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      The international WAO/EAACI guideline for the management of hereditary angioedema – The 2021 revision and update

      research-article
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      The World Allergy Organization Journal
      World Allergy Organization
      Hereditary angioedema, C1-inhibitor, diagnosis, GRADE therapy, management, disease control, DELPHI, guideline, prophylaxis, quality of life, recommendations, self-administration

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          Abstract

          Hereditary Angioedema (HAE) is a rare and disabling disease for which early diagnosis and effective therapy are critical. This revision and update of the global WAO/EAACI guideline on the diagnosis and management of HAE provides up-to-date guidance for the management of HAE. For this update and revision of the guideline, an international panel of experts reviewed the existing evidence, developed 28 recommendations, and established consensus by an online DELPHI process. The goal of these recommendations and guideline is to help physicians and their patients in making rational decisions in the management of HAE with deficient C1-inhibitor (type 1) and HAE with dysfunctional C1-inhibitor (type 2), by providing guidance on common and important clinical issues, such as: 1) How should HAE be diagnosed? 2) When should HAE patients receive prophylactic on top of on-demand treatment and what treatments should be used? 3) What are the goals of treatment? 4) Should HAE management be different for special HAE patient groups such as children or pregnant/breast feeding women? 5) How should HAE patients monitor their disease activity, impact, and control? It is also the intention of this guideline to help establish global standards for the management of HAE and to encourage and facilitate the use of recommended diagnostics and therapies for all patients.

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          Defining consensus: a systematic review recommends methodologic criteria for reporting of Delphi studies.

          To investigate how consensus is operationalized in Delphi studies and to explore the role of consensus in determining the results of these studies. Systematic review of a random sample of 100 English language Delphi studies, from two large multidisciplinary databases [ISI Web of Science (Thompson Reuters, New York, NY) and Scopus (Elsevier, Amsterdam, NL)], published between 2000 and 2009. About 98 of the Delphi studies purported to assess consensus, although a definition for consensus was only provided in 72 of the studies (64 a priori). The most common definition for consensus was percent agreement (25 studies), with 75% being the median threshold to define consensus. Although the authors concluded in 86 of the studies that consensus was achieved, consensus was only specified a priori (with a threshold value) in 42 of these studies. Achievement of consensus was related to the decision to stop the Delphi study in only 23 studies, with 70 studies terminating after a specified number of rounds. Although consensus generally is felt to be of primary importance to the Delphi process, definitions of consensus vary widely and are poorly reported. Improved criteria for reporting of methods of Delphi studies are required. Copyright © 2014 Elsevier Inc. All rights reserved.
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            The EAACI/GA²LEN/EDF/WAO Guideline for the Definition, Classification, Diagnosis and Management of Urticaria. The 2017 Revision and Update

            This evidence- and consensus-based guideline was developed following the methods recommended by Cochrane and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group. The conference was held on 1 December 2016. It is a joint initiative of the Dermatology Section of the European Academy of Allergology and Clinical Immunology (EAACI), the EU-founded network of excellence, the Global Allergy and Asthma European Network (GA²LEN), the European Dermatology Forum (EDF) and the World Allergy Organization (WAO) with the participation of 48 delegates of 42 national and international societies. This guideline was acknowledged and accepted by the European Union of Medical Specialists (UEMS). Urticaria is a frequent, mast cell-driven disease, presenting with wheals, angioedema, or both. The lifetime prevalence for acute urticaria is approximately 20%. Chronic spontaneous urticaria and other chronic forms of urticaria are disabling, impair quality of life and affect performance at work and school. This guideline covers the definition and classification of urticaria, taking into account the recent progress in identifying its causes, eliciting factors and pathomechanisms. In addition, it outlines evidence-based diagnostic and therapeutic approaches for the different subtypes of urticaria.
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              Hereditary angioedema: new findings concerning symptoms, affected organs, and course.

              Hereditary angioedema (HAE) due to C1 inhibitor deficiency is clinically characterized by relapsing skin swellings, abdominal pain attacks, and life-threatening upper airway obstruction. Our aim was to examine a temporal and spatial pattern of the edema episodes by evaluating the long-term course of hereditary angioedema in order to establish a specific swelling pattern. Data were generated from 221 patients with C1 inhibitor deficiency by asking them about symptoms they experienced during their edema episodes. Documentation was accomplished through the use of standardized questionnaires. A total of 131110 edema episodes were observed. Clinical symptoms started at a mean age of 11.2 (SD 7.7) years. During the following cumulative 5736 years, only 370 (6.5%) symptom-free years occurred. Skin swellings, including extremity, facial, genital, and trunk swellings, and abdominal attacks occurred in 97.4% of all edema episodes of the disease. The other episodes were laryngeal edema (0.9%); edema of the soft palate (0.6%); tongue swellings (0.3%); headache episodes (0.7%); episodes affecting urinary bladder (0.3%), chest (0.2%), muscles (0.4%), joints (0.1%), kidneys (0.1%), and esophagus (0.05%), and were partly combined with other edema episodes. The per-patient analysis and the per-episode analysis revealed markedly discrepant results. On average, women had a more severe course of the disease than men. Patients with early onset of clinical symptoms were affected more severely than those with late onset. The described swelling pattern is specific for HAE and allows a tentative diagnosis based on clinical symptoms and the course of the disease.
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                Author and article information

                Contributors
                Journal
                World Allergy Organ J
                World Allergy Organ J
                The World Allergy Organization Journal
                World Allergy Organization
                1939-4551
                07 April 2022
                March 2022
                07 April 2022
                : 15
                : 3
                : 100627
                Affiliations
                [a ]Institute of Allergology, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
                [b ]Frauhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology and Allergology, Berlin, Germany
                [c ]University of Toronto, Toronto, Ontario, Canada
                [d ]Department of Dermatology, Medical University of Graz, Graz, Austria
                [e ]Department of Allergy & Immunology, Hospital Quironsalúd Bizkaia, Bilbao-Errandio, Spain
                [f ]Center for Children and Adolescents, University Hospital Frankfurt, Frankfurt, Germany
                [g ]Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Boston, MA, United States
                [h ]Romanian Hereditary Angioedema Expertise Centre, Mediquest Clinical Research Center, Sangeorgiu de Mures, Romania
                [i ]National Reference Center for Angioedema (CREAK), Angioedema Center of Reference and Excellence (ACARE), Grenoble Alpes, France
                [j ]University Hospital, Grenoble, France
                [k ]Department of Dermatology, University Medical Center, Johannes Gutenberg University, Mainz, Germany
                [l ]HAE International (HAEi), Skanderborg, Denmark
                [m ]Department of Pediatric Immunology, Childrens Hospital, Skåne University Hospital, Lund, Sweden
                [n ]Icahn School of Medicine at Mount Sinai, New York, NY, United States
                [o ]Clinical Institute, University of Southern Denmark, Odense, Denmark
                [p ]Department of Clinical Genetics, Odense University Hospital, Odense, Denmark
                [q ]Allergy Department, Hospital Universitario La Paz, IdiPaz, CIBERER U754, Madrid, Spain
                [r ]Department of Systems Medicine, University Hospital of Padua, Padua, Italy
                [s ]Department of Vascular Medicine, Amsterdam UMC/University of Amsterdam, Amsterdam, the Netherlands
                [t ]Department of Internal Medicine and Haematology, Hungarian Angioedema Center of Reference and Excellence, Semmelweis University, Budapest, Hungary
                [u ]Clinical Immunology, North Bristol NHS Trust, Bristol, United Kingdom
                [v ]Marycliff Clinical Research, Principle Research Solutions, Spokane, WA, United States
                [w ]Clinical Immunology, Centro Universitario FMABC, Sao Paulo, Brazil
                [x ]Instituto Politécnico Nacional SEPI-ENMH, Mexico City, Mexico
                [y ]Department of Dermatology, Hiroshima Citizens Hospital, Hiroshima, Japan
                [z ]Department of Dermatology, Hiroshima University, Hiroshima, Japan
                [aa ]Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea
                [ab ]Division of Pulmonary, Critical Care, Allergy and Immunology, Medical University of South Carolina, Charleston, SC, United States
                [ac ]Department of Medicine, Campbelltown Hospital and Western Sydney University, Sydney, NSW, Australia
                [ad ]Department of Immunology, Barts Health NHS Trust, London, United Kingdom
                [ae ]Division of Allergy, Immunology, and Rheumatology, Department of Pediatrics, Mackay Memorial Hospital, Hsinchu, Taiwan
                [af ]Division of Allergy and Immunology, Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, United States
                [ag ]Department of Immunology, Auckland District Health Board and Department of Medicine, University of Auckland, Auckland, New Zealand
                [ah ]Internal Medicine, Allergy Division, University of Texas Health Science Center, Dallas, TX, United States
                [ai ]Division of Immunology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States
                [aj ]Unidad de Alergia, Asma e Inmunología Clínica, Buenos Aires, Argentina
                [ak ]Pediatrics, Haemophilia Centre Rhine Main (HZRM), Moerfelden-Walldorf, Germany
                [al ]UMAE Hospital Especialidades C.M.N.SXXI, I.M.S.S., México City, Mexico
                [am ]Department of Dermatology, Venereology and Allergology, Division of Evidence-Based Medicine Charité–Universitätsmedizin, Berlin, Germany
                [an ]Corporate Member of Free University of Berlin, Humboldt University of Berlin, Berlin Institute of Health, Berlin, Germany
                [ao ]Respiratory, Allergy and Clinical Immunology Unit, Internal Medicine Department, Vinmec Healthcare System, College of Health Sciences, VinUniversity, Hanoi, Viet Nam
                [ap ]Genetic Unit of Nutrition, National Institute of Pediatrics, Mexico City, Mexico
                [aq ]Department of Pediatrics, Nippon Medical School, Tokyo, Japan
                [ar ]Division of Allergy and Clinical Immunology, University of Cape Town, Cape Town, South Africa
                [as ]Allergy and Immunology Unit, University of Cape Town Lung Institute, Cape Town, South Africa
                [at ]Department of Clinical and Environmental Allergology, Jagiellonian University Medical College, Krakow, Poland
                [au ]Allergy, Hospital Universitario Severo Ochoa, Madrid, Spain
                [av ]Angiedema Center, Barzilai University Medical Center, Ashkelon, Israel
                [aw ]Division of Rheumatology, Allergy and Immunology, University of California San Diego, La Jolla, CA, USA
                [ax ]Departments of Medicine and Medical Oncology, University of Alberta, Edmonton, AB, Canada
                [ay ]Section of Adult Allergy & Immunology, Department of Medicine, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
                [az ]Clinical Immunology and Allergy, Royal Adelaide Hospital, Adelaide, SA, Australia
                [ba ]Institute of Pharmacology, University of Bern, Bern, Switzerland
                [bb ]Division of Allergy and Clinical Immunology, Bnai Zion Medical Center, Affiliated with Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
                [bc ]Department of Internal Medicine, ASST Fatebenefratelli Sacco, Ospedale Luigi Sacco-University of Milan, Milan, Italy
                [bd ]Department of Allergy and Clinical Immunology, Bejing Union Medical College Hospital, Chinese Academy of Medical Sciences, Bejing, China
                [be ]University of California, San Diego, San Diego, CA, United States
                [bf ]Departments of Medicine and Pediatrics, Penn State University, Hershey, PA, USA
                Author notes
                []Corresponding and marcus.maurer@ 123456charite.de
                [∗∗ ]co-corresponding authors. Marcus Maurer and Markus Magerl. Institute of Allergology, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany. Frauhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology and Allergology, Berlin, Germany. markus.magerl@ 123456charite.de
                [1]

                Marcus Maurer, Markus Magerl, Stephen Betschel and Timothy Craig contributed equally.

                Article
                S1939-4551(22)00003-5 100627
                10.1016/j.waojou.2022.100627
                9023902
                35006617
                79afa57c-5466-4fe5-8082-bdd2867a7d08
                © 2022 The Author(s)

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 5 November 2021
                : 5 November 2021
                : 21 December 2021
                Categories
                Position Article and Guidelines

                Immunology
                hereditary angioedema,c1-inhibitor,diagnosis,grade therapy,management,disease control,delphi,guideline,prophylaxis,quality of life,recommendations,self-administration

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