WAO GUIDELINE
`
`WAO Guideline for the Management of Hereditary
`Angioedema
`
`Timothy Craig, D0,’ Emel Aygdren Pilrsfin, MD,2 Konrad Bork, MD,3 Tom Bowen, MD,‘ Henrik Boysen,5
`Henriette Farkas, MD PhD.6 Anete Grumach; MD PhD,7 Constance H. Katelaris, MB BS PhD,8
`Richard Lockey. MD,9 Hilary Longhurst, MD,m William Lumry, MD,’ I Markus Magerl, MD, ’2
`Immaculada Martinez-Saguer, MD PhD,2 Bruce Ritchie, MD,” Alexander Nast, MD,”
`Ruby Pawankar, MD PhD, 14 Bruce Zuraw, MD,” and Marcus Maurer, MD”
`
`Abstract: Hereditary Angioedema (HAE) is a rare disease and for
`this reason proper diagnosis and appropriate therapy are often
`unknown or not available for physicians and other health care
`providers. For this reason we convened a group of specialists that
`focus upon HAE from around the world to develop not only a con-
`sensus on diagnosis and management of HAE, but to also provide
`evidence based grades. strength of evidence and classification for the
`consensus. Since both consensus and evidence grading were adhered
`to the document meets criteria as a guideline. The outcome of the
`guideline is to improve diagnosis and management of patients with
`HAE throughout the world and to help initiate uniform care and
`availability of therapies to all with the diagnosis no matter where the
`residence of the individual with HAE exists.
`
`Key Words: Hereditary Angioedema. Guidelines. HAE, therapy,
`management. diagnosis. medications. international
`
`(WAO Journal 2012; 51182—199)
`
`Review Board Consultation Group
`ichard Gower, rgower@marycliffallergycom (United
`States)
`Aleena Banerji (United States)
`Marc Riedel (United States)
`Paula Busse (United States)
`Paul Potter (South Africa)
`Yuxiang Zhi (China)
`Reshef Avner (Israel)
`Dumitru Moldovan (Romania)
`Andrew MacGinnitie (United States)
`Mark Gompels (United Kingdom)
`Wolfhart Kreuz (Germany)
`Laurence Bouillet (France)
`Peter Spaeth (Switzerland)
`Wei Te Lei (Taiwan)
`William Smith (Australia)
`Hiok Hee Chng (Singapore)
`
`From the 'Depanrnent of Medicine. Pediatrics and Graduate Studies. Penn Stan: University. Hershey. PA: 2Center for Pediatric and Juvenile Medicine. J.W. Goethe
`University. Frankfurt/(Main). Germany ’Department of Dermatology. Johannes Gutenberg University Muinz, Mainz. Germany; ‘Deparm-rents of Medicine and
`Pediatrics. University of Calgrry. Calgary. Canada; 51 ME. Orsay. France; “3'" Department of Internal Medicim. Semmelwcis University. Budapest. Hungary;
`7Outpatiem Group of Recurrent lnfoetims and laboratory of lmmtrnokrgy. Faculty ofMedicine ABC: Departmental Dcmratology, Faculty of Medicine. University
`of Sin Paulo. sro Paulo. Brazil; I‘Deprrrtrncrrt of Medicine. Campbelltown Hospital. University ofWestern Sydney. Sydney. New South Wales. Australia; ”Allergy.
`Asthma and Immunology Associates ol‘Tampn Bay. University of South Florida. Tampa. FL; I"ilepartrnent of lnrrmnology. Bats Health NHS Trust London.
`United Kingdom; ”Allergy and Asthma Specialists. Dallas. TX; Ichpanmcnt of Dermatology and Allergy. Allergichntrum-Clmrité. Chnrité‘Unchrsiu'itsmedizin
`Berlin, Berlin. Sexuality; Department ochdicine. University ol'Albem. Edmonton. Canada; "Division ofAllcrgy. Dept. of Pediatrics. Nippon Medical School.
`Tokyo. Japan: "President WAO. Professor of Medicine. Department of Medicine. University of California San Diego and San Diego VA lletrlthcare.
`T. Craig, Research: CSL Behring, Dyax. Pharming, Shire, and Virophanna. Speaker: CSL Behring. Dyax. Shire. and Virophamra. Unrestricted Educational
`Grants: CSL Behring, Dyax. and Virophamia. Consultant: CSL Behring. E. Aygfiren Pfirsiin has received speaker fees from CSL Behring. Shire. and
`Viropharma and has served on advrsory boards for CSL Behring. Pharming, Shire. and Viropharma K. Bork: consultant of CSL Behring. Shire. and
`ViroPhamra. T. Bowen. in the past year. has served on an Advisory Board for CSL Behring Canada. H. Boysen is an Executive Director of Hereditary
`Angioedema Association International. H. Farkas has received speaker fees from Shire and served an Advisory Board for CSL Behring. Shire. Pharming. and
`Virophamra. A. S. Grumaeh has served on Advisory Boards and as speaker for Shire (Brazil). Dr C, H. Katclaris has served an Advisory Boards for Shire.
`Australia, and CSL Behring, Australia. R. Lockcy is the Past President of World Allergy Association. H. Longhurst: (research) CSL Behring, Shire. and
`Viropharma. Speaker: CSL Behring. Shire, $081. and Viropharma. Unrestricted Educational Grants: CSL Behring and Shire. Consultant: CSL Behring,
`Shire, and 8081. W. R. Lumry. Consultant Arrangements: CSL Behring, Dyax. Shire HOT, and Viropharma Pharmaceuticals. Grants/Research Support: CSL
`Behring, Dysx, Pharming, Shire HGT. Viropharma Pharmaceuticals. Speaker's Bureau: CSL Behring, Dyax, Shire HGT, and Viropharma Pharmaceuticals.
`M. Magerl is or has been a speaker/consultant for Jerini, Shire, Sobi. Virophanna.
`l. Boccon-Gihod: CSL Behring. Shire, and Viropharma. B. Ritchie
`(research): CSL Behring, Dyax, Pharrning, and Shire. B. L. Zuraw is a consultant of Dyax, Shire. BioCryst; research support: Shire. M. Maurer is or has been
`a speaker/consultant for and/or has received research fimding from Biocryst. Jenni, Shire. and Viropharma.
`l. Manincz-Saguer (research): CSL Behring.
`Shire, Viropharma. and Pharrning and speaker fees from CSL Behring and Shire. Advisory Boards for CSL Behring, Shire, and Pharming.
`The authors have no conflicts of interest to disclose.
`Correspondence to: Marcus Maurer, MD, Department of Dermatology and Allergy. AllergieCentrum-Charité—Universitfitsmedizin Berlin. Charitéplatz l. IOI l7
`Berlin. Germany. Telephone: +49 30 450 518 043. Fax: +49 30 450 518 972. E-mail: marcus.maurer@eharite.de.
`Copyright © 2012 by World Allergy Organimtion
`
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`
`0 December 2012
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`WAO loumal 0 December 2012
`
`Hereditary Angioedema WAO Guideline
`
`Kazuo Akiyama (Japan)
`Werner Aberer (Austria)
`Isabelle Boccon-Gibot (France)
`Teresa Caballero (Spain)
`Dorottya Csuka (Hungary)
`Gullerrno Guidos—Fogelbaeh (Mexico)
`Allen Kaplan (United States)
`Alex Malbran (Argentina)
`Juan Matta Campos (Mexico)
`Sandra Nieto (Mexico)
`Nieves Prior (Spain)
`Elias Toubi (Israel)
`Lillian Varga (Hungary)
`Andrea Zanichelli (Italy)
`
`VOTING MEMBER SOCIETIES OF THE WORLD
`
`ALLERGY ORGANIZATION (OCTOBER 2012)
`Albanian Society of Allergology and Clinical Immunology
`Allergy & Immunology Society of Sri Lanka
`Allergy and Clinical Immunology Society (Singapore)
`Allergy Society of South Africa
`Allergy, Asthma and Immunology Society of Thailand
`American Academy of Allergy, Asthma and Immunology
`American College of Allergy, Asthma and Immunology
`Argentine Association of Allergy and Clinical Immunology
`Argentine Society of Allergy and Immunopathology
`Australasian Society of Clinical Immunology and Allergy
`Austrian Society of Allergology and Immunology
`Azerbaijan Society for Asthma, Allergy and Clinical
`Immunology
`Brazilian Society of Allergy and Immunopathology
`British Society for Allergy and Clinical Immunology
`Bulgarian National Society of Allergology
`Canadian Society of Allergy and Clinical Immunology
`Colombian
`Allergy,
`Asthma,
`and
`Immunology
`Association
`
`Croatian Society of Allergology and Clinical Immunology
`Cuban Society of Allergology
`Czech Society of Allergology and Clinical Immunology
`Danish Society for Allergology
`Dutch Society of Allergology
`Egyptian Society of Allergy and Clinical Immunology
`Egyptian Society of Pediatric Allergy and Immunology
`Finnish Society of Allergology and Clinical Immunology
`German Society for Allergology and Clinical Immunology
`Honduran Society of Allergy and Clinical Immunology
`Hong Kong Institute of Allergy
`Hungarian
`Society
`of Allergology
`Immunology
`Icelandic Society of Allergy and Immunology
`Indian College of Allergy, Asthma
`Immunology
`Indonesian Society for Allergy and Immunology
`Israel Association of Allergy and Clinical Immunology
`Italian Society for Allergology and Clinical Immunology
`Japanese Society of Allergology
`Jordanian Society for Allergy and Clinical Immunology
`
`and Clinical
`
`and Applied
`
`and Clinical
`
`in
`
`Korean Academy of Allergy, Asthma
`Immunology
`Kuwait Society of Allergy and Clinical Immunology
`Latvian Association of Allergists
`Lebanese Society of Allergy and Immunology
`Malaysian Society of Allergy and Immunology
`Mexican
`College
`of
`Pediatricians
`Specialized
`Allergy and Clinical Immunology
`Mongolian Society of Allergology
`Norwegian Society of Allergology and Immunopathology
`Panamanian Association of Allergology
`and Clinical
`Immunology
`Philippine Society of Allergy, Asthma and Immunology
`Polish Society of Allergology
`Romanian
`Society
`of Allergology
`Immunology
`Russian Association of Allergology
`Immunology
`Slovenian Association for Allergology and Clinical
`Immunology
`Spanish Society of Allergology and Clinical Immunology
`Swiss Society of Allergology and Immunology
`Turkish National Society of Allergy and Clinical
`Immunology
`Uruguayan Society of Allergology
`
`and Clinical
`
`and Clinical
`
`Contributing Regional Member Societles
`American Academy of Allergy, Asthma and Immunology
`American College of Allergy, Asthma and Immunology
`Asia Pacific Association of Allergy, Asthma and Clinical
`Immunology
`European Academy of Allergy and Clinical Immunology
`Latin American Society of Allergy and Immunology
`
`a global health
`is
`Hereditary angioedema (HAE)
`problem, and evidence-based guideline recommendations
`are needed to inform and guide clinical decision makers.
`This document presents the first global guideline for the
`management of HAE and was developed by the World
`Allergy Organization (WAO) HAE International Alliance.
`The WAO guideline on the management of HAE differs from
`previous consensus reports and position papers.
`It results
`from a complete review of the underlying evidence based on
`systematic and transparent assessments of the quality of this
`evidence in evidence profiles. Furthermore, we used a Grading
`of Recommendations Assessment, Development and Evalua-
`tion (GRADE)—based approach for developing the recommen-
`dations provided by this guideline.1 GRADE is recommended
`by the World Health Organization and takes into account that
`evidence alone is insufficient and that values and preferences,
`clinical circumstances, and clinical expertise inevitably influ-
`ence decisions.
`
`During the planning of the WAO HAE International
`Guidelines, Dr Richard Lockey, then President of the WAC,
`and Dr Timothy Craig, Chair of the committee, requested
`nominations from WAD-Affiliated Allergy and Immunology
`Associations to appoint members to the steering committee.
`
`© 2012 World Allergy Organization
`
`183
`
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`

`Craig, 6! al
`
`WAO lourna/ 0 December 2012
`
`the Steering
`In the development of this guideline,
`Committee first agreed, during a consensus meeting in
`September 2010 in Gargnano, Italy, on the clinical questions
`to be addressed by me guideline. Working groups were
`assigned to review and assess the evidence available to
`answer these questions.2
`Based on the assessment of the evidence, the panel
`members,
`in a consensus conference at
`the European
`Academy of Allergy and Clinical Immunology (EAACI)
`Annual Meeting in June 2011 in Istanbul, Turkey, devel-
`oped recommendations. Strong recommendations indicate
`that most physicians would want and only few would not
`want the recommended course of action, that adherence to
`the recommendation in clinical practice could be used as
`a quality criterion, and that the recommendation can be
`adapted as policy in most situations. Weak recommenda-
`tions should be interpreted to indicate that the majority of
`physicians would want, but that many would not want, the
`suggested course of action, that in clinical practice, different
`choices will be appropriate for individual patients, and that
`policy making will
`require substantial debate and the
`involvement of various stakeholders. Understanding the
`interpretation of these 2 grades—either strong or conditio-
`nal—of the strength of recommendations is essential for
`clinical decision making.
`A second uniqueness of this document is that world
`involvement was ensured by requesting nominations for
`the committee from affiliated Allergy and Immunology
`Associations of the WAO. This worldwide approach was
`necessary to have global appeal and opinion in the care of
`HAE. Even though therapies are limited in certain areas of
`the world, it is hoped that this consensus will help justify
`the use of therapies for all patients. Furthermore,
`this
`consensus hopefully will assist clinicians, medical associ-
`ations, HAE patient associations, and national medical
`communities to appeal for the appropriate therapies for all
`patients with HAE.
`The goal of this guideline is to provide clinicians and
`their patients with guidance for rational decisions in the
`management of HAE types 1 and 2 (HAE-l/Z). To this end,
`20 recommendations [numbered and given in framed boxes]
`were developed. The key clinical questions covered by these
`recommendations are (1) How should HAE be defined and
`classified? (2) How should HAE be diagnosed? (3) Should
`HAE-l/Z patients receive prophylactic and/or on-demand
`treatment and what treatment options should be used? (4)
`Should HAE-l/Z management be different
`for
`special
`HAE-1/2 patient groups such as pregnant/lactating women
`or children? and (5) Should HAE-l/Z management incor-
`porate self—administration of therapies and patient support
`measures?
`
`(2) relevant publications in the field of HAE, and (3)
`relevant experience in evidence-based medicine. Emphasis
`was placed on selecting a representative panel of experts
`from throughout the world to ensure global expertise and
`consensus. In addition, the WAO requested a representative
`from the international HAE patient association (HAEi) to
`participate as a steering committee member. Nine patient
`representatives were nominated by HAEi and participated
`in the process (selection of key questions and consensus
`conference).2
`
`Support for the Consensus
`The consensus conference held in Gargnano del
`Garda, Italy, from September 26 to 29, 2010, hosted 58
`experienced HAE expert physicians from 17 countries
`(listed as Hereditary Angioedema International Working
`Group). In addition, there were 22 representatives of the 5
`pharmaceutical companies producing drugs for HAE. The
`latter were invited to provide additional data on their
`products. These representatives did not take part in any
`voting procedures.
`Four of the 5 pharmaceutical companies producing
`drugs for HAE (CSL Behring, Marburg, Germany; Dyax,
`Cambridge, MA; Pharming, Leiden,
`the Netherlands;
`Shire, Dublin, Ireland; and ViroPharma, Exton, PA) pro-
`vided the financial support for the document and required
`meetings. Pharming did not have a product on the market
`at the time of the initiation of this endeavor. No company
`was present during the meetings, had input into the manuscript,
`or allowed to provide feedback. The pharmaceutical com-
`panies were not allowed to view the document before
`publication. This was essential to prevent bias and real or
`perceived commercial
`influence on the outcomes. All
`participants were required to submit conflict of interest
`statements to participate on the committee and were also
`required to submit conflict of interest documents with the
`manuscript.
`
`Selection of Key Questions
`the
`At
`the 2010 Gargnano Consensus Conference,
`guideline steering committee selected key questions by means
`of majority vote. Expert panel members were assigned to topic-
`focused working groups. These working groups performed
`targeted literature searches and used those results together with
`the outcome of the 2010 Gargnano Consensus Conference—
`developed guideline recommendations. These recommendations
`were then discussed and finalized during the 2011 Istanbul Con-
`sensus Conference. The working groups determined that for
`many of the key questions in HAE management, little or no
`evidence is available to base answers and recommendations on.
`
`MATERIALS AND METHODS
`
`The expert panel recognizes this cun'ent limitation.
`
`Nomination of Experts
`Individuals were nominated to the expert panel and
`group of authors by the WAO and affiliated associations.
`At least one of the following criteria had to be fulfilled:
`(l) extensive clinical experience in the treatment of HAE,
`
`Literature Search
`To find relevant literature for the identified key ques-
`tions, we performed systematic searches of the MEDLINE
`and COCHRANE databases. Our search covered the period
`
`184
`
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`
`© 2012 World Allergy Organization
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`

`

`WAO journal 0 December 2012
`
`Hereditary Angioedema WAO Guideline
`
`from January 1985 through September 2010. The search
`strategies were as follows:
`
`Step
`[3
`
`Search Term
`8 "AND danazol[ti] OR Slanozolofii] OR tibolonel'li]
`
`Hits
`6
`
`Hits
`Search Term
`Step
`832
`‘hereditary angioedema”
`1
`10
`“hereditary angiooedema”
`2
`85
`“hereditary angio-oedema"
`3
`292
`“hereditary angioneurotic edema"
`4
`9|
`“hereditary angioneurotic oedema"
`5
`l275
`l0R20R3OR4OR5
`6
`894
`limit 6 to yr=“l985 -Current”
`7
`
`
`8 33 limit 7 to “Clinical Trial"
`
`Results of search 8: Munch and Weeke,3 Lewis,“ Gluszko
`et 211,5 Cicardi et at,“ Waytes et at,7 Cicardi ct at.“ Goring et at,“
`Kunschak ct 81,", Farlcas ct a1,“ Bork and Bamstedt,l2 Gompcls
`et al,'3 Weiler et aLN Szeplaki et al,'5 van Doom et al.1"
`Bas ct al.l7 Bork et al.'8 Ott ct al,” Schneider or 211,29 Varga
`et a1,“ Visy et al,22 Birjmohun et al,"J Cedzynski et a1.” Szegedi
`et al,” Craig et al,26 Kreuz et :11,” Bas et al,28 Bernstein et a1,29
`Cicardi ct alf‘0 Cicardi et al,’1 Craig et al,32 Levy et al.33 Zuraw
`et a1,“ Zuraw et al.35
`Reasons for excluding a study from the 33 hits of search
`8 were as follows: (1) no original phase 3 (or 4) trials for acute
`treatment of HAE, (2) no human data, (3) no clinical data, and
`(4) not dealing with the management of HAE/not suitable to
`answer selected key questions. The bibliographic information
`of the included trials was transferred to an endnote database,
`and full-text publications were obtained. Further analysis was
`done using a standardized Literature Evaluation Form. Eval-
`uation was done by 2 independent assessors, who had been
`trained in using the Literature Evaluation Form. Any discrep-
`ancies were reviewed by a third assessor and resolved through
`discussion.
`
`the
`Using the Literature Evaluation Form (Fig. 1),
`methodologists evaluated a total of 33 studies. Of these stud-
`ies, 8 phase 3 trials were ultimately included.7'1°’26’3°'3"33‘35
`To further facilitate the evidence review, we also searched
`for meta-analyses, guidelines, and consensus statements.
`
`
`
`Hits
`Search Term
`Step
`0
`Limit 7 to “Meta-Analysis"
`9
`0
`Limit 7 to “Practice Guideline"
`to
`0
`Limit 7 to “Guideline”
`ll
`
`
`7 AND “consensus"12 12
`
`Results of search 12: Bissler et a1,” Zhang et a1,37
`Bowen et
`:1],38 Bowen et at,” Bracho,“ Chinen and
`Shearer,‘l Gompels et al,42 Bowen et al,"3 Bowen,“ Bowen
`et al.“5 Bowen er al.“5 and Longhurst et al.“7
`Four out of 12 (search l2)
`identified international
`consensus articles were considered relevant and were distributed
`to the group as a basis for discussion and adaptation.39"”"“""‘7
`To answer selected key questions,
`the search was
`further specified to the following:
`
`Results ofsearch 13: Cicardi et al,3 Farkas et at,“ Szeplaki
`et al,ls Ott et al,'9 Birjmohun et a1,23 and Szegedi et al.25
`Reasons for excluding a study were as follows: (1) no
`original data, (2) no human data, (3) no clinical data, and
`(4) not dealing with the management of HAE/not suitable to
`answer selected key questions. After screening, all hits
`fulfilled the inclusion criteria.
`
`Grade of Evidence
`Each trial included in the guideline was evaluated with
`regard to its methodological quality and assigned a grade of
`evidence according to the grading system used in previous
`guidelines: A, Randomized, double-blind, clinical trial of high
`quality (eg, sample size calculation,
`flow chart of patient
`inclusion, intention-to-u'eat analysis, sufficient sample size); B,
`Randomized clinical trial of lesser quality (eg, only single blind
`and limited sample size: at least 15 patients per study arm); C,
`Comparative trial with severe methodological limitations (eg,
`not blinded, very small sample size, and no randomization)
`or large retrospective observational studies; D, Adapted from
`existing consensus document or statement based on expert opin-
`ion voting during consensus conference.
`
`Strength of Recommendation
`To avoid any potential confusion, standardized phrases
`were used to express the strength of a recommendation
`throughout the guideline. The following GRADE definitions
`for recommendation strength were used: Strong recommenda-
`tions indicate that the desirable eflects of an intervention
`clearly outweigh the undesirable effects. When the trade-offs
`were less certain, a “conditional” strength of recommendations
`was assigned. In case of strong expert support, a strong rec-
`ommendation was applied even in cases where only very little
`evidence was available.
`
`Classification of Evidence
`
`A level of evidence was assigned to each clinical question
`based on the available trials/articles. The following levels of
`evidence for relevant key questions were applied; low levels
`of evidence indicate a need for more high-quality research in
`these areas.
`
`
`Number of Trials
`
`Authors
`
`Grade of
`Evidence
`
`A
`
`6
`
`Craig et al,” Cicardi et at,”
`Cicardi er al," Levy er a1.33
`Zuraw et a1,“ Zuraw et al35
`Kunschak et al '°
`Wuytcs ct al,7 Cicardi ct all,a
`Farkas et aL” Szeplaki
`ct al.'5 on et al,'°
`Birjmohun et al,23 Smgedi
`et al25
`Bowen ct al.39'““° Longhurst
`et al‘"
`
`© 2012 World Allergy Organization
`
`185
`
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`

`WAO loumal 0 December 2012
`Craig. et al
`
`
`
`General
`
`
`
`_N
`
`
`
`
`o oruingi data
`atients
`Fewer than 10
`
`
`Not a controlled
`
`
`No relevant efficacy data
`
`
`
`Ste: here if any item above is ticked
`
`
`ndh C1 iNH
`
`odh C1 INH na nofiltered
`
`
`rh C1 NH
`
`SKI-Ant
`
`KK-Ant
`
`Danazol
`
`
`Stanozolol
`
`FFP
`
`other .......
`
`
`Randomhtion
`
`
`
`
`
`
`
`
`not blinded O
`single 0
`
`
`
`
`
`0
`
`no 0
`
`not sure 0
`
`
`lntorfuin. eta-medication?
`
`
`
`a
`
`
`
`Number of patients after randomisation (n) =
`
` Number of arms =
`
`
`
`
`Grade at evidence
`
`
`A Randomized, double~blind clinical trial ofhigh quality (for example, sample-sire calculation, flow chart
`
`of patient inclusion, Intention-to—treat (ITI') analysis, sufficient sample size)
`Randomized clinical trial otlesser quality (for example, only single-blind, limited sample size: at least
`15 patients per study arm)
`
`
`C Comparative trial with severe methodological limitations [lor example, not blinded, very small
`
`
`sample size, no randomization) or large retrospective observational studies.
`
`
`D Adapted lrom existing consensus domment or statement based on expert opinion voting during
`
`consensus conference
`
`
`FIGURE 1. Literature evaluation form.
`
`Final Consensus Conference
`Based on the assessment of the evidence, the panel
`members, during a consensus conference in June 2011 in
`Istanbul, Turkey, the expert group developed recommenda-
`tions and agreed on the strength of these recommendations.
`
`International experts in HAE (the review board consultation
`group) were requested to review the Guidelines and provide
`feedback, suggestions and areas of dispute with the authors.
`The guidelines were then reviewed by the official body of
`the WAC composed of the regional allergy societies and the
`
`186
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`
`
`WAO [oumal 0 December 2012 Hereditary Angioedema WAO GuidelineH
`
`E T
`
`ABLE 1. Classification of AngioedemaH
`
` Bradyldnin-Induced AE
`
`Mast Cell Mediator—Induced AE
`
`U“"“°‘"‘
`Mediator
`Idiopathic
`Non-lgE
`lgE
`
`
`Cl-INH Normal Mediated MediatedCl-INH Deficiency/Defect Alla
`
`
`
`
`
`Inherited
`
`Acquired
`
`Inherited
`
`Acquired
`
`HAE-l
`HAE-2
`
`AAE
`
`HAE-3
`
`ACE-I
`
`Angiocdcma
`with
`anaphylaxis
`Urtiearia
`-
`
`Angiocdema
`with unicana
`
`—
`
`—
`
`--
`
`AAE. acquired angioedema due to Cl InhlblIOI' deficiency; ACE-l, angiotensin—converting enzyme-induced angioedcma: AB. angioedema; HAE-l. hereditary angioedema due to
`Cl inhibitor deficiency; HAE-2. hereditary angioedem: due to Cl Inhibitor defect; HAE-3. hereditary angioedema with normal Cl inhibitor levels.
`
`content and document were approved by the House of Dele-
`gates as the international guideline for HAE.
`
`DEFINITIONS, NOMENCLATURE,
`AND CLASSIFICATION
`
`Angioedema is defined as a vascular reaction of the deep
`dermis or subcutaneous/submucosal tissues with localized dila-
`tation and increased permeability of blood vessels resulting in
`tissue swelling.MHZ Angioedema can be mediated by bradyki-
`nin or mast cell mediators including histamine (Table l).53
`Bradykinin-mediated angioedema can occur either on a heredi—
`tary or acquired basis, due to a deficiency/defect of C1 inhibitor
`(Cl-INH) or not (Table 1).“""56 Three forms of HAE have been
`defined: (1) HAE due to Cl-INH deficiency (type 1 HAE,
`HAE-l), characterized by low antigenic and functional Cl-
`INH levels; (2) HAE due to Cl-INH dysfunction (type 2
`HAE, HAE-2), characterized by normal (or elevated) antigenic
`but low fimctional Cl-INH levels; and (3) HAE with normal
`C l -INH antigenic and functional levels (HAE-3). Acquired C1-
`INH deficiency refers to patients with an iocdema due to C1-
`INH deficiency on an acquired basis.”"°‘ 7 There are a variety
`of acquired types of angioedcma not due to Cl-INH deficiency,
`and these may be bradykinin mediated [eg, angiotensin-convert-
`ing enzyme inhibitor (ACE-I)-induced angioedema] or mast cell
`mediator histamine mediated (eg, urticaria] angioedema, ana-
`phylactic angioedema).
`
`PATHOPHYSIOLOGY
`
`Type 1 HAE and Type 2 HAE
`HAE due to Cl-INI-l deficiency/defect (HAE) is a rare
`disorder affecting approximately l:50,000 individuals. It is
`transmitted in an autosomal dominant genetic pattern. HAE-
`1/2 are caused by a large array of different mutations of the
`SERPINGI gene, which codes for Cl-INH. In approximately
`20%—25%, a de novo mutation of SERPING! is responsible
`for the disease.12'53‘”
`
`Cl-INH is a member of the serine protease inhibitor
`(serpin) superfamily and the major inhibitor of several comple-
`ment proteases (Clr, C15, and mannose-binding [econ-associated
`serine protease l and 2) and contact system proteases (plasma
`kallikrein and coagulation factor X1121) and a relatively minor
`inhibitor of the fibrinolytic protease plasmin and the coagulation
`protease factor Maw—(’2
`
`Compelling laboratory and clinical data have conclusively
`shown that bradykinin is the primary mediator of swelling in
`HAE-l/Z. The nanopeptide bradykinin is generated when active
`plasma kallikrein cleaves high-molecular weight kininogen.
`Plasma kallikrein is activated from its inactive zymogen by
`the protease factor XII, and both plasma kallikrcin and factor
`XII are normally inhibited by Cl—l'Nl-l. Bradykinin has a number
`of important effects on the body including nomial homeostasis,
`normal immune responses, inflammation, vascular tone, and vas-
`cular permeability. The vascular permeability—increasing effect
`of bradykinin in angioedcma is primarily mediated through the
`bradykinin BZ receptor,°3‘°5
`
`Type 3 HAE
`HAE with normal Cl-INH (HAE-3) is a very rare disease.
`The symptoms are very similar to HAE-U2. A subset of HAE-3
`patients exhibits mutations in factor XII, which are thought to
`likely be responsible for the disease. The genetic abnormality of
`most HAE-3 patients has not yet been defined. Because of the
`lack of a clear genetic definition of this type of HAE, the diag-
`nosis requires a family history of angioedema. There is clinical
`evidence that bradykinin also plays a major role in HAE-3.6M8
`
`Diagnosis
`HAE-l/2 should be suspected when a patient presents
`with a history of recurrent angioedema, especially if whcals
`(hives) are absent. This suspicion is further substantiated when
`patients report (1) a positive family history; (2) onset of sym-
`ptoms in childhood/adolescence; (3) reeun'ent abdominal pain
`attacks; (4) occurrence of upper airway edema; (5) failure to
`respond to antihistamines, glucocorticoid, or epinephrine; and
`(6) presence of prodromal signs or symptoms before swellings.
`Suspicion of HAE-U2 should prompt laboratory worku as the
`diagnosis of HAE-l/Z requires laboratory confirmation.
`‘43’“‘69
`
`Recommendation 1
`
`All patients suspected to have HAE-1/2(ie, recurrent
`angioedema in the absence of a known cause) should be
`assessed for blood levels of C4, Cl-INH protein, and CI-
`IN'H function, and these tests, if abnormally low, should be
`repeated to confirm the diagmsis. Evidence grade: D,
`
`strength of recommendation: strong.
`
`© 2012 World Allergy Organization
`
`187
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`Crag, et a1
`
`WAO lourna/ 0 December 2012
`
`Measurements of serum levels of C4, C1 inhibitor protein,
`and the Cl inhibitor functional activity are the major laboratory
`tests used to diagnose I-IAE-l/Z. In some cases, measuring the
`Clq level may be useful to help exclude AAE. Abnormal results
`should be confirmed, and normal results may need to be
`checked during an attack of angioedema. C4 is the single best
`screening test, and repeating the C4 during an attack increases
`the probability that a low C4 will be found. However, C4 is not
`a definitive test because neither the sensitivity nor specificity is
`absolute. There are occasional false-negative results that will be
`encountered, particularly in patients who are taking anabolic
`androgens. The C4 level should virtually always, however, be
`reduced during an attack of angioedema. Measurement of the
`activation product C4d may avoid false-negative results. False
`positives can also be encountered. In summary, the C4 level is
`useful for screening but cannot be relied upon to confirm or
`exclude a diagnosis of I-IAIS-l/2.'3'7°'71
`In a patient with a high index of suspicion for HAE, the
`Cl-INH antigenic level and/or functional activity should be
`directly measured. The Cl-INI-I antigenic level is low in HAE-l
`and acquired Cl-INH deficiency patients but is normal in HAE-Z
`patients. The Cl-INH functional activity is low in HAE-l and
`HAE-Z and acquired Cl-INH deficiency patientsn’u'72
`In rare patients, sequencing of the SERPINGI gene can
`be done to pursue diagnosis of HAE-l/Z; sequencing of factor
`XII genes can help to diagnose HAE-3; however, it is rare that
`this approach is needed. Complement C3 levels are expected
`to be normal, and testing CHSO is not usefiil. Many patients
`with acquired Cl-INH deficiency have autoantibodies that
`recognize and inactivate Cl-INH.73"75
`
`Differential Diagnosis
`The differential diagnoses of HAE—1/2 include HAE-3 (ie,
`HAE with normal Cl-INH), acquired CI-INI-I deficiency
`(AAE), ACE-induced angioedema, mast cell mediator-induced
`angioedema (eg, chronic spontaneous urticaria, allergic angio-
`edema), and idiopathic angioedema (Fig. 2). Because the path-
`ophysiology and the treatment of these diseases are different
`than those of HAE-l/Z, it is important to determine the exact
`diagnosis so that appropriate therapy for the specific
`e of
`angioedema the patient is manifesting can be usedwfi’4 3’76
`Mast cell mediator-induced angioedema is fi'equently
`associated with wheal- and flare-type skin reactions (hives),
`ie, in patients with chronic urticaria, and is more common than
`bradykinin-induced angioedema. Antihistamines, epinephrine,
`and glucoconicosteroids are effective in treating mast cell
`mediator—induced angioedema, but higher than standard doses
`of antihistamines are frequently necessary. Because mast cell
`mediator-induced angioedema is
`far more common than
`I-IAE-l/2, therapy with antihistamines and, if necessary, with
`epinephrine and glucocorticosteroids,
`is indicated when the
`diagnosis is not yet determined and the history seems to be
`inconsistent with HAE.”78
`HAE-3 is similar to HAE-l/Z but shows differences in
`
`the underlying pathophysiological pathways. Because of this,
`the management may be different and it should not be assumed
`that HAE-3 will
`respond similarly to available therapies
`designed to treat HAE- l/2.w"(’7'79 Angioedema may be second-
`ary to medications and frequently complicates the use of ACE
`
`188
`
`Page 7 of 18
`
`inhibitors (ACE-I). One in 200 to 1000 patients treated with
`ACE-I will develop angioedema. Angioedema from ACE-I is
`bradykinin-induced but has a different mechanism than HAE—
`1/2. Because of the difference in pathophysiology, response to
`medications used for I-IAE-l and HAE-Z cannot be assumed to
`
`work in ACE-I angioedema.
`Angioedema due to acquired Cl-INH deficiency is
`a rare disease that presents similarly to HAE. Differences
`include onset in later age, ofien underlying diseases such as
`lymphoma or monoclonal gammopathy, occasional constitu-
`tional symptoms, and depressed C1 q-r-s levels. Clq level
`measurements should be obtained to investigate pa