibant, and Ecallantide are not available,other therapies may include increasing (usually dou-bling) the androgen (Danazol or Stanozolol) dose orantifibrinolytics [8,17,19,29,31,35]. However, unlikeFigure 3 Treatment of Acute Hereditary Angioedema - HAE - Attacks.Bowen et al. Allergy, Asthma & Clinical Immunology 2010, 6:24http://www.aacijournal.com/content/6/1/24Page 8 of 13pdC1INH, Icatibant, and Ecallantide, there are limiteddata to support this recommendation [3-5]. Use of sol-vent detergent plasma (SDP; preferred for viral trans-mission reasons over FP/FFP) could theoretically worsenattacks and remains controversial and again there are noclinical trials to support its use [8,19,29,31,35]. Adrena-line has been used but is usually of only modest andtransient benefit [8,19,29,31,75]. Pain management,intravenous fluids, and supportive care are essential butdo not affect the outcome of an attack and therefore arenot a replacement for early intervention with pdC1INH,Icatibant, Ecallantide or possibly recombinant C1INH orother emerging therapies.Comprehensive Care Clinics - Home Therapy: seeAppendix 1Comprehensive care clinics for immunedeficiencies, rareblood disorders, hemophilia, cystic fibrosis, asthma, can-cers and many other disorders have improved survival[76,77] and contributed to improved standard of carefor these disorders (see proceedings of the CanadianNational Rare Blood Disorders meeting:http://www.hemophilia.ca/en/about-the-chs/collabora-tion/network-of-rare-blood-disorder-organizations/2009-progress-in-comprehensive-care-for-rare-blood-disor-ders-conference——presented-by-csl-behring/#c969).Comprehensive care for HAE is based on the recogni-tion that HAE is a chronic disease and care is complex,requiring a highly specialized and multidisciplinaryapproach. A comprehensive care clinic must provideaccountability for in-hospital and home use of expensiveand potentially toxic treatments, track outcomes (bothbeneficial and adverse), and develop and meet Standardsof Care for HAE. It is recommended that HAE patientsbe linked with comprehensive care clinic programs(bringing together clinical care, education and research)to facilitate diagnosis, therapy, management; facilitatedata base registries; allow rigorous safety efficacymonitoring of emerging therapies of HAE; and to facili-tate access to home therapy programs (similar tothe model for comprehensive care of hemophilia)(see blood disorder conference link above;[8,16,19,29,31,36,35,37,54,68]). One clinic model can befound in Appendix 1 (also see [19,29,31]). Patients areencouraged to carry “alert” identification (wallet cardexample may be found at: http://www.haecanada.com/files/WalletCard_Bilingual.pdf) and an accompanyingletter indicating the diagnosis of HAE (with type), mate-rials necessary to be carried for care for presentation atair line and other security areas, and outlining instruc-tions for administration of intervention therapy (such asinfusion of pdC1INH). It is recommended that HAEorganization websites provide infusion instructions fordownloading by patients and comprehensive care clinics(example of home infusion technique may be viewed at:http://haecanada.com/infusion/index.html) Home ther-apy and particularly home pdC1INH infusion programsshould be offered to patients. Such programs should becreated similar to hemophilia home infusion programswhich have existed for 35 years (see blood disorders linkabove; [8,14,16,17,19,29,31,35-37,52,54,68]). Home carewas discussed at the 6th International HAE Conferenceheld in Budapest in June 2009 http://www.haenet.hu/new/program_C1INH2009.pdf and the resulting homecare consensus approach has been assembled [16].PediatricsMost of the pediatric considerations of HAE are incor-porated in the above algorithms (Figures 1, 2 and 3 andAppendix 1) and have been reviewed elsewhere. Mosttreatment drugs have been licensed for adults withpediatric licensing pending [6,8,14,18,19,29-31,35].Pregnancy and LactationMost of the pregnancy and lactation considerations ofHAE are incorporated in the above algorithms (Figures1, 2 and 3 and Appendix 1) and have been reviewedelsewhere. Most treatment drugs have not been trialedin pregnancy and are not licensed for use in this settingalthough there is anecdotal use of pdC1INH use inpregnancy and lactation [6,15,19,29,32,33,52,53]. Tra-nexamic acid can be found in breast milk [44].ConclusionSince our first Canadian International Consensus meet-ing in 2003 when plasma-derived C1-inhibitor concen-trates had been available for decades in Europe but notwidely outside Europe, many new therapies haveemerged in HAE management. Many phase III clinicaltrials have been completed and some reported on. Sev-eral products are now licensed for prophylaxis and ther-apy of HAE and hopefully are reducing the morbidityand mortality in this disorder. These therapies andhome care concepts are providing freedom for work,travel, and every day activities including sports activitieswith more normalization of life style and improved qual-ity of life for HAE patients. We must strive to elevatethe standard of care for HAE patients through compre-hensive care clinics and home care programs and insti-tute safety, efficacy, and cost benefit monitoring. Database registries may provide the health care systems,patients, and patient groups with the necessary data tochoose the most appropriate individualized managementof one’s HAE. Consensus approaches are only interimguides to chronic and rare diseases such as HAE andshould be replaced as soon as possible with more phaseIII studies, meta analyses, large phase IV post-marketingtrials, and head-to-head studies using data base registryBowen et al. Allergy, Asthma & Clinical Immunology 2010, 6:24http://www.aacijournal.com/content/6/1/24Page 9 of 13validation of consensus approaches including quality oflife and cost-benefit analyses followed by guidelines andthen standards for HAE disease management.Appendix 1 - Comprehensive Care Clinics forHereditary Angioedema - 2010 05 27(Modified by permission from: http://www.haecanada.com - comprehensive care clinics)Comprehensive Patient Care Clinics: Clinical care,Education, and ResearchComprehensive care for HAE is based on the recogni-tion that HAE is a chronic disease and care is complex,requiring a highly specialized and multidisciplinaryapproach. A comprehensive care clinic must provideaccountability for in-hospital and home use of expensiveand potentially toxic treatments, track outcomes (bothbeneficial and adverse), and develop and meet Standardsof Care for HAE.Comprehensive HAE Clinics will Provide1 Best Clinical Treatment outcomes including:a. a comprehensive care team made up of nursecoordinator, clinician, social worker, data man-ager, pain management specialist, genetic coun-sellor, and administrative support;b. access to specialized diagnostic testing;c. access to home treatment;d. a networked Patient Information System tofacilitate product recalls - collect data on therapyoutcome measures and safety, and facilitate parti-cipation in clinical trialse. access to clinical advances as they becomeavailable;f. access to 24 hour support;g. access to up-to-date standards of care, includ-ing standardized wallet cards;h. tracking and intermittent audit of quality out-comes including beneficial and adverse outcomesthrough secure, comprehensive and networkeddata management.2 Education of patients and staff regarding:a. responsible Self/Family Care (home caremodel) with home and self infusion/administra-tion instruction and support;b. developments in the cause, diagnosis, treat-ment, outcomes, and prognosis of HAEc. changes in the administrative management ofthe clinic3 An environment conducive to research including:a. access to and support for clinical trials of newtreatments;b. access to and support for translationalresearch in diagnosis and prognosis;c. accesss to and support for psychosocialresearch such as quality of life studies.4 An advisory or oversight board with patient grouprepresentation for each clinicAcknowledgementsFigures 1, 2, 3 and Appendix 1 are reprinted or modified from: [18]Bowen T, Cicardi M, Farkas H, Bork K, Kreuz W, Zingale L, et al. Canadian2003 International Consensus Algorithm For the Diagnosis, Therapy, andManagement of Hereditary Angioedema. J Allergy Clin Immunol2004;114:629-37, Copyright 2004, with permission from American Academyof Allergy, Asthma, and Immunology and from: [19]Bowen T, Cicardi M, Bork K, Zuraw B, Frank M, Ritchie B, et al. Hereditaryangioedema: a current state-of-the-art review, VII: Canadian Hungarian 2007International Consensus Algorithm for the Diagnosis, Therapy, andManagement of Hereditary Angioedema. Ann Allergy Asthma Immunol 2008;100(Suppl 2):S30-40, Copyright 2008, with permission from the AmericanCollege of Allergy, Asthma & Immunology. We have continued to useconsensus formats similar to previous publications to facilitate comparisonsof new versus old approaches. A comparison of previous consensusguidelines has recently been submitted (Bowen T [35]) and we havebenefited greatly from that comparison study (Bowen T [35]; ImmunologyAllergy Clin NA; 2010).Author details1Departments of Medicine and Paediatrics, University of Calgary, Calgary,Alberta, Canada. 2Department of Internal Medicine, Universita degli Studi diMilano, Ospedale L. Sacco, Milan, Italy. 33rd Department of Internal Medicine,Faculty of Medicine, Semmelweis University, Budapest, Hungary.4Department of Dermatology, University Hospital of the JohannesGutenberg-University of Mainz, Mainz, Germany. 5Department ofImmunology, Barts and the London NHS Trust, London, England, UK.6University of California, San Diego, San Diego, California, USA. 7JohannWolfgang Goethe University, Frankfurt/Main, Germany. 8Departments ofMedicine and Pediatrics, Penn State University, Hershey, Pennsylvania, USA.9Department of Medicine, University of Toronto, Toronto, Canada.10Department of Medicine, Laval University, Quebec City, Quebec, Canada.11Departments of Medicine and Medical Oncology, University of Alberta,Edmonton, Alberta, Canada. 12Department of Medicine, CHU de Grenoble,Grenoble, France. 13Member, Patient Advisory Committee, CanadianHereditary Angioedema Network (CHAEN)/Réseau Canadien d’angioédèmehéréditaire (RCAH). 705 South Tower, 3031 Hospital Dr. NW, Calgary, Alberta,Canada. 14Portage La Prairie, Manitoba, Canada. 15Department of Pediatrics,University of British Columbia, Vancouver, British Columbia, Canada.16Department of Medicine, Regina, Saskatchewan, Canada. 17MemorialUniversity and Janeway Child Health Centre, St. John’s, Newfoundland,Canada. 18Department of Medicine, McMaster University, Hamilton, Ontario,Canada. 19Department of Medicine, Dalhousie University, Halifax, NovaScotia, Canada. 20Department of Medicine, University of Toronto, Oakville,Ontario, Canada. 21Ancaster, Ontario, Canada. 22St. Catharines, Ontario,Canada; Member and Chair, Patient Advisory Committee, CanadianHereditary Angioedema Network (CHAEN)/Réseau Canadien d’angioédèmehéréditaire (RCAH. 23Transfusion Medicine, Ottawa Hospital, Ottawa, Ontario,Canada. 24Department of Medicine, University of Calgary, Calgary, Alberta,Canada. 25Department of Pediatrics, CHU Sainte-Justine, University ofMontreal, Montreal, Quebec, Canada. 26Department of Medicine, Universityof British Columbia, Vancouver, British Columbia, Canada. 27Halifax, NovaScotia, Canada. 28Brampton, Ontario, Canada. 29Queen’s University, Kingston,Ontario, Canada. 30Department of Medicine, University of Manitoba,Winnipeg, Manitoba, Canada. 31University of Auckland, Auckland, NewZealand. 32Department of Internal Medicine, University of Cincinnati,Cincinnati, Ohio, USA. 33Department of Clinical and Experimental Medicine,County Hospital Ryhov, Jönköping, Sweden. 34Calgary, Alberta, Canada.35Department of Dermatology and Allergy Centre, Odense UniversityHospital, Denmark. 36Hospital La Paz Health Research Institute, Madrid, Spain.37Duke University Medical Center, Durham, North Carolina, USA. 38Heim PalPediatric Hospital, Budapest, Hungary. 39Dept of Medicine, Academic MedicalCenter, Amsterdam Area, Netherlands. 40Institute for Asthma & Allergy,Bowen et al. Allergy, Asthma & Clinical Immunology 2010, 6:24http://www.aacijournal.com/content/6/1/24Page 10 of 13Wheaton and Chevy Chase, Maryland, USA. 414th Medical Clinic, University ofMedicine and Pharmacy, Tirgu Mures, Romania. 42Hungarian Association ofAngioedema Patients, Budapest, Hungary. 43Nordland Hospital, Bodo,University of Tromso, Norway. 44Department of Medicine, County HospitalRyhov, Jonkoping, Sweden. 45Tel Hashomer, and Sackler Faculty of Medicine,Tel Aviv University, Ramat Aviv, Israel. 46Asociación Española de AngioedemaFamiliar por Deficiencia del inhibidor de C1 (AEDAF), Madrid, Spain.47Institute of Pharmacology, University of Bern, Switzerland. 48Peking UnionMedical College Hospital, Beijing, China.Authors’ contributionsTB prepared the manuscript. All authors have read, revised and approvedthe manuscript.Competing interestsMany of the authors have either entered consultancy with or have beeninvolved in educational programs and their organization, had direct fundingfrom, have been speakers for, or have had consultation agreements withCSL Behring, Dyax, Jerini, Pharming, ViroPharma, Shire. The 2010International Consensus Algorithm for the Diagnosis, Therapy andManagement of Hereditary Angioedema was arrived at during the CanadianHereditary Angioedema Network (CHAEN)/Réseau Canadien d’angioédèmehéréditaire (RCAH) second meeting held May 15th/16th, 2010, Toronto,Canada and was cosponsored by CHAEN/RCAH, the Canadian Society ofAllergy and Clinical Immunology, and the University of Calgary and wasfunded through an unrestricted educational grant from CSL Behring.Publication of this manuscript is sponsored by University of Calgary.Received: 3 June 2010 Accepted: 28 July 2010 Published: 28 July 2010References1. 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Am JHematol 1994, 45:112-21.doi:10.1186/1710-1492-6-24Cite this article as: Bowen et al.: 2010 International consensus algorithmfor the diagnosis, therapy and management of hereditary angioedema.Allergy, Asthma & Clinical Immunology 2010 6:24.Submit your next manuscript to BioMed Centraland take full advantage of: • Convenient online submission• Thorough peer review• No space constraints or color figure charges• Immediate publication on acceptance• Inclusion in PubMed, CAS, Scopus and Google Scholar• Research which is freely available for redistributionSubmit your manuscript at www.biomedcentral.com/submitBowen et al. Allergy, Asthma & Clinical Immunology 2010, 6:24http://www.aacijournal.com/content/6/1/24Page 13 of 13


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