global atlas of asthma

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GLOBAL

ATLAS

OF

ASTHMAP u b l i s h e d b y t h e E u r o p e a n A c a d e m y o f A l l e r g y a n d C l i n i c a l I m m u n o l o g y


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Asthma from

epidemiology,

risk factors and

mechanisms to

phenotypes and

management

Major currentproblems

in asthma

Diseases

associated with

asthma

Prevention

and control

of asthma

JC Virchow 2 What is asthmaJM Drazen 4 History of asthma

MI Asher 7The asthma epidemic - Global and time trends of asthma inchildren

J Genuneit, D Jarvis, C Flohr 10The asthma epidemic - Global and time trends of asthma inadults

P Burney 14 Death and disability due to asthmaRG van Wijk 18 Socio-economic costs of asthma

U Wahn 21 Natural history of asthmaR Lauener 23 Genetics of asthma

ST Weiss, K Tantisira 25 Pharmacogenetics of asthmaM Akdis 28 The pathogenesis of asthma

M Triggiani, M Jutel, EF Knol 31 The underlying mechanisms of asthma

S Wenzel 34 Phenotypes & endotypes: emerging concepts on asthmaheterogeneity

I Annesi-Maesano 36 Environmental risk factors for asthmaE von Mutius 39 Life style risk and protective factors for asthma

J Schwarze 42 Infections and asthmaG Roberts 45 Emerging risk and protective factors for asthma

PG Holt 48 Perinatal and early life inuences on asthma developmentH Smith 52 Psychological factors and asthma

A Custovic 55 The complex network of asthma risk and protective factorsNG Papadopoulos 57 Asthma in childhood

DK Ledford 60 Asthma in the elderlyLP Boulet 65 Asthma in the elite athlete

JA Namazy, M Schatz 68 Asthma in pregnancyS Quirce, E Hefer 71 Work-related asthma

B Marku, A Papi 75 Asthma management

J Fingleton, R Beasley 79 Asthma monitoring

CA Akdis 106 Unmet needs in asthma

DJ Jackson, SL Johnston 109 Asthma exacerbationsTB Casale 112 Severe asthma

K Ohta, O Nagase 115 Adherence to asthma treatmentRS Gupta, CM Warren 118 Social determinants of asthma

HE Neffen 120 Inequities and asthma

AJ Frew 84 Atopy and asthmaPW Hellings 86 Upper airway diseases and asthma

PG Gibson 89 Asthma and obesity, the twin epidemicsML Kowalski, S Bavbek 92 Aspirin exacerbated respiratory disease

RF Lockey 95 Gastro-esophageal reux disease and asthmaM Cazzola 98 Cardiovascular diseases and asthma

R van Ree, A Muraro 100 Food allergy and asthmaT Werfel, C Grattan 102 Skin and lung: atopic dermatitis, urticaria and asthma

KH Carlsen, KC Ldrup Carlsen 124 Primary and secondary prevention of asthmaMB Bil, M Caldern, V Cardona 127 Allergen immunotherapy in asthma

PM O'Byrne 130 Asthma controlI Agache 132 Best buys for asthma prevention and control

T Haahtela 135Evidence for asthma control zero tolerance to asthma with theFinnish programmes

J Bousquet 138The need for integrated and complimentary strategies in thepolitical agenda

OM Yusuf 140Policies and strategies to facilitate access to asthma diagnosisand treatment

G WK Wong 145 Policies and strategies to reduce risk factors for asthmaNC Thomson 147 Tobacco control and asthma

L Delgado, R Barros, A Moreira 151 Implementation of a healthy life style and asthmaP Eigenmann 155 Individual interventions for asthma prevention and control

D Ryan 157 The role of Primary Care in the prevention and control of asthm

B Flood, G Schppi 161Role of patient organisations in the control and prevention ofasthma

E Valovirta 164 Social mobilisation for prevention and control of asthmaS Mendis 167 Asthma in resource constrained settings

P Demoly 169Dealing with the implementation gap for asthma prevention andcontrol

B Samoliski, A Czupryniak 171 Generating resources for prevention and control of asthma

WW Busse 173

Asthma prevention and control: Why it should not be ignored

any longer?CA Akdis 175 Vision, roadmap and a land-marking event


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GLOBAL ATLAS

OF ASTHMA

Published by the European Academy of Allergy and Clinical Immunology

2013

Cezmi A. Akdis

Ioana Agache

Editors

Editorial Board

Victria Cardona

Adnan CustovicPascal Demoly

Jan LtvallAntonella Muraro

Nikolaos G. PapadopoulosJ. Christian Virchow


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GLOBAL ATLAS OF ASTHMA

II

BOARD OF OFFICERS

Cezmi A. Akdis, PresidentNikolaos G. Papadopoulos, Secretary General

Antonella Muraro, Treasurer

Victria Cardona, Vice-President Communication and Membership

Pascal Demoly, Vice-President Education and Specialty

J. Christian Virchow, Vice-President Congresses

Jan Ltvall, Past President

SECTION CHAIRPERSONS

Adnan Custovic, Asthma

Clive Grattan, Dermatology

Peter W. Hellings, ENT

Edward F. Knol, Immunology

Graham Roberts, Pediatrics

Enrico Hefer, Junior Members and Afliates

INTEREST GROUP REPRESENTATIVES

M. Beatrice Bil

Thomas Werfel

MEMBERS AT LARGE

Ioana Agache

Sevim Bavbek

Philippe Eigenmann

Marek Jutel

MassimoTriggiani

Ronald van Ree

ADJUNCT MEMBERS

Fulvio Braido, CME Committee Chairperson

Jan de Monchy, Specialty Committee Chairperson

Jacques Gayraud, Ethics Committee Secretary

Peter Schmid-Grendelmeier, Exam Committee Chairperson

Marek Jutel, SPC Co-ordinator

Chrysanthi Skevaki, Web Editor

Michael Walker, Executive Director

EAACI Executive Committee

EAACI EXECUTIVE COMMITTEE


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III

Ioana Agache, MD, PhDAssociate Professor, Faculty

of Medicine, Department ofAllergy and Clinical Immunology,Transylvania University of Brasov,Romania

Mbeccel Akdis, MD, PhDSwiss Institute of Allergy and Asthma

Research (SIAF), University ofZurich, Davos, Switzerland

Cezmi A. Akdis, MDSwiss Institute of Allergy and Asthma

Research (SIAF), University ofZurich, Davos, Switzerland

Christine Khne-Center for AllergyResearch and Education (CK-CARE), Davos

Professor, Medical Faculty, Universityof Zurich

Cezmi A. Akdis, MDPresident of the European Academy

of Allergy and Clinical Immunology

Isabella Annesi-Maesano, MD, PhDEpidemiology of Allergic and

Respiratory Diseases DepartmentUnit Mixte de Recherche -S 707

Institut National de la Sant et

de la Recherche Mdicale andUniversit Pierre et Marie Curie,Paris, France

M. Innes Asher, MDDepartment of Paediatrics: Child

and Youth Health, Faculty ofMedical and Health Sciences, TheUniversity of Auckland

Honorary Consultant Paediatrician,Starship Childrens Health

Renata Barros, PhDFaculty of Nutrition and Food

Sciences, University of Porto

Sevim Bavbek, MDDepartment of Immunology and

Allergy, Ankara University, Schoolof Medicine, Ankara, Turkey

Richard Beasley, MD, PhDDirector, Medical Research Institute

of New Zealand, Wellington, NewZealand

Adjunct Professor, VictoriaUniversity of Wellington

Adjunct Professor, University of

Otago WellingtonVisiting Professor, University of

Southampton, Southampton, NewZealand

M. Beatrice Bil, MDAllergy Unit, Department of

Immunology, Allergy &Respiratory Diseases, UniversityHospital Ospedali Riuniti diAncona, Ancona, Italy

Louis-Philippe Boulet, MDInstitut Universitaire de Cardiologie

et de Pneumologie de Qubec,Canada

Jean Bousquet, MD, PhDProfessor of Pulmonary Medicine,University of Montpellier, France

Chairman of the WHO Global AllianceAgainst Chronic RespiratoryDiseases (GARD)

Director of the WHO CollaboratingCentre for Asthma and Rhinitis inMontpellier

Chair, MeDALL (Mechanisms of theDevelopment of Allergy, FP7)

PeterBurney, MDRespiratory Epidemiology and

Public Health, National Heart &Lung Institute, Imperial College,London, UK

William W. Busse, MDDepartment of Medicine, Section of

Allergy, Pulmonary and CriticalCare Medicine, University ofWisconsin School of Medicineand Public Health, Madison,Wisconsin, USA

Moiss Caldern, MD, PhDSection of Allergy and Clinical

Immunology, Imperial College,

NHLI, Royal Brompton Hospital,London, UK

Victria Cardona, MD, PhDAllergy Section, Department of

Internal Medicine, Hospital ValldHebron, Barcelona, Spain

Kai-Hkon Carlsen, MD, PhDUniversity of Oslo, Institute of

Clinical MedicineOslo University Hospital, Department

of Paediatrics

Norwegian School of Sport Sciences,Oslo, Norway

Thomas B. Casale, MDProfessor Of Medicine, Chief

Allergy/Immunology, CreightonUniversity, Omaha, NE, USA

Mario Cazzola, MDUnit of Respiratory Clinical

Pharmacology, Department ofSystem Medicine, University ofRome Tor Vergata, Italy

Adnan Custovic, MD, PhDProfessor of Allergy, University

of Manchester, Second Floor,Education and Research Centre,University Hospital of SouthManchester, UK

Agnieszka CzupryniakExpert in European Programmes and

Healthcare, Warsaw, Poland

Luis Delgado, MD, PhDFaculty of Medicine, Porto UniversityCentro Hospitalar So Joo EPE,

Porto, Portugal

Pascal Demoly, MD, PhDProfessor of Pulmonary Medicine,

University Hospital of Montpellier,

Montpellier, FranceAllergy Division, Pulmonary

Department, Institut Nationalde la Sant et de la RechercheMdicale

Hpital Arnaud de Villeneuve

Jeffrey Drazen, MDEditor-in-Chief, New England Journal

of MedicineDistinguished Parker B. Francis

Professor of Medicine, HarvardMedical School

Professor of Physiology, Harvard

School of Public Health, Boston,Massachusetts, USA

Philippe Eigenmann, MDAssociate Professor at the

Department of Infants andAdolescents at the Hpitalcantonal Universitaire Genve(HUG)

Pediatric Allergy Unit, Departmentof Pediatrics, Childrens Hospital,University Hospitals of Geneva,

Contributors

CONTRIBUTORS


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IV

Geneva, Switzerland

James Fingleton, MDMedical Research Fellow, Medical

Research Institute of NewZealand, Wellington, New Zealand

School of Biological Sciences, VictoriaUniversity of Wellington

Carsten Flohr, MDSt Thomas Hospital & Kings College

London, UK

Breda FloodPresident, European Federation of

Allergy and Airways DiseasesPatients Associations (EFA)

Anthony J Frew, MDDept of Allergy & Respiratory

Medicine, Royal Sussex County,Hospital Brighton, UK

Jon Genuneit, MDInstitute of Epidemiology and

Medical Biometry, Ulm University,Germany

Peter G. Gibson, MBBSCentre for Asthma and Respiratory

Diseases, University of Newcastle,NSW, Australia

Department of Respiratory andSleep Medicine, Hunter MedicalResearch Institute, John HunterHospital, Newcastle, NSW,Australia

Clive Grattan, MD

Norfolk & Norwich UniversityHospital, Norwich, UK

Ruchi Gupta, MDAssociate Professor of Pediatrics,

Center for Healthcare Studies,Institute for Public Health andMedicine, Feinberg Schoolof Medicine, NorthwesternUniversity

Director, Program for Maternal andChild Health

Clinical Attending Ann and RobertH. Lurie Childrens Hospital of

Chicago, USATari Haahtela, MD, PhD

Professor, Skin and Allergy Hospital,Helsinki University Hospital,Finland

Enrico Hefer, MDDepartment of Medical Sciences,

Division of Allergy & ClinicalImmunology, MaurizianoUmberto I Hospital, Universityof Torino, Italy

Peter W. Hellings, MD, PhDProfessor, Clinic Head, Department

of Otorhinolaryngology, Head andNeck Surgery, University Hospitalsof Leuven, Catholic University ofLeuven

Patrick G. Holt, MD, PhD

Telethon Institute for Child HealthResearch and Centre for ChildHealth Research, Division of CellBiology

The University of Western Australia,Perth, Australia

David J. Jackson, MDAirway Disease Infection Section,

National Heart and Lung Institute,Imperial College, London

MRC & Asthma UK Centre in AllergicMechanisms of Asthma

Imperial College Healthcare NHS

Trust, UKDeborah Jarvis, MD

Respiratory Epidemiology and PublicHealth Group, National Heart &Lung Institute, Imperial CollegeLondon, UK

Sebastian L. Johnston, MD, PhDAirway Disease Infection Section,

National Heart and Lung Institute,Imperial College, London

MRC & Asthma UK Centre in AllergicMechanisms of Asthma

Imperial College Healthcare NHSTrust, UK

Marek Jutel, MDDepartment of Clinical ImmunologyWroclaw Medical University, PolandMedical Research Institute - ALL

MED Wroclaw

Edward F. Knol, PhDDepartments of Immunology and

Dermatology / Allergology,University Medical CenterUtrecht, The Netherlands

Marek L. Kowalski, MD, PhD

Department of Immunology,Rheumatology and Allergy, MedicalUniversity of d, Poland

Roger Lauener, MDChildrens Hospital of Eastern

Switzerland, St. Gallen,Switzerland

Christine Khne-Center for AllergyResearch and Education (CK-CARE), Davos

Childrens Hospital, Faculty of

Medicine, University of Zurich

Dennis K. Ledford, MDMabel and Ellsworth Simmons

Professor of AllergyMorsani College of Medicine,

University of South FloridaJames A. Haley V.A. Hospital, Tampa,

Florida, USARichard F. Lockey, MDDistinguished University Health

ProfessorProfessor of Medicine, Pediatrics and

Public HealthDirector, Division of Allergy and

Immunology, Department ofInternal Medicine

Joy McCann Culverhouse Chair ofAllergy and Immunology

Morsani College of Medicine,University of South Florida

James A. Haley Veterans Hospital,Tampa, Florida, USA

Karin C. Ldrup Carlsen, MD, PhDUniversity of Oslo, Institute of

Clinical MedicineOslo University Hospital, Department

of Paediatrics

Brunilda Marku, MD, PhDRespiratory Medicine, University of

Ferrara, ItalyResearch Centre on Asthma and

COPD, Department of Clinical

and Experimental Medicine,University of Ferrara, Italy

Shanthi Mendis, MD, PhDDirector a.i., Department

of Management ofNoncommunicable Diseases,World Health Organization,Geneva, Switzerland

Andr Moreira, MDFaculty of Medicine, University of

PortoCentro Hospitalar So Joo EPE,

Porto, Portugal

Antonella Muraro, MD, PhDCenter for Food Allergy Diagnosis

and Treatment, Veneto Region,Department of Woman and ChildHealth, University of Padua,Padua, Italy

Hiroyuki Nagase, MD, PhDAssociate Professor of Medicine,

Teikyo University, Tokyo, Japan

Jennifer A. Namazy, MDScripps Clinic, San Diego, USA

Contributors


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V

Hugo E. Neffen, MDHead of the Respiratory Medicine

Unit, Childrens Hospital OrlandoAlassia, Santa Fe, Argentina

Paul M. OByrne, MDFirestone Institute of Respiratory

Health, St. Josephs Healthcare

and Department of Medicine,McMaster University, Hamilton,Canada

Ken Ohta, MD, PhDPresident National Hospital

Organization Tokyo NationalHospital

Visiting Professor of Medicine atTeikyo University and ShowaUniversity, Tokyo

Nikolaos G. Papadopoulos, MD,PhD

Associate Professor in Allergology-

Pediatric Allergology, Head,Allergy Department, 2nd PediatricClinic, University of Athens,Greece

Alberto Papi, MDProfessor of Respiratory Medicine,

University of Ferrara, ItalyResearch Center on Asthma and

COPD, Department of Clinicaland Experimental Medicine,University of Ferrara, Italy

Santiago Quirce, MD, PhDHead, Department of Allergy,

Hospital La Paz Institute forHealth Research (IdiPAZ), Madrid,Spain.

Graham Roberts, MDProfessor and Honorary Consultant

Paediatrician in PaediatricAllergy and Respiratory Medicine,University of Southampton, UK

Dermot Ryan, MDGeneral Practitioner, Woodbrook UKHonorary Fellow, Allergy and

Respiratory Research Group,

Centre for Population HealthSciences: GP Section, Universityof Edinburgh.

Bolesaw Samoliski, MD, PhDMedical University of Warsaw,

Poland

Georg Schppi, PhDDirector, aha! Swiss Centre for

AllergyChristine Khne-Center for Allergy

Research and Education (CK-

CARE), Davos

Michael Schatz, MDChief, Department of Allergy, Kaiser

Permanente Medical Center, SanDiego, USA

Jrgen Schwarze, MDChild Life and Health and MRC-

Centre for InammationResearch, Queens MedicalResearch Institute, The Universityof Edinburgh, UK

Helen Smith, MDChair of Primary Care and Head

of Division of Primary Care andPublic Health, Brighton and SussexMedical School, Brighton, UK

Kelan Tantisira, MDAssistant Professor of Medicine,

Harvard Medical School, Boston,Massachusetts, USA

Channing Division of NetworkMedicine , Division of Pulmonaryand Critical Care Medicine,Brigham and Womens Hospitaland Harvard Medical School

Neil C. Thomson, MDProfessor, Institute of Infection,

Immunity & Inammation,University of Glasgow

Respiratory Medicine, GartnavelGeneral Hospital, Glasgow, UK

Massimo Triggiani, MD, PhD

Division of Allergy and ClinicalImmunology, University ofSalerno, Italy

Erkka Valovirta, MD, PhDProfessor, Department of Pulmonary

Diseases and Clinical Allergology,University of Turku, Finland

Chief Pediatrician and PediatricAllergist, Terveystalo, Turku,Finland

Ronald van Ree, MD, PhDProfessor, Department of

Experimental Immunology

and Department ofOtorhinolaryngology, AcademicMedical Center, Amsterdam, TheNetherlands

Roy Gerth van Wijk, MD, PhDProfessor of Allergology, Section

of Allergology, Dept. of InternalMedicine, Erasmus MedicalCentre, Rotterdam

J. Christian Virchow, MDDepartment of Pneumology/

Intensive Care Medicine,University Clinic, Rostock,Germany

Erika von Mutius, MD, PhDDr. von Haunersche Kinderklinik,

Ludwig Maximilian UniversittMnchen, Germany

Ulrich Wahn, MDDepartment of Pediatric Pneumology

and Immunology, Charite, Berlin,Germany

Christopher M. Warren, PhDResearch Project Coordinator, Center

for Healthcare Studies, Institutefor Public Health and Medicine,Feinberg School of Medicine,Northwestern University, USA

Scott T. Weiss, MD

Professor of Medicine, HarvardMedical School, Boston,Massachusetts, USA

Associate Director, ChanningDivision of Network Medicine,Brigham and Womens Hospital

Director, Partners Center forPersonalized Genetic Medicine,Partners HealthCare System

Sally Wenzel, MDProfessor of Medicine, University

of Pittsburgh, Department of

Medicine, Division of PulmonaryAllergy and Critical Care Medicine,USA

Thomas Werfel, MDHannover Medical School, Hannover,

Germany

Gary W.K. Wong, MDProfessor, Department of Paediatrics

and School of Public Health,Chinese University of Hong Kong

Prince of Wales Hospital, Hong KongSAR, China

Osman M. Yusuf, MDChief Consultant, The Allergy &

Asthma Institute, Islamabad,Pakistan.

Member, Planning Group, GlobalAlliance against RespiratoryDiseases (GARD)

Director & Former Chair of Research,The International Primary CareRespiratory Group

Contributors


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VII

SECTION A

ASTHMA FROM EPIDEMIOLOGY, RISK FACTORS AND MECHANISMS TO PHENOTYPESAND MANAGEMENT

2 What is asthmaJ. Christian Virchow

4 History of asthmaJeffrey M. Drazen

7 The asthma epidemic - Global and time trendsof asthma in childrenM. Innes Asher

10 The asthma epidemic - Global and time trends

of asthma in adultsJon Genuneit, Deborah Jarvis, Carsten Flohr

14 Death and disability due to asthmaPeter Burney

18 Socio-economic costs of asthmaRoy Gerth van Wijk

21 Natural history of asthmaUlrich Wahn

23 Genetics of asthmaRoger Lauener

25 Pharmacogenetics of asthma

Scott T. Weiss, Kelan Tantisira

28 The pathogenesis of asthmaMbeccel Akdis

31 The underlying mechanisms of asthmaMassimo Triggiani, Marek Jutel, Edward F. Knol

34 Phenotypes & endotypes: emerging conceptson asthma heterogeneitySally Wenzel

36 Environmental risk factors for asthmaIsabella Annesi-Maesano

39 Life style risk and protective factors forasthmaErika von Mutius

42 Infections and asthmaJrgen Schwarze

45 Emerging risk and protective factors forasthmaGraham Roberts

48 Perinatal and early life inuences on asthmadevelopment

Patrick G. Holt

52 Psychological factors and asthmaHelen Smith

55 The complex network of asthma risk andprotective factorsAdnan Custovic

57 Asthma in childhoodNikolaos G. Papadopoulos

60 Asthma in the elderlyDennis K. Ledford

65 Asthma in the elite athleteLouis-Philippe Boulet

68 Asthma in pregnancyJennifer A. Namazy, Michael Schatz

71 Work-related asthmaSantiago Quirce, Enrico Hefer

75 Asthma managementBrunilda Marku, Alberto Papi

79 Asthma monitoring

James Fingleton, Richard Beasley

CONTENTS

Contents

SECTION BDISEASES ASSOCIATED WITH ASTHMA

84 Atopy and asthmaAnthony J. Frew

86 Upper airway diseases and asthmaPeter W. Hellings

89 Asthma and obesity, the twin epidemicsPeter G. Gibson

92 Aspirin exacerbated respiratory diseaseMarek L. Kowalski, Sevim Bavbek


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VIII

SECTION CMAJOR CURRENT PROBLEMS IN ASTHMA

106 Unmet needs in asthmaCezmi A. Akdis

109 Asthma exacerbationsDavid J. Jackson, Sebastian L. Johnston

112 Severe asthmaThomas B. Casale

115 Adherence to asthma treatmentKen Ohta, Hiroyuki Nagase

118 Social determinants of asthmaRuchi S. Gupta, Christopher M. Warren

120 Inequities and asthmaHugo E. Neffen

SECTION DPREVENTION AND CONTROL OF ASTHMA

124 Primary and secondary prevention of asthmaKai-Hkon Carlsen, Karin C. Ldrup Carlsen

127 Allergen immunotherapy in asthmaM. Beatrice Bil, Moiss Caldern, Victria Cardona

130 Asthma controlPaul M. OByrne

132 Best buys for asthma prevention and control

Ioana Agache

135 Evidence for asthma control zero toleranceto asthma with the Finnish programmesTari Haahtela

138 The need for integrated and complimentarystrategies in the political agendaJean Bousquet

140 Policies and strategies to facilitate access toasthma diagnosis and treatmentOsman M. Yusuf

145 Policies and strategies to reduce risk factorsfor asthmaGary W.K. Wong

147 Tobacco control and asthmaNeil C. Thomson

151 Implementation of a healthy life style andasthmaLuis Delgado, Renata Barros, Andr Moreira

155 Individual interventions for asthmaprevention and controlPhilippe Eigenmann

157 The role of Primary Care in the preventionand control of asthmaDermot Ryan

161 Role of patient organisations in the control

and prevention of asthmaBreda Flood, Georg Schppi

164 Social mobilization for prevention and controlof asthmaErkka Valovirta

167 Asthma in resource constrained settingsShanthi Mendis

169 Dealing with the implementation gap forasthma prevention and controlPascal Demoly

171 Generating resources for prevention andcontrol of asthmaBolesaw Samoliski, Agnieszka Czupryniak

173 Asthma prevention and control: Why itshould not be ignored any longer?William W. Busse

175 Vision, roadmap and a land-marking eventCezmi A. Akdis

Contents

95 Gastro-esophageal reux disease and asthma

Richard F. Lockey

98 Cardiovascular diseases and asthma

Mario Cazzola

100 Food allergy and asthmaRonald van Ree, Antonella Muraro

102 Skin and lung: atopic dermatitis, urticaria andasthmaThomas Werfel, Clive Grattan


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IX

An estimated 36 million deaths, or 63% of the 57 million deaths that occurred globally in 2008, were dueto noncommunicable diseases including chronic respiratory diseases. 80% of deaths (29 million) due tononcommunicable diseases occurred in low- and middle-income countries.

Global efforts to tackle the challenge of noncommunicable diseases including asthma have gained momentumsince the 2011 United Nations Political Declaration on the prevention and control of noncommunicable diseases.The World Health Organization is developing a Global Plan of Action, for 2013-2020, to provide a roadmapfor country-led action for prevention and control of noncommunicable diseases including chronic respiratorydiseases. It will be submitted for consideration to the 66th World Health Assembly this year.

Premature death, disability, loss of income and health-care expenditure due to asthma take a toll on families,communities and national health nances. In low- and middle-income countries many people cannot accesstreatment for asthma, because it is prohibitively expensive. Households often then spend a substantial share oftheir income on hospitalization to treat exacerbations and complications of asthma.

I wish to congratulate the European Academy of Allergy and Clinical Immunology for developing the Global

Atlas of Asthma. It provides simplied and useful information on a range of topics related to prevention andcontrol of asthma including magnitude of the problem, risk factors, associated diseases, barriers to treatmentand sustainable strategies to address asthma in resource constrained settings.

I hope that the knowledge prevention and control of asthma, imparted by this document to decision makers,health workers, the civil society, private sector and the public will benet people in all countries.

Dr. Oleg Chestnov, Assistant Director General

Noncommunicable Diseases and Mental Health Cluster

World Health Organization

Foreword

FOREWORD


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XI

PREFACE

Asthma is a major public health problem affecting the lives of several hundred million people around theworld, with an increasing prevalence in developing countries. Governments, and the general public, face hugedirect and indirect costs, with major effects on macroeconomics due to health-care costs, loss of productivityand the absenteeism of patients. Unfortunately, a high number of unmet needs remain to be resolved, due togaps in current scientic knowledge in pathophysiology and in patient care, and as a result of the global social

determinants of health.

To tackle this huge global health problem, we at the EAACI decided to develop a Global Atlas of Asthma. With thisAtlas, our aims were: to gather evidence to call attention to the burden of asthma, to warrant its recognition asa main concern in national health strategies; to demonstrate its priority as an issue for research; to describe riskfactors for asthma; to evaluate the best ways to prevent and control it; to provide guidance on how to overcomebarriers; and to alert political bodies to the issue of asthma to ensure a global management approach.

The Global Atlas of Asthma has been developed as an essential reference source for multi-sectoral use, coveringall aspects of asthma, from epidemiology, risk factors and mechanisms to phenotypes and management, to majorcurrent problems in asthma, associated diseases, and asthma prevention and control. With 59 chapters writtenby 80 contributing authors, and containing 147 illustrations and 46 tables, the Atlas will also be a comprehensive

educational tool and desktop reference for medical students, allied health workers, primary care physicians,medical industry, policy makers, patient organizations and specialists dealing with asthma and other comorbiddiseases.

I would like to thank all of the authors for their contributions, the EAACI Executive Committee Members, andparticularly Prof. Dr Ioana Agache, with whom working on this highly exciting project was a great pleasure, andCostel Agache and Macarena Guillamon for their focus, devotion and prociency.

Cezmi A. AkdisPresident of the

European Academy of Allergy and Clinical Immunology


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Section A

ASTHMA FROM EPIDEMIOLOGY, RISK FACTORS AND

MECHANISMS TO PHENOTYPES AND MANAGEMENT

* What is asthma* History of asthma* The asthma epidemic - Global and time trends of asthma

in children* The asthma epidemic - Global and time trends of asthma

in adults* Death and disability due to asthma* Socio-economic costs of asthma* Natural history of asthma* Genetics of asthma* Pharmacogenetics of asthma* The pathogenesis of asthma* The underlying mechanisms of asthma* Phenotypes & endotypes: emerging concepts on asthma

heterogeneity

* Environmental risk factors for asthma* Life style risk and protective factors for asthma* Infections and asthma* Emerging risk and protective factors for asthma* Perinatal and early life inuences on asthma development* Psychological factors and asthma* The complex network of asthma risk and protective

factors* Asthma in childhood* Asthma in the elderly* Asthma in the elite athlete* Asthma in pregnancy* Work-related asthma* Asthma management

* Asthma monitoring


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Asthma is one of the most common chronic inammatorydisorders

Asthma affects patients of all ages and is a serious challengeto public health and has large effects on school and workperformance of patients

Asthma symptoms can be treated effectively in many patientshowever, at considerable costs

There is no cure and many patients remain uncontrolled despiteavailable treatment

Combined efforts in public health, basic and clinical researchneed to be upscaled to ght this highly prevalent and increasingdisorder

Epidemiologicallyasthma is a verycommon chronic condition. Itsprevalence varies worldwide but

more than 5% of any investigatedpopulation suffer from asthma.In some regions this percentageis much higher. Asthma affects allages: it is the most common chronicdisease of childhood, adolescenceand adulthood and affects patientsin their most productive years.Everybody is either personally af-fected or will know someone whosuffers from asthma. Every physi-cian will see patients with asthmaduring his/ her career. Asthma is aserious challenge to public health.Its direct and indirect costs arehigh, but the costs of not treat-ing asthma are even higher. It hasdetrimental inuences on schooland work performance and pro-ductivity. About 10% of all asthmais caused by or occurs in the work-place. As more people reach oldage it is also an important disease

of the elderly. Asthma not onlyleads to limitations in daily life, butcan end fatally in some cases, espe-cially if untreated.

Pathophysiologically asthma isan inammatory disorder of thelungs. It leads to widespread air-ow limitation. The resulting signsand symptoms are dyspnea, dis-comfort, wheezing, anxiety and

panic and occasionally fatal res-piratory arrest. The pathogenesisof asthma is highly complex and asof today incompletely understood.Based on clinical and laborato-ry ndings different phenotypes

have been suggested (Figure 1).Whether they all represent differ-ent features or severities of a sin-

gle disease or are separate diseas-es within the syndrome of asthmaremains unclear. The majority ofasthma occurs on an IgE-mediat-ed background with sensitisationsto inhaled allergens called allergicasthma. Asthma which occurs on anon-allergic background is termedintrinsic asthma. Asthma often re-sults in chronic persistent airway

inammation unrelated to aller-gen contact and has features ofautoimmunity. Long term chronicinammation has been associated

with airway remodelling with anincreasingly xed airow limita-tion as a result of scarring of theairways.

Clinically signs and symptoms ofasthma vary from patient to pa-tient. Episodic shortness of breath,wheezing and the sensation that in-spiration is no longer possible dueto hyperination of the lungs are

common. The pathophysiologicalequivalent in pulmonary functiontests is a reduced FEV1 (Forced Ex-piratory Volume of the rst second)

J. Christian VirchowUniversity Clinic

Rostock, Germany

WHAT IS ASTHMA1

K EY MES S AG ES

What is asthma


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What is asthma

Figure 1 Clinically observed characteristics and asthma phenotypes.(Reproduced fromAgache I, Akdis C, Jutel M, et al. Untangling asthma phenotypes and

endotypes. Allergy 2012; 67:835-846; with permission from Wiley-Blackwell.)

and PEF (Peak Expiratory Flow).A circadian peak of symptoms inthe early morning hours is typical.Bronchial hyperresponsiveness tonon-specic airway irritants such

as smoke, cold air, odours, etc. ischaracteristic and can be test-ed with bronchoprovocation testwith histamine or methacholine.Allergic asthma is associated withincreased levels of circulating totaland specic IgE. Elevated numbersof eosinophils can be found in theblood, the airway mucosa and thebronchoalveolar lavage uid. Asth-

matic symptoms and/or asthma at-tacks increase following inhalationof allergens, but can also persistin the absence of allergenic trig-gers. The fraction of NO in exhaled

breath (FeNO) can be elevated inasthma. Many patients experienceworsening airow obstructionand symptoms following exercise.Some suffer from severe attacksupon ingestion of non-steroidalanti-inammatory drugs (AspirinExacerbated Respiratory Disease).None of these signs or symptoms,however, is characteristic. Asthma

therefore remains a clinical diag-nosis.

Therapeutically there is no curefor asthma available. Most patientsprot from inhalation therapy with

little if any side effects. However,

many patients with more severeasthma or failure to adhere totreatment remain uncontrolled.Brief attacks of asthma usuallyrespond well to the inhalation of2-agonists. Persistent asthma re-sponds to inhaled corticosteroids.Leukotriene-antagonists, theo-phylline, anti-IgE-antibodies andanticholinergic drugs can be addedin more severe or therapy refracto-ry cases.

KEY REFERENCES1. Virchow JC, Pichler WJ. Aller-

gische Atemwegserkrankun-gen. In: Petter HH, Pichler WJ,Mller-Ladner, editors. KlinischeImmunologie. Munchen :Urban &Fischer, 2012.

2. Agache I, Akdis C, Jutel M, Vir-chow JC. Untangling asthma phe-notypes and endotypes. Allergy2012; 67:835-846.

3. Lommatzsch M. Airway hyperre-sponsiveness: new insights intothe pathogenesis. Semin Respir CritCare Med2012;33:579-587.

4. Knudsen TB, Thomsen SF, Nolte H,Backer V. A population-based clin-ical study of allergic and non-aller-gic asthma.J Asthma2009;46:9194.

5. Tepper RS, Wise RS, Covar R, Ir-vin CG, Kercsmar CM, Kraft M, etal. Asthma outcomes: pulmonary

physiology. J Allergy Clin Immunol2012;129:S65-87.

6. Murray CS. Can inhaled corticos-teroids inuence the natural his-tory of asthma? Curr Opin AllergyClin Immunol2008;8:7781.

7. Bjermer L. Evaluating combina-tion therapies for asthma: pros,cons, and comparative benets.

Ther Adv Respir Dis 2008;2:149-161.


18/1964


The term asthma has been in use for millennia, but the descriptionof the condition that now bears that name has been in place sincethe writings of Aretus the Cappadocian about 2000 years ago

Both attacks and chronic dyspnea are characteristic of asthma Treatments of asthma based on bronchial smooth muscle rela-

xation have been in use for over 200 years, with sympathomimeticreliever treatment introduced in the early 1900s

The use of glucocorticoids to treat asthma was introduced in themid-20th century; inhaled corticosteroid treatment was startedin the late 1960s

Jeffrey M. DrazenHarvard Medical School

Boston, USA

HISTORY OF ASTHMA2

K EY MES S AG ES

THE TERM ASTHMAThe term asthma is derived fromthe Greek aazein, which means topant. Before the writings of Aretae-us in the 2nd century and well intothe 20th century, many physiciansand lay people alike used the termasthma to refer to any conditioncharacterized by acute nonphysi-ologic shortness of breath. For ex-ample, acute congestive heart fail-ure would often be termed cardiacasthma. Aretaeuss and, much lat-er, Floyers (1698) descriptions of

asthma largely match those in usetoday (Figure 1).

CLINICAL DESCRIPTIONSThere are two key components ofthe clinical description that havesurvived two millennia. The rst is

the acute asthmatic episode, alsoknown as an asthma attack. This isthe sudden onset (as quickly as sec-onds, but more usually minutes tohours) of shortness of breath often

accompanied by wheezing audibleto the patient and those close tohim or her; this resolves spontane-ously or as a result of treatment.The second is dyspnea of much lessseverity between these episodes.Exercise and allergen exposurehave been recognized as causes ofasthma attacks over this entire re-corded history.

The physicians examining patientswith asthma were able to appre-ciate wheezing long before Laen-necs treatise on diseases of thechest was published in 1819. WithLaennecs work, it became clearthat there were many other con-ditions characterized by wheezingother than asthma.

ASTHMA TREATMENTS

Anticholinergic asthma treatmentwas known to Floyer. At that time,patients were instructed to inhalesmoke from the burning of certainplants containing belladonna al-kaloids. The three most common-ly used plants were known as thesinister sisters because, if takenin excess amounts, they could havesevere side effects including death.

These were hyoscyamus, stramoni-um, and belladonna (Figure 2). Af-ter a century of disuse, long-actingmuscarinic antagonists are beingre-introduced into asthma treat-ment.

Sympathomimetic treatment ofasthma dates from the original useof ma huang in traditional Chinesemedicine, likely over 5000 yearsago. The active ingredient in ma

huangis ephedra, and epinephrine,rst by injection and later by inha-lation, became the standard of carefor acute asthma treatment. In the1950s, inhaled isoproterenol (iso-prenaline) was introduced for overthe counter sales for asthma thera-py, but high potency isoproterenoluse was associated with asthmadeaths (Figure 3). Restriction of

History of asthma


19/1965


Figure 1 Title page from Floyers classic monographon asthma published in 1696. This contains a clear

description of the condition we now recognize as asthma.

Figure 2 Sinister sisters plants. Smoking the leavesfrom these plants has been used as an asthma remedy for

decades. a - Datura stramonium; b - Hyoscyamus niger; c -Atropa belladonna.

History of asthma

this treatment led to a reversal in

asthma deaths. In the 1960s, se-lective

2agonists (Figure 4), such

as albuterol, became available forinhalation and now have becomethe standard of care. The introduc-tion of inhaled beta agonists withduration of action of over 12 hoursoccurred in the 1990s. Althoughthese are highly effective thera-pies, there has been concern abouttheir long-term safety. Large safetystudies are ongoing at this time.

GLUCOCORTICOIDSAND ASTHMAThe use of adrenocorticotropichormone (ACTH) or injections ofbiologically derived or synthet-ic steroids as an asthma therapywas introduced in the early 1950s.Because of the severe side effectsof systemic steroid use, inhaled

glucocorticoids were introduced

in asthma treatment in the 1960s(Figure 5).

TARGETEDASTHMA TREATMENTSLeukotriene modier treatments-- both antagonists of the actionof leukotriene D

4 at the CysLT1

receptor or inhibitors of the actionof the enzyme ALOX-5 were intro-duced into the market in the mid-1990s. Although their impact on

lung function is less than inhaledglucocorticoids, they have a mini-mal adverse event prole and theiroral action has led to their reason-ably common use. Anti-IgE therapywas approved about the turn of the21stcentury.

KEY REFERENCES1. Floyer JA. Treatise of the Asthma.

London: Richard Wilkin, 1698.

2. von Mutius E, Drazen JM. A pa-tient with asthma seeks medicaladvice in 1828, 1928, and 2012. NEngl J Med2012;366:827-834.

3. Tatterseld AE, McNicol MW.Salbutamol and isoproterenol.A double-blind trial to com-pare bronchodilator and cardi-ovascular activity. N Engl J Med1969;281:1323-1326.

4. Brown HM, Storey G, George WH.Beclomethasone dipropionate: a

new steroid aerosol for the treat-ment of allergic asthma. Br Med J1972;1:585-590.

5. Drazen JM, Israel E, OByrne PM.Treatment of asthma with drugsmodifying the leukotriene path-way. N Engl J Med1999;341:1632.

6. Speizer FE, Doll R, Heaf P. Ob-servations on recent increase inmortality from asthma. Br Med J1968;1:335-339.


20/1966


History of asthma

Figure 3 Asthma deaths in Britain from 1952 to 1966showing the impact of high potency isoproterenol inhalers,introduced for over the counter sales in the late 1950s andsubsequently limited to prescription use in the late 1960s.

(Reproduced from Br Med J, Speizer FE, Doll R, Heaf P, 1, 335-339,Copyright 1968 with permission from BMJ Publishing Group Ltd.)

Figure 5 Data from an early casereport of the effects of inhaled

glucocorticosteroids in asthma. DSCGdenotes disodium cromoglycate.

(Adapted from Br Med J, Brown HM,Storey G, George WH, 1, 585-590,

Copyright 1972 with permission fromBMJ Publishing Group Ltd.)

Figure 4 Chemical structures of epinephrine, thenonselective beta-adrenergic agonist, isoproterenol

(isoprenaline), and the selective beta2-agonist, albuterol(salbutamol). The components of the structure in redshow the differences from the preceeding structure.

Epinephrine

Isoproterenol

Salbutamol / Albuterol


21/1967


ASTHMA CONTEXTAsthma has been recognized formore than 3000 years but it is onlyin the last three to four decadesthat it has become a serious publichealth concern. This was precipi-tated by a new epidemic of asthmadeaths in 1977, affecting New Zea-land, more than any other country,that stimulated a great deal of re-search which continues to this day.About the same time admissions tohospital for asthma were increas-ing dramatically in New Zealand,

Australia, The United Kingdom,Canada and USA and the highestrates were in New Zealand chil-dren. Until two decades ago sci-entists in these countries believedthat asthma affected predominant-ly people in high income countriesand was negligible in developingcountries.

GLOBAL VARIATIONThe International Study of Asthma

and Allergies in Childhood (ISAAC)was formed to examine variationaround the world in asthma and al-lergies by development of the nec-essary standardized methodology.At the time ISAAC started (1991),there were fewer than 30 centresin the world where the prevalenceof asthma in children had beenstudied at all, and most had used

different methodologies. ThroughISAAC, which, in the third phase in-

cluded 237 centres in 98 countries,we now know that asthma occursin all countries studied, with strik-ing variations in the prevalence ofasthma symptoms throughout theworld, up to 15-fold between coun-tries (Figure 1). Although asthmasymptoms were more commonin some high income countries,some low and middle income coun-tries also had high levels of asth-ma symptom prevalence. Among

children with asthma symptoms,asthma is more severe in low andmiddle income than high incomecountries (Figure 2).

TIME TRENDSStudies from English-languagecountries in the 1990s reportedincreases in asthma prevalencefrom the 1980s, and therefore

continuing increases in prevalencewere expected. Indeed, ISAAC

found that asthma in children wason the increase in many countriesfrom 1993 to 2003. However, inmost high prevalence countries,particularly the English-languagecountries, the prevalence of asth-ma symptoms changed little dur-ing that time, and even declinedin some cases. In contrast, prev-alence increased in many coun-tries over that time, especiallylow and middle income countries

with large populations (Figure 3).The overall percentage of childrenand adolescents reported to haveever had asthma increased signif-icantly, possibly reecting greaterawareness of this condition and/orchanges in diagnostic practice.

CONCLUSIONThe 20-year ISAAC programme

Asthma in children is a disease of low and middle income, as wellas high income countries

Asthma in children is more severe in low and middle incomecountries

Asthma in children is on the increase in many countries especiallyin low and middle income countries

Further asthma surveillance and research is needed

M. Innes AsherThe University of Auckland

New Zealand

THE ASTHMA EPIDEMIC -GLOBAL AND TIME TRENDS

OF ASTHMA IN CHILDREN

3a

K EY MES S AG ES

The asthma epidemic - Global and time trends of asthma in children


22/1968


has shown that childhood asthmais a common disease in both highincome and lower income coun-tries. It is relatively more severeand increasing in prevalence inmany lower income countries. Itis vital to continue surveillance ofasthma, research its causes andreach all asthma sufferers withgood management as summarisedin The Global Asthma Report 2011.These are the aspirations of thenew Global Asthma Network.

KEY REFERENCES1. Asher MI, Montefort S, Bjrkstn

B, Lai CK, Strachan DP, WeilandSK, et al. Worldwide time trendsin the prevalence of symptomsof asthma, allergic rhinoconjunc-tivitis,and eczema in childhood:ISAAC Phases One and Three re-peat multicountry crosssectionalsurveys. Lancet 2006;368:733-743.

2. ISAAC Steering Committee.Worldwide variations in the prev-alence of asthma symptoms: theInternational Study of Asthma andAllergies in Childhood (ISAAC).Eur Resp J 1998;12: 315-335.

3. Lai CK, Beasley R, Crane J, FoliakiS, Shah J, Weiland S, et al. Globalvariation in the prevalence andseverity of asthma symptoms:Phase Three of the Internation-al Study of Asthma and Allergiesin Childhood (ISAAC). Thorax2009;64:476-483.

4. Pearce N, At-Khaled N, BeasleyR, Mallol J, Keil U, Mitchell E, etal. Worldwide trends in the preva-lence of asthma symptoms: PhaseIII of the International Study ofAsthma and Allergies in Childhood(ISAAC). Thorax 2007;62:758-766.

5. The Global Asthma Report 2011.Paris, France: The InternationalUnion Against Tuberculosis andLung Disease, 2011.

6. The Global Asthma Networkhttp://www.globalasthmanet-work.org, accessed May 20, 2013.


Figure 2 Prevalence of symptoms of severe asthma according to the writtenquestionnaire in the 1314 year age group. The symbols indicate prevalence

values of


23/1969



Figure 3 World map showing direction of change in prevalence of asthma symptoms for 6-7 year age-group and 13-14year age-group. Each symbol represents a centre. Blue triangle=prevalence reduced by 1 SE per year. Green square=littlechange (


24/19610


lence of asthma symptoms, asth-ma attacks, and the use of asthmamedication in the general popu-lation aged 20 to 44 years. It wasconducted at different sites, most-ly in Western Europe, between1991 and 1994. Information from48 study centres in 22 countriesshowed wide variations in the prev-

alence of wheeze and diagnosedasthma, the latter being dened asa report of an asthma attack or cur-rent use of asthma medication (seeTable 1).

THE WORLD HEALTH SURVEY(WHS)The WHS was conducted amongadults (aged 18 years) in 70 coun-

tries in 2002/2003. The prevalenceof respiratory symptoms was as-sessed in 68 countries, and of asth-ma diagnosis in 64. The WHS addsto the ECRHS because it providesinformation on adult asthma inlow-income countries. The surveyshowed that there are wide varia-tions in the prevalence of wheeze

(Figure 1) and asthma (Figure 2) re-gardless of overall national income.

THE GLOBAL ALLERGY ANDASTHMA NETWORK OFEXCELLENCE (GA2LEN)The GA2LEN survey was conductedamong adults aged 15-74 years in15 European countries in 2008/09.The data on asthma prevalence

MEASURING ADULT ASTHMAFOR GLOBAL COMPARISONThe assessment of adult asthma inepidemiological studies is difcult.Use of objective markers, such asbronchial hyperreactivity, is usual-ly impracticable in large, interna-tional population-based surveys,which therefore primarily rely onthe reporting of asthma symptomslike wheeze and/or a physician-di-agnosis. A complicating factor isthe lack of a commonly agreedterminology for asthma symptoms

across languages. Even if this couldbe overcome, the perception andreporting of asthma symptoms dif-fers between subjects, who comefrom diverse socio-cultural back-grounds. In addition, diagnosticcriteria vary between physicians,for instance as a result of workingin different health care systems.Furthermore, reported asthmasymptoms in the elderly are dif-cult to distinguish from symptoms

of chronic obstructive pulmonarydisease (COPD). To date threelarge international surveys haveprovided data to make internation-al comparisons.

THE EUROPEAN COMMUNITYRESPIRATORY HEALTH SURVEY(ECRHS)The ECRHS assessed the preva-

K EY MES S AG ES

Three large international surveys on adult asthma have beenconducted: ECRHS I (1991-1994), WHS (2002-2003), and GA2LEN(2008-2009)

Comparison of prevalence estimates across the surveys is difcultdue to the different methods and disease denitions

Each survey suggests substantial geographical variation in adultasthma prevalence between countries

Analysis of the ECRHS and information from the GA2LEN surveyprovides some evidence of cohort-related increases in adultasthma

Repeat surveys need to be conducted to reliably assess globaltime trends of adult asthma prevalence

Jon GenuneitUlm University

Germany

Deborah JarvisImperial College

London, UK

Carsten FlohrSt Thomas Hospital &

Kings College London, UK

THE ASTHMA EPIDEMIC -GLOBAL AND TIME TRENDS

OF ASTHMA IN ADULTS

3b

The asthma epidemic - Global and time trends of asthma in adults


25/19611



TABLE 1

Prevalence (in %) of wheeze and diagnosed asthma in the European Community Respiratory Health Survey (ECRHS)and the Global Allergy and Asthma Network of Excellence (GA 2LEN) *

Country CentreECRHS GA2LEN

Country CentreECRHS GA2LEN

wheeze1 dg asthma2 asthma3 wheeze1 dg asthma2 asthma3

Iceland Reykjavik 18.0 3.4 UK Caerphilly 29.8 8.0Norway Bergen 24.6 4.3 Cambridge 25.2 8.4

Sweden Gteborg 23.2 5.8 7.1 Dundee 28.4

Stockholm 8.6 Ipswich 25.5 7.8

Ume 19.8 6.8 11.2 London 11.4

Uppsala 19.2 6.0 9.5 Norwich 25.7 7.5

Finland Helsinki 7.8 Southampton 14.2

Estonia Tartu 26.8 2.0 Ireland Dublin 32.0 5.0

Denmark Aarhus 24.1 4.0 Kilkenny-Wexford 24.0 5.4Odense 8.6

Poland Katowice 5.2 Greece Athens 16.0 2.9

Krakow 7.1 Italy Palermo 10.7Lodz 6.0 Pavia 8.5 3.3

Netherlands Amsterdam 6.4 Turin 10.7 4.5

Bergen opZoom 19.7 4.7

Verona 9.7 4.2

Spain Albacete 25.0 3.9

Geleen 20.9 4.4 Barcelona 19.2 3.1

Groningen 21.1 4.3 Galdakao 16.2 2.1

Belgium Antwerp city 20.6 4.6 Huelva 29.2 6.3

Antwerp south 12.8 2.7 Oviedo 21.0 3.6

Ghent 7.6 Seville 22.6 5.0

Germany Brandenburg 6.3 Portugal Coimbra 19.0 6.0 16.8

Duisburg 10.1 Oporto 17.7 4.3Erfurt 13.3 2.1 Algeria Algiers 4.2 3.0

Hamburg 21.1 4.4 India Bombay 4.1 3.5

Austria Vienna 14.3 3.1 NewZealand

Auckland 25.2 10.1

France Bordeaux 15.7 5.5 Christchurch 26.7 11.2

Grenoble 14.6 3.5 Hawkes Bay 24.2 9.0

Montpellier 14.4 5.0 10.3 Wellington 27.3 11.3

Nancy 13.6 3.7 Australia Melbourne 28.8 11.9

Paris 14.5 5.1 USA Portland,Oregon

25.7 7.1

Macedonia Skopje 5.1

* Reproduced with permission of the European Respiratory Society. Eur Respir J April 1, 1996 9:687-695 and from Jarvis D, NewsonR, Lotvall J, et al. Asthma in adults and its association with chronic rhinosinusitis: the GA2LEN survey in Europe. Allergy 2012;67:91-98, Wiley-Blackwell.1Age and sex standardized prevalence of a positive response to Have you had wheezing or whistling in your chest at any time in thelast 12 months? in 20-44 year olds.2dg asthma = diagnosed asthma. Age and sex standardized prevalence of a positive response to at least one of the following: (i) Haveyou had an asthma attack in the last 12 months?, or (ii) Are you currently taking medication for the treatment of asthma? in 20-44year olds.3Age and sex standardized prevalence of reporting ever had asthma AND reporting at least one of the following symptoms in thelast 12 months (i) wheeze or whistling in the chest, (ii) waking with chest tightness, (iii) waking with shortness of breath, and (iv)waking with an attack of coughing in 15-74 year olds.


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Figure 1 World map of the prevalence of current wheezing symptoms 1among 20-44 year olds in the WHS.1positive response to at least one of the two options in the following question: During the last 12 months, have you

experienced any of the following: (i) attacks of wheezing or whistling breathing? or (ii) attacks of wheezing that came onafter you stopped exercising or some other physical activity?(Reproduced with permission of the European Respiratory Society.

Eur Respir J February 2010 35:279-286; published ahead of print September 9, 2009, doi:10.1183/09031936.00027509.)

Figure 2 World map of the prevalence of diagnosed asthma 1in the WHS.1 positive response to any of the following: (i) have you ever been diagnosed with asthma (an allergic respiratory disease)?;(ii) have you ever been treated for it?; (iii) have you been taking any medications or other treatment for it during the last2 weeks? (Reproduced with permission of the European Respiratory Society. Eur Respir J February 2010 35:279-286; published

ahead of print September 9, 2009, doi:10.1183/09031936.00027509.)



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from 19 centres (12 countries) fol-lowing the full study protocol aredisplayed in the table.

COMPARABILITYBETWEEN THE SURVEYSThe WHS used different sam-pling methods to ECRHS andGA2LEN, and ECRHS (unlike WHSand GA2LEN) studied only youngadults. Different questions wereemployed to dene the prevalence

of asthma. The footnotes to thetable and gures explain some ofthese differences.

TIME TRENDS IN ADULTASTHMA PREVALENCENeither of these three surveys hasbeen repeated on an internationallevel to assess time trends in adultasthma prevalence. At single sites,repeat surveys have been conduct-

ed using the ECRHS methodology.In two examples from Italy andSweden the prevalence of diag-nosed asthma increased. Some-what contradictory, over the sameperiod, the prevalence of wheezedecreased in Sweden but increasedin Italy.

Over the last sixty years there hasbeen a well documented cohort

related increase in asthma in chil-dren, and we would expect thisto be reected in higher asthmaprevalence in adults as the affect-ed cohorts have aged. Consistentwith this, there is evidence fromGA2LEN that the prevalence ofasthma in younger adults is high-er than in older adults in most (al-though not all) parts of Europe.An alternative explanation couldbe that asthma remits with aging.Within the ECRHS, data from 15industrialized countries on age atrst asthma attack were used toestimate the incidence of asthmawithin birth cohorts representedin the study population, suggest-ing that the cumulative incidenceof asthma increased progressivelyacross the birth cohorts from sub-jects born in 1946-1950 (Figure 3).However, the retrospective assess-

ment of age at onset of asthma maybe subject to recall bias and secularchanges in labelling of asthma mayadditionally affect the results.

KEY REFERENCES1. Variations in the prevalence of

respiratory symptoms, self-re-ported asthma attacks, and useof asthma medication in the Eu-ropean Community Respiratory

Health Survey (ECRHS). Eur RespirJ 1996;9:687-695.

2. Sembajwe G, Cifuentes M, TakSW, Kriebel D, Gore R, PunnettL. National income, self-reportedwheezing and asthma diagnosisfrom the World Health Survey. EurRespir J2010;35:279-286.

3. Jarvis D, Newson R, Lotvall J,Hastan D, Tomassen P, Keil T, et al.Asthma in adults and its associa-tion with chronic rhinosinusitis:

the GA2LEN survey in Europe. Al-lergy2012;67:91-98.

4. Bjerg A, Ekerljung L, MiddelveldR, Dahln S-E, Forsberg B, Frank-lin K, et al. Increased prevalenceof symptoms of rhinitis but not ofasthma between 1990 and 2008in Swedish adults: comparisons ofthe ECRHS and GA2LEN surveys.PLoS ONE2011;6:e16082.

5. de Marco R, Cappa V, Accordini S,Rava M, Antonicelli L, Bortolami

O, et al. Trends in the prevalenceof asthma and allergic rhinitis inItaly between 1991 and 2010. EurRespirJ 2012;39:883-892.

6. Sunyer J, Ant JM, Tobias A, Bur-ney P. Generational increase ofself-reported rst attack of asth-ma in fteen industrialized coun-tries. European Community Res-piratory Health Study (ECRHS).Eur Respir J 1999;14:885-891.

0 10 20 30 40

Age

194619511956

19611966

0

0.05

0.10

Cumulativeincidence

Figure 3 Cumulative incidence of asthma 1by

age at rst asthma attack and birth cohort.1positive response to Have you ever had asthma?(Reproduced with permission of the European

Respiratory Society. Eur Respir J October 1, 199914:885-891.)



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Recorded asthma mortality ratesvary very widely across age groupsrising (as with most causes ofdeath) exponentially with age,rates being slightly lower amongwomen than men at all ages (Figure1). Death rates are also very une-ven between different regions. In2010 the highest death rates fromasthma were experienced in Oce-ania with high rates also in southand south-east Asia southern andcentral and east sub-Saharan Afri-ca and in north Africa the middle

east and central Asia. Much lowermortality rates were observed inAustralasia, Europe and North andSouth America (Figure 2).

Over the last two decades mor-tality rates have been falling. In1990 the global mortality rate forasthma (age adjusted) was around25/100,000 men and around17/100,000 women, by 2010these gures had fallen to around

13/100,000 for men and just over9/100,000 for women (Figure 3).This downward trend was univer-sal, though some regions, such asAustralia/New Zealand, experi-enced a relatively more rapid de-cline.

The disability associated withasthma varies with the amount ofcontrol of the condition. Well-con-

trolled asthma has relatively littleeffect on daily life, but uncontrolledasthma has a serious impact, esti-mated to be considerably more dis-abling than, for instance, moderateangina pectoris (Figure 4).

In many parts of the world accessto medication is severely limitedand lack of access to inhaled cor-

ticosteroids severely reduces thechances of asthma being adequate-ly controlled. This may explain inpart why in areas such as in sub-Sa-haran Africa, where access to med-ication may be poor severe asthmais more common than would other-wise might be predicted from theprevalence of asthma (Figure 5).

Peter BurneyImperial College

London, UK

DEATH AND DISABILITYDUE TO ASTHMA4

K EY MES S AG ES

Asthma mortality rates rise rapidly with age and are higher inboys and men

Asthma mortality rates vary widely across different regions ofthe world and are highest in Oceania and lowest in the developedeconomies

Since 1990 mortality rates from asthma have been falling in allregions of the world

Disability associated with asthma is highest in uncontrolledasthma

Uncontrolled asthma is associated with more disability thanis moderate angina pectoris, but less disability than moderateCOPD or Parkinsonism

Undertreated asthma is associated with a heavy economic andsocial burden

Although many areas where asthma is common also have a highprevalence of severe disease, there are areas such as sub-Saharan Africa where severe asthma is relatively more common

The relative importance depends on the prevalence of otherpathologies; in Australia and New Zealand, where mortality ratesare relatively low, asthma is the 15th most common cause ofdisability adjusted life years (DALYs) lost, whereas in South Asiawhere mortality rates are higher, it is the 25th cause of DALYs lost

Death and disability due to asthma


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Figure 1 Global death rates/100 000 from asthmaby age in 2010. (Data from Murray CJ, Vos T, Lozano

R, et al. Disability-adjusted life years (DALYs) for 291diseases and injuries in 21 regions, 1990-2010: asystematic analysis for the Global Burden of Disease

Study 2010. Lancet 2012;380:2197-2223.)

Figure 3 Global trends in age standardisedmortality from asthma by sex.

Figure 4 Disability score in various chronic diseases.(Data from Salomon JA, Wang H, Freeman MK, et al. Healthylife expectancy for 187 countries, 1990-2010: a systematicanalysis for the Global Burden Disease Study 2010. Lancet

2012;380:2144-2162.)

Figure 2 Male Asthma Mortality/100 000 by Global Burden of Diseases Region (2010). (Data from Lozano R, Naghavi M,Foreman K, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis

for the Global Burden of Disease Study 2010. Lancet 2012;380:2095-2128.)


30/19616


causing loss of disability adjustedlife years, as in Central and East Af-

rica. Although sub-Saharan Africa

has consistently higher death rates

from asthma compared with West-

ern Europe, asthma is relatively

less important there when com-

pared with other causes of death

and disability.

KEY REFERENCES1. Lozano R, Naghavi M, Foreman K,

Lim S, Shibuya K, Aboyans V, etal. Global and regional mortalityfrom 235 causes of death for 20age groups in 1990 and 2010: asystematic analysis for the Glob-al Burden of Disease Study 2010.Lancet2012;380:2095-2128.

2. Salomon JA, Wang H, FreemanMK, Vos T, Flaxman AD, Lopez

Figure 6 Loss of work related to asthma treatment in the GASP study. (Datafrom Burney P, Potts J, At-Khaled N, et al. A multinational study of treatment failures

in asthma management. Int J Tuberc Lung Dis 2008;12:13-18.)

The implications of this for pa-tients and for the economy can besubstantial. Figure 6 shows resultsfrom a study of patients attend-ing emergency rooms for asthma,mostly in low and middle incomecountries. The patients level oftreatment was compared to thatrecommended for the severity oftheir disease and they were askedhow much work they had missed inthe previous weeks. Over 50% ofthose taking two or more steps be-low the recommended treatmenthad missed over a day a week ofwork, compared with about 5% ofthose who were on the appropriatetreatment.

There are however other determi-nants of asthma control, and theseare partly unknown. In Europe theproportion of patients on inhaledcorticosteroids who have uncon-trolled asthma is fairly constantat around 10%-20%, but there iswider variation in the proportionof patients who are taking inhaledcorticosteroids and who are stilluncontrolled, and this varies from20% to 65% (Figure 7).

Because asthma is a commoncondition and one that in manyinstances starts very young andpersists throughout life, its impactis substantial, and this impact, rel-ative to that of other diseases, isparadoxically higher in some re-gions with relatively low mortality(Figure 8). Asthma ranks in the top20 conditions affecting the disabili-ty adjusted life years in Australasia

as well as in Oceania, South EastAsia and tropical Latin America,and ranks in the top 25 in NorthAmerica and Western Europe aswell as in North Africa and theMiddle East, Southern Africa andSouthern Latin America. Converse-ly, in some places, where severedisease is common, it still falls fur-ther down the rank of conditions


Figure 5 Prevalence of severe asthma in 13-14 year olds in the ISAAC studies.The symbols indicate prevalence values of


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Figure 7 Percentage of patientswith asthma in the European

Community Respiratory Health

Survey who were uncontrolledaccording to use of Inhaled

Corticosteroids (ICS). (Reprintedfrom J Allergy Clin Immunol, 120/6,

Cazzoletti L, Marcon A, Janson C,et al, Asthma control in Europe: a

real-world evaluation based on aninternational population-basedstudy, 1360-1367, Copyright2007, with permission from

Elsevier.)

Figure 8 Importance ofasthma relative to other

conditions. Rank of disabilityadjusted life years by region(2010). (Data from Murray CJ,

Vos T, Lozano R, et al. Disability-adjusted life years (DALYs)

for 291 diseases and injuriesin 21 regions, 1990-2010:

a systematic analysis for theGlobal Burden of Disease Study2010. Lancet 2012;380:2197-

2223.)

AD, et al. Healthy life expectancyfor 187 countries, 1990-2010: asystematic analysis for the GlobalBurden Disease Study 2010. Lan-cet2012;380:2144-2162.

3. At-Khaled N, Auregan G, Bencha-rif N, Camara LM, Dagli E, Djank-ine K, et al. Affordability of inhaledcorticosteroids as a potentialbarrier to treatment of asthmain some developing countries.[erratum in Int J Tuberc Lung Dis2001;5:689]. Int J Tuberc Lung Dis2000;4:268-271.

4. Lai CK, Beasley R, Crane J, FoliakiS, Shah J, Weiland S, et al. Globalvariation in the prevalence andseverity of asthma symptoms:

Phase Three of the Internation-al Study of Asthma and Allergiesin Childhood (ISAAC). Thorax2009;64:476-483.

5. Burney P, Potts J, At-Khaled N,Sepulveda RM, Zidouni N, Bena-li R, et al. A multinational studyof treatment failures in asthmamanagement. Int J Tuberc Lung Dis2008;12:13-18.

6. Cazzoletti L, Marcon A, JansonC, Corsico A, Jarvis D, Pin I, et al.Asthma control in Europe: a re-al-world evaluation based on an

international population-basedstudy. J Allergy Clin Immunol2007;120:1360-1367.

7. Murray CJ, Vos T, Lozano R, Nagha-vi M, Flaxman AD, Michaud C, etal. Disability-adjusted life years(DALYs) for 291 diseases and in-

juries in 21 regions, 1990-2010: asystematic analysis for the GlobalBurden of Disease Study 2010.Lancet2012;380:2197-2223.

Iceland

Norway

France

Germany

Belgium

Spain

Sweden

UK

Switzerland

Italy

Overallprevalence

0 10 20 30 40 50 60 70 80 90 100

Iceland

Spain

Germany

Switzerland

Italy

UK

Belgium

Sweden

Norway

France

Overallprevalence

0 10 20 30 40 50 60 70 80 90 100

% of subjects with uncontrolled asthma

ICS users [p


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Asthma is characterized by a ma-jor impact on patients in terms ofimpairment of quality of life, workand school performance. Patientsmay experience sleep disorders,impairment of cognitive function,depression and anxiety. The highand increasing prevalence of thesedisorders in particular allergic rhi-nitis and asthma may lead to sub-stantial direct and indirect costs ofdisease.

ECONOMIC

IMPACT OF ASTHMAIn a Global Initiative of Asthma(GINA) report on the burden ofasthma, it has been estimated thatasthma is one of the most commonchronic diseases in the world: 300million people in the world haveasthma. The number of disabili-ty-adjusted life years (DALYs) lostdue to asthma worldwide has beenestimated to be currently about 15million per year. Worldwide, asth-

ma accounts for around 1% of allDALYs lost, which reects the high

prevalence and severity of asthma.The number of DALYs lost due toasthma is similar to that for diabe-tes, cirrhosis of the liver, or schizo-phrenia. When ranking chronic dis-eases, asthma was the 25thleadingcause of DALYs lost worldwide in2001 (Figure 1).

An analysis of the burden of asth-ma in the US estimated the annualcosts per patient at $ 1907 and thetotal national medical expendi-ture at $ 18 billion. The ERS Whitebook, published in 2003 estimatedthe total costs of asthma in Europeat approximately 17.7 billion perannum. The countries with themost asthma related consultationswere the UK, followed by Greeceand Germany. The countries withthe least consultations were Po-land and Turkey. A 2012 analysisderived from the European Com-munity Respiratory Health SurveyII (ECRHS II) estimated the annualcosts per patient in Europe at 1583.

An estimate of the costs of asthma

in children in 25 EU countries hasbeen published in 2005. The totalcosts of asthma for the 25 coun-tries of the European Union areestimated at 3 billion. The useof wheeze as denition of asthma

leads to considerable higher costsof 5.2 billion. Annual costs forchildhood asthma per country varywidely (Figure 2).

DIRECT AND INDIRECT COSTSThe direct costs of disease com-prise the health care expenditureassociated with hospitalizations,emergency visits, physician vis-its, diagnostic tests and medicaltreatment, whereas indirect costsinclude the impact on employment,loss of work productivity and oth-er social costs. The most impor-

K EY MES S AG ES

The economic burden of asthma is substantially high Uncontrolled asthma is an important cost-enhancing factor Hospital admissions and medication costs are the major

components of direct costs A national approach may be useful in reducing the burden of

asthma Indirect costs of asthma are substantial and for a major part

caused by productivity losses Increase of asthma prevalence and costs of medication are

responsible for the rise in the cost of illness

Roy Gerth van WijkErasmus Medical Centre

Rotterdam, the Netherlands

SOCIO-ECONOMIC

COSTS OF ASTHMA

5

Socio-economic costs of asthma


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tant cost components are hospitaladmissions and asthma medica-tion. Australian, US and Canadianstudies found that direct costs ac-count for the greatest part of thetotal costs. However, the Ameri-

can TENOR study focusing on se-vere and difcult to treat asthma

demonstrated higher indirect thandirect costs. Also, several Europe-an studies among of which a largeGerman study demonstrated thatup to 75% of the total costs of asth-ma could be attributed to indirectcosts. An analysis of adult asthmain 11 ECRHS countries showedthat 62.5% of the total costs were

caused by working days lost anddays with limited, not work relat-ed activities. These studies un-derwrite that the indirect costs ofasthma are substantial (Figure 3).

COST-ENHANCING FACTORS

More than 20 studies suggest thatmore severe disease is a major fac-tor inuencing the increase in asth-ma-related costs. Comparisons be-

tween mild and severe disease mayresult in 1.3 - 5 fold differences.Other cost-enhancing factors com-prise poor asthma control, comor-bidity, and disability status (Figure3).

TRENDS IN COSTS

The costs of asthma are rising. Forinstance, in Canada the costs ofasthma increased due to a rise inprevalence and cost of medication.The increase was observed in spiteof a reduction in hospitalizationsand physician visits. In contrast,the National Asthma Programmein Finland has been proven to beeffective in reducing the costsper patient per year by 36% in tenyears.

Figure 1 Disability-adjusted life years lost due to asthma worldwide rankingwith other common disorders. GINA report Global burden of asthma 2001. (Datafrom Masoli M, Fabian D, Holt S, et al. The global burden of asthma: executive summary

of the GINA Dissemination Committee report. Allergy 2004;59:469-478.)



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KEY REFERENCES1. Masoli M, Fabian D, Holt S, Beas-

ley R. The global burden of asth-

ma: executive summary of theGINA Dissemination Committeereport.Allergy2004;59:469-478.

Figure 2 Annual costs of childhood asthma per country. Yellow: less than 100million ; orange: between 100 and 300 million ; red: more than 300 million

. (Data from van den Akker-van Marle ME, Bruil J, Detmar SB. Evaluation of cost ofdisease: assessing the burden to society of asthma in children in the European Union.

Allergy 2005;60:140-149.)


Figure 3 Direct and indirect costs of asthma and cost-enhancing factors.

2. Sullivan PW, Ghushchyan VH, Sle-jko JF, Belozeroff V, Globe DR, LinSL. The burden of adult asthma inthe United States: evidence fromthe Medical Expenditure Pan-el Survey. J Allergy Clin Immunol2011;127:363-369 e1-3.

3. European Respiratory Society.European lung white book. Hud-derseld: European Respiratory

Society Journals Ltd., 2003.

4. Accordini S, Corsico AG, Brag-gion M, Gerbase MW, Gislason D,Gulsvik A, et al. The cost of persis-tent asthma in europe: an inter-national population-based studyin adults. Int Arch Allergy Immunol2013;160:93-101.

5. van den Akker-van Marle ME,

Bruil J, Detmar SB. Evaluationof cost of disease: assessing theburden to society of asthma inchildren in the European Union.

Allergy2005;60:140-149.

6. Bahadori K, Doyle-Waters MM,Marra C, Lynd L, Alasaly K, Swis-ton J, et al. Economic burden ofasthma: a systematic review. BMCPulm Med2009;9:24.

7. Chipps BE, Zeiger RS, Borish L,Wenzel SE, Yegin A, Hayden ML,

et al. Key ndings and clinical im-plications from The Epidemiologyand Natural History of Asthma:Outcomes and Treatment Regi-mens (TENOR) study.J Allergy ClinImmunol2012;130:332-342 e10.

8. Stock S, Redaelli M, Luengen M,Wendland G, Civello D, Lauter-bach KW. Asthma: prevalenceand cost of illness. Eur Respir J2005;25:47-53.

9. Bedouch P, Marra CA, Fitzger-

ald JM, Lynd LD, Sadatsafavi M.Trends in asthma-related directmedical costs from 2002 to 2007in british columbia, Canada: a pop-ulation based-cohort study. PLoSOne 2012;7:e50949.

10. Haahtela T, Tuomisto LE, Pietinal-ho A, Klaukka T, Erhola M, Kaila M,et al. A 10 year asthma programmein Finland: major change for thebetter. Thorax2006;61:663-670.

Economic burden of asthma

Direct costs Indirect costs

Hospital admissions

Emergency visits

Physician visits

Diagnostics

Medication

Productivity loss

Absenteism

Presenteism

Unemployment

School days lost

Travelling (time)

Disability costs

Cost-enhancing factors

Asthma severity

Poor asthma control

Comorbidity

Disability status


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K EY MES S AG ES

Most children with recurrent wheeze in infancy will grow intoremission

Long term outcome may be inuenced by early exposure tocertain viruses (Rhinovirus, RSV)

Early domestic exposure to indoor allergens together with earlysensitization may lead to impaired lung function in school-age

Tobacco smoke exposure during pregnancy increases the risk forlong-term asthma

Atopic sensitization to indoor allergens in preschool age is a riskfactor for persistence of asthma

Strategies trying to prevent asthma up to now have not beensuccessful

Future initiatives for asthma-prevention should focus on viral-triggers and tolerance-induction to indoor allergens

Ulrich WahnCharite - University Medicine

Berlin, Germany

NATURAL HISTORY

OF ASTHMA

6

Natural history of asthma

The highest annual incidence ofwheeze is observed during infan-cy. Long-term longitudinal cohortstudies have clearly demonstratedthat the vast majority of wheezyinfants will not grow into a chronicasthma during the following dec-ades. However, early exposure tocertain viruses like Rhinovirus orRespiratory Syncytial Virus (RSV)increase the risk of recurrent asth-matic wheeze in school-age and ad-olescence. In preschool-age differ-ent clusters of asthmatic children

are emerging. The natural historyof asthma is strongly determinedby parental phenotypes: asthmaand atopy in father and mother isassociated with higher prevalenceof asthma during the rst two dec-ades of life. During the rst years

of life asthma prevalence is higherin boys. Between the age of 12 to14 years old girls are catching up sothat after adolescence most stud-ies nd higher prevalence rates in

females.

A number of environmental factorshave been shown to signicantly

contribute to a poor outcome ofchildhood asthma. Among them do-mestic tobacco-smoke exposure,particularly during pregnancy andinfancy, is clearly one of the mostimportant risk factors. In many

adolescents asthma is associatedwith sensitization to indoor-aller-gens, particularly house-dust mitesand cats. For children who ac-quire this sensitization during therst three years of life it has been

demonstrated that the chance for

long-term asthma remission is sig-nicantly reduced (Figure 1), and

long function will be impaired byschool-age.

Future challenges for paediatricallergists and chest physicians in-clude the need to nd appropriate

strategies for asthma prevention.After a variety of pharmacother-

apeutical approaches like inhaledcorticosteroids, antihistamines orcalcineurin inhibitors have failed, itappears likely, that future activitieswill have to address the role of viralinfections in infancy as well as themechanism of early sensitization

or tolerance induction to indoor al-lergens (Figure 2).

KEY REFERENCES1. Neuman , Hohmann C, Orsini N,

Pershagen G, Eller E, Kjaer HF, etal. Maternal smoking in pregnancyand asthma in preschool children:a pooled analysis of eight birthcohorts.Am J Respir Crit Care Med2012;186:1037-1043.


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0

10

20

30

40

50

60

70

80

1 2Age (years)

Atopic (n=94)

Non-atopic (n=59)

3 4 5 6 7 8 9 10 11 12 13

Prevalence(%)

Asthma

risk

Asthma risk

Asthma risk

FcR1-enhanced inflammation

Myeloid cells: activation and trafficking

TH2 memory cell trafficking

Bone marrowamplification

Atopic march

Upperrespiratoryinfection

Lowerrespiratoryinfection

Episodicmoderate-intensity

airway inflammation

Perennialaeroallergensensitization Continuous exposure

Persistent low-levelairway inflammation

Infection resistance Local inflammation

Atopic sensitization: prevention and reversal

Antivirals, IE,type 1 IFN

IE, topical IL-4/IL-13Rantagonist,mAb to IgE, T

regstimulants

SystemicIL-4/IL-13Rantagonist

Potentialtarget

Potentialtarget

SCIT, SLIT

SCIT,SLIT

Immuno-prophylaxis

Figure 2 Strategies for Asthma Treatment and Prevention. (Reprinted by permission from Macmillan Publishers Ltd: Nat Med,Holt PG, Sly PD, Viral infections and atopy in asthma pathogenesis: new rationales for asthma prevention and treatment,18, 726-

735, copyright 2012.)

Figure 1 Prevalence of currentwheeze from birth to age 13 years in

children with any wheezing episode atschool-age (5-7 years), stratied for

atopy. (Reprinted from The Lancet, 368,Illi S, von Mutius E, Lau S, et al, Perennial

allergen sensitisation early in life andchronic asthma in children: a birth cohort

study, 763-770, Copyright 2006, withpermission from Elsevier.)

Natural history of asthma

2. Holt PG, Sly PD. Viral infectionsand atopy in asthma pathogene-sis: new rationales for asthma pre-vention and treatment. Nat Med2012;18:726-735.

3. Illi S, von Mutius E, Lau S, Nigge-mann B, Grber C, Wahn U, et al.Perennial allergen sensitisationearly in life and chronic asthma in

children: a birth cohort study. Lan-cet2006;368:763-770.

4. Lau S, Illi S, Sommerfeld C, Nig-gemann B, Bergmann R, von Mu-tius E, et al. Early exposure tohouse-dust mite and cat allergensand development of childhoodasthma: a cohort study. Multicen-tre Allergy Study Group. Lancet

2000;356:1392-1397.

5. Wahn U, Lau S, Bergmann R, KuligM, Forster J, Bergmann K, et al.Indoor allergen exposure is a riskfactor for sensitization during therst three years of life. J AllergyClin Immunol1997;99:763-769.


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Genetics of asthma

A precise denition of the clinical phenotype and biologicalendotype is required as a base for genetic investigations

Asthma is a polygenetic disease with many genes involved indifferent biological mechanisms

Identifying genes responsible for the individual differences inresponse to asthma drugs is essential for improving treatmentoutcomes

Gene-gene interactions: different genes interact with each otherin the pathogenesis of asthma. While the effect of one singlepolymorphism may be modest, the combined effect of differentgenes may be substantial

Gene-environment interactions: genes interact with environ-mental exposures in determining the risk for asthma

Epigenetic mechanisms are likely to play a role in the developmentof asthma and may be activated by environmental exposure

HERITABILITY OF ASTHMAChildren of asthmatic mothershave an odds ratio (OR) of approxi-mately 3 to suffer themselves fromasthma. The fathers inuence isslightly smaller, but still sizeable(OR about 2.5), according to a me-ta-analysis aggregating data from33 studies. For adult-onset asthmaless data are available, but the re-sults point towards the same direc-tion. Thus, hereditary factors clear-ly do play a role in the developmentof asthma.

During the last one or two decadesasthma research has identied animpressive number of the parts ofthe puzzle: many genes, gene-geneinteractions, gene-environmentinteractions, epigenetic modica-tions. The next challenge is to as-semble the puzzle in order to seethe bigger picture.

GENES ASSOCIATED WITHASTHMA

In the early days of asthma genet-ics the hope was to nd one singlegene explaining asthma. Mean-while, using candidate-gene ap-proaches and linkage studies fol-lowed by positional cloning manygenes have been linked to asthma;in 2008 over 30 candidate geneshave been listed. During the lastdecade, using whole genome se-

quencing many more genes havebeen added to the list which keepsgrowing.

Asthma is a complex disease withseveral clinical phenotypes anddifferent endotypes, as dened

by various biological mechanisms,which, in turn, involve differentgenes. For example STAT6, a geneencoding a transcription factor in-volved in Th2 cell differentiationhas been described to be associ-ated with total serum IgE levels.Atopy is a component of asthma,however, it is neither required norsufcient to explain asthma; thus,

different variants of the STAT6gene will only explain a part of thegenetic basis of asthma. Polymor-phisms of the ADAM33 gene (ADisintegrin And Metalloprotein-ase gene family-member), to give

another example, are associatedwith diminished lung function andrelate to another part of the patho-genesis of asthma.

Genes found to be associated withasthma can be grouped accordingto different criteria. March et alhave proposed several functionalcategories (Table 1).

GENETICS OF ASTHMA7

K EY MES S AG ES

Roger LauenerChildrens Hospital of Eastern Switzerland

St. Gallen, Switzerland


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Genetics of asthma

ASTHMA PHARMACOGENETICSOf note in asthma genetics, re-search has also identied genes re-sponsible for individual differencesin response to treatment. Polymor-phisms in the 2-adrenoreceptorencoding gene have been implicat-ed in the variable response to treat-

ment with 2-adrenoreceptor ago-nists. Other genes such as CRHR1(corticotrophin-releasing hormonereceptor 1) or GLCCI1 (glucocor-ticoid-induced transcript 1 gene)have been suggested to modifyresponses to corticosteroids. Suchobservations may pave the way topersonalized treatment of asthma,but remain to be conrmed.

GENE-GENE INTERACTIONS

In a given patient not only one genewill determine whether or not thepatient will suffer from asthma.Rather, variants of different geneswill interact, enhancing or atten-uating each others effect on thedisease development. As an exam-ple, for the participants in a largeGerman birth cohort study theeffect of polymorphisms of IL-4, IL-

13, IL-4RA and STAT 6 each had amodest effect on the childrens riskto suffer from asthma. However,when combined, the asthma riskincreased 16.8 fold. This exampleillustrates the effect of the interac-tion of genes involved in one aspectof asthma pathogenesis, such as

regulation of Th2-mediated cell re-sponses. There are, however, manymore biological processes involvedin the development of asthma, suchas inammatory responses or epi-thelial barrier function, and vari-ants in each of the genes involvedin these processes will likely inter-act with other genes leading to orprotecting from disease.

GENE-ENVIRONMENT

INTERACTIONSFor some asthma risk or protec-tive genes, conicting results havebeen described in different studies.One explanation is that the effectof a genetic variant may depend onenvironmental exposures and viceversa. Well studied examples forthis are effects of polymorphismsin the endotoxin receptor CD14 or

TABLE 1

Functional categories of genes associated with asthma

Th2-mediated cell responses GATA3IL-4STAT6IL-13

TBX21IL-4RAIL-12BFcR1

Inammation IL-18TNFLeukotriene C4 synthase

IL-18R1

ALOX-5

Environmental sensing,innate immune receptors formicrobes

CD14TLR-4TLR-10HLA class II genes

TRL-2TLR-6NOD1/CARD4

Airway remodeling ADAM33DPP10

COL6A5GPRA

Bronchoconstriction CHRNA3/5NOS1

PDE4D

Epithelial barrier dysfunction Filaggrin (FLG)CC16 DEFB1Chemokines CCL-5, 11, 24, 26

in the TLR2 genes that depend onthe microbial load in the environ-ment. When

global atlas of asthma

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