GINA 2020 Full Report - Final - Wms PDF

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GLOBAL STRATEGY FOR

ASTHMA MANAGEMENT AND PREVENTION
Updated 2020
© 2020 Global Initiative for Asthma

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Global Strategy for Asthma Management and Prevention
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(2020 update)
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The reader acknowledges that this report is intended as an evidence-based asthma management strategy, for
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the use of health professionals and policy-makers. It is based, to the best of our knowledge, on current best
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evidence and medical knowledge and practice at the date of publication. When assessing and treating patients,
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health professionals are strongly advised to use their own professional judgment, and to take into account local
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and national regulations and guidelines. GINA cannot be held liable or responsible for inappropriate healthcare
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associated with the use of this document, including any use which is not in accordance with applicable local or
national regulations or guidelines.
This document should be cited as: Global Initiative for Asthma. Global Strategy for Asthma Management and
Prevention, 2020. Available from: www.ginasthma.org
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Table of contents
Tables and figures ............................................................................................................................................................. 5
Preface ................................................................................................................................................................................ 7
Members of GINA committees (2019-20) ......................................................................................................................... 8
Methodology ..................................................................................................................................................................... 11
What’s new in GINA 2020? .............................................................................................................................................. 14
Peer-reviewed publications about the GINA report ..................................................................................................... 14
Interim guidance on asthma management during the COVID-19 pandemic ............................................................. 17
SECTION 1. ADULTS, ADOLESCENTS AND CHILDREN 6 YEARS AND OLDER ...........................................................19
Chapter 1. Definition, description, and diagnosis of asthma .................................................................................... 19
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Definition of asthma ................................................................................................................................................... 20
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Description of asthma ................................................................................................................................................ 20
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Making the initial diagnosis ........................................................................................................................................ 21
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Confirming the diagnosis of asthma in patients already taking controller treatment .................................................26
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Differential diagnosis .................................................................................................................................................. 27
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How to make the diagnosis of asthma in other contexts ........................................................................................... 28
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Chapter 2. Assessment of asthma ................................................................................................................................ 31

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Overview .................................................................................................................................................................... 32
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Assessing asthma symptom control .......................................................................................................................... 33

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Assessing future risk of adverse outcomes ............................................................................................................... 37

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Role of lung function in assessing asthma control..................................................................................................... 37

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Assessing asthma severity ........................................................................................................................................ 39

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Chapter 3. Treating asthma to control symptoms and minimize risk ....................................................................... 41

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Part A. General principles of asthma management ....................................................................................................... 42

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Long-term goals of asthma management .................................................................................................................. 42

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The patient-health care provider partnership ............................................................................................................. 43

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Personalized control-based asthma management .................................................................................................... 44

Part B. Medications and strategies for symptom control and risk reduction .................................................................. 47
Asthma medications ................................................................................................................................................... 48
Asthma treatment steps ............................................................................................................................................. 57
Reviewing response and adjusting treatment ............................................................................................................ 64
Treating other modifiable risk factors ......................................................................................................................... 67
Other therapies .......................................................................................................................................................... 68
Non-pharmacological strategies ................................................................................................................................ 70
Indications for referral for expert advice..................................................................................................................... 78
Part C. Guided asthma self-management education and skills training ........................................................................ 79
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Overview .................................................................................................................................................................... 79
Skills training for effective use of inhaler devices ...................................................................................................... 79
Adherence with medications and other advice .......................................................................................................... 80
Asthma information .................................................................................................................................................... 82
Training in guided asthma self-management ............................................................................................................ 83
Part D. Managing asthma with comorbidities and in specific populations ..................................................................... 85
Managing comorbidities ............................................................................................................................................. 85
Managing asthma in specific populations or settings ................................................................................................ 88
Part E. Difficult-to-treat and severe asthma in adults and adolescents ......................................................................... 94
Definitions: uncontrolled, difficult-to-treat and severe asthma ................................................................................... 94
Prevalence: how many people have severe asthma? ............................................................................................... 95
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Importance: the impact of severe asthma.................................................................................................................. 95
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Investigate and manage adult and adolescent patients with difficult-to-treat asthma ............................................. 101
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Assess and treat severe asthma phenotypes .......................................................................................................... 103
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Manage and monitor severe asthma treatment ....................................................................................................... 108
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Chapter 4. Management of worsening asthma and exacerbations ......................................................................... 111
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Overview .................................................................................................................................................................. 113
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Diagnosis of exacerbations ...................................................................................................................................... 114

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Self-management of exacerbations with a written asthma action plan ................................................................... 114

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Management of asthma exacerbations in primary care........................................................................................... 118

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Management of asthma exacerbations in the emergency department ................................................................... 121

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Chapter 5. Diagnosis and initial treatment of adults with features of asthma, COPD or both (‘asthma-COPD
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overlap’) .......................................................................................................................................................................... 129

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Objectives ................................................................................................................................................................ 131

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Background to diagnosing asthma and/or COPD in adult patients ......................................................................... 131

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Assessment and management of patients with chronic respiratory symptoms ....................................................... 132
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Future research ........................................................................................................................................................ 137

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SECTION 2. CHILDREN 5 YEARS AND YOUNGER ......................................................................................................... 139

Chapter 6. Diagnosis and management of asthma in children 5 years and younger........................................... 139
Part A. Diagnosis ......................................................................................................................................................... 140
Asthma and wheezing in young children ................................................................................................................ 140
Clinical diagnosis of asthma .................................................................................................................................... 141
Tests to assist in diagnosis ...................................................................................................................................... 143
Differential diagnosis ............................................................................................................................................... 144
Part B. Assessment and management ........................................................................................................................ 146
Goals of asthma management ................................................................................................................................. 146
Assessment of asthma ............................................................................................................................................ 146
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Medications for symptom control and risk reduction ................................................................................................ 148
Asthma treatment steps for children aged 5 years and younger ............................................................................. 150
Reviewing response and adjusting treatment ......................................................................................................... 153
Choice of inhaler device .......................................................................................................................................... 153
Asthma self-management education for carers of young children ......................................................................... 154
Part C. Management of worsening asthma and exacerbations in children 5 years and younger ...............................155
Diagnosis of exacerbations ...................................................................................................................................... 155
Initial home management of asthma exacerbations ................................................................................................ 156
Primary care or hospital management of acute asthma exacerbations ................................................................... 158
Chapter 7. Primary prevention of asthma .................................................................................................................. 163
Factors contributing to the development of asthma in children ............................................................................... 164
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Factors associated with increased or decreased risk of asthma in children............................................................ 164
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Advice about primary prevention of asthma ............................................................................................................ 167
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SECTION 3. TRANSLATION INTO CLINICAL PRACTICE ................................................................................................ 169
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Chapter 8. Implementing asthma management strategies into health systems ....................................................169
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Introduction .............................................................................................................................................................. 170
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Adapting and implementing asthma clinical practice guidelines .............................................................................. 170
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Barriers and facilitators ............................................................................................................................................ 172

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Examples of high impact implementation interventions ........................................................................................... 172

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Evaluation of the implementation process ............................................................................................................... 172

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How can GINA help with implementation? .............................................................................................................. 173

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REFERENCES .................................................................................................................................................................... 174

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Tables and figures
DIAGNOSIS
Box 1-1. Diagnostic flowchart for clinical practice – initial presentation 22
Box 1-2. Diagnostic criteria for asthma in adults, adolescents, and children 6–11 years 23
Box 1-3. Steps for confirming the diagnosis of asthma in a patient already taking controller treatment 26
Box 1-4. How to step down controller treatment to help confirm the diagnosis of asthma 27
Box 1-5. Differential diagnosis of asthma in adults, adolescents and children 6–11 years 27
ASSESSMENT
Box 2-1. Assessment of asthma in adults, adolescents, and children 6–11 years 33
Box 2-2. GINA assessment of asthma control in adults, adolescents and children 6–11 years 35
Box 2-3. Specific questions for assessment of asthma in children 6–11 years 36
Box 2-4. Investigating a patient with poor symptom control and/or exacerbations despite treatment 40
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ASTHMA MANAGEMENT
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Box 3-1. Communication strategies for health care providers 43
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Box 3-2. The asthma management cycle for personalized asthma care 44
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Box 3-3. Population level versus patient level decisions about asthma treatment 46
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Box 3-4A. Initial asthma treatment - recommended options for adults and adolescents 50
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Box 3-4B. Selecting initial controller treatment in adults and adolescents with a diagnosis of asthma 51
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Box 3-4C. Initial asthma treatment - recommended options for children aged 6–11 years 52
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Selecting initial controller treatment in children aged 6–11 years with a diagnosis of asthma 53
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Box 3-5A. Personalized management for adults and adolescents to control symptoms and minimize future risk 54
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Box 3-5B. Personalized management for children 6–11 years to control symptoms and minimize future risk 55
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Box 3-6. Low, medium and high daily doses of inhaled corticosteroids 56
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Box 3-7. Options for stepping down treatment once asthma is well controlled 66
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Box 3-8. Treating modifiable risk factors to reduce exacerbations 67

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Box 3-9. Non-pharmacological interventions - summary 70

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Box 3-10. Effectiveness of avoidance measures for indoor allergens 74

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Box 3-11. Indications for considering referral for expert advice, where available 78
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Box 3-12. Strategies to ensure effective use of inhaler devices 80

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Box 3-13. Poor medication adherence in asthma 81

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Box 3-14. Asthma information 82

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Difficult-to-treat and severe asthma

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Box 3-15. What proportion of adults have difficult-to-treat or severe asthma? 95

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Box 3-16A. Decision tree – investigate and manage adult and adolescent patients with difficult-to-treat asthma 97
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Box 3-16B. Decision tree – assess and treat severe asthma phenotypes 98
Box 3-16C. Decision tree – consider add-on biologic Type 2 targeted treatments 99
Box 3-16D. Decision tree – monitor and manage severe asthma treatment 100
EXACERBATIONS
Box 4-1. Factors that increase the risk of asthma-related death 113
Box 4-2. Self-management of worsening asthma in adults and adolescents with a written asthma action plan 117
Box 4-3. Management of asthma exacerbations in primary care (adults, adolescents, children 6–11 years) 119
Box 4-4. Management of asthma exacerbations in acute care facility, e.g. emergency department 123
Box 4-5. Discharge management after hospital or emergency department care for asthma 127
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ASTHMA, COPD AND ASTHMA+COPD
Box 5-1. Current definitions of asthma and COPD, and clinical description of asthma-COPD overlap 132
Box 5-2. Approach to initial treatment in patients with asthma and/or COPD 133
Box 5-3. Spirometric measures in asthma and COPD 134
Box 5-4. Specialized investigations sometimes used in distinguishing asthma and COPD 136
CHILDREN 5 YEARS AND YOUNGER
Box 6-1. Probability of asthma diagnosis in children 5 years and younger 141
Box 6-2. Features suggesting a diagnosis of asthma in children 5 years and younger 142
Box 6-2A. Questions that can be used to elicit features suggestive of asthma 142
Box 6-3. Common differential diagnoses of asthma in children 5 years and younger 145
Box 6-4. GINA assessment of asthma control in children 5 years and younger 147
Box 6-5. Personalized management of asthma in children 5 years and younger 152
Box 6-6. Low daily doses of inhaled corticosteroids for children 5 years and younger 153
Box 6-7. Choosing an inhaler device for children 5 years and younger 154
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Box 6-8. Primary care management of acute asthma or wheezing in children 5 years and younger 157
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Box 6-9. Initial assessment of acute asthma exacerbations in children 5 years and younger 158
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Box 6-10. Indications for immediate transfer to hospital for children 5 years and younger 159
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Box 6-11. Initial emergency department management of asthma exacerbations in children 5 years and younger 160
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PRIMARY PREVENTION OF ASTHMA
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Box 7-1. Advice about primary prevention of asthma in children 5 years and younger 167
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IMPLEMENTATION STRATEGIES
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Box 8-1. Approach to implementation of the Global Strategy for Asthma Management and Prevention 171
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Box 8-2. Essential elements required to implement a health-related strategy 171

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Box 8-3. Examples of barriers to the implementation of evidence-based recommendations 172

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Box 8-4 Examples of high-impact interventions in asthma management 172

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Preface
Asthma is a serious global health problem affecting all age groups. Its prevalence is increasing in many countries,
especially among children. Although some countries have seen a decline in hospitalizations and deaths from asthma,
asthma still imposes an unacceptable burden on health care systems, and on society through loss of productivity in the
workplace and, especially for pediatric asthma, disruption to the family.
In 1993, the National Heart, Lung, and Blood Institute collaborated with the World Health Organization to convene a
workshop that led to a Workshop Report: Global Strategy for Asthma Management and Prevention.1 This was followed by
the establishment of the Global Initiative for Asthma (GINA), a network of individuals, organizations, and public health
officials to disseminate information about the care of patients with asthma, and to provide a mechanism to translate
scientific evidence into improved asthma care. The GINA Assembly was subsequently initiated, as an ad hoc group of
dedicated asthma care experts from many countries. The Assembly works with the Science Committee, the Board of
Directors and the Dissemination and Implementation Committee to promote international collaboration and dissemination
of information about asthma. The GINA report (“Global Strategy for Asthma Management and Prevention”), has been
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updated annually since 2002, and publications based on the GINA reports have been translated into many languages. In
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2001, GINA initiated an annual World Asthma Day, raising awareness about the burden of asthma, and becoming a focus
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for local and national activities to educate families and health care professionals about effective methods to manage and
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control asthma.
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In spite of these efforts, and the availability of effective therapies, international surveys provide ongoing evidence for
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suboptimal asthma control in many countries. It is clear that if recommendations contained within this report are to
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improve care of people with asthma, every effort must be made to encourage health care leaders to assure availability of,
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and access to, medications, and to develop means to implement and evaluate effective asthma management programs.
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To this end, the major revision of the GINA report published in May 2014 not only reflected new evidence about asthma
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and its treatment, but also integrated evidence into strategies that would be both clinically relevant and feasible for
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implementation into busy clinical practice, and presented recommendations in a user-friendly way with extensive use of
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summary tables and flow-charts. For clinical utility, recommendations for clinical practice are contained in the core GINA
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Report, while additional resources and background supporting material are provided online at www.ginasthma.org. New
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recommendations about treatment of mild asthma, described in the present report, represent the outcome of more than a
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decade of work by GINA members and others, and may be considered the most fundamental change in asthma
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management in the past 30 years.

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It is essential that we acknowledge the superlative work of all who have contributed to the success of the GINA program,
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and the many people who have participated in it; in particular, the outstanding and dedicated work of Drs Suzanne Hurd
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as Scientific Director and Claude Lenfant as Executive Director over the many years since GINA was first established,
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until their retirement in December 2015. Through their tireless contributions, Dr Hurd and Dr Lenfant fostered and
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facilitated the development of GINA. In January 2016, we were delighted to welcome Ms Rebecca Decker, BS, MSJ, as
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the new Program Director for GINA and GOLD, and we appreciate the commitment and skills that she has brought to this
demanding role.
The work of GINA is now supported only by income generated from the sale of materials based on the report. The
members of the GINA Committees are solely responsible for the statements and conclusions presented in this publication.
They receive no honoraria or expenses to attend the scientific review meetings, nor for the many hours spent reviewing
the literature and contributing substantively to the writing of the report.
We hope you find this report to be a useful resource in the management of asthma and that, in using it, you will recognize
the need to individualize the care of each and every asthma patient you see.
Helen K Reddel, MBBS PhD Louis-Philippe Boulet, MD

Chair, GINA Science Committee Chair, GINA Board of Directors
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Members of GINA committees (2019-20)
GINA SCIENTIFIC COMMITTEE

Helen K. Reddel, MBBS PhD, Chair Kevin Mortimer, BA/MA, MB/BChir, PhD
Woolcock Institute of Medical Research, University of Liverpool School of Tropical Medicine
Sydney Liverpool, UK
Sydney, Australia Soren Erik Pedersen, MD (to May 2019)
Leonard B. Bacharier, MD Kolding Hospital
Washington University School of Medicine Kolding, Denmark
St Louis, MO, USA Aziz Sheikh, BSc, MBBS, MSc, MD
Eric D. Bateman, MD The University of Edinburgh
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University of Cape Town Lung Institute Edinburgh, United Kingdom
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Cape Town, South Africa
GINA BOARD OF DIRECTORS
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Louis-Philippe Boulet, MD
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Louis-Philippe Boulet, MD, Chair
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Université Laval
Université Laval
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Québec, QC, Canada
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Québec, QC, Canada
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Christopher Brightling, FMedSci, PhD
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Eric D. Bateman, MD
Leicester NIHR Biomedical Research Centre,
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University of Cape Town Lung Institute
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University of Leicester
Cape Town, South Africa
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Leicester, UK
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Guy Brusselle, MD, PhD

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Ghent University Hospital

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Ghent, Belgium
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Alvaro A. Cruz, MD
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Roland Buhl, MD PhD

Federal University of Bahia
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Mainz University Hospital

Salvador, BA, Brazil
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Mainz, Germany
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J. Mark FitzGerald, MD
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J. Mark FitzGerald, MD
University of British Columbia
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University of British Columbia

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Vancouver, BC, Canada

Vancouver, BC, Canada
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Hiromasa Inoue, MD
Louise Fleming, MBChB MD
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Kagoshima University
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Royal Brompton Hospital

Kagoshima, Japan
London, United Kingdom
Jerry A. Krishnan, MD PhD
Hiromasa Inoue, MD
University of Illinois Hospital & Health Sciences System
Chicago, IL, USA
Kagoshima, Japan
Mark L. Levy, MD
Fanny Wai-san Ko, MD
Locum GP
The Chinese University of Hong Kong
London, UK
Hong Kong
Jiangtao Lin, MD
China-Japan Friendship Hospital
Peking University
Chicago, IL, USA
Beijing, China
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Members of GINA Board (continued) GINA PROGRAM
Soren Erik Pedersen, MD (to May 2019) Rebecca Decker, BS, MSJ
University of Southern Denmark and Kolding Hospital
Kolding, Denmark EDITORIAL ASSISTANCE
Helen K. Reddel, MBBS PhD Ruth Hadfield, BSc, DPhil, GCBiostat
Woolcock Institute of Medical Research, University of Jenni Harman, BVSc, BA
Sydney
Sydney, Australia GRAPHICS ASSISTANCE
Arzu Yorgancioglu, MD Kate Chisnall
Celal Bayar University
Department of Pulmonology INFORMATION DESIGN
Manisa, Turkey
Tomoko Ichikawa, MS
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Hugh Musick, MBA
GINA DISSEMINATION AND IMPLEMENTATION
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COMMITTEE Institute for Healthcare Delivery Design
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University of Illinois, Chicago, USA
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Mark L. Levy, MD Chair (to Sept 2019)
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Locum GP
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London, UK
Alvaro A. Cruz, MD Chair (from Sept 2019) PY
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Federal University of Bahia
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Salvador, BA, Brazil

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Louis-Philippe Boulet, MD
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Université Laval
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Québec, QC, Canada

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Ghent, Belgium
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Hiromasa Inoue, MD
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Kagoshima, Japan
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Chicago, IL, USA
Arzu Yorgancioglu, MD
Celal Bayar University
Department of Pulmonology
Manisa, Turkey
Disclosures for members of GINA Board of Directors and Science Committee can be found at www.ginasthma.org
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Methodology
GINA SCIENCE COMMITTEE
The GINA Science Committee was established in 2002 to review published research on asthma management and
prevention, to evaluate the impact of this research on recommendations in GINA documents, and to provide yearly
updates to these documents. The members are recognized leaders in asthma research and clinical practice with the
scientific expertise to contribute to the task of the Committee. They are invited to serve for a limited period and in a
voluntary capacity. The Committee is broadly representative of adult and pediatric disciplines as well as from diverse
geographic regions. The Science Committee meets twice yearly in conjunction with the American Thoracic Society
(ATS) and European Respiratory Society (ERS) international conferences, to review asthma-related scientific literature.
Statements of interest for Committee members are found on the GINA website www.ginasthma.org.
PROCESSES FOR UPDATES AND REVISIONS OF THE GINA REPORT
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GINA processes for the review of evidence and development of recommendations for GINA reports, including handling
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of conflict of interest, were reviewed by the Science Committee and approved by the Board in September 2018, and are
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described below.
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Literature search
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For each meeting of the GINA Science Committee, a rolling PubMed search is performed covering approximately 18
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months, using filters established by the Committee: 1) asthma, all fields, all ages, only items with abstracts, clinical trial,
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human; and 2) asthma and meta-analysis, all fields, all ages, only items with abstracts, human. The ‘clinical trial’
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publication type includes not only conventional randomized controlled trials, but also pragmatic, real-life and
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observational studies. The respiratory community is also invited to submit to the Program Director any other peer-
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reviewed publications that they believe should be considered, providing an abstract and the full paper are submitted in
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(or translated into) English; however, because of the comprehensive process for literature review, such ad hoc
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submissions have rarely resulted in substantial changes to the report.

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Screening and review

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After initial screening of articles identified by a cumulative search of the literature by the Editorial Assistant and Chair of
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the Science Committee, each publication identified by the above search is reviewed for relevance and quality by
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members of the Science Committee. Each publication is allocated to at least two Committee member reviewers, neither
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of whom may be an author (or co-author) or declare a conflict of interest in relation to the publication. All members
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receive a copy of all of the abstracts and non-conflicted members have the opportunity to provide comments during the
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pre-meeting review period. Members evaluate the abstract and, by their judgment, the full publication, and answer
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written questions about whether the scientific data impact on GINA recommendations, and if so, what specific changes
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should be made. A list of all publications reviewed by the Committee is posted on the GINA website
(www.ginasthma.org).
Discussion and decisions during Science Committee meetings
During Committee meetings, each publication that is assessed by at least one member to potentially impact on the GINA
report is discussed. This process comprises three parts: (1) evaluation of the relevance and quality of the publication;
(2) a decision about inclusion of the publication in the report; and (3) (if relevant) discussion about related changes to
the report. First, the Committee considers the relevance of the study to the GINA report, the quality of the study, the
reliability of the findings and the interpretation of the results, based on the responses from reviewers and discussion
among members of the Committee. During this discussion, an author may be requested to provide clarification or
respond to questions relating to the study, but they may not take part in the second phase, during which the Committee
decides whether the publication should be included in the GINA report. These decisions to modify the report or its
references are made by consensus by Committee members present. If the chair is an author on a publication being
reviewed, an alternative chair is appointed to lead the discussion in part 1 and the decision in part 2 for that publication.
Methodology 11
If the committee resolves to include the publication in the report, the author is permitted to take part in the third phase
that involves discussions about and decisions on changes to the report, including the positioning of the study findings in
the report and the way that they would be integrated with existing (or other new) components of the GINA management
strategy. These discussions may take place immediately, or over the course of time as new evidence emerges or as
other changes to the report are agreed and implemented. The above conflict of interest considerations also apply to
members of the GINA Board who ex-officio attend GINA Science Committee meetings.
In 2009, after carrying out two sample reviews using the GRADE system,2 GINA decided not to adopt this methodology
for its general processes because of the major resource challenges that it would present. This decision also reflected
that, unique among evidence-based recommendations in asthma, and most other therapeutic areas, GINA conducts an
ongoing twice-yearly update of the evidence base for its recommendations. As with all previous GINA reports, levels of
evidence are assigned to management recommendations where appropriate. A description of the current criteria is
found in Table A, which was developed by the National Heart Lung and Blood Institute. From 2019, GINA has also
described the values and preferences that were taken into account in making major new recommendations.
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Table A. Description of levels of evidence used in this report
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Evidence Sources
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Definition
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level of evidence
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A Randomized controlled Evidence is from endpoints of well designed RCTs, meta-analyses of relevant
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trials (RCTs) and meta- studies, or strong observational evidence that provide a consistent pattern of
analyses. Rich body of PY
findings in the population for which the recommendation is made. Category A
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data. requires substantial numbers of studies involving substantial numbers of
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participants.
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B Randomized controlled Evidence is from endpoints of intervention studies that include only a limited
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trials (RCTs) and meta- number of patients, post hoc or subgroup analysis of RCTs or meta-analysis of
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analyses. Limited body such RCTs. In general, Category B pertains when few randomized trials exist, they
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of data. are small in size, they were under-taken in a population that differs from the target
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population of the recommendation, or the results are somewhat inconsistent.

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C Nonrandomized trials. Evidence is from outcomes of uncontrolled or non-randomized trials or from

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Observational studies. observational studies.

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D Panel consensus This category is used only in cases where the provision of some guidance was
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judgment. deemed valuable but the clinical literature addressing the subject was insufficient to
justify placement in one of the other categories. The Panel Consensus is based on
clinical experience or knowledge that does not meet the above listed criteria.
New therapies and indications

The GINA report is a global strategy document. Since regulatory approvals differ from country to country, and
manufacturers do not necessarily make regulatory submissions in all countries, some GINA recommendations are likely
to be off-label in some countries. This is a particular issue for pediatrics, where across different diseases, many
treatment recommendations for pre-school children and for children aged 6–11 years are off-label.
For new therapies, the GINA Science Committee makes recommendations after approval for asthma by at least one
major regulatory agency (e.g. European Medicines Agency, Food and Drug Administration). The reason is that
12 Methodology
regulators often receive substantially more safety data on new medications than are available to GINA through the peer-
reviewed literature. However, decisions by GINA to make or not make a recommendation about any therapy, or in any
particular subpopulation, are based on the best available peer-reviewed evidence and not on labeling directives from
regulators.
For existing therapies with evidence for new regimens or in different populations than are covered by existing regulatory
labels, the Science Committee and Board agreed in May 2018, in the context of new evidence for use of long-term low
dose macrolides in moderate-severe asthma, that the Committee may consider making recommendations that are not
necessarily covered by regulatory indications in any country at the time, provided the Committee is satisfied with the
available evidence around safety and efficacy/effectiveness. The same approach was again taken in 2019 with
recommendations for mild asthma about treatment with as-needed inhaled corticosteroid (ICS)-formoterol and taking
ICS whenever SABA is taken.
Since the GINA report represents a global strategy, the 2020 report therefore no longer refers to recommendations
being ‘off-label’. However, readers are advised that when assessing and treating patients, they should use their own
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professional judgment and should also take into account local and national guidelines and eligibility criteria, as well as
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licensed drug doses.
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LITERATURE REVIEWED FOR GINA 2020 UPDATE
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The GINA report has been updated in 2020 following the routine twice-yearly review of the literature by the GINA
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Science Committee. The literature searches for ‘clinical trial’ publication types (see above) and meta-analyses identified
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a total of 2,420 publications, of which 1,860 were screened out for duplicates, relevance and/or quality. The remaining
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560 publications (377 ‘clinical trials’ and 183 meta-analyses) were reviewed by at least two members of the Science
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Committee; a total of 89 were subsequently discussed at face-to-face meetings in May 2019 in Dallas, USA and in
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September 2019 in Madrid, Spain. A list of key changes in GINA 2020 can be found starting on p.14, and a tracked
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changes copy of the 2019 report is archived on the GINA website at www.ginasthma.org/archived-reports/.
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FUTURE CHALLENGES
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In spite of laudable efforts to improve asthma care over the past 20 years, many patients globally have not benefited
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from advances in asthma treatment and often lack even the rudiments of care. Many of the world’s population live in
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areas with inadequate medical facilities and meager financial resources. The GINA Board of Directors recognizes that
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‘fixed’ international guidelines and ‘rigid’ scientific protocols will not work in many locations. Thus, the recommendations
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found in this report must be adapted to fit local practices and the availability of health care resources.
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At the most fundamental level, patients in many areas may not have access even to low dose inhaled corticosteroids,
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which are the cornerstone of care for asthma patients of all severity. More broadly, medications remain the major
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contributor to the overall costs of asthma management, so the access to and pricing of high quality asthma medications
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continues to be an issue of urgent need and a growing area of research interest.3 With budesonide-formoterol now on
the World Health Organization (WHO) essential medicines list, the changes to treatment of mild asthma first included in
the 2019 report may provide a feasible solution to reduce the risk of severe exacerbations with very low dose treatment.4
A challenge for the GINA Board of Directors for the next several years is to continue working with primary health care
providers, public health officials and patient support organizations to design, implement, and evaluate asthma care
programs to meet local needs in various countries. The Board continues to examine barriers to implementation of
asthma management recommendations, especially in primary care settings and in developing countries, and to examine
new and innovative approaches that will ensure the delivery of the best possible asthma care. GINA is a partner
organization in a program launched in March 2006 by WHO, the Global Alliance against Chronic Respiratory Diseases
(GARD). Through the work of the GINA Board of Directors, and in cooperation with GARD, substantial progress toward
better care for all patients with asthma should be achieved in the next decade.
Methodology 13
What’s new in GINA 2020?
The GINA report has been updated in 2020 following the routine twice-yearly cumulative review of the literature by the
GINA Scientific Committee. Full details of the changes can be found in the tracked version archived on the GINA
website. In summary, the key changes are:
• Interim guidance about asthma and COVID-19: Brief advice has been added (p.17) about management of asthma
in the context of the COVID-19 pandemic, with a focus on safety of patients and healthcare workers, based on
evidence available at the time of publication.
• Methodology: Additional detail has been added (p.12) about GINA recommendations for new and existing therapies.
Since GINA is a global strategy, and regulatory indications vary between countries, specific therapies are no longer
stated to be ‘off-label’. Clinicians are reminded in several locations throughout the report to use their own professional
judgment in assessing and treating individual patients, and to check local eligibility, licensed drug dosages, payer
criteria, and national guidelines when prescribing.
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• Assessment of symptom control: It is clarified that the reliever use criterion forming part of the assessment of
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asthma symptom control (Box 2-2, p.35) relates to as-needed short-acting β2-agonist (SABA). Our current view is that
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frequency of as-needed ICS-formoterol should not be included in the assessment of symptom control, particularly for
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patients not taking maintenance ICS, as it is providing the patient’s controller therapy. Further data are awaited, and
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this issue will be reviewed again next year.
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• Additional evidence supporting the role of as-needed ICS-formoterol in mild asthma: The 2019 GINA
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recommendations for use of as-needed ICS-formoterol in mild asthma (p.57) are further supported by the results of
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two additional randomized controlled trials (RCTs) in adults. These open-label studies represented the way that
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patients with mild asthma would use as-needed ICS-formoterol in real life. They included patients using SABA at
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baseline between twice a month and twice a day.

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• Inflammatory phenotyping is not needed for prescribing as-needed ICS-formoterol in mild asthma: In two
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studies, the benefit of as-needed ICS-formoterol for risk reduction and symptom control was independent of baseline
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characteristics, including inflammatory markers (blood eosinophils and exhaled nitric oxide) (p.48).
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• New resources for initial treatment of newly-diagnosed asthma: New figures have been added to help explain
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initial treatment options for adults and adolescents (Box 3-4B, p.51) and children 6–11 years (Boxes 3-4D, p.53) with
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newly-diagnosed asthma.
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• Maximum daily dose of ICS-formoterol: For patients prescribed maintenance and reliever treatment with ICS-
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formoterol, the maximum recommended total dose in a single day is 48mcg formoterol for beclometasone-formoterol,
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and 72mcg formoterol for budesonide-formoterol (Steps 3 and 4, p.60 and p.61). This also applies to as-needed-only
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use of budesonide-formoterol in mild asthma. However, in randomized controlled trials in mild asthma, such high
usage was rarely seen, and average use was around 3–4 doses per week. This information has been added in text
about Steps 1 (p.57) and Step 2 (p.59).
• Taking ICS whenever SABA is taken, in mild asthma: Additional support for this treatment option in children 6-17
years with mild asthma is provided by a randomized controlled trial in African-American children (p.59).
• Low, medium and high dose ICS: Table 3-6 (p.56) has been revised to reflect the use of ICS formulations at different
doses in clinical practice. Of note, this is not an equivalence table, but instead represents suggested doses of various
ICS formulations for the ‘low’, ‘medium’ and ‘high’ dose ICS options included in treatment recommendations. However,
doses and regulatory labelling will vary from country to country.
• Additional evidence about management of asthma in children: New evidence added in 2020 includes a
systematic review showing that school-based programs including asthma self-management reduced emergency
department visits, hospitalizations and days of reduced activity (p.84); and that in pre-schoolers with asthma, daily ICS
14 Methodology
is more effective than leukotriene receptor antagonists (LTRA) for symptom control and exacerbation reduction
(p.150).
• Mepolizumab: this biologic agent has been approved for children aged 6 years and older with severe eosinophilic
asthma, but efficacy data in this age group are limited to a small open-label uncontrolled study (p.63 and p.107).
• Risk of adverse effects of montelukast: Alerts have been added about the risk of serious mental health adverse
effects with montelukast, including the requirement by the FDA for a boxed warning (p.59 and elsewhere).
• Asthma and COPD: Chapter 5 (p.129) is about patients with features of both asthma and chronic obstructive
pulmonary disease (COPD), also described as ‘asthma-COPD overlap’ or ‘asthma+COPD’. This chapter has been
rewritten, and a new, simpler summary figure included (Box 5-2, p.133). The emphasis of this chapter is on advice for
primary care and general clinicians, including evidence that patients with features of both asthma and COPD should
be treated with ICS-containing therapy, as this reduces their risk of hospitalization and death compared with long-
acting bronchodilators alone.
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• Asthma in pregnancy: A review of guidelines for asthma in pregnancy highlighted the need for more clinical trials,
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and for clarity in recommendations (p.89).
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• Acute asthma: References to ‘high flow oxygen’ in previous reports have been corrected to ‘high concentration
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oxygen’.
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• Identification of severe asthma exacerbations in children 5 years and younger: Assessment criteria have been
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revised (Box 6-8 p.157 and Box 6-9, p.158), with respiratory rate added, retractions removed and pulse rates revised
lower. PY
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• Role of trained lay health workers: Asthma outcomes can be improved with interventions by trained lay health
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workers, as well as by trained nurses and pharmacists (p.82).

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• Factors contributing to development of asthma: New evidence suggests that 13% of global asthma incidence in
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children may be attributable to traffic-related air pollution, and that obesity may be a risk factor for developing asthma
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(p.163).
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Methodology 15
Peer-reviewed publications about the GINA report
The following articles about the GINA report in peer-reviewed journals have been published on behalf of GINA.
Boulet LP, Reddel HK, Brightling CEB, Brusselle G. GINA fosters World Asthma Day 2020 to prevent asthma deaths. Am
J Physiol Lung Cell Mol Physiol 2020 (doi: 10.1152/ajplung.00075.2020)
Reddel HK. GINA recommendations in adults with symptomatic mild asthma and a smoking history. Eur Respir J.
2020;55:2000068 (doi: 10.1183/13993003.00068-2020).
Licskai C, Yang CL, Lemiere C, Ducharme FM, Lougheed MD, Radhakrishnan D, Podgers D, et al. Are the 2019 Global
Initiative for Asthma (GINA) strategy recommendations applicable to the Canadian context? A conversation between the
Canadian Thoracic Society Asthma Assembly and Professor Helen Reddel, Chair of the GINA Scientific Committee. Can J
Respir Crit Care Sleep Med 2019:1-4 (open access: doi.org/10.1080/24745332.2019.1679553).
Reddel HK, FitzGerald JM, Bateman ED, Bacharier LB, Becker A, Brusselle G, Buhl R, Cruz AA, Fleming L, Inoue H, Ko
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FW, Krishnan JA, Levy ML, Lin J, Pedersen SE, Sheikh A, Yorgancioglu A, Boulet L-P. GINA 2019: a fundamental change
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in asthma management. Treatment of asthma with short-acting bronchodilators alone is no longer recommended for
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adults and adolescents. Eur Respir J 2019;53:1901046 (open access: doi: 10.1183/13993003.01046-2019)
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Boulet LP, Reddel HK, Bateman ED, Pedersen S, FitzGerald JM and O’Byrne PM. The Global Initiative for Asthma
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(GINA): 25 years later. Eur Respir J 2019;54:1900598 (doi: 10.1183/13993003.00598-2019).
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Reddel HK. The impact of the Global Initiative for Asthma (GINA): compass, concepts, controversies and challenges. BRN
Rev 2019;5:4-18 (open access: doi: 10.23866/BRNRev:2017-0034) PY
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Reddel HK, Bateman ED, Becker A, Boulet LP, Cruz AA, Drazen JM, Haahtela T, Hurd SS, Inoue H, de Jongste JC,
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Lemanske RF Jr, Levy ML, O'Byrne PM, Paggiaro P, Pedersen SE, Pizzichini E, Soto-Quiroz M, Szefler SJ, Wong GW,
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FitzGerald JM. A summary of the new GINA strategy: a roadmap to asthma control. Eur Respir J 2015;46:622-39 (open
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access; doi 10.1183/13993003.00853-2015).

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Reddel HK, Hurd SS, FitzGerald JM. World Asthma Day. GINA 2014: a global asthma strategy for a global problem. Int J
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Tuberc Lung Dis 2014;18:505-6 (open access: doi.org/10.5588/ijtld.14.0246).

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Boulet LP, FitzGerald JM, Reddel HK. The revised 2014 GINA strategy report: opportunities for change. Curr Opin Pulm
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Med 2015;21:1-7.
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Reddel HK, Levy ML. The GINA asthma strategy report: what's new for primary care? NPJ Prim Care Respir Med
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2015;25:15050 (open access: doi 10.1038/npjpcrm.2015.50).

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Bateman ED, Hurd SS, Barnes PJ, Bousquet J, Drazen JM, FitzGerald JM, Gibson P, et al. Global strategy for asthma
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management and prevention: GINA executive summary. Eur Respir J. 2008;31:143-78.

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Bousquet J. Global initiative for asthma (GINA) and its objectives. Clin Exp Allergy. 2000;30 Suppl 1:2-5.
Bousquet J, Clark TJ, Hurd S, Khaltaev N, Lenfant C, O'Byrne P, Sheffer A. GINA guidelines on asthma and beyond.
Allergy. 2007;62:102-12.
Fitzgerald JM, Bateman E, Hurd S, Boulet LP, Haahtela T, Cruz AA, Levy ML. The GINA Asthma Challenge: reducing
asthma hospitalisations. Eur Respir J. 2011;38:997-8.
Masoli M, Fabian D, Holt S, Beasley R, Global Initiative for Asthma P. The global burden of asthma: executive summary of
the GINA Dissemination Committee report. Allergy. 2004;59:469-78.
O'Byrne PM. 2007 update of the Global Initiative for Asthma management and prevention: what's new? Pol Arch Med
Wewn. 2008;118:179-80.
16 Methodology
Interim guidance on asthma management during the
COVID-19 pandemic
Advise patients with asthma to continue taking their prescribed asthma medications, particularly inhaled
corticosteroid (ICS)-containing medications, and oral corticosteroids (OCS) if prescribed
It is important for patients to continue taking their prescribed asthma medications as usual during the COVID-19
(‘coronavirus disease 2019’) pandemic. This includes ICS-containing medications (alone or in combination with a long-
acting beta2-agonist [LABA]), and add-on therapy including biologic therapy for severe asthma. Stopping ICS often leads
to potentially dangerous worsening of asthma. See Chapter 3B (p.47) for information about asthma medications and
regimens and non-pharmacologic strategies, and Chapter 3C (p.79) for guided asthma self-management education and
skills training.
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For a small proportion of patients with severe asthma, long-term OCS may sometimes be needed, and it is very
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dangerous to stop these suddenly. See Chapter 3E (p.94) for advice about investigation and management of difficult-to-
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treat and severe asthma, including addition of biologic therapy for minimizing use of OCS.
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Advise patients to discuss with you before stopping any asthma medication.
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Make sure that all patients have a written asthma action plan
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An action plan tells the patient how to recognize worsening asthma, how to increase their reliever and controller
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medications, and when to seek medical help. A short course of OCS may be needed during severe asthma flare-ups
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(exacerbations). See Box 4-2 (p.117) for more information about specific action plan options for increasing controller and
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reliever medications, depending on the patient’s usual therapeutic regimen.

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At present, there is no clear evidence about how to distinguish between worsening asthma due to respiratory viral
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infections such as rhinovirus and influenza, and COVID-19.

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Where possible, avoid use of nebulizers due to the risk of transmitting infection to other patients and to
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healthcare workers
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Nebulizers can transmit respiratory viral particles for approximately 1 meter. Instead, to deliver short-acting beta2-agonist
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for acute asthma in adults and children, use a pressurized metered-dose inhaler and spacer, with a mouthpiece or tightly
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fitting face mask, if required. Check the manufacturer’s instructions about whether a spacer can be autoclaved. If not (as
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is the case for many types of spacers), or if in doubt, spacers should be restricted to single patient use.
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Remind patients not to share inhaler devices or spacers with family members, to avoid transmitting infection.
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Avoid spirometry in patients with confirmed/suspected COVID-19

Spirometry can disseminate viral particles and expose staff and patients to risk of infection. While community
transmission of the virus is occurring in your region, postpone spirometry and peak flow measurement within health care
facilities unless there is an urgent need. If spirometry is needed urgently for clinical management, follow infection control
precautions for contact and droplet precautions. World Health Organization (WHO) recommendations are found here:
www.who.int/publications-detail/infection-prevention-and-control-during-health-care-when-novel-coronavirus-(ncov)-
infection-is-suspected-20200125.
Interim advice about COVID-19 and asthma 17

Follow infection control recommendations if other aerosol-generating procedures are needed
Other aerosol-generating procedures include oxygen therapy (including with nasal prongs), sputum induction, manual
ventilation, non-invasive ventilation and intubation. World Health Organization (WHO) recommendations are found here:
www.who.int/publications-detail/infection-prevention-and-control-during-health-care-when-novel-coronavirus-(ncov)-
infection-is-suspected-20200125.
Follow local health advice about hygiene strategies and use of personal protective equipment, as new
information becomes available in your country or region
The website of the US Centers for Disease Control and Prevention (CDC) provides up-to-date information about COVID-
19 for health professionals: www.cdc.gov/coronavirus/2019-nCoV/hcp/index.html, and for patients:
https://www.cdc.gov/coronavirus/2019-ncov/index.html.
The website of the World Health Organization (WHO) provides comprehensive advice for health professionals and
health systems about prevention and management of COVID-19: www.who.int/emergencies/diseases/novel-coronavirus-
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2019/technical-guidance.
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Global Initiative for Asthma, April 3, 2020
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Additional advice about management of asthma in the context of COVID-19 will be posted on the GINA website
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(www.ginasthma.org) as it becomes available.
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18 Interim advice about COVID-19 and asthma

SECTION 1. ADULTS, ADOLESCENTS AND
CHILDREN 6 YEARS AND OLDER
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Chapter 1.
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Definition,
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description, and diagnosis

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of asthma
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KEY POINTS
What is asthma?
• Asthma is a heterogeneous disease, usually characterized by chronic airway inflammation. It is defined by the
history of respiratory symptoms such as wheeze, shortness of breath, chest tightness and cough that vary over time
and in intensity, together with variable expiratory airflow limitation. Airflow limitation may later become persistent.
• Recognizable clusters of demographic, clinical and/or pathophysiological characteristics are often called ‘asthma
phenotypes’; however, these do not correlate strongly with specific pathological processes or treatment responses.
• Asthma is usually associated with airway hyperresponsiveness and airway inflammation, but these are not
necessary or sufficient to make the diagnosis.
How is asthma diagnosed?
• The diagnosis of asthma is based on the history of characteristic symptom patterns and evidence of variable airflow
limitation. This should be documented from bronchodilator reversibility testing or other tests.
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• Test before treating, wherever possible, i.e. document the evidence for the diagnosis of asthma before starting
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controller treatment, as it is often more difficult to confirm the diagnosis afterwards.
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• Additional strategies may be needed to confirm the diagnosis of asthma in particular populations, including patients
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already on controller treatment, the elderly, and those in low-resource settings.
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DEFINITION OF ASTHMA
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Asthma is a heterogeneous disease, usually characterized by chronic airway inflammation. It is defined by the history
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of respiratory symptoms such as wheeze, shortness of breath, chest tightness and cough that vary over time and in
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intensity, together with variable expiratory airflow limitation.

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This definition was reached by consensus, based on consideration of the characteristics that are typical of asthma
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before controller treatment is commenced, and that distinguish it from other respiratory conditions. However, airflow
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limitation may become persistent later in the course of the disease.

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DESCRIPTION OF ASTHMA
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Asthma is a common, chronic respiratory disease affecting 1–18% of the population in different countries (Appendix
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Chapter 1). Asthma is characterized by variable symptoms of wheeze, shortness of breath, chest tightness and/or
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cough, and by variable expiratory airflow limitation. Both symptoms and airflow limitation characteristically vary over time
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and in intensity. These variations are often triggered by factors such as exercise, allergen or irritant exposure, change in
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weather, or viral respiratory infections.

Symptoms and airflow limitation may resolve spontaneously or in response to medication, and may sometimes be
absent for weeks or months at a time. On the other hand, patients can experience episodic flare-ups (exacerbations) of
asthma that may be life-threatening and carry a significant burden to patients and the community (Appendix Chapter 1).
Asthma is usually associated with airway hyperresponsiveness to direct or indirect stimuli, and with chronic airway
inflammation. These features usually persist, even when symptoms are absent or lung function is normal, but may
normalize with treatment.
Asthma phenotypes
Asthma is a heterogeneous disease, with different underlying disease processes. Recognizable clusters of
demographic, clinical and/or pathophysiological characteristics are often called ‘asthma phenotypes’.5-7 In patients with
more severe asthma, some phenotype-guided treatments are available. However, no strong relationship has been found
20 1. Definition, description and diagnosis of asthma

between specific pathological features and particular clinical patterns or treatment responses. More research is needed
to understand the clinical utility of phenotypic classification in asthma.
Many clinical phenotypes of asthma have been identified.5-7 Some of the most common are:
• Allergic asthma: this is the most easily recognized asthma phenotype, which often commences in childhood and is
associated with a past and/or family history of allergic disease such as eczema, allergic rhinitis, or food or drug
allergy. Examination of the induced sputum of these patients before treatment often reveals eosinophilic airway
inflammation. Patients with this asthma phenotype usually respond well to inhaled corticosteroid (ICS) treatment.
• Non-allergic asthma: some patients have asthma that is not associated with allergy. The cellular profile of the sputum
of these patients may be neutrophilic, eosinophilic or contain only a few inflammatory cells (paucigranulocytic).
Patients with non-allergic asthma often demonstrate less short-term response to ICS.
• Adult-onset (late-onset) asthma: some adults, particularly women, present with asthma for the first time in adult life.
These patients tend to be non-allergic, and often require higher doses of ICS or are relatively refractory to
corticosteroid treatment. Occupational asthma (i.e. asthma due to exposures at work) should be ruled out in patients
presenting with adult-onset asthma.
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• Asthma with persistent airflow limitation: some patients with long-standing asthma develop airflow limitation that is
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persistent or incompletely reversible. This is thought to be due to airway wall remodeling.
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• Asthma with obesity: some obese patients with asthma have prominent respiratory symptoms and little eosinophilic
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airway inflammation.
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There are limited data about the natural history of asthma after diagnosis, but one study showed that approximately 16%
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of adults with recently-diagnosed asthma may experience remission within 5 years. 8
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Additional information can be found in Appendix Chapter 2 about factors predisposing to the development of asthma,
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and in Appendix Chapter 3 about pathophysiological and cellular mechanisms of asthma.

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MAKING THE INITIAL DIAGNOSIS

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Making the diagnosis of asthma, as shown in Box 1-1 (p22) is based on identifying both a characteristic pattern of
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respiratory symptoms such as wheezing, shortness of breath (dyspnea), chest tightness or cough, and variable
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expiratory airflow limitation.9 The pattern of symptoms is important, as respiratory symptoms may be due to acute or
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chronic conditions other than asthma. If possible, the evidence supporting a diagnosis of asthma (Box 1-2, p5) should be
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documented when the patient first presents, as the features that are characteristic of asthma may improve
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spontaneously or with treatment; as a result, it is often more difficult to confirm a diagnosis of asthma once the patient
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Patterns of respiratory symptoms that are characteristic of asthma

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The following features are typical of asthma and, if present, increase the probability that the patient has asthma:9
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Respiratory symptoms of wheeze, shortness of breath, cough and/or chest tightness:

• Patients (especially adults) experience more than one of these types of symptoms
• Symptoms are often worse at night or in the early morning
• Symptoms vary over time and in intensity
• Symptoms are triggered by viral infections (colds), exercise, allergen exposure, changes in weather, laughter, or
irritants such as car exhaust fumes, smoke or strong smells.
The following features decrease the probability that respiratory symptoms are due to asthma:
• Isolated cough with no other respiratory symptoms (see p.28)
• Chronic production of sputum
• Shortness of breath associated with dizziness, light-headedness or peripheral tingling (paresthesia)
• Chest pain
• Exercise-induced dyspnea with noisy inspiration.
1. Definition, description and diagnosis of asthma 21

Box 1-1. Diagnostic flowchart for clinical practice – initial presentation
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ICS: inhaled corticosteroids; PEF: peak expiratory flow (highest of three readings). When measuring PEF, use the same meter each time as the value
may vary by up to 20% between different meters; prn: as-needed; SABA: short-acting beta2-agonist.
Bronchodilator reversibility may be lost during severe exacerbations or viral infections, and in long-standing asthma. If bronchodilator reversibility is
not found at initial presentation, the next step depends on the availability of tests and the clinical urgency of need for treatment. See Box 1-3 (p.27) for
diagnosis of asthma in patients already taking controller treatment.

Box 1-2. Diagnostic criteria for asthma in adults, adolescents, and children 6–11 years
Asthma is a heterogeneous disease, usually characterized by chronic airway inflammation. It is defined by the history
of respiratory symptoms such as wheeze, shortness of breath, chest tightness and cough that vary over time and in
intensity, together with variable expiratory airflow limitation. Wherever possible, the diagnosis should be confirmed
before ICS are started. See Box 1-3 (p.26) for how to confirm the diagnosis in patients already taking ICS.
DIAGNOSTIC FEATURE CRITERIA FOR MAKING THE DIAGNOSIS OF ASTHMA

1. History of variable respiratory symptoms
Wheeze, shortness of breath, chest • Generally more than one type of respiratory symptom
tightness and cough (in adults, isolated cough is seldom due to asthma)
Descriptors may vary between cultures and • Symptoms occur variably over time and vary in intensity
by age, e.g. children may be described as • Symptoms are often worse at night or on waking
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having heavy breathing • Symptoms are often triggered by exercise, laughter, allergens, cold air
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• Symptoms often appear or worsen with viral infections
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2. Confirmed variable expiratory airflow limitation
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Documented excessive variability in lung The greater the variations, or the more occasions excess variation is
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function* (one or more of the tests below) seen, the more confident the diagnosis
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AND documented expiratory airflow
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At a time when FEV1 is reduced, confirm that FEV1/FVC is reduced (it is
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limitation* usually >0.75–0.80 in adults, >0.90 in children10)
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Positive bronchodilator (BD) reversibility Adults: increase in FEV1 of >12% and >200 mL from baseline, 10–15
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test* (more likely to be positive if BD minutes after 200–400 mcg salbutamol (albuterol) or equivalent (greater
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medication is withheld before test: SABA confidence if increase is >15% and >400 mL).
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≥4 hours, LABA ≥15 hours) Children: increase in FEV1 of >12% predicted

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Excessive variability in twice-daily PEF Adults: average daily diurnal PEF variability >10%**
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over 2 weeks* Children: average daily diurnal PEF variability >13%**

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Significant increase in lung function after Adults: increase in FEV1 by >12% and >200 mL (or PEF† by >20%) from
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4 weeks of anti-inflammatory treatment baseline after 4 weeks of treatment, outside respiratory infections
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Positive exercise challenge test* Adults: fall in FEV1 of >10% and >200 mL from baseline
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Children: fall in FEV1 of >12% predicted, or PEF >15%

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Positive bronchial challenge test Fall in FEV1 from baseline of ≥20% with standard doses of methacholine
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(usually only performed in adults) or histamine, or ≥15% with standardized hyperventilation, hypertonic
saline or mannitol challenge
Excessive variation in lung function Adults: variation in FEV1 of >12% and >200 mL between visits, outside of
between visits* (good specificity but poor respiratory infections
sensitivity) Children: variation in FEV1 of >12% in FEV1 or >15% in PEF† between
visits (may include respiratory infections)
BD: bronchodilator (SABA or rapid-acting LABA); FEV1: forced expiratory volume in 1 second; ICS: inhaled corticosteroid; LABA: long-acting beta2-
agonist; PEF: peak expiratory flow (highest of three readings); SABA: short-acting beta2-agonist. See Box 1-4 (p.27) for how to confirm the diagnosis in
patients already taking controller treatment.
*These tests can be repeated during symptoms or in the early morning. **Daily diurnal PEF variability is calculated from twice daily PEF as ([day’s
highest minus day’s lowest] / mean of day’s highest and lowest), averaged over one week. †For PEF, use the same meter each time, as PEF may vary
by up to 20% between different meters. BD reversibility may be lost during severe exacerbations or viral infections,11 and airflow limitation may become
persistent over time. If reversibility is not present at initial presentation, the next step depends on the availability of other tests and the urgency of the
need for treatment. In a situation of clinical urgency, asthma treatment may be commenced and diagnostic testing arranged within the next few weeks
(Box 1-4, p.27), but other conditions that can mimic asthma (Box 1-5) should be considered, and the diagnosis confirmed as soon as possible.

Why is it important to confirm the diagnosis of asthma?
This is important to avoid unnecessary treatment or over-treatment, and to avoid missing other important diagnoses. In
adults with an asthma diagnosis in the last 5 years, one-third could not be confirmed as having asthma after repeated
testing over 12 months and staged withdrawal of controller treatment. The diagnosis of asthma was less likely to be
confirmed in patients who had not had lung function testing performed at the time of initial diagnosis. Some patients
(2%) had serious cardiorespiratory conditions that had been misdiagnosed as asthma.12
History and family history

Commencement of respiratory symptoms in childhood, a history of allergic rhinitis or eczema, or a family history of
asthma or allergy, increases the probability that the respiratory symptoms are due to asthma. However, these features
are not specific for asthma and are not seen in all asthma phenotypes. Patients with allergic rhinitis or atopic dermatitis
should be asked specifically about respiratory symptoms.
Physical examination
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(rhonchi) on auscultation, but this may be absent or only heard on forced expiration. Wheezing may also be absent
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during severe asthma exacerbations, due to severely reduced airflow (so called ‘silent chest’), but at such times, other
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physical signs of respiratory failure are usually present. Wheezing may also be heard with inducible laryngeal
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obstruction, chronic obstructive pulmonary disease (COPD), respiratory infections, tracheomalacia, or inhaled foreign
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body. Crackles (crepitations) and inspiratory wheezing are not features of asthma. Examination of the nose may reveal
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signs of allergic rhinitis or nasal polyposis.
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Lung function testing to document variable expiratory airflow limitation

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Asthma is characterized by variable expiratory airflow limitation, i.e. expiratory lung function varies over time and in
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magnitude, to a greater extent than in healthy populations. In asthma, lung function may vary between completely
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normal and severely obstructed in the same patient. Poorly controlled asthma is associated with greater variability in
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lung function than well-controlled asthma.11

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Lung function testing should be carried out by well-trained operators with well-maintained and regularly calibrated
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equipment.13 Forced expiratory volume in 1 second (FEV1) from spirometry is more reliable than peak expiratory flow
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(PEF). If PEF is used, the same meter should be used each time, as measurements may differ from meter to meter by
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up to 20%.14
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A reduced FEV1 may be found with many other lung diseases (or poor spirometric technique), but a reduced ratio of
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FEV1 to FVC (FEV1/FVC) compared with the lower limit of normal indicates expiratory airflow limitation. Many
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spirometers now include multi-ethnic age-specific predicted values.10

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In clinical practice, once an obstructive defect has been confirmed, variation in airflow limitation is generally assessed
from variation in FEV1 or PEF. ‘Variability’ refers to improvement and/or deterioration in symptoms and lung function.
Excessive variability may be identified over the course of one day (diurnal variability), from day to day, from visit to visit,
or seasonally, or from a reversibility test. ‘Reversibility’ (also called ‘responsiveness’)13 generally refers to rapid
improvements in FEV1 (or PEF), measured within minutes after inhalation of a rapid-acting bronchodilator such as
200–400 mcg salbutamol,15 or more sustained improvement over days or weeks after the introduction of effective
controller treatment such as ICS.15
In a patient with typical respiratory symptoms, obtaining evidence of excessive variability in expiratory lung function is an
essential component of the diagnosis of asthma. Some specific examples are:
• An increase in lung function after administration of a bronchodilator, or after a trial of controller treatment
• A decrease in lung function after exercise or during a bronchial provocation test
• Variation in lung function beyond the normal range when it is repeated over time, either on separate visits, or on
home monitoring over at least 1–2 weeks

Specific criteria for demonstrating excessive variability in expiratory lung function are listed in Box 1-2 (p.23). A decrease
in lung function during a respiratory infection, while commonly seen in asthma, does not necessarily indicate that a
person has asthma, as it may also be seen in otherwise healthy individuals or people with COPD.
Additional information about tests for diagnosis of asthma can be found in Appendix Chapter 4.
How much variation in expiratory airflow is consistent with asthma?
There is overlap in bronchodilator reversibility and other measures of variation between health and disease.16 In a
patient with respiratory symptoms, the greater the variations in their lung function, or the more times excess variation is
seen, the more likely the diagnosis is to be asthma (Box 1-2, p.23). Generally, in adults with respiratory symptoms
typical of asthma, an increase or decrease in FEV1 of >12% and >200 mL from baseline, or (if spirometry is not
available) a change in PEF of at least 20%, is accepted as being consistent with asthma.
Diurnal PEF variability is calculated from twice daily readings as the daily amplitude percent mean, i.e. ([Day’s highest –
day’s lowest]/mean of day’s highest and lowest) x 100, then the average of each day’s value is calculated over 1–2
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weeks. The upper 95% confidence limit of diurnal variability (amplitude percent mean) from twice daily readings is 9% in
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healthy adults,17 and 12.3% in healthy children,18 so in general, diurnal variability >10% for adults and >13% for children
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is regarded as excessive.
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If FEV1 is within the predicted normal range when the patient is experiencing symptoms, this reduces the probability that
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the symptoms are due to asthma. However, patients whose baseline FEV1 is >80% predicted can have a clinically
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important increase in lung function with bronchodilator or controller treatment. Predicted normal ranges (especially for
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PEF) have limitations, so the patient’s own best reading (‘personal best’) is recommended as their ‘normal’ value.
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When can variable airflow limitation be documented?
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If possible, evidence of variable airflow limitation should be documented before treatment is started. This is because
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variability usually decreases with treatment as lung function improves. In addition, any increase in lung function after
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initiating controller treatment can help to confirm the diagnosis of asthma. Bronchodilator reversibility may not be present
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between symptoms, during viral infections or if the patient has used a beta2-agonist within the previous few hours; and in
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some patients, airflow limitation may become persistent or irreversible over time.
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If spirometry is not available, or variable airflow limitation is not documented, a decision about whether to investigate
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further or start controller treatment immediately depends on clinical urgency and access to other tests. Box 1-4 (p.27)
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describes how to confirm the diagnosis of asthma in a patient already taking controller treatment.
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Other tests
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Bronchial provocation tests

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airway hyperresponsiveness. Challenge agents include inhaled methacholine, histamine, exercise,19 eucapnic voluntary
hyperventilation or inhaled mannitol. These tests are moderately sensitive for a diagnosis of asthma but have limited
specificity;20,21 for example, airway hyperresponsiveness to inhaled methacholine has been described in patients with
allergic rhinitis,22 cystic fibrosis,23 bronchopulmonary dysplasia24 and COPD.25 This means that a negative test in a
patient not taking ICS can help to exclude asthma, but a positive test does not always mean that a patient has asthma –
the pattern of symptoms (Box 1-2, p.23) and other clinical features (Box 1-3, p.26) must also be taken into account.
Allergy tests
The presence of atopy increases the probability that a patient with respiratory symptoms has allergic asthma, but this is
not specific for asthma nor is it present in all asthma phenotypes. Atopic status can be identified by skin prick testing or
by measuring the level of specific immunoglobulin E (sIgE) in serum. Skin prick testing with common environmental
allergens is simple and rapid to perform and, when performed by an experienced tester with standardized extracts, is
inexpensive and has a high sensitivity. Measurement of sIgE is no more reliable than skin tests and is more expensive,
but may be preferred for uncooperative patients, those with widespread skin disease, or if the history suggests a risk of

anaphylaxis.26 The presence of a positive skin test or positive sIgE, however, does not mean that the allergen is causing
symptoms - the relevance of allergen exposure and its relation to symptoms must be confirmed by the patient’s history.
Does exhaled nitric oxide have a role in the diagnosis of asthma?
The fractional concentration of exhaled nitric oxide (FeNO) is modestly associated with levels of sputum and blood
eosinophils.27 FeNO has not been established as useful for ruling in or ruling out a diagnosis of asthma, as defined on
p.20. FeNO is higher in asthma that is characterized by Type 2 airway inflammation28 but it is also elevated in non-
asthma conditions (e.g. eosinophilic bronchitis, atopy, allergic rhinitis, eczema), and it is not elevated in some asthma
phenotypes (e.g. neutrophilic asthma). FeNO is lower in smokers and during bronchoconstriction29 and the early phases
of allergic response;30 it may be increased or decreased during viral respiratory infections.29 See Chapter 3B, p.48 for
discussion about FeNO in the context of decisions about initial asthma treatment.
CONFIRMING THE DIAGNOSIS OF ASTHMA IN PATIENTS ALREADY TAKING CONTROLLER TREATMENT

If the basis of a patient’s diagnosis of asthma has not previously been documented, confirmation with objective testing
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should be sought. Many patients (25–35%) with a diagnosis of asthma in primary care cannot be confirmed as having
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asthma.12,31-34
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The process for confirming the diagnosis in patients already on controller treatment depends on the patient’s symptoms
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and lung function (Box 1-3, p.26). In some patients, this may include a trial of either a lower or a higher dose of controller
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treatment. If the diagnosis of asthma cannot be confirmed, refer the patient for expert investigation and diagnosis. For
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some patients, it may be necessary to step down the controller treatment in order to confirm the diagnosis of asthma.
The process is described in Box 1-4, p.27.
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Box 1-3. Steps for confirming the diagnosis of asthma in a patient already taking controller treatment
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Current status Steps to confirm the diagnosis of asthma

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Variable respiratory Diagnosis of asthma is confirmed. Assess the level of asthma control (Box 2-2, p.35) and review
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symptoms and variable controller treatment (Box 3-5, p.54).

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airflow limitation
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Variable respiratory Repeat spirometry after withholding BD (4 hrs. for SABA, 12 hrs. for twice-daily ICS+LABA, 24hrs.
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symptoms but no for once-daily ICS+LABA) or during symptoms. Check between-visit variability of baseline FEV1,
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variable airflow and bronchodilator reversibility. If still normal, consider alternative diagnoses (Box 1-5, p.27).
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limitation If FEV1 is >70% predicted: consider a bronchial provocation test. If negative, consider stepping
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down controller treatment (see Box 1-5) and reassess in 2–4 weeks
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If FEV1 is <70% predicted: consider stepping up controller treatment for 3 months (Box 3-5), then
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reassess symptoms and lung function. If no response, resume previous treatment and refer
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patient for diagnosis and investigation

Few respiratory Repeat BD reversibility test again after withholding BD as above or during symptoms. If normal,
symptoms, consider alternative diagnoses (Box 1-5, p.27).
normal lung function, Consider stepping down controller treatment (see Box 1-5):
and no variable airflow
• If symptoms emerge and lung function falls: asthma is confirmed. Step up controller treatment
limitation
to previous lowest effective dose.
• If no change in symptoms or lung function at lowest controller step: consider ceasing
controller, and monitor patient closely for at least 12 months (Box 3-7).
Persistent shortness of Consider stepping up controller treatment for 3 months (Box 3-5, p.54), then reassess symptoms
breath and persistent and lung function. If no response, resume previous treatment and refer patient for diagnosis and
airflow limitation investigation. Consider asthma–COPD overlap (Chapter 5, p.129).
BD: bronchodilator; LABA: long-acting beta2-agonist; SABA: short-acting beta2-agonist.

Box 1-4. How to step down controller treatment to help confirm the diagnosis of asthma
1. ASSESS
• Document the patient’s current status including asthma control (Box 2-2, p.35) and lung function. If the patient has
risk factors for asthma exacerbations (Box 2-2B), do not step down treatment without close supervision.
• Choose a suitable time (e.g. no respiratory infection, not going away on vacation, not pregnant).
• Provide a written asthma action plan (Box 4-2, p.117) so the patient knows how to recognize and respond if
symptoms worsen. Ensure they have enough medication to resume their previous dose if their asthma worsens.
2. ADJUST
• Show the patient how to reduce their ICS dose by 25–50%, or stop extra controller (e.g. LABA, leukotriene receptor
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antagonist) if being used (Box 3-7, p.66). Schedule a review visit for 2–4 weeks.
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3. REVIEW RESPONSE
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• Repeat assessment of asthma control and lung function tests in 2–4 weeks (Box 1-2, p.23).
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• If symptoms increase and variable airflow limitation is confirmed after stepping down treatment, the diagnosis of
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asthma is confirmed. The controller dose should be returned to the lowest previous effective dose.
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• If, after stepping down to a low dose controller treatment, symptoms do not worsen and there is still no evidence of
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variable airflow limitation, consider ceasing controller treatment and repeating asthma control assessment and lung
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function tests in 2–3 weeks, but follow the patient for at least 12 months
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DIFFERENTIAL DIAGNOSIS
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The differential diagnosis in a patient with suspected asthma varies with age (Box 1-5). Any of these alternative
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diagnoses may also be found together with asthma.

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Box 1-5. Differential diagnosis of asthma in adults, adolescents and children 6–11 years
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Age Symptoms Condition

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6–11 Sneezing, itching, blocked nose, throat-clearing Chronic upper airway cough syndrome
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years Sudden onset of symptoms, unilateral wheeze Inhaled foreign body

Recurrent infections, productive cough Bronchiectasis
Recurrent infections, productive cough, sinusitis Primary ciliary dyskinesia
Cardiac murmurs Congenital heart disease
Pre-term delivery, symptoms since birth Bronchopulmonary dysplasia
Excessive cough and mucus production, gastrointestinal Cystic fibrosis
symptoms
(continued next page)

Box 1-5 (continued). Differential diagnosis of asthma in adults, adolescents and children 6–11 years
Age Symptoms Condition

12–39 Sneezing, itching, blocked nose, throat-clearing Chronic upper airway cough syndrome
years Dyspnea, inspiratory wheezing (stridor) Inducible laryngeal obstruction
Dizziness, paresthesia, sighing Hyperventilation, dysfunctional breathing
Productive cough, recurrent infections Bronchiectasis
Excessive cough and mucus production Cystic fibrosis
Cardiac murmurs Congenital heart disease
Shortness of breath, family history of early emphysema Alpha1-antitrypsin deficiency
Sudden onset of symptoms Inhaled foreign body
40+ Dyspnea, inspiratory wheezing (stridor) Inducible laryngeal obstruction
years Dizziness, paresthesia, sighing Hyperventilation, dysfunctional breathing
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Cough, sputum, dyspnea on exertion, smoking or noxious COPD*
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Productive cough, recurrent infections Bronchiectasis
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Dyspnea with exertion, nocturnal symptoms Cardiac failure
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Treatment with angiotensin converting enzyme (ACE) inhibitor Medication-related cough
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Dyspnea with exertion, non-productive cough, finger clubbing Parenchymal lung disease
Sudden onset of dyspnea, chest pain
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Dyspnea, unresponsive to bronchodilators Central airway obstruction
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All Chronic cough, hemoptysis, dyspnea; and/or fatigue, fever, (night) Tuberculosis
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ages sweats, anorexia, weight loss

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*For more detail, see Chapter 5 (p.129). Any of the above conditions may also contribute to respiratory symptoms in patients with confirmed asthma.
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HOW TO MAKE THE DIAGNOSIS OF ASTHMA IN OTHER CONTEXTS

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Patients presenting with persistent non-productive cough as the only respiratory symptom
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Diagnoses to be considered are chronic upper airway cough syndrome (often called ‘postnasal drip’), cough induced by
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angiotensin converting enzyme (ACE) inhibitors, gastroesophageal reflux, chronic sinusitis, and inducible laryngeal
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obstruction.35,36 Patients with so-called ‘cough-variant asthma’ have persistent cough as their principal or only symptom,
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associated with airway hyperresponsiveness. It is often more problematic at night. Lung function may be normal, and for
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these patients, documentation of variability in lung function (Box 1-2, p.23) is important.37 Cough-variant asthma must be
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distinguished from eosinophilic bronchitis in which patients have cough and sputum eosinophilia but normal spirometry
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and airway responsiveness.37
Occupational asthma and work-exacerbated asthma

Asthma acquired in the workplace is frequently missed. Asthma may be induced or (more commonly) aggravated by
exposure to allergens or other sensitizing agents at work, or sometimes from a single, massive exposure. Occupational
rhinitis may precede asthma by up to a year and early diagnosis is essential, as persistent exposure is associated with
worse outcomes.38
An estimated 5–20% of new cases of adult-onset asthma can be attributed to occupational exposure.38 Adult-onset
asthma requires a systematic inquiry about work history and exposures, including hobbies.39 Asking patients whether
their symptoms improve when they are away from work (weekends or vacation) is an essential screening question.40 It is
important to confirm the diagnosis of occupational asthma objectively as it may lead to the patient changing their
occupation, which may have legal and socioeconomic implications. Specialist referral is usually necessary, and frequent

PEF monitoring at and away from work is often used to help confirm the diagnosis. Further information about
occupational asthma is found in Chapter 3 (p.91) and in specific guidelines.38
Athletes
The diagnosis of asthma in athletes should be confirmed by lung function tests, usually with bronchial provocation
testing.19 Conditions that may either mimic or be associated with asthma, such as rhinitis, laryngeal disorders (e.g.
inducible laryngeal obstruction36), dysfunctional breathing, cardiac conditions and over-training, must be excluded.41
Pregnant women
Pregnant women and women planning a pregnancy should be asked whether they have asthma so that appropriate
advice about asthma management and medications can be given (see Chapter 3: Managing asthma in special
populations or settings, p.89).42 If objective confirmation of the diagnosis is needed, it would not be advisable to carry
out a bronchial provocation test or to step down controller treatment until after delivery.
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The elderly
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Asthma is frequently undiagnosed in the elderly,43 due to poor perception of airflow limitation; acceptance of dyspnea as
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being ‘normal’ in old age; lack of fitness; and reduced physical activity. The presence of comorbid diseases also
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complicates the diagnosis. In a large population based survey of asthma patients older than 65 years, factors associated
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with a history of asthma hospitalization included co-diagnosis of COPD, coronary artery disease, depression, diabetes
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mellitus, and difficulty accessing medications or clinical care because of cost.44 Symptoms of wheezing, breathlessness
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and cough that are worse on exercise or at night can also be caused by cardiovascular disease or left ventricular failure,
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which are common in this age group. A careful history and physical examination, combined with an electrocardiogram
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and chest X-ray, will assist in the diagnosis.45 Measurement of plasma brain natriuretic polypeptide (BNP) and
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assessment of cardiac function with echocardiography may also be helpful.46 In older people with a history of smoking or
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biomass fuel exposure, COPD and overlapping asthma and COPD (asthma–COPD overlap) should be considered
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(Chapter 5, p.129).
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Smokers and ex-smokers

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Asthma and COPD may be difficult to distinguish in clinical practice, particularly in older patients and smokers and ex-
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smokers, and these conditions may overlap (asthma-COPD overlap). The Global Strategy for Diagnosis, Management
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and Prevention of COPD (GOLD)47 defines COPD on the basis of chronic respiratory symptoms, exposure to a risk
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factor such as smoking, and post-bronchodilator FEV1/FVC <0.7. Clinically important bronchodilator reversibility (>12%
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and >200 mL) is often found in COPD.48 Low diffusion capacity is more common in COPD than asthma. The history and
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pattern of symptoms and past records can help to distinguish these patients from those with long-standing asthma who
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have developed persistent airflow limitation (see Chapter 5, p.129). Uncertainty in the diagnosis should prompt early
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referral for specialized investigation and treatment recommendations, as patients with asthma-COPD overlap have
worse outcomes than those with asthma or COPD alone.49
Obese patients
While asthma is more common in obese than non-obese people,50 respiratory symptoms associated with obesity can
mimic asthma. In obese patients with dyspnea on exertion, it is important to confirm the diagnosis of asthma with
objective measurement of variable airflow limitation. One study found that non-obese patients were just as likely to be
over-diagnosed with asthma as obese patients (around 30% in each group).31 Another study found both over- and
under-diagnosis of asthma in obese patients.51
Low resource settings

Communities with limited resources are found not only in low- and middle-income countries, but also in high-income
countries. In low resource settings, diagnosis of respiratory symptoms commences with a symptom-based or syndromic

approach. Questions about duration of symptoms and about fever, chills, sweats, weight loss, pain on breathing and
hemoptysis help to distinguish chronic respiratory infections such as tuberculosis, HIV/AIDS and parasitic or fungal lung
diseases from asthma and COPD.9,52
Variable airflow limitation can be confirmed using PEF meters; these have been proposed by the World Health
Organization as essential tools in the Package of Essential Non-communicable Diseases Interventions.53
In low resource settings, documentation of symptoms and PEF before and after a therapeutic trial with as-needed SABA
and regular ICS, often together with a 1 week course of oral corticosteroids, can help to confirm the diagnosis of asthma
before long-term treatment is commenced.54
In low and middle-income countries, a comparison between the prevalence of asthma symptoms and of a doctor’s
diagnosis of asthma among adolescents and young adults suggests that, at the population level, as many as 50% of
cases may be undiagnosed.55,56 In a recent review, it has been reported that, among doctors working in primary care
health services, the precision of the diagnosis of asthma is far from ideal, varying from 54% under-diagnosis to 34%
over-diagnosis.57 Poverty is commonly associated with restrictive spirometry, so where possible, both FEV1 and FVC
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should be recorded.58 These observations demonstrate how important it is to build capacity of primary care physicians
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for asthma diagnosis and management.
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Chapter 2.
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Assessment of
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asthma
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KEY POINTS
About asthma control and severity

• The level of asthma control is the extent to which the features of asthma can be observed in the patient, or have
been reduced or removed by treatment.
• Asthma control is assessed in two domains: symptom control and future risk of adverse outcomes. Poor symptom
control is burdensome to patients and increases the risk of exacerbations, but patients with apparently mild asthma,
i.e. with few or no symptoms, can still have severe exacerbations.
• Asthma severity is assessed retrospectively, after at least 2–3 months of treatment, from the level of treatment
required to control symptoms and exacerbations. It is important to distinguish between severe asthma and asthma
that is uncontrolled, e.g. due to incorrect inhaler technique and/or poor adherence.
How to assess a patient with asthma
• Assess symptom control from the frequency of daytime and night-time asthma symptoms and SABA use, and from
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activity limitation. Symptom control tools include Asthma Control Test and Asthma Control Questionnaire.
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• Assess the patient’s future risk for exacerbations, even when symptom control is good. Risk factors for
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exacerbations that are independent of symptom control include a history of ≥1 exacerbation in the previous year,
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socioeconomic problems, poor adherence, incorrect inhaler technique, low lung function, smoking, and blood
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eosinophilia.
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• Also assess risk factors for persistent airflow limitation and medication side-effects, treatment issues such as
inhaler technique and adherence, and comorbidities, and ask the patient about their asthma goals
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• Once the diagnosis of asthma has been made, lung function is most useful as an indicator of future risk. It should
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be recorded at diagnosis, 3–6 months after starting treatment, and periodically thereafter.
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• Investigate further if there are few symptoms but impaired lung function, or frequent symptoms and good lung function.
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OVERVIEW
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For every patient, assessment of asthma should include the assessment of asthma control (both symptom control and
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future risk of adverse outcomes), treatment issues particularly inhaler technique and adherence, and any comorbidities
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that could contribute to symptom burden and poor quality of life (Box 2-1, p33). Lung function, particularly forced
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expiratory volume in 1 second (FEV1) as a percentage of predicted, is an important part of the assessment of future risk.
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What is meant by ‘asthma control’?

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The level of asthma control is the extent to which the manifestations of asthma can be observed in the patient, or have
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been reduced or removed by treatment.17,59 It is determined by the interaction between the patient’s genetic background,
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underlying disease processes, the treatment that they are taking, environment, and psychosocial factors.59
Asthma control has two domains: symptom control (previously called ‘current clinical control’) and future risk of adverse
outcomes (Box 2-2, p.35). Both should always be assessed. Lung function is an important part of the assessment of
future risk; it should be measured at the start of treatment, after 3–6 months of treatment (to identify the patient’s
personal best), and periodically thereafter for ongoing risk assessment.
How to describe a patient’s asthma control
Asthma control should be described in terms of both symptom control and future risk domains, for example:
Ms X has good asthma symptom control, but she is at increased risk of future exacerbations because she has had a
severe exacerbation within the last year.
Mr Y has poor asthma symptom control. He also has several additional risk factors for future exacerbations including low
lung function, current smoking, and poor medication adherence.
32 2. Assessment of asthma
What does the term ‘asthma control’ mean to patients?
Many studies describe discordance between the patient’s and health provider’s assessment of the patient’s level of
asthma control. This does not necessarily mean that patients ‘over-estimate’ their level of control or ‘under-estimate’ its
severity, but that patients understand and use the word ‘control’ differently from health professionals, e.g. based on how
quickly their symptoms resolve when they take reliever medication.59,60 If the term ‘asthma control’ is used with patients,
the meaning should always be explained.
Box 2-1. Assessment of asthma in adults, adolescents, and children 6–11 years
1. Assess asthma control = symptom control and future risk of adverse outcomes
• Assess symptom control over the last 4 weeks (Box 2-2A)
• Identify any other risk factors for exacerbations, persistent airflow limitation or side-effects (Box 2-2B)
• Measure lung function at diagnosis/start of treatment, 3–6 months after starting controller treatment, then
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periodically, e.g. at least once every 1–2 years, but more often in at-risk patients and those with severe asthma
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2. Assess treatment issues
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• Document the patient’s current treatment step (Box 3-5, p.54)
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• Watch inhaler technique, assess adherence and side-effects
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• Check that the patient has a written asthma action plan
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• Ask about the patient’s attitudes and goals for their asthma and medications
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3. Assess comorbidities
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• Rhinitis, rhinosinusitis, gastroesophageal reflux, obesity, obstructive sleep apnea, depression and anxiety can
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contribute to symptoms and poor quality of life, and sometimes to poor asthma control
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ASSESSING ASTHMA SYMPTOM CONTROL

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Asthma symptoms such as wheeze, chest tightness, shortness of breath and cough typically vary in frequency and
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intensity, and contribute to the burden of asthma for the patient. Poor symptom control is also strongly associated with
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an increased risk of asthma exacerbations.61-63

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Asthma symptom control should be assessed at every opportunity, including during routine prescribing or dispensing.
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Directed questioning is important, as the frequency or severity of symptoms that patients regard as unacceptable or
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bothersome may vary from current recommendations about the goals of asthma treatment, and differs from patient to
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patient. For example, despite having low lung function, a person with a sedentary lifestyle may not experience
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bothersome symptoms and so may appear to have good symptom control.

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To assess symptom control (Box 2-2A) ask about the following in the past four weeks: frequency of asthma symptoms
(days per week), any night waking due to asthma or limitation of activity, and frequency of short-acting beta2-agonist
(SABA) reliever use for relief of symptoms. In general, do not include reliever taken before exercise, since this is often
habitual. Our current view is that frequency of as-needed ICS-formoterol should not be included in the assessment of
symptom control, particularly for patients not taking maintenance ICS, as it is providing the patient’s controller therapy.
Further data are awaited, and this issue will be reviewed again next year.
Asthma symptom control tools for adults and adolescents

Simple screening tools: these can be used in primary care to quickly identify patients who need more detailed
assessment. Examples include the consensus-based GINA symptom control tool (Part A, Box 2-2A). This classification
correlates with assessments made using numerical asthma control scores.64,65 It can be used, together with a risk
assessment (Box 2-2B), to guide treatment decisions (Box 3-5, p.54). Other examples are the Primary Care Asthma
Control Screening Tool (PACS),66 and the 30-second Asthma Test, which also includes time off work/school.67
2. Assessment of asthma 33
Categorical symptom control tools: examples include the consensus-based ‘Royal College of Physicians (RCP) Three
Questions’ tool,68 which asks about difficulty sleeping, daytime symptoms and activity limitation due to asthma in the
previous month. Another example is the Asthma APGAR tool which includes a patient-completed asthma control
assessment covering 5 domains: activity limitations, daytime and nighttime symptom frequency (based on US criteria for
frequency of night waking), triggers, adherence, and patient-perceived response to treatment. This assessment is linked
to a care algorithm for identifying problems and adjusting treatment up or down. A study in the US showed that
introduction of the Asthma APGAR tools for patients aged 5-45 in primary care improved rates of asthma control;
reduced asthma-related urgent care, and hospital visits; and increased practices’ adherence to asthma management
guidelines.69
Numerical ‘asthma control’ tools: these tools provide scores and cut points to distinguish different levels of symptom
control, validated against health care provider assessment. Many translations are available. These scores may be useful
for assessing patient progress; they are commonly used in clinical research, but may be subject to copyright restrictions.
Numerical asthma control tools are more sensitive to change in symptom control than categorical tools.64
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Examples of numerical asthma control tools for assessing symptom control are:
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• Asthma Control Questionnaire (ACQ):70,71 Scores range from 0–6 (higher is worse). A score of 0.0–0.75 is
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classified as well-controlled asthma; 0.75–1.5 as a ‘grey zone’; and >1.5 as poorly controlled asthma. The ACQ
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score is calculated as the average of 5, 6 or 7 items: all versions of the ACQ include five symptom questions;
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ACQ-6 includes reliever use; and in ACQ-7, a score for pre-bronchodilator FEV1 is averaged with symptom and
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reliever items. The minimum clinically important difference is 0.5.72
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• Asthma Control Test (ACT):65,73,74 Scores range from 5–25 (higher is better). Scores of 20–25 are classified as
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well-controlled asthma; 16–19 as not well-controlled; and 5–15 as very poorly controlled asthma. The ACT
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includes four symptom/reliever questions plus a patient self-assessed level of control. The minimum clinically
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important difference is 3 points.74

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When different systems are used for assessing asthma symptom control, the results correlate broadly with each other,
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but are not identical. Respiratory symptoms may be non-specific so, when assessing changes in symptom control, it is
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important to clarify that symptoms are due to asthma.

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Asthma symptom control tools for children 6–11 years of age

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In children, as in adults, assessment of asthma symptom control is based on symptoms, limitation of activities and use
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of rescue medication. Careful review of the impact of asthma on a child’s daily activities, including sports, play and social
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life, and on school absenteeism, is important. Many children with poorly controlled asthma avoid strenuous exercise so
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their asthma may appear to be well controlled. This may lead to poor fitness and a higher risk of obesity.
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Children vary considerably in the degree of airflow limitation observed before they complain of dyspnea or use their
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reliever therapy, and marked reduction in lung function is often seen before it is recognized by the parents. Parents may
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report irritability, tiredness, and changes in mood in their child as the main problems when the child’s asthma is not
controlled. Parents have a longer recall period than children, who may recall only the last few days; therefore, it is
important to include both the parent’s and child’s information when the level of symptom control is being assessed.
Several numeric asthma control scores have been developed for children. These include:
• Childhood Asthma Control Test (c-ACT)75 with separate sections for parent and child to complete
• Asthma Control Questionnaire (ACQ)76,77
Some asthma control scores for children include exacerbations with symptoms. These include:
• Test for Respiratory and Asthma Control in Kids (TRACK)78-80
• Composite Asthma Severity Index (CASI)81
The results of these various tests correlate to some extent with each other and with the GINA classification of symptom
control. Box 2-3 provides more details about assessing asthma control in children.
Box 2-2. GINA assessment of asthma control in adults, adolescents and children 6–11 years
A. Asthma symptom control Level of asthma symptom control
In the past 4 weeks, has the patient had: Well Partly Uncontrolled
controlled controlled
• Daytime asthma symptoms more than twice/week? Yes No
• Any night waking due to asthma? Yes No
None 1–2 3–4
• SABA reliever for symptoms more than twice/week?* Yes No of these of these of these
• Any activity limitation due to asthma? Yes No
B. Risk factors for poor asthma outcomes

Assess risk factors at diagnosis and periodically, particularly for patients experiencing exacerbations.
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Measure FEV1 at start of treatment, after 3–6 months of controller treatment to record the patient’s personal best lung
function, then periodically for ongoing risk assessment.
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Having uncontrolled asthma symptoms is an important risk factor for exacerbations.82
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Additional potentially modifiable risk factors for flare-ups (exacerbations), even in patients
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with few symptoms† include:
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• Medications: high SABA use83 (with increased mortality if >1 x 200-dose canister/month84);
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inadequate ICS: not prescribed ICS; poor adherence;85 incorrect inhaler technique86
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Having any of
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• Comorbidities: obesity;87,88 chronic rhinosinusitis;88,89 GERD;88 confirmed food allergy;90

these risk factors
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pregnancy91
increases the
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• Exposures: smoking;92 allergen exposure if sensitized;92 air pollution.93-95

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patient’s risk of
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• Context: major psychological or socioeconomic problems96 exacerbations

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even if they have few

• Lung function: low FEV1, especially <60% predicted92,97; high BD reversibility88,98,99
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asthma symptoms
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• Other tests in patients with Type 2 inflammation: blood eosinophils;88,98,100; elevated FeNO
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(in adults with allergic asthma taking ICS)101

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Other major independent risk factors for flare-ups (exacerbations)

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• Ever intubated or in intensive care unit for asthma102

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• ≥1 severe exacerbation in last 12 months103,104

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Risk factors for developing persistent airflow limitation

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• History: preterm birth, low birth weight and greater infant weight gain;105 chronic mucus hypersecretion106,107
• Medications: lack of ICS treatment108
• Exposures: tobacco smoke;106 noxious chemicals; occupational exposures38
• Investigations: low initial FEV1;107 sputum or blood eosinophilia107
Risk factors for medication side-effects

• Systemic: frequent OCS; long-term, high dose and/or potent ICS; also taking P450 inhibitors109
• Local: high-dose or potent ICS;109,110 poor inhaler technique111
BD: bronchodilator; FEV1: forced expiratory volume in 1 second; ICS: inhaled corticosteroid; OCS: oral corticosteroid; P450 inhibitors: cytochrome P450
inhibitors such as ritonavir, ketoconazole, itraconazole; SABA: short-acting beta2-agonist. *Based on SABA (as-needed ICS-formoterol reliever not
included); excludes reliever taken before exercise. For children 6–11 years, also refer to Box 2-3, p.36. See Box 3-8, p.67 for specific risk reduction
strategies. †‘Independent’ risk factors are those that are significant after adjustment for the level of symptom control.
Box 2-3. Specific questions for assessment of asthma in children 6–11 years
Asthma symptom control
Day symptoms Ask: How often does the child have cough, wheeze, dyspnea or heavy breathing (number of times
per week or day)? What triggers the symptoms? How are they handled?
Night symptoms Cough, awakenings, tiredness during the day? (If the only symptom is cough, consider other
diagnoses such as rhinitis or gastroesophageal reflux disease).
Reliever use How often is reliever medication used? (check date on inhaler or last prescription) Distinguish
between pre-exercise use (sports) and use for relief of symptoms.
Level of activity What sports/hobbies/interests does the child have, at school and in their spare time? How does the
child’s level of activity compare with their peers or siblings? How many days is the child absent from
school? Try to get an accurate picture of the child’s day from the child without interruption from the
parent/carer.
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Risk factors for adverse outcomes
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Exacerbations Ask: How do viral infections affect the child’s asthma? Do symptoms interfere with school or sports?
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How long do the symptoms last? How many episodes have occurred since their last medical
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review? Any urgent doctor/emergency department visits? Is there a written action plan? Risk
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factors for exacerbations include a history of exacerbations, poor symptom control, poor adherence
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and poverty,104 and persistent bronchodilator reversibility even if the child has few symptoms.99
Lung function PY
Check curves and technique. Main focus is on FEV1 and FEV1/FVC ratio. Plot these values as
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percent predicted to see trends over time.
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Side-effects Check the child’s height at least yearly, as poorly controlled asthma can affect growth,112 and
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growth velocity may be lower in the first 1-2 years of ICS treatment.113 Ask about frequency and
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dose of ICS and OCS.

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Treatment factors
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Inhaler technique Ask the child to show how they use their inhaler. Compare with a device-specific checklist.
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Adherence Is there any controller medication in the home at present? On how many days does the child use
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their controller in a week (e.g. 0, 2, 4, 7 days)? Is it easier to remember to use it in the morning or
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evening? Where is inhaler kept – is it in plain view to reduce forgetting? Check date on inhaler.
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Goals/concerns Does the child or their parent/carer have any concerns about their asthma (e.g. fear of medication,
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side-effects, interference with activity)? What are the child’s/parent’s/carer’s goals for treatment?
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Comorbidities
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Allergic rhinitis Itching, sneezing, nasal obstruction? Can the child breathe through their nose? What medications
are being taken for nasal symptoms?
Eczema Sleep disturbance, topical corticosteroids?
Food allergy Is the child allergic to any foods? (confirmed food allergy is a risk factor for asthma-related death90)
Obesity Check age-adjusted BMI. Ask about diet and physical activity.
Other investigations (if needed)
2-week diary If no clear assessment can be made based on the above questions, ask the child or parent/carer to
keep a daily diary of asthma symptoms, reliever use and peak expiratory flow (best of three) for 2
weeks (Appendix Chapter 4).
Exercise challenge Provides information about airway hyperresponsiveness and fitness (Box 1-2, p.23). Only
(laboratory) undertake a challenge if it is otherwise difficult to assess asthma control.
FEV1: forced expiratory volume in 1 second; FVC: forced vital capacity; ICS: inhaled corticosteroids; OCS: oral corticosteroids.
ASSESSING FUTURE RISK OF ADVERSE OUTCOMES
The second component of assessing asthma control (Box 2-2B, p.35) is to identify whether the patient is at risk of
adverse asthma outcomes, particularly exacerbations, persistent airflow limitation, and side-effects of medications (Box
2-2B). Asthma symptoms, although an important outcome for patients, and themselves a strong predictor of future risk
of exacerbations, are not sufficient on their own for assessing asthma because:
• Asthma symptoms can be controlled by placebo or sham treatments114,115 or by inappropriate use of long-acting
beta2-agonist (LABA) alone,116 which leaves airway inflammation untreated.
• Respiratory symptoms may be due to other conditions such as lack of fitness, or comorbidities such as inducible
laryngeal obstruction.36
• Anxiety or depression may contribute to symptom reporting.
• Some patients have few symptoms despite low lung function.
Asthma symptom control and exacerbation risk should not be simply combined numerically, as poor control of symptoms
and of exacerbations may have different causes and may need different treatment approaches.
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Risk factors for exacerbations
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Poor asthma symptom control itself substantially increases the risk of exacerbations.61-63 However, several additional
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independent risk factors have been identified, i.e. factors, that, when present, increase the patient’s risk of exacerbations
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even if symptoms are few. These risk factors (Box 2-2B) include a history of ≥1 exacerbations in the previous year, poor
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adherence, incorrect inhaler technique, chronic sinusitis and smoking, all of which can be assessed in primary care.117
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In children, the risk of exacerbations is greatly increased if there is a history of previous exacerbations; it is also
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increased with poor symptom control, suboptimal drug regimen, comorbid allergic disease and poverty.104
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Risk factors for development of persistent airflow limitation

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The average rate of decline in FEV1 in non-smoking healthy adults is 15–20 mL/year.118 People with asthma may have
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an accelerated decline in lung function and develop airflow limitation that is not fully reversible. This is often associated
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with more persistent dyspnea. Independent risk factors that have been identified for persistent airflow limitation include
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exposure to cigarette smoke or noxious agents, chronic mucus hypersecretion, and asthma exacerbations in patients
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not taking ICS108 (see Box 2-2B). Children with persistent asthma may have reduced growth in lung function, and some
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are at risk of accelerated decline in lung function in early adult life.119

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Choices with any medication are based on the balance of benefit and risk. Most people using asthma medications do
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not experience any side-effects. The risk of side-effects increases with higher doses of medications, but these are
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needed in few patients. Systemic side-effects that may be seen with long-term, high dose ICS include easy bruising; an
increase beyond the usual age-related risk of osteoporosis, cataracts and glaucoma; and adrenal suppression. Local
side effects of ICS include oral thrush and dysphonia. Patients are at greater risk of ICS side-effects with higher doses
or more potent formulations,109,110 and, for local side-effects, with incorrect inhaler technique.111
ROLE OF LUNG FUNCTION IN ASSESSING ASTHMA CONTROL
Does lung function relate to other asthma control measures?

Lung function does not correlate strongly with asthma symptoms in adults120 or children.121 In some asthma control tools,
lung function is numerically averaged or added with symptoms,70,122 but if the tool includes several symptom items,
these can outweigh clinically important differences in lung function.123 In addition, low FEV1 is a strong independent
predictor of risk of exacerbations, even after adjustment for symptom frequency.
Lung function should be assessed at diagnosis or start of treatment; after 3–6 months of controller treatment to assess
the patient’s personal best FEV1; and periodically thereafter. For example, in most adult patients, lung function should
be recorded at least every 1-2 years, but more frequently in higher risk patients including those with exacerbations and
those at risk of decline in lung function (see Box 2-2B). Lung function should also be recorded more frequently in
children based on asthma severity and clinical course (Evidence D).
Once the diagnosis of asthma has been confirmed, it is not generally necessary to ask patients to withhold their regular
or as-needed medications before visits,17 but preferably the same conditions should apply at each visit.
How to interpret lung function test results in asthma

A low FEV1 percent predicted:
• Identifies patients at risk of asthma exacerbations, independent of symptom levels, especially if FEV1 is <60%
predicted92,97,124,125
• Is a risk factor for lung function decline, independent of symptom levels107
• If symptoms are few, suggests limitation of lifestyle, or poor perception of airflow limitation,126 which may be due
to untreated airway inflammation.127
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A ‘normal’ or near-normal FEV1 in a patient with frequent respiratory symptoms (especially when symptomatic):
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• Prompts consideration of alternative causes for the symptoms; e.g. cardiac disease, or cough due to post-nasal
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drip or gastroesophageal reflux disease (Box 1-3, p.26).
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Persistent bronchodilator reversibility:
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• Finding significant bronchodilator reversibility (increase in FEV1 >12% and >200 mL from baseline15) in a patient
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taking controller treatment, or who has taken a short-acting beta2-agonist within 4 hours, or a LABA within 12
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hours (or 24 hours for a once-daily LABA), suggests uncontrolled asthma.
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In children, spirometry cannot be reliably obtained until age 5 years or more, and it is less useful than in adults. Many
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children with uncontrolled asthma have normal lung function between flare-ups (exacerbations).
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How to interpret changes in lung function in clinical practice

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With regular ICS treatment, FEV1 starts to improve within days, and reaches a plateau after around 2 months.128 The
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patient’s highest FEV1 reading (personal best) should be documented, as this provides a more useful comparison for
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clinical practice than FEV1 percent predicted. If predicted values are used in children, measure their height at each visit.
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Some patients may have a faster than average decrease in lung function, and develop persistent (incompletely
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reversible) airflow limitation. While a trial of higher dose ICS-LABA and/or systemic corticosteroids may be appropriate
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to see if FEV1 can be improved, high doses should not be continued if there is no response.
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The between-visit variability of FEV1 (≤12% week to week or 15% year to year in healthy individuals15) limits its use in
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adjusting asthma treatment in clinical practice. The minimal important difference for improvement and worsening in FEV1
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based on patient perception of change has been reported to be about 10%.129,130
The role of short-term and long-term PEF monitoring

Once the diagnosis of asthma is made, short-term peak expiratory flow (PEF) monitoring may be used to assess
response to treatment, to evaluate triggers (including at work) for worsening symptoms, or to establish a baseline for
action plans. After starting ICS, personal best PEF (from twice daily readings) is reached on average within 2 weeks.131
Average PEF continues to increase, and diurnal PEF variability to decrease, for about 3 months.120,131 Excessive
variation in PEF suggests sub-optimal asthma control, and increases the risk of exacerbations.132
Long-term PEF monitoring is now generally only recommended for patients with severe asthma, or those with impaired
perception of airflow limitation127,133-136 (Appendix Chapter 4). For clinical practice, displaying PEF results on a
standardized chart may improve accuracy of interpretation.137
ASSESSING ASTHMA SEVERITY
How to assess asthma severity in clinical practice
Currently, asthma severity is assessed retrospectively from the level of treatment required to control symptoms and
exacerbations.17,59,138 It can be assessed once the patient has been on controller treatment for several months and, if
appropriate, treatment step down has been attempted to find the patient’s minimum effective level of treatment. Asthma
severity is not a static feature and may change over months or years.
Asthma severity can be assessed when the patient has been on controller treatment for several months:17,138
• Mild asthma is asthma that is well controlled with Step 1 or Step 2 treatment (Box 3-5, p.54), i.e. with as-needed
ICS-formoterol alone, or with low-intensity maintenance controller treatment such as low dose ICS, leukotriene
receptor antagonists or chromones. For patients prescribed as-needed ICS-formoterol, the frequency of use that
should be considered to represent well-controlled asthma has not yet been determined.
• Moderate asthma is asthma that is well controlled with Step 3 treatment e.g. low dose ICS-LABA.
• Severe asthma is asthma that requires Step 4 or 5 treatment (Box 3-5, p.54), e.g. high dose ICS-LABA, to
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prevent it from becoming ‘uncontrolled’, or asthma that remains ‘uncontrolled’ despite this treatment. While
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many patients with uncontrolled asthma may be difficult to treat due to inadequate or inappropriate treatment, or
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persistent problems with adherence or comorbidities such as chronic rhinosinusitis or obesity, the European
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Respiratory Society/American Thoracic Society Task Force on Severe Asthma considered that the definition of
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severe asthma should be reserved for patients with refractory asthma and those in whom response to treatment
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of comorbidities is incomplete.138 See Chapter 3E (p.94) for more detail about the assessment of patients with
difficult to treat or severe asthma. PY
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How to classify asthma severity in epidemiologic studies and clinical trials

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For descriptions of participants in epidemiological studies and clinical trials, classification of asthma severity has often
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been based on prescribed treatment step (Box 3-5, p.54). For example, patients prescribed Step 1 or 2 treatments are
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often described as having mild asthma; those prescribed Step 3–4 as having moderate asthma; and those prescribed
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Step 4–5 as having moderate-to-severe asthma. This approach is based on the assumption that patients are receiving
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appropriate treatment, and that those prescribed more intense treatment are likely to have more severe underlying
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disease. However, this is only a surrogate measure, and it causes confusion since most studies also require participants
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to have uncontrolled symptoms at entry. For epidemiological studies or clinical trials, it is preferable to categorize
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patients by the type of treatment that they are prescribed, without inferring severity. In particular, to avoid confusion,
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SABA-only treatment should not be described as ‘Step 1’ treatment.

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For low resource countries that do not currently have access to medications such as ICS, the World Health Organization
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definition of severe asthma139 includes a category of ‘untreated severe asthma’. This category corresponds to other
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classifications of uncontrolled asthma in patients not taking controller treatment.

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‘Severe’ is often also used to describe the intensity of asthma symptoms, the magnitude of airflow limitation, or the
nature of an exacerbation. In older asthma literature, many different severity classifications have been used; many of
these were similar to current concepts of asthma control.59
The patient’s view of asthma severity
Patients may perceive their asthma as severe if they have intense or frequent symptoms, but this does not necessarily
indicate underlying severe disease, as symptoms may rapidly become well controlled with ICS. It is important that health
professionals communicate clearly to patients what they mean by the word ‘severe’.
How to distinguish between uncontrolled asthma and severe asthma
Although most asthma patients can achieve good symptom control and minimal exacerbations with regular controller
treatment, some patients will not achieve one or both of these goals even with maximal therapy.122 In some patients this
is due to truly refractory severe asthma, but in many others, it is due to comorbidities, persistent environmental
exposures, or psychosocial factors.
It is important to distinguish between severe asthma and uncontrolled asthma, as the latter is a much more common
reason for persistent symptoms and exacerbations, and may be more easily improved. Box 2-4 shows the initial steps
that can be carried out to identify common causes of uncontrolled asthma. More details are given in Section 3E (p.94)
about investigation and management of difficult-to-treat and severe asthma, including referral to a respiratory physician
or severe asthma clinic where possible. The most common problems that need to be excluded before a diagnosis of
severe asthma can be made are:
• Poor inhaler technique (up to 80% of community patients)86 (Box 3-12, p.80)
• Poor medication adherence140 (Box 3-13, p.81)
• Incorrect diagnosis of asthma, with symptoms due to alternative conditions such as inducible laryngeal
obstruction, cardiac failure or lack of fitness (Box 1-3, p.26)
• Comorbidities and complicating conditions such as rhinosinusitis, gastroesophageal reflux, obesity and
obstructive sleep apnea (Chapter 3, Part D, p.85)88
• Ongoing exposure to sensitizing or irritant agents in the home or work environment.
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Box 2-4. Investigating a patient with poor symptom control and/or exacerbations despite treatment
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Chapter 3.
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Treating asthma to
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control symptoms
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and minimize risk

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This chapter is divided into five parts:
Part A. General principles of asthma management (p.42)
Part B. Medications and strategies for asthma symptom control and risk reduction
• Medications (p.47)
• Treating modifiable risk factors (p.67)
• Non-pharmacological therapies and strategies (p.67)
Part C. Guided asthma self-management education and skills training (p.79)
• Information, inhaler skills, adherence, written asthma action plan, self-monitoring, regular review
Part D. Managing asthma with comorbidities and in special populations (p.85)
Part E. Difficult-to-treat and severe asthma in adults and adolescents (including decision tree) (p.94)
Management of worsening and acute asthma is described in Chapter 4 (p.111).
PART A. GENERAL PRINCIPLES OF ASTHMA MANAGEMENT
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KEY POINTS
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Goals of asthma management
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• The long-term goals of asthma management are to achieve good symptom control, and to minimize future risk of
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asthma-related mortality, exacerbations, persistent airflow limitation and side-effects of treatment. The patient’s
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own goals regarding their asthma and its treatment should also be identified.
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The patient-health professional partnership
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• Effective asthma management requires a partnership between the person with asthma (or the parent/carer) and
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their health care providers.

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• Teaching communication skills to health care providers may lead to increased patient satisfaction, better health
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• The patient’s ‘health literacy’ – that is, the patient’s ability to obtain, process and understand basic health
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information to make appropriate health decisions – should be taken into account.

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Making decisions about asthma treatment

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• Asthma treatment is adjusted in a continuous cycle of assessment, treatment, and review of the patient’s response
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in both symptom control and future risk (of exacerbations and side-effects)
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• For population-level decisions about asthma treatment, the ‘preferred option’ at each step represents the best
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treatment for most patients, based on group mean data for efficacy, effectiveness and safety from randomized
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controlled trials, meta-analyses and observational studies, and net cost.

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• For individual patients, treatment decisions should also take into account any patient characteristics or phenotype
that predict the patient’s likely response to treatment, together with the patient’s preferences and practical issues
(inhaler technique, adherence, and cost to the patient).
LONG-TERM GOALS OF ASTHMA MANAGEMENT

The long-term goals of asthma management are:
• To achieve good control of symptoms and maintain normal activity levels
• To minimize the risk of asthma-related death, exacerbations, persistent airflow limitation and side-effects.
It is also important to elicit the patient’s own goals regarding their asthma, as these may differ from conventional medical
goals. Shared goals for asthma management can be achieved in various ways, taking into account differing health care
systems, medication availability, and cultural and personal preferences.
42 3. Treating to control symptoms and minimize future risk

THE PATIENT-HEALTH CARE PROVIDER PARTNERSHIP
Effective asthma management requires the development of a partnership between the person with asthma (or the
parent/carer) and health care providers.141 This should enable the person with asthma to gain the knowledge,
confidence and skills to assume a major role in the management of their asthma. Self-management education reduces
asthma morbidity in both adults142 (Evidence A) and children143 (Evidence A).
There is emerging evidence that shared decision-making is associated with improved outcomes.144 Patients should be
encouraged to participate in decisions about their treatment, and given the opportunity to express their expectations and
concerns. This partnership needs to be individualized to each patient. A person’s willingness and ability to engage in
self-management may vary depending on factors such as ethnicity, literacy, understanding of health concepts (health
literacy), numeracy, beliefs about asthma and medications, desire for autonomy, and the health care system.
Good communication
Good communication by health care providers is essential as the basis for good outcomes145-147 (Evidence B). Teaching
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health care providers to improve their communication skills (Box 3-1) can result in increased patient satisfaction, better
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health outcomes, and reduced use of health care resources145-147 without lengthening consultation times.148 It can also
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enhance patient adherence.148 Training patients to give information clearly, seek information, and check their
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understanding of information provided is also associated with improved adherence with treatment recommendations.148
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Health literacy and asthma
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There is increasing recognition of the impact of low health literacy on health outcomes, including in asthma.149,150 Health
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literacy means much more than the ability to read: it is defined as ‘the degree to which individuals have the capacity to
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obtain, process and understand basic health information and services to make appropriate health decisions’.149 Low
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health literacy is associated with reduced knowledge and worse asthma control.151 In one study, low numeracy among
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parents of children with asthma was associated with higher risk of exacerbations.150 Interventions adapted for cultural
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and ethnicity perspectives have been associated with improved knowledge and significant improvements in inhaler
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technique.152 Suggested communication strategies for reducing the impact of low health literacy are shown in Box 3-1.
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Box 3-1. Communication strategies for health care providers

AT
M
Key strategies to facilitate good communication146,147

D
TE
• A congenial demeanor (friendliness, humor and attentiveness)

H
• Allowing the patient to express their goals, beliefs and concerns

IG
R
• Empathy, reassurance, and prompt handling of any concerns

PY
• Giving encouragement and praise

O
C
• Giving appropriate (personalized) information

• Providing feedback and review
How to reduce the impact of low health literacy149
• Order information from most to least important.

• Speak slowly and use simple words (avoid medical language, if possible).
• Simplify numeric concepts (e.g. use numbers instead of percentages).
• Frame instructions effectively (use illustrative anecdotes, drawings, pictures, table or graphs).
• Confirm understanding by using the ‘teach-back’ method (ask patients to repeat instructions).
• Ask a second person (e.g. nurse, family member) to repeat the main messages.
• Pay attention to non-verbal communication by the patient.
• Make patients feel comfortable about asking questions.
3. Treating to control symptoms and minimize future risk 43

PERSONALIZED CONTROL-BASED ASTHMA MANAGEMENT
In control-based asthma management, pharmacological and non-pharmacological treatment is adjusted in a continuous
cycle that involves assessment, treatment and review by appropriately trained personnel (Box 3-2). Asthma outcomes
have been shown to improve after the introduction of control-based guidelines153,154 or practical tools for implementation
of control-based management strategies.144,155 The concept of control-based management is also supported by the
design of most randomized controlled medication trials, with patients identified for a change in asthma treatment on the
basis of features of poor symptom control with or without other risk factors such as low lung function or a history of
exacerbations. From 2014, GINA asthma management has focused not only on asthma symptom control, but also on
personalized management of the patient’s risk factors for exacerbations, other adverse outcomes and comorbidities, and
taking into account the patient’s preferences and goals.
Box 3-2. The asthma management cycle for personalized asthma care
TE
U
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IS
D
R
O
PY
O
C
T
O
N
O
D
L-
IA
ER
AT
M
D
TE
For many patients in primary care, symptom control is a good guide to a reduced risk of exacerbations.156 When inhaled
H
IG
corticosteroids (ICS) were introduced into asthma management, large improvements were observed in symptom control
R
and lung function, and exacerbations and asthma-related mortality decreased.

PY
O
However, with other asthma therapies (including ICS-long-acting beta2-agonists (LABA)157,158) or different treatment
C
regimens (such as ICS-formoterol maintenance and reliever therapy159), and in patients with severe asthma, there may
be discordance between responses for symptom control and exacerbations. Patients with apparently mild asthma
and few or intermittent symptoms may be still at risk of severe exacerbations160 (Box 2-2B, p.35). In addition,
some patients continue to have exacerbations despite well-controlled symptoms, and for patients with ongoing
symptoms, side-effects may be an issue if ICS doses continue to be stepped up.
Therefore, in control-based management, both domains of asthma control (symptom control and future risk – see Box
2-2, p.35) should be taken into account when choosing asthma treatment and reviewing the response.17,59

Alternative strategies for adjusting asthma treatment
Some alternative strategies have been evaluated for adjusting asthma treatment:
• Treatment guided by sputum eosinophil count: in adults, this approach, when compared with guidelines-based
treatment, leads to a reduced risk of exacerbations and similar levels of symptom control and lung function.161 The
benefits have primarily been seen in patients requiring secondary care.156 However, only a limited number of
centers have routine access to induced sputum analysis. There are insufficient data available in children to assess
this approach.161
• Treatment guided by fractional concentration of exhaled nitric oxide (FeNO): In several studies of FeNO-guided
treatment, problems with the design of the intervention and/or control algorithms make comparisons and
conclusions difficult.162 Results of FeNO measurement at a single point in time should be interpreted with caution
(see p.26).29,163 In children and young adults with asthma, FeNO-guided treatment was associated with a
significant reduction in the number of patients with ≥1 exacerbation (OR 0.67 [95% CI 0.51-0.90]) and in
exacerbation rate (mean difference -0.27 [-0.49- -0.06] per year) compared with guidelines-based treatment
TE
(Evidence A); similar differences were seen in comparisons between FeNO-guided treatment and non-guidelines-
U
based algorithms.164 However, in non-smoking adults with asthma, no significant reduction in risk of exacerbations
IB
and in exacerbation rates was observed when compared to guideline-based treatment; a difference was only seen
TR
in studies with other (non-standard) comparator approaches.165 No significant differences were seen in symptoms
IS
D
or ICS dose with FeNO-guided treatment compared with other strategies.164,165
R
O
At present, neither sputum- nor FeNO-guided treatment is recommended for the general asthma population. Sputum-
PY
guided treatment is recommended for adult patients with moderate or severe asthma who are managed in (or can be
O
referred to) centers experienced in this technique138 (Evidence A). In children, FeNO-guided treatment significantly
C
reduces exacerbation rates compared with guidelines-based treatment (Evidence A).164 However, further studies are
T
O
needed to identify the populations most likely to benefit from sputum-guided or FeNO-guided treatment, and the optimal
N
O
frequency of FeNO monitoring.

D
L-
Choosing between asthma treatment options

IA
ER
At each treatment step in asthma management, different medication options are available that, although not of identical
AT
efficacy, may be alternatives for controlling asthma. Different considerations apply to recommendations or choices made
M
for broad populations compared with those for individual patients (Box 3-3, p. 45), as follows:
D
TE
• Population-level medication choices: These aim to represent the best option for most patients in the population.
H
For each treatment step, a ‘preferred’ controller medication is recommended that provides the best benefit to risk
IG
ratio for both symptom control and risk reduction. Choice of the preferred controller is based on group mean data
R
PY
from efficacy studies (highly controlled studies in well-characterized populations) and effectiveness studies (from
O
pragmatically controlled studies, or studies in broader populations, or strong observational data),166 as well as on
C
safety data and cost. Population-level medication choices are often applied by bodies such as national formularies
or managed care organizations.
• Patient-level medication choices: Choices at this level also take into account any patient characteristics or
phenotype that may predict a clinically important difference in their response compared with other patients,
together with the patient’s preferences and practical issues (cost, ability to use the medication and adherence).
The extent to which asthma treatment can be individualized according to patient characteristics or phenotypes depends
on the health system, the clinical context, the potential magnitude of difference in outcomes, cost and available
resources. At present, most research activity about individualized treatment is focused on severe asthma167,168 (see
Chapter 3E, p.94).

Box 3-3. Population level versus patient level decisions about asthma treatment
Choosing between treatment options at a population level

(e.g. national formularies, health maintenance organizations, national guidelines)
The ‘preferred’ medication at each step is the best treatment for most patients, based on:
• Efficacy
• Effectiveness Based on group mean data for symptoms, exacerbations and lung function
(from randomized controlled trials, pragmatic studies and observational data)
• Safety
• Availability and cost at the population level
Choosing between controller options for individual patients
TE
Use shared decision-making with the patient/parent/carer to discuss the following:
U
IB
1. Preferred treatment (as above) for symptom control and risk reduction
T R
2. Patient characteristics or phenotype
IS
D
• Does the patient have any features that predict differences in their future risk or treatment response compared
R
with other patients (e.g. smoker; history of exacerbations, blood eosinophilia)?
O
PY
• Are there any modifiable risk factors or comorbidities that may affect outcomes?
O
C
3. Patient preference
T
O
• What are the patient’s goals, beliefs and concerns about asthma and medications?
N
O
4. Practical issues
D
L-
• Inhaler technique – can the patient use the inhaler correctly after training?
IA
• Adherence – how often is the patient likely to take the medication?

ER
AT
• Cost to patient – can the patient afford the medication?

M
D
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H
IG
R
PY
O
C

PART B. MEDICATIONS AND STRATEGIES FOR SYMPTOM CONTROL AND RISK REDUCTION
KEY POINTS
• For safety, GINA no longer recommends treatment of asthma in adults and adolescents with SABA alone.
• All adults and adolescents with asthma should receive ICS-containing controller treatment to reduce their risk of
serious exacerbations and to control symptoms. ICS-containing controller can be delivered either with regular daily
treatment or, in mild asthma, with as-needed ICS-formoterol taken whenever needed for symptom relief.
Steps 1 and 2
• Treatment with regular daily low dose ICS, with as-needed SABA, is highly effective in reducing asthma symptoms
and reducing the risk of asthma-related exacerbations, hospitalization and death, but adherence with ICS is poor.
• In adults and adolescents with mild asthma, treatment with as-needed low dose ICS-formoterol reduces the risk of
severe exacerbations by about two-thirds compared with SABA-only treatment, and is non-inferior to daily low dose
ICS for severe exacerbations.
TE
Stepping up if asthma remains uncontrolled despite good adherence and inhaler technique
U
• For patients with persistent symptoms and/or exacerbations despite low dose ICS, consider step up but first check
IB
R
for common problems such as inhaler technique, adherence, persistent allergen exposure and comorbidities.
T
IS
• For adults and adolescents, the preferred step-up is to combination low dose ICS-long-acting beta2-agonist (LABA).
D
• For adults and adolescents with exacerbations despite other therapies, the risk of exacerbations is reduced with
R
O
combination low dose ICS-formoterol (with beclometasone or budesonide) as both maintenance and reliever,
compared with maintenance controller treatment plus as-needed SABA.
PY
O
C
• For children 6–11 years, Step 3 options include medium dose ICS and combination low dose ICS-LABA, as
T
maintenance therapy with as-needed SABA.

O
N
Stepping down to find the minimum effective dose

O
D
• Consider step down once good asthma control has been achieved and maintained for about 3 months, to find the
L-
patient’s lowest treatment that controls both symptoms and exacerbations

IA
ER
o Provide the patient with a written asthma action plan, monitor closely, and schedule a follow-up visit.
o Do not completely withdraw ICS unless this is needed temporarily to confirm the diagnosis of asthma.
AT
M
For all patients with asthma

D
TE
• Provide asthma education and training in essential skills

o Provide inhaler skills training: this is essential for medications to be effective, but technique is often incorrect
H
IG
o Encourage adherence with controller medication, even when symptoms are infrequent.
R
PY
o Provide training in asthma self-management (self-monitoring of symptoms and/or PEF, written asthma action
plan and regular medical review) to control symptoms and minimize the risk of exacerbations.
O
C
For patients with one or more risk factors for exacerbations

• Prescribe regular daily ICS-containing medication, provide a written asthma action plan, and arrange review more
frequently than for low-risk patients.
• Identify and address modifiable risk factors, (e.g. smoking, low lung function).
• Consider non-pharmacological strategies and interventions to assist with symptom control and risk reduction,
(e.g. smoking cessation advice, breathing exercises, some avoidance strategies).
• For all patients, use your own professional judgment, and always check local eligibility and payer criteria.
Difficult-to-treat and severe asthma (see section 3E, p.94)
• Patients with poor symptom control and/or exacerbations despite Step 4 or 5 treatment should be assessed for
contributing factors, and asthma treatment optimized. If the problems continue or diagnosis is uncertain, refer to a
specialist center for phenotypic assessment and consideration of add-on therapy including biologics.

ASTHMA MEDICATIONS
Categories of asthma medications

When compared with medications used for other chronic diseases, most of the medications used for treatment of
asthma have very favorable therapeutic ratios (Appendix Chapter 5). The pharmacological options for long-term
treatment of asthma fall into the following three main categories:
• Controller medications: these are used to reduce airway inflammation, control symptoms, and reduce future risks
such as exacerbations and decline in lung function. In patients with mild asthma, controller treatment may be
delivered through as-needed low dose ICS-formoterol, taken when symptoms occur and before exercise.
• Reliever (rescue) medications: these are provided to all patients for as-needed relief of breakthrough symptoms,
including during worsening asthma or exacerbations. They are also recommended for short-term prevention of
exercise-induced bronchoconstriction. Reducing and, ideally, eliminating the need for SABA reliever is both an
important goal in asthma management and a measure of the success of asthma treatment.
• Add-on therapies for patients with severe asthma (Section 3E, p.94): these may be considered when patients
have persistent symptoms and/or exacerbations despite optimized treatment with high dose controller medications
TE
(usually a high dose of ICS plus a LABA) and treatment of modifiable risk factors (see Box 3-8, p.67).
U
IB
R
Initial controller treatment
T
IS
D
For the best outcomes, ICS-containing controller treatment should be initiated as soon as possible after the diagnosis of
R
asthma is made, as the evidence suggests that:
O
PY
• Early initiation of low dose ICS in patients with asthma leads to a greater improvement in lung function than if
O
symptoms have been present for more than 2–4 years.169,170 One study showed that after this time, higher ICS
C
doses were required, and lower lung function was achieved.171

T
O
• Patients not taking ICS who experience a severe exacerbation have a greater long-term decline in lung function
N
than those who have already started ICS.108

O
D
• For patients with occupational asthma, early removal from exposure to the sensitizing agent and early controller
L-
treatment increase the probability of resolution of symptoms and airway hyperresponsiveness.38

IA
ER
Recommended options for initial controller treatment in adults and adolescents, based on evidence (where available)
AT
and consensus, are listed in Box 3-4A (p.50) and shown in Box 3-4B (p.51). The corresponding resources for children
M
6--11 years are on p.52 and p.53. The patient’s response should be reviewed, and treatment stepped down once good
D
TE
control is achieved. Recommendations for a stepwise approach to ongoing treatment are found in Box 3-5 (p.54).
H
Does FeNO help in deciding whether to commence ICS?

IG
R
In studies mainly limited to non-smoking patients, FeNO >50 parts per billion (ppb) has been associated with a good
PY
short-term response to ICS.163,172 However, these studies did not examine the longer-term risk of exacerbations. Such
O
C
evidence therefore does not mean that it is safe with regard to exacerbations to withhold ICS in patients with low initial
FeNO. More recently, in two 12-month studies in mild asthma, severe exacerbations were reduced with as-needed ICS-
formoterol versus as-needed SABA and versus maintenance ICS, independent of baseline inflammatory characteristics
including FeNO.173,174
Consequently, in patients with a diagnosis or suspected diagnosis of asthma, measurement of FeNO can support the
decision to start ICS, but cannot be used to decide against treatment with ICS. Based on past and current evidence,
GINA recommends treatment with daily low dose ICS or as-needed low dose ICS-formoterol for all patients with mild
asthma, to reduce the risk of serious exacerbations.175

Personalized approach for adjusting asthma treatment in adults, adolescents and children 6–11 years old
Once asthma treatment has been commenced (Boxes 3-4A-D), ongoing treatment decisions are based on a
personalized cycle of assessment, adjustment of treatment, and review of the response. For each patient, in addition to
treatment of modifiable risk factors, controller medication can be adjusted up or down in a stepwise approach (Box 3-5A-
B) to achieve good symptom control and minimize future risk of exacerbations, persistent airflow limitation and
medication side-effects. Once good asthma control has been maintained for 2–3 months, treatment may be stepped
down in order to find the patient’s minimum effective treatment (Box 3-7, p.66).
If a patient has persisting uncontrolled symptoms and/or exacerbations despite 2–3 months of controller treatment,
assess and correct the following common problems before considering any step up in treatment:
• Incorrect inhaler technique
• Poor adherence
• Persistent exposure at home/work to agents such as allergens, tobacco smoke, indoor or outdoor air pollution, or
to medications such as beta-blockers or (in some patients) nonsteroidal anti-inflammatory drugs (NSAIDs)
• Comorbidities that may contribute to respiratory symptoms and poor quality of life
TE
• Incorrect diagnosis.
U
IB
R
T
IS
D
R
O
PY
O
C
T
O
N
O
D
L-
IA
ER
AT
M
D
TE
H
IG
R
PY
O
C

Box 3-4A. Initial asthma treatment - recommended options for adults and adolescents
Presenting symptoms Preferred INITIAL treatment
Infrequent asthma symptoms, e.g. As-needed low dose ICS-formoterol (Evidence B)

less than twice a month and no risk Other options include taking ICS whenever SABA is taken, in combination
factors for exacerbations (Box 2-2B, or separate inhalers (Evidence B)
p.35)
Asthma symptoms or need for reliever Low dose ICS with as-needed SABA (Evidence A), or
twice a month or more As-needed low dose ICS-formoterol (Evidence A)
Other options include daily LTRA (less effective than ICS, Evidence A), or
taking ICS whenever SABA is taken in combination or separate inhalers
(Evidence B). Consider likely adherence with controller if reliever is SABA.
Troublesome asthma symptoms most Low dose ICS-LABA as maintenance and reliever therapy with ICS-
TE
days; or waking due to asthma once a formoterol (Evidence A) OR
U
IB
week or more, especially if any risk Maintenance-only ICS-LABA with as-needed SABA (Evidence A), OR
R
factors exist (Box 2-2B)
T
Medium dose ICS with as-needed SABA (Evidence A)
IS
D
R
Initial asthma presentation is with Start regular controller treatment with high dose ICS (Evidence A), or
O
severely uncontrolled asthma, or with medium dose ICS-LABA (Evidence D)
an acute exacerbation PY
A short course of oral corticosteroids may also be needed
O
C
Before starting initial controller treatment

T
O
N
• Record evidence for the diagnosis of asthma

O
D
• Record the patient’s level of symptom control and risk factors, including lung function (Box 2-2, p.35)
L-
• Consider factors influencing choice between available treatment options (Box 3-3, p.45)
IA
ER
• Ensure that the patient can use the inhaler correctly

AT
• Schedule an appointment for a follow-up visit

M
After starting initial controller treatment

D
TE
• Review patient’s response (Box 2-2, p.35) after 2–3 months, or earlier depending on clinical urgency
H
IG
• See Box 3-5 (p.54) for recommendations for ongoing treatment and other key management issues
R
• Step down treatment once good control has been maintained for 3 months (Box 3-7, p.66).
PY
O
ICS: inhaled corticosteroids; LABA: long-acting beta2-agonist; LTRA: leukotriene receptor antagonist; OCS: oral corticosteroids; SABA: short-acting
C
beta2-agonist. This table is based on evidence from available studies and consensus, including considerations of cost. See also Box 3-4B (p.51) for
where to start on the main treatment figure for adults and adolescents.

Box 3-4B. Selecting initial controller treatment in adults and adolescents with a diagnosis of asthma
TE
U
IB
TR
IS
D
R
O
PY
O
C
T
O
N
O
D
L-
IA
E R
AT
M
D
TE
H
IG
R
PY
O
C
HDM: house dust mite; ICS: inhaled corticosteroid; LABA: long-acting beta2-agonist; LTRA: leukotriene receptor antagonist; OCS: oral corticosteroids; SABA: short-acting beta2-agonist;
SLIT: sublingual immunotherapy

Box 3-4C. Initial asthma treatment - recommended options for children aged 6–11 years
Presenting symptoms Preferred INITIAL treatment
Infrequent asthma symptoms, As-needed SABA

e.g. less than twice a month and no Other options include taking ICS whenever SABA is taken, in combination
risk factors for exacerbations (Box 2- or separate inhalers
2B, p.35)
Asthma symptoms or need for reliever Low dose ICS** with as-needed SABA (Evidence A), or
twice a month or more Other options include daily LTRA (less effective than ICS, Evidence A), or
taking ICS whenever SABA is taken in combination or separate inhalers
(Evidence B). Consider likely adherence with controller if reliever is SABA.
Troublesome asthma symptoms most Low dose ICS-LABA with as needed SABA, OR
days; or waking due to asthma once a Medium dose ICS† with as-needed SABA (Evidence A)
TE
week or more, especially if any risk
U
Other options include low-dose ICS with daily LRTA, with as needed SABA
IB
factors exist (Box 2-2B)
TR
Initial asthma presentation is with Start regular controller treatment with medium dose ICS-LABA with as-needed
IS
D
severely uncontrolled asthma, or with SABA. A short course of OCS may also be needed.
R
an acute exacerbation
O
Other options include daily high dose ICS-LABA, or add on tiotropium or
PY
add on LRTA, with as needed SABA
O
Before starting initial controller treatment
C
T
O
• Record evidence for the diagnosis of asthma, if possible

N
O
• Record the child’s level of symptom control and risk factors, including lung function (Box 2-2, p.35, Box 2-3, p.36)
D
• Consider factors influencing choice between available treatment options (Box 3-3, p.45)
L-
IA
• Ensure that the child can use the inhaler correctly

ER
• Schedule an appointment for a follow-up visit

AT
After starting initial controller treatment

M
D
TE
• Review child’s response (Box 2-2, p.35) after 2–3 months, or earlier depending on clinical urgency
H
• See Box 3-5B (p.55) for recommendations for ongoing treatment and other key management issues
IG
• Step down treatment once good control has been maintained for 3 months (Box 3-7, p.66).
R
PY
ICS: inhaled corticosteroids; LABA: long-acting beta2-agonist; LTRA: leukotriene receptor antagonist; OCS: oral corticosteroids; SABA: short-acting
O
beta2-agonist. This table is based on evidence from available studies and consensus, including considerations of cost. See also Box 3-4D (p.53) for
C
where to start on the main treatment figure for children 6–11 years.

Box 3-4D. Selecting initial controller treatment in children aged 6–11 years with a diagnosis of asthma
TE
U
IB
TR
IS
D
R
O
PY
O
C
T
O
N
O
D
L-
IA
E R
AT
M
D
TE
H
IG
R
PY
O
C
ICS: inhaled corticosteroid; LABA: long-acting beta2-agonist; LTRA: leukotriene receptor antagonist; OCS: oral corticosteroids; SABA: short-acting beta2-agonist

Box 3-5A. Personalized management for adults and adolescents to control symptoms and minimize future risk
TE
U
IB
TR
IS
D
R
O
PY
O
C
T
O
N
O
D
L-
IA
E R
AT
M
D
TE
H
IG
R
PY
O
C
HDM: house dust mite; ICS: inhaled corticosteroid; LABA: long-acting beta2-agonist; LTRA: leukotriene receptor antagonist; OCS: oral corticosteroids; SABA: short-acting beta2-agonist;
SLIT: sublingual immunotherapy. For recommendations about initial asthma treatment in adults and adolescents, see Box 3-4A (p.50) and 3-4B (p.51).

Box 3-5B. Personalized management for children 6–11 years to control symptoms and minimize future risk
TE
U
IB
TR
IS
D
R
O
PY
O
C
T
O
N
O
D
L-
IA
E R
AT
M
D
TE
H
IG
R
PY
O
C
ICS: inhaled corticosteroid; LABA: long-acting beta2-agonist; LTRA: leukotriene receptor antagonist; OCS: oral corticosteroids; SABA: short-acting beta2-agonist
For recommendations about initial asthma treatment in children aged 6–11 years, see Box 3-4C (p.52) and Box 3-4D (p.53)

Box 3-6. Low, medium and high daily doses of inhaled corticosteroids
This is not a table of equivalence, but instead, suggested total daily doses for the ‘low’, ‘medium’ and ‘high’ dose ICS
options for adults/adolescents, p.54 and children 6–11 years, p.55, based on available studies and product information.
Data on comparative potency are not readily available and therefore this table does NOT imply potency equivalence.
Doses may be country-specific depending on local availability, regulatory labelling and clinical guidelines.
Low dose ICS provides most of the clinical benefit of ICS for most patients with asthma. However, ICS responsiveness
varies between patients, so some patients may need medium dose ICS if their asthma is uncontrolled despite good
adherence and correct technique with low dose ICS (with or without LABA). High dose ICS (in combination with LABA
or separately) is needed by very few patients, and its long-term use is associated with an increased risk of local and
systemic side-effects, which must be balanced against the potential benefits.
Adults and adolescents (12 years and older)
TE
Total daily ICS dose (mcg) – see notes above
Inhaled corticosteroid
U
Low Medium High
IB
R
Beclometasone dipropionate (pMDI, standard particle, HFA) 200-500 >500-1000 >1000
T
IS
Beclometasone dipropionate (pMDI, extrafine particle*, HFA) 100–200 >200–400 >400
D
R
Budesonide (DPI) 200–400 >400–800 >800
O
Ciclesonide (pMDI, extrafine particle*, HFA) 80–160 >160–320 >320
PY
O
Fluticasone furoate (DPI) 100 200
C
Fluticasone propionate (DPI) 100–250 >250–500 >500

T
O
N
Fluticasone propionate (pMDI, standard particle, HFA) 100–250 >250–500 >500

O
Mometasone furoate (DPI) 200 400

D
L-
Mometasone furoate (pMDI, standard particle, HFA) 200-400 >400

IA
ER
Children 6–11 years – see notes above (for children 5 years and younger, see Box 6-6, p.153)
AT
Beclometasone dipropionate (pMDI, standard particle, HFA) 100–200 >200–400 >400

M
D
Beclometasone dipropionate (pMDI, extrafine particle*, HFA) 50-100 >100-200 >200

TE
Budesonide (DPI) 100–200 >200–400 >400

H
IG
Budesonide (nebules) 250–500 >500–1000 >1000

R
PY
Ciclesonide (pMDI, extrafine particle*, HFA) 80 >80-160 >160

O
Fluticasone furoate (DPI) 50 n.a.

C
Fluticasone propionate (DPI) 50-100 >100-200 >200

Fluticasone propionate (pMDI, standard particle, HFA) 50-100 >100-200 >200
Mometasone furoate (pMDI, standard particle, HFA) 100 200
DPI: dry powder inhaler; HFA: hydrofluoroalkane propellant; ICS: inhaled corticosteroid; n.a. not applicable; pMDI: pressurized metered dose inhaler
(non-chlorofluorocarbon formulations); ICS by pMDI should preferably be used with a spacer. *See product information.
Most of the clinical benefit from ICS is seen at low doses, and clear evidence of dose-response relationships is seldom
available within the dose ranges evaluated for regulatory purposes. ‘High’ doses are arbitrary, but for most ICS are
those that, with prolonged use, are associated with increased risk of systemic side-effects.
For new preparations, including generic ICS, the manufacturer’s information should be reviewed carefully; products
containing the same molecule may not be clinically equivalent. For more detailed discussion see Raissy et al.109

Choice of medication, device and dose
In clinical practice, the choice of medication, device and dose should be based for each individual patient on
assessment of symptom control, risk factors, patient preference, and practical issues (cost, ability to use the device, and
adherence) (Box 3-3, p.45). It is important to monitor the response to treatment and any side-effects, and to adjust the
dose accordingly (Box 3-5, p.54). Once good symptom control has been maintained for 3 months, the ICS dose should
be carefully titrated to the minimum dose that will maintain good symptom control and minimize exacerbation risk, while
reducing the potential for side-effects (Box 3-7). Patients who are being considered for a high daily dose of ICS (except
for short periods) should be referred for expert assessment and advice, where possible (Chapter 3E, p.94). There is
currently insufficient good quality evidence to support use of extra-fine particle ICS aerosols over others.176 More detail
about asthma medications is provided in Appendix Chapter 5 (adults and adolescents: Part 5A; children 6–11 years:
Part 5B).
Below is more detail about the evidence for each of the treatments shown in Box 3-5A and 3-5B. Clinicians should check
local eligibility and payer criteria before prescribing. As shown in these figures, GINA recommends that all adults and
TE
adolescents should receive an ICS-containing controller, incorporated as part of the patient’s personalized asthma
U
management. The ICS-containing medication should be taken every day or, in mild asthma, an alternative is to take
IB
as-needed low dose ICS-formoterol for symptom relief. Box 3-6 (p.56) lists suggested low, medium and high doses for
TR
several different ICS formulations.
IS
D
R
ASTHMA TREATMENT STEPS
O
PY
O
STEP 1: Preferred controller: as-needed low dose combination ICS-formoterol (adults and adolescents)
C
T
O
Preferred Step 1 controller for adults and adolescents: low dose combination ICS-formoterol taken as needed for
N
O
relief of symptoms, and if needed before exercise

D
L-
GINA Step 1 recommendations are for:

IA
• Initial asthma treatment in patients with symptoms less than twice a month and no exacerbation risk factors, a
ER
group that is rarely studied

AT
• Step-down treatment for patients whose asthma is well-controlled on Step 2 treatment

M
D
Use of low dose ICS-formoterol as needed for symptom relief in Step 1 for adults and adolescents (Evidence B) is
TE
supported by indirect evidence from a large double-blind study comparing this regimen with SABA-only treatment and
H
IG
with regular low dose ICS plus as-needed SABA in patients with mild asthma eligible for Step 2 therapy (see below).177
R
These results are now further supported by two open-label randomized controlled trials, representing the way that
PY
patients with mild asthma would use as-needed ICS-formoterol in real life.173,174 These studies included patients with
O
C
SABA use between twice a month and twice a day.

The most important considerations for GINA in recommending as-needed low dose ICS-formoterol in Step 1 were:
• The evidence that patients with few interval asthma symptoms can still have severe or fatal exacerbations.178
GINA recommends assessing risk factors for exacerbations as well as symptom control (Box 2-2)
• The two-thirds reduction in severe exacerbation rate in the Step 2 study of as-needed low dose budesonide-
formoterol compared with SABA-only therapy, and the fact that this was achieved with <20% of the average ICS
dose compared with daily ICS.177 A 60% reduction in severe exacerbations compared with SABA alone was also
seen in an open-label randomized controlled trial.173
• The evidence that in patients with infrequent symptoms, adherence with prescribed daily ICS is very poor,179
exposing them to risks of SABA-only treatment
• The priority to avoid conflicting messages in asthma education. Previously, at the start of asthma treatment,
patients were provided only with SABA for symptom relief, but later, despite this treatment being effective from
the patient’s perspective, they were then told that they needed to take a daily controller even when they had no
symptoms, in order to reduce their SABA use. Recommending that all patients should be provided with a

controller from the start of therapy (including, in mild asthma, the option of as-needed ICS-formoterol) allows
consistent messaging about the need for both symptom relief and risk reduction, and may avoid establishing
patient reliance on SABA as their main asthma treatment.
The maximum recommended usage of as-needed budesonide-formoterol in a single day corresponds to a total of
72 mcg formoterol. However, in randomized controlled trials in mild asthma, such high usage was rarely seen, with
average use around 3–4 doses per week.173,177,180
So far, all evidence for as-needed ICS-formoterol in mild asthma is with low dose budesonide-formoterol, but
beclometasone-formoterol may also be suitable. Both of these medications are well-established for as-needed use
within maintenance and reliever therapy in GINA Steps 3–5,181 and no new safety signals were seen in four studies with
as-needed budesonide-formoterol in mild asthma.173,174,180,182
There have been no studies of as needed ICS-formoterol in children aged 6–11 years. However, concerns around
SABA-only treatment are also relevant to children and should be considered when initiating Step 1 treatment (see other
controller options for children below).
TE
U
For pre-exercise use in patients with mild asthma, one 6-week study showed that use of low dose budesonide-
IB
formoterol for symptom relief and before exercise reduced exercise-induced bronchoconstriction to a similar extent as
TR
regular daily low dose ICS with SABA for symptom relief and before exercise.183 More studies are needed, but this study
IS
suggests that patients with mild asthma who are prescribed as-needed ICS-formoterol to prevent exacerbations and
D
R
control symptoms can use the same medication prior to exercise, if needed, and do not need to be prescribed a SABA
O
for pre-exercise use (Evidence B).
PY
O
Other Step 1 controller options for adults and adolescents
C
T
Low dose ICS taken whenever SABA is taken (Evidence B): In Step 1, the evidence for this strategy is indirect, from
O
N
studies with separate or combination ICS and SABA inhalers in patients eligible for Step 2 treatment (see below).184-187
O
In making this recommendation, the most important considerations were reducing the risk of severe exacerbations, and
D
the difficulty of achieving good adherence with regularly-prescribed ICS in patients with infrequent symptoms. The as-
L-
IA
needed use of ICS whenever SABA is taken may be an option in countries where ICS-formoterol is not available or
ER
affordable.
AT
Regular daily low dose ICS has been suggested by GINA since 2014 for consideration in Step 1, for patients with
M
symptoms less than twice a month, to reduce the risk of exacerbations. This was based on indirect evidence from
D
TE
studies in patients eligible for Step 2 treatment160,182,188 (Evidence B). However, patients with symptoms less than twice a
H
month are extremely unlikely to take ICS regularly even if prescribed, leaving them exposed to the risks of SABA-only
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treatment, so for feasibility reasons, this regimen is no longer recommended for general use in such patients.
R
PY
Step 1 controller options for children 6–11 years

O
C
Possible controller options for this age-group include taking ICS whenever SABA is taken, based on indirect evidence
from Step 2 studies with separate inhalers. One of these showed substantially fewer exacerbations compared with
SABA-only treatment,185 and another showed similar outcomes as physician-adjusted treatment but with lower average
ICS dose187 (Evidence B). Regular ICS with as-needed SABA is also a possible option for this age-group (Evidence B),
but the likelihood of poor adherence in children with infrequent symptoms should be taken into account.
Not recommended
GINA no longer recommends SABA-only treatment of asthma in adults or adolescents. Although inhaled SABAs
are highly effective for the quick relief of asthma symptoms,189 patients whose asthma is treated with SABA alone
(compared with ICS) are at risk of asthma-related death (Evidence A)190 and urgent asthma-related healthcare
(Evidence A),191 even if they have good symptom control.192 One long-term study of regular SABA in patients with newly-
diagnosed asthma showed worse outcomes and lower lung function than in patients who were treated with daily low
dose ICS from the start.193

In adults, inhaled anticholinergic agents like ipratropium are potential alternatives to SABA for routine relief of asthma
symptoms; however, these agents have a slower onset of action than inhaled SABA. Oral SABA and theophylline have
a higher risk of side-effects. No long-term safety studies have been performed to assess the risk of severe
exacerbations with these reliever medications in patients not also taking ICS.
The rapid-onset LABA, formoterol, is as effective as SABA as a reliever medication in adults and children,194 and
reduces the risk of severe exacerbations by 15–45% compared with as-needed SABA,195-197 but use of regular or
frequent LABA without ICS is strongly discouraged because of the risk of exacerbations116,198 (Evidence A).
STEP 2: Preferred controller options: Daily low dose ICS plus as-needed SABA (adults, adolescents and
children), OR as-needed low dose ICS-formoterol (adults and adolescents)
Preferred Step 2 controller (adults, adolescents and children): regular daily low dose ICS plus as-needed SABA
TE
There is a large body of evidence from RCTs and observational studies showing that the risks of severe exacerbations,
U
hospitalizations and mortality are substantially reduced with regular low dose ICS; symptoms and exercise-induced
IB
R
bronchoconstriction are also reduced182,188,190,199,200 (Evidence A). Severe exacerbations are halved with low dose ICS
T
IS
even in patients with symptoms 0–1 days a week.160
D
For this recommendation, the most important consideration was to reduce the risk of severe exacerbations. When
R
O
prescribing daily ICS for patients with mild asthma, clinicians should be aware of the likelihood of poor adherence,
exposing patients to SABA-only treatment.
PY
O
C
Preferred Step 2 controller (adults and adolescents): low dose ICS-formoterol, taken as-needed for relief of
T
O
symptoms and, if needed, before exercise

N
O
The evidence for this controller option to date is with low dose budesonide-formoterol. A large double-blind study in mild
D
asthma found a 64% reduction in severe exacerbations compared with SABA-only treatment,177 with a similar finding in
L-
an open-label study in patients with mild asthma previously taking SABA alone.173 (Evidence A). Two large double-blind
IA
ER
studies in mild asthma showed as-needed budesonide-formoterol was non-inferior for severe exacerbations compared
AT
with regular ICS.177,180 In two open-label randomized controlled trials, representing the way that patients with mild
M
asthma would use as-needed ICS-formoterol in real life, as-needed budesonide-formoterol was superior to maintenance
D
ICS in reducing the risk of severe exacerbations173,174 (Evidence A). In all four studies, the as-needed ICS-formoterol
TE
strategy was associated with a substantially lower average ICS dose than with maintenance low dose ICS.
H
IG
In making this recommendation, the most important considerations for GINA were to prevent severe exacerbations and
R
PY
to avoid the need for daily ICS in patients with mild asthma, who in clinical practice are often poorly adherent with
O
prescribed ICS. The small differences compared with regular ICS in FEV1, (~30–50 mL), symptom control (difference in
C
ACQ-5 of ~0.15 vs minimal clinically important difference 0.5), and symptom-free days (mean difference 10.6 days per
year)177,180 were considered to be less important. FeNO was measured in two studies; it was significantly reduced with
both as-needed budesonide-formoterol and maintenance ICS, and there was no significant difference in treatment effect
with as-needed budesonide-formoterol by baseline eosinophils or baseline FeNO.173,174
Based on product information, the maximum recommended dose of ICS-formoterol in a single day is a total of 48mcg
formoterol for beclometasone-formoterol, and 72mcg formoterol for budesonide-formoterol. However, in the randomized
controlled trials in mild asthma, such high usage was rarely seen, and average use of as-needed ICS-formoterol was
around 3–4 doses per week.173,174,177,180
In patients with mild asthma, one study showed that budesonide-formoterol taken as-needed and before exercise had
similar benefit in reducing exercise-induced bronchoconstriction as daily ICS with SABA as-needed and pre-exercise.183
More studies are needed, but this suggests that patients with mild asthma who are prescribed as-needed ICS-formoterol
to prevent exacerbations and control symptoms can use the same medication prior to exercise, if needed, and do not
need to be prescribed a SABA for pre-exercise use (Evidence B).

If as-needed ICS-formoterol is not available, another option is for low dose ICS to be taken whenever SABA is taken.
The evidence is from studies with separate or combination ICS and SABA inhalers,184-186,201 showing no difference in
exacerbations compared with daily ICS.
Leukotriene receptor antagonists (LTRA) are less effective than ICS,202 particularly for exacerbations (Evidence A). They
may be appropriate for initial controller treatment for some patients who are unable or unwilling to use ICS; for patients
who experience intolerable side-effects from ICS; or for patients with concomitant allergic rhinitis203,204 (Evidence B).
Before prescribing montelukast, health professionals should consider its benefits and risks, and patients should be
counselled about the risk of neuropsychiatric events. The US Food and Drug Administration (FDA) recently required a
boxed warning to be provided about the risk of serious mental health adverse effects with montelukast.205
For adult or adolescent patients not previously using controller treatment, regular daily combination low dose ICS-LABA
as the initial maintenance controller treatment reduces symptoms and improves lung function compared with low dose
ICS alone.206 However, it is more expensive and does not further reduce the risk of exacerbations compared with ICS
TE
alone206 (Evidence A).
U
IB
For patients with purely seasonal allergic asthma, e.g. with birch pollen, with no interval asthma symptoms, regular daily
TR
ICS or as-needed ICS-formoterol should be started immediately symptoms commence, and be continued for four weeks
IS
after the relevant pollen season ends (Evidence D).
D
R
O
PY
The preferred controller option for children at Step 2 is regular low dose ICS (see Box 3-6, p.56 for ICS dose ranges in
O
children).
C
T
O
Other controller options for children are daily LTRA, which overall is less effective than ICS,202 or taking low dose ICS
N
whenever SABA is taken, based on the results of two studies with separate ICS and SABA inhalers in patients aged
O
D
between 5 years and 17 or 18 years.185,187 Interviews with parents indicated that those whose children were randomized
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to as-needed ICS+SABA felt more in control of their child’s asthma than those whose children were randomized to
IA
physician-based adjustment.187 The FDA warning about montelukast (above) also applies to its use in children.205
ER
AT
Not recommended for routine use

M
Sustained-release theophylline has only weak efficacy in asthma207-209 (Evidence B) and side-effects are common, and
D
TE
may be life-threatening at higher doses.210 Chromones (nedocromil sodium and sodium cromoglycate) have a favorable
H
safety profile but low efficacy211-213 (Evidence A), and their inhalers require burdensome daily washing to avoid blockage.
IG
R
PY
STEP 3: Preferred controller options: Low dose ICS-LABA maintenance plus as-needed SABA, OR low dose
O
C
ICS-formoterol maintenance and reliever therapy (adults and adolescents); medium dose ICS plus as-needed
SABA OR low-dose combination ICS-LABA plus as-needed SABA (children 6–11 years)
Before considering a step up, check for common problems such as incorrect inhaler technique, poor adherence, and
environmental exposures, and confirm that the symptoms are due to asthma (Box 2-4, p.40).
Preferred Step 3 controller options for adults and adolescents
For adults and adolescents, there are two ‘preferred’ Step 3 options:
• combination low dose ICS-LABA as maintenance treatment with as-needed SABA as reliever, and
• low dose ICS-formoterol as both maintenance and reliever treatment.
For patients receiving maintenance ICS treatment with as-needed SABA, adding LABA in a combination inhaler
provides additional improvements in symptoms and lung function with a reduced risk of exacerbations compared with
the same dose of ICS,214,215 (Evidence A) but there is only a small reduction in reliever use.216,217 Currently approved

combination ICS-LABA inhalers for Step 3 maintenance treatment of asthma include low doses of fluticasone
propionate-formoterol, fluticasone furoate-vilanterol, fluticasone propionate-salmeterol, beclometasone-formoterol,
budesonide-formoterol and mometasone-formoterol (see Box 3-6, p.56). Effectiveness of fluticasone furoate-vilanterol
over usual care was demonstrated for asthma symptom control in a large real-world study, but there was no difference
in risk of exacerbations.69,218
The ICS-formoterol maintenance and reliever regimen can be prescribed with low dose beclometasone-formoterol or
budesonide-formoterol. In adult and adolescent patients with ≥1 exacerbation in the previous year, the ICS-formoterol
maintenance and reliever regimen significantly reduces exacerbations and provides similar levels of asthma control at
relatively low doses of ICS, compared with a fixed dose of ICS-LABA as maintenance treatment or a higher dose of ICS,
both with as-needed SABA219-224 (Evidence A). Low dose ICS-formoterol is the preferred reliever for patients prescribed
the maintenance and reliever treatment regimen. It should not be used as the reliever for patients taking combination
ICS-LABA medications with a different LABA. For patients prescribed ICS-formoterol maintenance and reliever therapy,
the maximum recommended dose of formoterol in a single day, based on product information, is 48 mcg (for
beclometasone-formoterol) or 72mcg (for budesonide-formoterol).
TE
U
IB
R
For adult patients with allergic rhinitis and sensitized to house dust mite, with suboptimally controlled asthma despite low
T
IS
to high dose ICS, consider adding sublingual allergen immunotherapy (SLIT), provided FEV1 is >70% predicted.225,226
D
(see p.68).
R
O
Another option for adults and adolescents is to increase ICS to medium dose130 (see Box 3-6, p.56), but at a group level
PY
this is less effective than adding a LABA227,228 (Evidence A). Other less efficacious options are low dose ICS plus either
O
C
LTRA229 (Evidence A) or low dose, sustained-release theophylline230 (Evidence B). See note above about the FDA
T
warning for montelukast.205

O
N

O
D
In children, after checking inhaler technique and adherence, and treating modifiable risk factors, the preferred options at
L-
IA
a population level are to increase ICS to medium dose (see Box 3-6, p.56),231 (Evidence A) or change to combination
ER
low dose ICS-LABA (Evidence A).232 In a large study of children aged 4-11 years with a history of an exacerbation in the
AT
previous year, combination ICS-LABA was non-inferior to the same dose of ICS alone for severe exacerbations, with no
M
difference in symptom control or reliever use.233 In children, a single study of maintenance and reliever therapy with low
D
dose budesonide-formoterol showed a large reduction in exacerbations compared with the same dose of budesonide-
TE
formoterol with SABA reliever, or compared with higher dose ICS.234

H
IG
R
PY
STEP 4: Preferred controller: Low dose ICS-formoterol as maintenance and reliever therapy (adults and
O
adolescents), OR medium dose ICS-LABA maintenance plus as-needed SABA (adults, adolescents and
C
children)
Although at a group level most benefit from ICS is obtained at low dose, individual ICS responsiveness varies, and some
patients whose asthma is uncontrolled on low dose ICS-LABA despite good adherence and correct inhaler technique
may benefit from increasing the maintenance dose to medium. High dose ICS is no longer recommended at Step 4.
Preferred Step 4 controller options for adults and adolescents
The selection of Step 4 treatment depends on the prior selection at Step 3. Before stepping up, check for common
problems such as incorrect inhaler technique, poor adherence, and environmental exposures, and confirm that the
symptoms are due to asthma (Box 2-4, p.40).
For adult and adolescent patients with ≥1 exacerbations in the previous year, combination low dose ICS-formoterol as
maintenance and reliever treatment is more effective in reducing exacerbations than the same dose of maintenance
ICS-LABA or higher doses of ICS223 (Evidence A). This regimen can be prescribed with low dose budesonide-formoterol

or beclometasone-formoterol as in Step 3; the maintenance dose may be increased to medium if necessary. Based on
product information, the maximum recommended total dose of formoterol in a single day is 48mcg (for beclometasone-
formoterol) or 72mcg (for budesonide-formoterol).
Alternatively, for patients taking low dose maintenance ICS-LABA with as-needed SABA, whose asthma is not
adequately controlled, treatment may be increased to medium dose ICS-LABA158 (Evidence B); combination ICS-LABA
medications are as for Step 3.
Tiotropium (long-acting muscarinic antagonist) by mist inhaler may be used as add-on therapy in patients aged 6 years
and older; it modestly improves lung function235,236 (Evidence A) and modestly reduces exacerbations.235-237 In Step 4,
there is insufficient evidence to support ICS+tiotropium over ICS-LABA combination.237
For adult patients with allergic rhinitis and sensitization to house dust mite, with suboptimally controlled asthma despite
low-high dose ICS, consider adding sublingual allergen immunotherapy (SLIT), provided FEV1 is >70% predicted.225,226
TE
(see p.68).
U
For medium or high dose budesonide, efficacy may be improved with dosing four times daily238,239 (Evidence B), but
IB
R
adherence may be an issue. For other ICS, twice-daily dosing is appropriate (Evidence D). Other options for adults or
T
IS
adolescents that can be added to a medium or high dose ICS, but that are less efficacious than adding LABA, include
D
LTRA240-244 (Evidence A), or low dose sustained-release theophylline208 (Evidence B). See note above about the FDA
R
warning for montelukast.205
O
Preferred Step 4 options for children 6–11 years
PY
O
C
For children whose asthma is not adequately controlled by low dose maintenance ICS-LABA with as-needed SABA,
T
O
treatment may be increased to medium dose ICS-LABA233 (Evidence B).

N
O
If asthma is not well controlled on medium dose ICS (see Box 3-6B, p.56), the recommendation is to refer the child for
D
expert assessment and advice.

L-
IA
Other Step 4 options for children 6–11 years

ER
AT
Other controller options include increasing to high pediatric dose ICS-LABA (Box 3-6B, p.56), but adverse effects must
M
be considered. Tiotropium (long-acting muscarinic antagonist) by mist inhaler may be used as add-on therapy in children
D
aged 6 years and older; it modestly improves lung function and reduces exacerbations235 (Evidence A). If not trialed
TE
before, LTRA could be added (see note above about FDA warning).205 Add-on theophylline is not recommended for use
H
IG
in children due to lack of efficacy and safety data.

R
PY
O
STEP 5: Preferred option: Refer for phenotypic assessment and consideration of add-on treatment (adults,
C
adolescents and children)
Patients of any age with persistent symptoms or exacerbations despite correct inhaler technique and good adherence
with Step 4 treatment and in whom other controller options have been considered, should be referred to a specialist with
expertise in investigation and management of severe asthma138 (Evidence D).
In severe asthma, as in mild-moderate asthma,245 participants in randomized controlled trials may not be representative
of patients seen in clinical practice. For example, a registry study found that over 80% of patients with severe asthma
would have been excluded from recent studies evaluating biologic therapy.246

The GINA Pocket Guide and decision tree on Diagnosis and Management of difficult-to-treat and severe asthma in
adolescent and adult patients are included in Chapter 3E (p.94). Treatment options that may be considered after
optimization of existing therapy may include the following (always check local eligibility and payer criteria):
• Combination high dose ICS-LABA: this may be considered in adults and adolescents, but the increase in ICS
dose generally provides little additional benefit122,130,228 (Evidence A), and there is an increased risk of side-effects,
including adrenal suppression.247 A high dose is recommended only on a trial basis for 3–6 months when good
asthma control cannot be achieved with medium dose ICS plus LABA and/or a third controller (e.g. LTRA or
sustained-release theophylline208,243 Evidence B).
• Add-on tiotropium (long-acting muscarinic antagonist) in patients aged ≥6 years whose asthma is not well-
controlled with ICS-LABA. Add-on tiotropium (mostly 5μg once daily by mist inhaler) modestly improves lung
function (Evidence A) and modestly increases the time to severe exacerbation requiring oral corticosteroids
(Evidence B).236,237 Results with other LAMA preparations are awaited.236
• Add-on azithromycin (three times a week) for adult patients with persistent symptomatic asthma despite
TE
moderate-high dose ICS and LABA reduced asthma exacerbations in eosinophilic248 and non-eosinophilic
U
IB
asthma248,249 (Evidence B) and improved asthma-related quality of life248,249 (Evidence B). Diarrhea was more
R
common.248 Since macrolides such as azithromycin can cause ototoxicity and cardiac arrhythmia, asthma patients
T
IS
with hearing impairment248 or abnormal prolongation of the corrected QT interval248,249 were excluded from the
D
studies. Before considering add-on therapy with azithromycin in adult patients with uncontrolled or severe asthma,
R
O
ECG should be checked for long QTc, sputum should be checked for atypical mycobacteria, and the risk of
PY
increasing antimicrobial resistance at the patient and the population level should be taken into account. Treatment
O
for at least 6 months is suggested, as a clear benefit was not seen by 3 months. There is no clear evidence about
C
how long treatment should be continued.

T
O
N
• Add-on anti-immunoglobulin E (anti-IgE) (omalizumab) treatment: for patients aged ≥6 years with moderate or
O
severe allergic asthma that is uncontrolled on Step 4–5 treatment250,251 (Evidence A).
D
L-
• Add-on anti-interleukin-5/5R treatment (subcutaneous mepolizumab for patients aged ≥6 years; intravenous
IA
ER
reslizumab for ages ≥18 years) or anti-interleukin 5 receptor treatment (subcutaneous benralizumab for ages ≥12
AT
years), with severe eosinophilic asthma that is uncontrolled on Step 4–5 treatment (Evidence A).252-256 Efficacy
M
data for mepolizumab in children 6–11 years are limited to one very small open label uncontrolled study.257
D
TE
• Add-on anti-interleukin-4R α treatment (subcutaneous dupilumab) for patients aged ≥12 years with severe Type
H
2 asthma, or requiring treatment with maintenance OCS (Evidence A).258-260}

IG
R
• Sputum-guided treatment: for adults with persisting symptoms and/or exacerbations despite high dose ICS or
PY
ICS-LABA, treatment may be adjusted based on eosinophilia (>3%) in induced sputum. In severe asthma, this
O
C
strategy leads to reduced exacerbations and/or lower doses of ICS161 (Evidence A).
• Add-on treatment with bronchial thermoplasty: may be considered for some adult patients with severe
asthma138,261 (Evidence B). Evidence is limited and in selected patients (see p.69). The long-term effects
compared with control patients, including for lung function, are not known.
• Add-on low dose oral corticosteroids (≤7.5 mg/day prednisone equivalent): may be effective for some adults
with severe asthma138 (Evidence D), but are often associated with substantial side effects262,263 (Evidence A).
They should only be considered for adults with poor symptom control and/or frequent exacerbations despite good
inhaler technique and adherence with Step 4 treatment, and after exclusion of other contributory factors and other
add-on treatments including biologics where available and affordable. Patients should be counseled about
potential side-effects.263 They should be assessed and monitored for risk of corticosteroid-induced osteoporosis,
and those expected to be treated for ≥3 months should be provided with relevant lifestyle counselling and
prescription of therapy for prevention of osteoporosis (where appropriate).264

REVIEWING RESPONSE AND ADJUSTING TREATMENT
How often should asthma be reviewed?

Patients with asthma should be reviewed regularly to monitor their symptom control, risk factors and occurrence of
exacerbations, as well as to document the response to any treatment changes. For most controller medications,
improvement begins within days of initiating treatment, but the full benefit may only be evident after 3–4 months.265 In
severe and chronically under-treated disease, it may take longer.266
All health care providers should be encouraged to assess asthma control, adherence and inhaler technique at every
visit, not just when the patient presents because of their asthma.267 The frequency of visits depends upon the patient’s
initial level of control, their response to treatment, and their level of engagement in self-management. Ideally, patients
should be seen 1–3 months after starting treatment and every 3–12 months thereafter. After an exacerbation, a review
visit within 1 week should be scheduled268 (Evidence D).
Stepping up asthma treatment
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Asthma is a variable condition, and periodic treatment adjustments by the clinician and/or the patient may be needed.269
IB
R
• Sustained step up (for at least 2–3 months): Although at a group level most benefit from ICS is obtained at low
T
IS
dose, individual ICS responsiveness varies, and some patients whose asthma is uncontrolled on low dose ICS-
D
LABA despite good adherence and correct technique may benefit from increasing the maintenance dose to
R
medium. A step up in treatment may be recommended (Box 3-5, p31) if the symptoms are confirmed to be due to
O
PY
asthma; inhaler technique and adherence are satisfactory; and modifiable risk factors such as smoking have been
O
addressed (Box 3-8, p38). Any step-up should be regarded as a therapeutic trial, and the response reviewed after
C
2–3 months. If there is no response, treatment should be reduced to the previous level, and alternative treatment
T
O
options or referral considered.

N
• Short-term step up (for 1–2 weeks): An occasional short-term increase in maintenance ICS dose for 1–2 weeks
O
D
may be necessary; for example, during viral infections or seasonal allergen exposure. This may be initiated by the
L-
patient according to their written asthma action plan (Box 4-2, p61), or by the health care provider.
IA
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• Day-to-day adjustment: For patients prescribed combination budesonide-formoterol or beclometasone-formoterol

as maintenance and reliever treatment, the patient adjusts the number of as-needed doses of ICS-formoterol from
AT
day to day according to their symptoms, while continuing the maintenance dosage.
M
D
TE
Stepping down treatment when asthma is well controlled

H
IG
Once good asthma control has been achieved and maintained for 3 months and lung function has reached a plateau,
R
treatment can often be successfully reduced, without loss of asthma control. The aims of stepping down are:
PY
• To find the patient’s minimum effective treatment, i.e. to maintain good control of symptoms and exacerbations,
O
C
and to minimize the costs of treatment and potential for side-effects

• To encourage the patient to continue controller treatment. Patients often experiment with intermittent treatment
through concern about the risks or costs of daily treatment,270 but this leaves them exposed to the risks of
SABA-only treatment. For patients whose asthma is well-controlled on maintenance low dose ICS with
as-needed SABA, an alternative is to cease maintenance ICS and switch to as-needed ICS-formoterol.177,180

Before stepping down
The approach to stepping down will differ from patient to patient depending on their current treatment, risk factors and
preferences. There are few experimental data on the optimal timing, sequence and magnitude of treatment reductions in
asthma.
Factors associated with a greater risk of exacerbation after step-down include a history of exacerbations and/or
emergency department visit for asthma in the previous 12 months,271,272 and a low baseline FEV1.272 Other predictors of
loss of control during dose reduction include airway hyperresponsiveness and sputum eosinophilia,273 but these tests
are not readily available in primary care.
Any step-down of asthma treatment should be considered as a therapeutic trial, with the response evaluated in terms of
both symptom control and exacerbation frequency. Prior to stepping down treatment, the patient should be provided with
a written asthma action plan and instructions for how and when to resume their previous treatment if their symptoms
worsen.
TE
How to step treatment down
U
Decisions about treatment step-down should be made on an individual patient level. In one study of patients with well-
IB
R
controlled asthma on medium dose ICS-LABA, reducing the ICS dose and removing the LABA had similar effects on a
T
IS
composite treatment failure outcome. However, stopping LABA was associated with lower lung function and more
D
hospitalizations; and decreasing the ICS dose was inferior to maintaining a stable dose of ICS-LABA.274 If treatment is
R
stepped down too far or too quickly, exacerbation risk may increase even if symptoms remain reasonably controlled275
O
PY
(Evidence B). Complete cessation of ICS is associated with a significant risk of exacerbations276 (Evidence A).
O
Step-down strategies for different controller treatments are summarized in Box 3-7, p.66; these are based on current
C
T
evidence, but more research is needed. Only a small number of step-down studies have been performed in children.
O
N
O
D
L-
IA
ER
AT
M
D
TE
H
IG
R
PY
O
C

Box 3-7. Options for stepping down treatment once asthma is well controlled
General principles of stepping down asthma treatment
• Consider stepping down when asthma symptoms have been well controlled and lung function has been stable for
3 or more months (Evidence D). If the patient has risk factors for exacerbations (Box 2-2, p.35), for example a
history of exacerbations in the past year,271 or persistent airflow limitation, do not step down without close
supervision.
• Choose an appropriate time (no respiratory infection, patient not travelling, not pregnant).
• Approach each step as a therapeutic trial. Engage the patient in the process; document their asthma status
(symptom control, lung function and risk factors, Box 2-2, p.35); provide clear instructions; provide a written
asthma action plan (Box 4-2, p.117) and ensure the patient has sufficient medication to resume their previous
dose if necessary; monitor symptoms and/or PEF; and schedule a follow-up visit (Evidence D).
• Stepping down ICS doses by 25–50% at 3 month intervals is feasible and safe for most patients277 (Evidence A).
TE
U
Current Current medication
IB
Options for stepping down Evidence
step and dose
T R
IS
Step 5 High dose ICS-LABA plus • Continue high dose ICS-LABA and reduce OCS dose D
D
oral corticosteroids (OCS) B
• Use sputum-guided approach to reducing OCS
R
D
O
• Alternate-day OCS treatment
D
PY
• Replace OCS with high dose ICS O
C
High dose ICS-LABA plus • Refer for expert advice D
T
other add-on agents

O
N
Step 4 Moderate to high dose ICS- • Continue combination ICS-LABA with 50% reduction in ICS component, by B
O
LABA maintenance treatment using available formulations

D
A
L-
• Discontinuing LABA may lead to deterioration278

IA
ER
Medium dose ICS-formoterol* • Reduce maintenance ICS-formoterol* to low dose, and continue as-needed D
as maintenance and reliever low dose ICS-formoterol* reliever
AT
M
High dose ICS plus second • Reduce ICS dose by 50% and continue second controller277 B
D
controller
TE
Step 3 Low dose ICS-LABA D

H
• Reduce ICS-LABA to once daily

IG
maintenance A
• Discontinuing LABA may lead to deterioration278
R
PY
Low dose ICS-formoterol* as • Reduce maintenance ICS-formoterol* dose to once daily and continue C
O
maintenance and reliever as-needed low dose ICS-formoterol* reliever

C
Medium or high dose ICS • Reduce ICS dose by 50%277 A

• Adding LTRA† may allow ICS dose to be stepped down279 B
Step 2 Low dose ICS • Once-daily dosing (budesonide, ciclesonide, mometasone)280,281 A

• Switch to as-needed low dose ICS-formoterol 174,177,180 A
B
• Switch to taking ICS whenever SABA is taken184,185,187
Low dose ICS or LTRA • Switch to as-needed low dose ICS formoterol173,174,177,180 A
• Complete cessation of ICS in adults and adolescents is not advised as the A
risk of exacerbations is increased with SABA-only treatment276
BDP: beclometasone dipropionate; ICS: inhaled corticosteroids; LABA: long-acting beta2-agonist; LTRA: leukotriene receptor antagonist; OCS: oral
corticosteroids. *ICS-formoterol maintenance and reliever treatment can be prescribed with low dose budesonide-formoterol or BDP-formoterol. †Note
FDA warning on neuropsychiatric effects with montelukast.205

TREATING OTHER MODIFIABLE RISK FACTORS
Some patients continue to experience exacerbations even with maximal doses of current treatment. Having even one
exacerbation increases the risk that a patient will have another within the next 12 months.103 There is increasing
research interest in identifying at-risk patients (Box 2-2B, p.35), and in investigating new strategies to further reduce
exacerbation risk.
In clinical practice, exacerbation risk can be reduced both by optimizing asthma medications, and by identifying and
treating modifiable risk factors (Box 3-8). Not all risk factors require or respond to a step up in controller treatment.
Box 3-8. Treating modifiable risk factors to reduce exacerbations
Risk factor Treatment strategy Evidence

Any patient with ≥1 risk • Ensure patient is prescribed an ICS-containing controller A
factor for exacerbations • Ensure patient has a written action plan appropriate for their health literacy A
(including poor symptom A
TE
• Review patient more frequently than low-risk patients
control) A
U
• Check inhaler technique and adherence frequently
IB
D
R
• Identify any modifiable risk factors (Box 2-2, p.35)
T
IS
≥1 severe exacerbation • Consider alternative controller regimens to reduce exacerbation risk, A
D
in last year e.g. ICS-formoterol maintenance and reliever regimen
R
O
• Consider stepping up treatment if no modifiable risk factors A
PY
C
• Identify any avoidable triggers for exacerbations
O
C
Exposure to tobacco • Encourage smoking cessation by patient/family; provide advice and resources A
T
smoke B
O
• Consider higher dose of ICS if asthma poorly controlled

N
Low FEV1, especially • Consider trial of 3 months’ treatment with high dose ICS and/or 2 weeks’ OCS B
O
D
if <60% predicted • Exclude other lung disease, e.g. COPD D

L-
D
• Refer for expert advice if no improvement
IA
ER
Obesity • Strategies for weight reduction B

AT
• Distinguish asthma symptoms from symptoms due to deconditioning, D

M
mechanical restriction, and/or sleep apnea

D
TE
Major psychological • Arrange mental health assessment D

H
problems • Help patient to distinguish between symptoms of anxiety and asthma; provide D
IG
advice about management of panic attacks

R
PY
Major socioeconomic • Identify most cost-effective ICS-based regimen D

O
problems
C
Confirmed food allergy • Appropriate food avoidance; injectable epinephrine A

Allergen exposure if • Consider trial of simple avoidance strategies; consider cost C
sensitized • Consider step up of controller treatment D
B
• Consider adding SLIT in symptomatic adult HDM-sensitive patients with
allergic rhinitis despite ICS, provided FEV1 is >70% predicted
Sputum eosinophilia • Increase ICS dose independent of level of symptom control A*
(limited centers)
FEV1: forced expiratory volume in 1 second; HDM: house dust mite; ICS: inhaled corticosteroids; OCS: oral corticosteroids; SLIT: sublingual
immunotherapy.
* Based on evidence from relatively small studies in selected populations. Also see Box 3-9 and p.70 for more information about non-pharmacological
interventions.
The potential for local and/or systemic side-effects of medications can be minimized by ensuring correct inhaler
technique (Box 3-12, p.80), by reminding patients to rinse and spit out after using ICS, and, after good asthma control

has been maintained for 3 months, by finding each patient’s minimum effective dose (the lowest dose that will maintain
good symptom control and minimize exacerbations, Box 3-7, p.66).
OTHER THERAPIES
Allergen immunotherapy
Allergen-specific immunotherapy may be a treatment option where allergy plays a prominent role, including asthma with
allergic rhinoconjunctivitis.282,283 There are currently two approaches: subcutaneous immunotherapy (SCIT) and
sublingual immunotherapy (SLIT). In the past, few studies in asthma have compared immunotherapy with
pharmacological therapy, or used standardized outcomes such as exacerbations, and most studies have been in
patients with mild asthma. The allergens most commonly included in allergen immunotherapy studies have been house
dust mite and grass pollens. There is insufficient evidence about safety and efficacy of allergen immunotherapy in
patients sensitized to mold.284
Subcutaneous immunotherapy (SCIT)
TE
U
SCIT involves the identification and use of clinically relevant allergens, and administration of extracts in progressively
IB
R
higher doses to induce desensitization and/or tolerance. European physicians tend to favor single allergen
T
IS
immunotherapy whereas Northern American physicians often prescribe multiple allergens for treatment.285 In people
D
with asthma and allergic sensitization, SCIT is associated with a reduction in symptom scores and medication
R
requirements, and improved allergen-specific and non-specific airway hyperresponsiveness.285
O
PY
For SCIT, analysis of pooled safety data from clinical trials and post-marketing surveillance in house dust mite allergic
O
respiratory disease suggests the incidence of adverse drug reactions is approximately 0.5%.286 Studies to date suggest
C
T
that serious adverse effects of SCIT are uncommon, but may include life-threatening anaphylactic reactions.
O
N
Advice
O
D
• Compared to pharmacological and avoidance options, potential benefits of SCIT must be weighed against the risk of
L-
adverse effects and the inconvenience and cost of the prolonged course of therapy, including the minimum half-hour
IA
wait required after each injection (Evidence D).

ER
AT
Sublingual immunotherapy (SLIT)

M
Modest effects were identified in a systematic review of SLIT for asthma in adults and children,283,287,288 but there was
D
TE
concern about the design of many of the studies.289 There are few studies comparing SLIT with pharmacological therapy
H
for asthma.290 A recent trial of SLIT for house dust mites (HDM) in patients with asthma and HDM allergic rhinitis
IG
demonstrated a modest reduction of ICS with high dose SLIT.226 In another study in patients with asthma and HDM
R
PY
allergic rhinitis, SLIT added to low or medium dose ICS showed increased time to exacerbation during ICS reduction in
O
sub-optimally controlled asthma.225

C
Side effects291-293 from SLIT for inhalant allergens are predominantly limited to oral and gastrointestinal symptoms.283
Advice
• For adult patients with allergic rhinitis and sensitized to house dust mite, with persisting asthma symptoms despite
low-medium dose ICS-containing therapy, consider adding SLIT, provided FEV1 is >70% predicted (Evidence B)
• As for any treatment, potential benefits of SLIT for individual patients should be weighed against the risk of adverse
effects, and the cost to the patient and health system.
Vaccinations
Influenza causes significant morbidity and mortality in the general population, and contributes to some acute asthma
exacerbations. The risk of influenza infection itself can be reduced by annual vaccination. A systematic review of
placebo-controlled randomized controlled trials of influenza vaccination showed no reduction in asthma
exacerbations,294 but no such studies had been performed since 2001. However, a recent systematic review and meta-
analysis that included observational studies with a wide range of study designs suggested that influenza vaccination

reduced the risk of asthma exacerbations, although for most of the studies, bias could not be excluded.295. There is no
evidence for an increase in asthma exacerbations after influenza vaccination compared to placebo.295 Limited evidence
exists with respect to the safety and efficacy of live attenuated intranasal vaccination in children; most of the evidence
that does exist is restricted to children 3 years and older.
People with asthma, particularly children and the elderly, are at higher risk of pneumococcal disease,296 but there is
insufficient evidence to recommend routine pneumococcal vaccination in people with asthma.297
Advice
• Advise patients with moderate to severe asthma to receive an influenza vaccination every year, or at least when
vaccination of the general population is advised (Evidence C).
• There is insufficient evidence to recommend routine pneumococcal vaccination in people with asthma (Evidence D).
Bronchial thermoplasty
Bronchial thermoplasty is a potential treatment option at Step 5 in some countries for adult patients whose asthma
TE
remains uncontrolled despite optimized therapeutic regimens and referral to an asthma specialty center (Evidence B).
U
Bronchial thermoplasty involves treatment of the airways during three separate bronchoscopies with a localized
IB
R
radiofrequency pulse.115 The treatment is associated with a large placebo effect.115 In patients taking high dose ICS-
T
IS
LABA, bronchial thermoplasty was associated with an increase in asthma exacerbations during the 3 month treatment
D
period, and a subsequent decrease in exacerbations, but no beneficial effect on lung function or asthma symptoms
R
O
compared with sham-controlled patients.115 Extended follow up of some treated patients reported a sustained reduction
PY
in exacerbations compared with pre-treatment.298 However, longer-term follow up of larger cohorts comparing
O
effectiveness and safety, including for lung function, in both active and sham-treated patients is needed.
C
T
Advice
O
N
• For adult patients whose asthma remains uncontrolled despite optimization of asthma therapy and referral to a
O
severe asthma specialty center, bronchial thermoplasty is a potential treatment option at Step 5 in some countries
D
L-
(Evidence B).
IA
• Caution should be used in selecting patients for this procedure. The number of studies is small, people with chronic
ER
sinus disease, frequent chest infections or FEV1 <60% predicted were excluded from the pivotal sham-controlled
AT
study, and patients did not have their asthma treatment optimized before bronchial thermoplasty was performed.
M
• Bronchial thermoplasty should be performed in adults with severe asthma only in the context of an independent
D
TE
Institutional Review Board-approved systematic registry or a clinical study, so that further evidence about
H
effectiveness and safety of the procedure can be accumulated.138

IG
R
PY
Vitamin D
O
Several cross-sectional studies have shown that low serum levels of Vitamin D are linked to impaired lung function,
C
higher exacerbation frequency and reduced corticosteroid response.299 Vitamin D supplementation may reduce the rate
of asthma exacerbation requiring treatment with systemic corticosteroids in asthma patients with baseline 25(OH)D of
less than 25 nmol/L.300 In a meta-analysis, benefit for worsening asthma was seen in some studies, but to date, there is
no good-quality evidence that Vitamin D supplementation leads to improvement in asthma control or reduction in
exacerbations.301-303 More studies are needed.

NON-PHARMACOLOGICAL STRATEGIES
In addition to pharmacological treatments, other strategies may be considered where relevant, to assist in improving
symptom control and/or reducing future risk. The advice and evidence level are summarized in Box 3-9, with brief text
on the following pages.
Box 3-9. Non-pharmacological interventions - summary
Intervention Advice/recommendation (continued on next page) Evidence

Cessation of • At every visit, strongly encourage people with asthma who smoke to quit. Provide access to A
smoking and ETS counseling and smoking cessation programs (if available)
exposure
• Advise parents/carers of children with asthma not to smoke and not to allow smoking in rooms or A
cars that their children use
• Strongly encourage people with asthma to avoid environmental smoke exposure B
TE
U
• Assess smokers/ex-smokers for COPD or overlapping features of asthma and COPD (asthma– D
IB
COPD overlap, ACO, Chapter 5, p.129), as additional treatment strategies may be required
TR
Physical activity
IS
• Encourage people with asthma to engage in regular physical activity for its general health benefits A
D
• Provide advice about prevention of exercise-induced bronchoconstriction with regular ICS A
R
O
• Provide advice about prevention of breakthrough exercise-induced bronchoconstriction with
o warm-up before exercise PY A
O
C
o SABA before exercise A
T
B
O
o low dose ICS-formoterol before exercise

N
• Regular physical activity improves cardiopulmonary fitness, but confers no other specific benefit on B
O
D
lung function or asthma symptoms, with the exception of swimming in young people with asthma
L-
IA
• There is little evidence to recommend one form of physical activity over another D
ER
Avoidance of • Ask all patients with adult-onset asthma about their work history and other exposures A
AT
occupational
• In management of occupational asthma, identify and eliminate occupational sensitizers as soon as A
M
exposures
possible, and remove sensitized patients from any further exposure to these agents
D
TE
• Patients with suspected or confirmed occupational asthma should be referred for expert A
H
IG
assessment and advice, if available

R
Avoidance of A
PY
• Always ask about asthma before prescribing NSAIDs, and advise patients to stop using them if
medications that asthma worsens
O
may make
C
asthma worse • Always ask people with asthma about concomitant medications D
• Aspirin and NSAIDs (non-steroidal anti-inflammatory drugs) are not generally contraindicated A
unless there is a history of previous reactions to these agents (see p.92)
• Decide about prescription of oral or ophthalmic beta-blockers on a case-by-case basis. Initiate D
treatment under close medical supervision by a specialist
• If cardioselective beta-blockers are indicated for acute coronary events, asthma is not an absolute D
contra-indication, but the relative risks/benefits should be considered
Healthy diet • Encourage patients with asthma to consume a diet high in fruit and vegetables for its general A
health benefits

Box 3-9 (continued) Non-pharmacological interventions – Summary
Intervention Advice/recommendation Evidence

Avoidance of • Allergen avoidance is not recommended as a general strategy in asthma A
indoor allergens
• For sensitized patients, there is limited evidence of clinical benefit for asthma in most A
circumstances with single-strategy indoor allergen avoidance
• Remediation of dampness or mold in homes reduces asthma symptoms and medication use in A
adults
• For patients sensitized to house dust mite and/or pets, there is limited evidence of clinical benefit B
for asthma with avoidance strategies (only in children)
• Allergen avoidance strategies are often complicated and expensive, and there are no validated D
methods for identifying those who are likely to benefit
TE
Weight reduction • Include weight reduction in the treatment plan for obese patients with asthma B
U
• For obese adults with asthma a weight reduction program plus twice-weekly aerobic and strength
IB
B
exercises is more effective for symptom control than weight reduction alone
T R
IS
Breathing • Breathing exercises may be a useful supplement to asthma pharmacotherapy for symptoms and A
D
exercises quality of life, but they do not improve lung function or reduce exacerbation risk
R
O
Avoidance of • Encourage people with asthma to use non-polluting heating and cooking sources, and for sources B
PY
indoor air of pollutants to be vented outdoors where possible O
pollution
C
T
• For sensitized patients, when pollen and mold counts are highest, closing windows and doors,
O
Avoidance of D
N
outdoor allergens remaining indoors, and using air conditioning may reduce exposure to outdoor allergens
O
D
Dealing with • Encourage patients to identify goals and strategies to deal with emotional stress if it makes their D
L-
emotional stress asthma worse

IA
ER
• There is insufficient evidence to support one stress-reduction strategy over another, but relaxation B
AT
strategies and breathing exercises may be helpful

M
• Arrange a mental health assessment for patients with symptoms of anxiety or depression D
D
TE
• During unfavorable environmental conditions (very cold weather or high air pollution) it may be
H
Avoidance of D
IG
outdoor air helpful to stay indoors in a climate-controlled environment, and to avoid strenuous outdoor physical
R
pollutants/weather activity; and to avoid polluted environments during viral infections, if feasible
PY
conditions
O
C
Avoidance of • Food avoidance should not be recommended unless an allergy or food chemical sensitivity has D
foods and food been clearly demonstrated, usually by carefully supervised oral challenges
chemicals • For confirmed food allergy, food allergen avoidance may reduce asthma exacerbations D
• If food chemical sensitivity is confirmed, complete avoidance is not usually necessary, and D
sensitivity often decreases when asthma control improves
NSAID: non-steroidal anti-inflammatory drugs; SABA: short-acting beta2-agonist.
Interventions with highest level evidence are shown first.

Smoking cessation and avoidance of environmental tobacco smoke
Cigarette smoking has multiple deleterious effects in people with established asthma, in addition to its other well-known
effects such as increased risk of lung cancer, COPD and cardiovascular disease; and, with exposure in pregnancy,
increased risk of asthma and lower respiratory infections in children.
In people with asthma (children and adults), exposure to passive smoke increases the risk of hospitalization and poor
asthma control. Active smoking is associated with increased risk of poor asthma control, hospital admissions and, in
some studies, death from asthma; it increases the rate of decline of lung function and may lead to COPD; and it reduces
the effectiveness of inhaled and oral corticosteroids.304 After smoking cessation, lung function improves and airway
inflammation decreases.305 Reduction of passive smoke exposure improves asthma control and reduces hospital
admissions in adults and children.306
Advice
• At every visit, strongly encourage people with asthma who smoke to quit. They should be provided with access to
counseling and, if available, to smoking cessation programs (Evidence A).
TE
• Strongly encourage people with asthma to avoid environmental smoke exposure (Evidence B).
U
IB
• Advise parents/carers of children with asthma not to smoke and not to allow smoking in rooms or cars that their
R
children use (Evidence A).
T
IS
• Assess patients with a >10 pack-year smoking history for COPD or asthma–COPD overlap, as additional treatment
D
strategies may be required (see Chapter 5, p.129).
R
O
PY
Physical activity O
C
For people with asthma, as in the general population, regular moderate physical activity has important health benefits
T
including reduced cardiovascular risk and improved quality of life. Overall, physical activity has no benefit on lung
O
N
function or asthma symptoms,307 but improved cardiopulmonary fitness may reduce the risk of dyspnea unrelated to
O
airflow limitation being mistakenly attributed to asthma. In one study of non-obese patients with asthma, high intensity
D
L-
interval training together with a diet with high protein and low glycemic index improved asthma symptom control,
IA
although no benefit on lung function was seen.308 In young people with asthma, swimming training is well tolerated and
ER
leads to increased lung function and cardio-pulmonary fitness;309 however, there are some concerns about exposure to
AT
chlorine and trichloramine with indoor pools.19

M
D
Exercise is an important cause of asthma symptoms for many asthma patients, but EIB can usually be reduced with
TE
maintenance ICS.19 Breakthrough exercise-related symptoms can be managed with warm-up before exercise,19 and/or
H
by taking SABA19 or low dose ICS-formoterol183 before or during exercise.

IG
R
PY
Advice
O
• Encourage people with asthma to engage in regular physical activity because of its general health benefits (Evidence
C
A). However, regular physical activity confers no specific benefit on lung function or asthma symptoms per se, with
the exception of swimming in young people with asthma (Evidence B). There is insufficient evidence to recommend
one form of physical activity over another (Evidence D).
• Provide patients with advice about prevention and management of exercise-induced bronchoconstriction including
with daily treatment with ICS (Evidence A) plus SABA as-needed and pre-exercise (Evidence A), or with low dose
ICS-formoterol as-needed and before exercise (Evidence B), with warm-up before exercise if needed (Evidence A).
Avoidance of occupational exposures

Occupational exposures to allergens or sensitizers account for a substantial proportion of the incidence of adult-onset
asthma.310 Once a patient has become sensitized to an occupational allergen, the level of exposure necessary to induce
symptoms may be extremely low, and resulting exacerbations become increasingly severe. Attempts to reduce
occupational exposure have been successful, especially in industrial settings.38. Cost-effective minimization of latex
sensitization can be achieved by using non-powdered low-allergen gloves instead of powdered latex gloves.38

Advice
• Ask all patients with adult-onset asthma about their work history and other exposures (Evidence A).
• In management of occupational asthma, identify and eliminate occupational sensitizers as soon as possible, and
remove sensitized patients from any further exposure to these agents (Evidence A).
• Patients with suspected or confirmed occupational asthma should be referred for expert assessment and advice, if
available, because of the economic and legal implications of the diagnosis (Evidence A)
Avoidance of medications that may make asthma worse

Aspirin and other NSAIDs can cause severe exacerbations.311 Beta-blocker drugs, including topical ophthalmic
preparations, may cause bronchospasm312 and have been implicated in some asthma deaths. However, beta-blockers
have a proven benefit in the management of cardiovascular disease. People with asthma who have had an acute
coronary event and received beta-blockers within 24 hours of hospital admission have been found to have lower in-
hospital mortality rates than those who did not receive beta-blockers.313
TE
Advice
U
• Always ask people with asthma about concomitant medications, including eyedrops (Evidence A).
IB
• Always ask about asthma and previous reactions before prescribing NSAIDs, and advise patients to stop using these
TR
medications if asthma worsens.
IS
D
• Aspirin and NSAIDs are not generally contraindicated in asthma unless there is a history of previous reactions to
R
these agents (Evidence A). (See ‘Aspirin-exacerbated respiratory disease’, p.92)
O
PY
• For people with asthma who may benefit from oral or ophthalmic beta-blocker treatment, a decision to prescribe
O
these medications should be made on a case-by-case basis, and treatment should only be initiated under close
C
medical supervision by a specialist (Evidence D).

T
O
• Asthma should not be regarded as an absolute contraindication to use cardioselective beta-blockers when they are
N
indicated for acute coronary events, but the relative risks and benefits should be considered (Evidence D). The
O
D
prescribing physician and patient should be aware of the risks and benefits of treatment.314
L-
IA
Avoidance of indoor allergens

ER
AT
Because many asthma patients react to multiple factors that are ubiquitous in the environment, avoiding these factors
M
completely is usually impractical and very burdensome for the patient. Medications to maintain good asthma control
D
have an important role because patients are often less affected by environmental factors when their asthma is well-
TE
controlled.
H
IG
There is conflicting evidence about whether measures to reduce exposure to indoor allergens are effective at reducing
R
PY
asthma symptoms.315,316 The majority of single interventions have failed to achieve a sufficient reduction in allergen load
O
to lead to clinical improvement.315,317,318 It is likely that no single intervention will achieve sufficient benefits to be cost
C
effective (Box 3-10, p.74). One study of insecticidal bait in homes eradicated cockroaches for a year and led to a
significant decrease in symptoms, improvement in pulmonary function, and less health care use for children with
moderate to severe asthma.319
Domestic mites: these mites live and thrive in many sites throughout the house so they are difficult to reduce and
impossible to eradicate. A systematic review of multi-component interventions to reduce allergens including house dust
mite showed no benefit for asthma in adults and a small benefit for children.320 One study that used a rigorously applied
integrated approach to dust mite control led to a significant decrease in symptoms, medication use and improvement in
pulmonary function for children with dust mite sensitization and asthma.321 However, this approach is complicated and
expensive and is not generally recommended. A study in mite-sensitized children recruited after emergency department
presentation showed a decrease in emergency department visits, but not oral corticosteroids, with the use of mite-
impermeable encasement of the mattress, pillow and duvet.322
Furred pets: complete avoidance of pet allergens is impossible for sensitized patients as these allergens are ubiquitous
outside the home323 in schools,324 public transport, and even cat-free buildings, probably transferred on clothes.324

Although removal of such animals from the home of a sensitized patient is encouraged,325 it can be many months before
allergen levels decrease,326 and the clinical effectiveness of this and other interventions remains unproven.327
Pest rodents: symptomatic patients suspected of domestic exposure to pest rodents should be evaluated with skin prick
tests or specific IgE, as exposure may not be apparent unless there is an obvious infestation.328 High level evidence for
the effectiveness of removing rodents is lacking, as most integrated pest management interventions also remove other
allergen sources;328 one non-sham-controlled study showed comparable clinical improvement with pest reduction
education and integrated pest management.329
Box 3-10. Effectiveness of avoidance measures for indoor allergens

Evidence of effect Evidence of clinical
Measure
on allergen levels benefit
House dust mites
Encase bedding in impermeable covers Some (A) Adults - none (A)
TE
Children - some (A)
U
IB
Wash bedding on hot cycle (55–60°C) Some (C) None (D)
R
T
IS
Replace carpets with hard flooring Some (B) None (D)
D
Acaricides and/or tannic acid Weak (C) None (D)
R
O
Minimize objects that accumulate dust None (D) None (D)
Vacuum cleaners with integral HEPA filter and double- PY Weak (C) None (D)
O
C
thickness bags
T
O
Remove, hot wash, or freeze soft toys None (D) None

N
Pets
O
D
Remove cat/dog from the home Weak (C) None (D)

L-
IA
Keep pet from the main living areas/bedrooms Weak (C) None (D)
ER
HEPA-filter air cleaners Some (B) None (A)

AT
Wash pet Weak (C) None (D)

M
D
Replace carpets with hard flooring None (D) None (D)

TE
H
Vacuum cleaners with integral HEPA filter and double- None (D) None (D)
IG
thickness bags
R
PY
Cockroaches
O
Bait plus professional extermination of cockroaches Minimal (D) None (D)

C
Baits placed in households Some (B) Some (B)

Rodents
Integrated pest management strategies Some (B) Some (B)
Fungi
Remediation of dampness or mold in homes A A
Air filters, air conditioning Some (B) None (D)
This table is adapted from Custovic et al330

Cockroaches: avoidance measures for cockroaches are only partially effective in removing residual allergens331 and
evidence of clinical benefit is lacking.
Fungi: fungal exposure has been associated with asthma exacerbations. The number of fungal spores can best be
reduced by removing or cleaning mold-laden objects.332 Air conditioners and dehumidifiers may be used to reduce
humidity to less than 50% and to filter large fungal spores. However, air conditioning and sealing of windows have also
been associated with increases in fungal and house dust mite allergens.333
Advice
• Allergen avoidance is not recommended as a general strategy for people with asthma (Evidence A).
• For sensitized patients, although it would seem logical to attempt to avoid allergen exposure in the home, there is
some evidence for clinical benefit with single avoidance strategies (Evidence A) and only limited evidence for benefit
with multi-component avoidance strategies (in children) (Evidence B).
• Although allergen avoidance strategies may be beneficial for some sensitized patients (Evidence B), they are often
complicated and expensive, and there are no validated methods for identifying those who are likely to benefit
TE
(Evidence D).
U
IB
Healthy diet
TR
IS
In the general population, a diet high in fresh fruit and vegetables has many health benefits, including prevention of
D
many chronic diseases and forms of cancer. Many epidemiological studies report that a high fruit and vegetable diet is
R
O
associated with a lower risk of asthma and lung function decline. There is some evidence that increasing fruit and
PY
vegetable intake leads to an improvement in asthma control and a reduced risk of exacerbations.334
O
C
Advice
T
• Encourage patients with asthma to consume a diet high in fruit and vegetables for its general health benefits
O
N
(Evidence A).
O
D
Weight reduction for obese patients

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Asthma can be more difficult to control in obese patients,335-337 the risk of exacerbations is greater,87,88 and response to
ER
ICS may be reduced.338 There is limited evidence about the effect of weight loss on asthma control. Studies have
AT
ranged from dietary restriction to multifactorial interventions with exercise training and cognitive behavioral therapy, but
M
D
populations have generally been small, and interventions and results have been heterogeneous.339 In some studies,
TE
weight loss has improved asthma control, lung function and health status, and reduced medication needs in obese
H
patients with asthma.340,341 The most striking results have been observed after bariatric surgery,342,343 but even 5–10%
IG
R
weight loss with diet, with or without exercise, can lead to improved asthma control and quality of life.344
PY
Advice
O
C
• Include weight reduction in the treatment plan for obese patients with asthma (Evidence B). Increased exercise alone
appears to be insufficient (Evidence B).
Breathing exercises
A systematic review of studies of breathing and/or relaxation exercises in adults with asthma and/or dysfunctional
breathing, including the Buteyko method and the Papworth method, reported improvements in symptoms, quality of life
and/or psychological measures, but not in physiological outcomes or risk of exacerbations.345 A subsequent large
pragmatic study of breathing training in patients aged 16–70 years with impaired asthma-related quality of life showed
significant but small improvements in quality of life, but no difference in asthma symptom control or risk of
exacerbations. Results with three face-to-face physiotherapy sessions and DVD-based training were similar.346
Breathing exercises used in some of these studies are available at www.breathestudy.co.uk346 and
www.woolcock.org.au/moreinfo.347

In order for studies of non-pharmacological strategies such as breathing exercises to be considered high quality, control
groups should be appropriately matched for level of contact with health professionals and for asthma education. A study
of two physiologically contrasting breathing exercises, which were matched for contact with health professionals and
instructions about rescue inhaler use, showed similar improvements in reliever use and ICS dose after down-titration in
both groups.347 This suggests that perceived improvement with breathing exercises may be largely due to factors such
as relaxation, voluntary reduction in use of rescue medication, or engagement of the patient in their care. The cost of
some programs may be a potential limitation.
Advice
• Breathing exercises may be considered as a supplement to conventional asthma management strategies for
symptoms and quality of life, but they do not improve lung function or reduce exacerbation risk (Evidence A).
Avoidance of indoor air pollution

In addition to passive and active smoking, other major indoor air pollutants that are known to impact on respiratory
TE
health include nitric oxide, nitrogen oxides, carbon monoxide, carbon dioxide, sulfur dioxide, formaldehyde, and
U
biologicals (endotoxin).348,349 Sources include cooking and heating devices, particularly if they are not externally flued
IB
(vented). Installation of non-polluting, more effective heating (heat pump, wood pellet burner, flued gas) in the homes of
TR
children with asthma does not significantly improve lung function but significantly reduces symptoms of asthma, days off
IS
school, healthcare utilization, and pharmacist visits.350
D
R
O
Advice
PY
• Encourage people with asthma to use non-polluting heating and cooking sources, and for sources of pollutants to be
O
vented outdoors where possible (Evidence B).
C
T
O
Strategies for dealing with emotional stress

N
O
Emotional stress may lead to asthma exacerbations in children351 and adults. Hyperventilation associated with laughing,
D
crying, anger, or fear can cause airway narrowing.352,353 Panic attacks have a similar effect.354,355 However, it is
L-
IA
important to note that asthma is not primarily a psychosomatic disorder. During stressful times, medication adherence
ER
may also decrease.

AT
Advice
M
• Encourage patients to identify goals and strategies to deal with emotional stress if it makes their asthma worse
D
TE
(Evidence D).
H
• There is insufficient evidence to support one strategy over another, but relaxation strategies and breathing exercises
IG
R
may be helpful in reducing asthma symptoms (Evidence B).

PY
• Arrange a mental health assessment for patients with symptoms of anxiety or depression (Evidence D).
O
C
Avoidance of outdoor allergens

For patients sensitized to outdoor allergens such as pollens and molds, these are impossible to avoid completely.
Advice
• For sensitized patients, closing windows and doors, remaining indoors when pollen and mold counts are highest, and
using air conditioning may reduce exposure (Evidence D).
• The impact of providing information in the media about outdoor allergen levels is difficult to assess.
Avoidance of outdoor air pollution

Meta-analysis of epidemiological studies showed a significant association between air pollutants such as ozone,
nitrogen oxides, acidic aerosols, and particulate matter and symptoms or exacerbations of asthma, including emergency
department visits and hospitalizations.94 Certain weather and atmospheric conditions like thunderstorms356,357 may
trigger asthma exacerbations by a variety of mechanisms, including dust and pollution, by increasing the level of

respirable allergens, and causing changes in temperature and/or humidity. Reduction of outdoor air pollutants usually
requires national or local policy changes. For example, short-term traffic restrictions imposed in Beijing during the
Olympics reduced pollution and was associated with a significant fall in asthma outpatient visits.358
Advice
• In general, when asthma is well-controlled, there is no need for patients to modify their lifestyle to avoid unfavorable
outdoor conditions (air pollutants, weather).
• It may be helpful during unfavorable environmental conditions (very cold weather, low humidity or high air pollution)
to avoid strenuous outdoor physical activity and stay indoors in a climate-controlled environment; and to avoid
polluted environments during viral infections (Evidence D)
Avoidance of food and food chemicals

Food allergy as an exacerbating factor for asthma is uncommon and occurs primarily in young children. Confirmed food
allergy is a risk factor for asthma-related mortality.90
TE
Food chemicals, either naturally occurring or added during processing, may also trigger asthma symptoms especially
U
when asthma is poorly controlled. Sulfites (common food and drug preservatives found in such foods as processed
IB
R
potatoes, shrimp, dried fruits, beer, and wine) have often been implicated in causing severe asthma exacerbations.359
T
IS
However, the likelihood of a reaction is dependent on the nature of the food, the level and form of residual sulfite, the
D
sensitivity of the patient, and the mechanism of the sulfite-induced reaction.359 There is little evidence to support any
R
O
general role for other dietary substances including benzoate, the yellow dye, tartrazine, and monosodium glutamate in
PY
worsening asthma. O
C
Advice
T
• Ask people with asthma about symptoms associated with any specific foods (Evidence D).
O
N
• Food avoidance should not be recommended unless an allergy or food chemical sensitivity has been clearly
O
demonstrated (Evidence D), usually by carefully supervised oral challenges.90

D
L-
• If food allergy is confirmed, food allergen avoidance can reduce asthma exacerbations (Evidence D).
IA
• If food chemical sensitivity is confirmed, complete avoidance is not usually necessary, and sensitivity often
ER
decreases when overall asthma control improves (Evidence D).

AT
M
D
TE
H
IG
R
PY
O
C

INDICATIONS FOR REFERRAL FOR EXPERT ADVICE
While the majority of people with asthma can usually be managed in primary care, some clinical situations warrant
referral for expert advice regarding diagnosis and/or management (Box 3-10). This list is based on consensus, and
indications for referral may vary, as there is substantial variation between health systems in the delivery of the majority
of asthma care: by primary health care providers in some countries, and by specialists in others.
Box 3-11. Indications for considering referral for expert advice, where available
Difficulty confirming the diagnosis of asthma
• Patient has symptoms of chronic infection, or features suggesting a cardiac or other nonpulmonary cause
(Box 1-3, p.26) (immediate referral recommended)
• Diagnosis is unclear even after a trial of therapy with ICS or systemic corticosteroids
• Patients with features of both asthma and COPD, if there is doubt about priorities for treatment
TE
Suspected occupational asthma
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IB
• Refer for confirmatory testing and identification of sensitizing or irritant agent, specific advice about eliminating
T R
exposure and pharmacological treatment. See specific guidelines (e.g. European Respiratory Society,38 American
IS
Thoracic Society39) for details.
D
R
O
Persistent or severely uncontrolled asthma or frequent exacerbations
PY
• Patient’s symptoms remain uncontrolled, or patient has ongoing exacerbations or low lung function despite correct
O
inhaler technique and good adherence with Step 4 treatment (medium dose ICS-LABA, Box 3-5, p.54). Before
C
T
referral, depending on the clinical context, identify and treat modifiable risk factors (Box 2-2, p.35; Box 3-8, p.67)
O
and comorbidities (p.85)

N
O
• Patient has frequent asthma-related health care utilization (e.g. multiple ED visits or urgent primary care visits)
D
• See Section 3E (p.94) on difficult to treat and severe asthma, including a decision tree
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Any risk factors for asthma-related death (see Box 4-1, p.113)
ER
AT
• Near-fatal asthma attack (ICU admission, or mechanical ventilation for asthma) at any time in the past
M
• Anaphylaxis or confirmed food allergy in a patient with asthma

D
TE
Evidence of, or risk of, significant treatment side-effects

H
IG
• Patients with significant side-effects from treatment

R
PY
• Need for long-term oral corticosteroid use

O
• Frequent courses of oral corticosteroids (e.g. two or more courses a year)

C
Symptoms suggesting complications or sub-types of asthma
• e.g. aspirin-exacerbated respiratory disease (p.92); allergic bronchopulmonary aspergillosis
Additional reasons for referral in children 6–11 years
• Doubts about diagnosis of asthma e.g. respiratory symptoms are not responding well to treatment in a child who
was born prematurely
• Symptoms or exacerbations remain uncontrolled despite medium dose ICS (Box 3-6B, p.56) with correct inhaler
technique and good adherence
• Suspected side-effects of treatment (e.g. growth delay)
• Asthma and confirmed food allergy
• Safeguarding concerns
ED: emergency department; ICS: inhaled corticosteroids; ICU: intensive care unit. For indications for referral in children 0-5 years, see p.145.

PART C. GUIDED ASTHMA SELF-MANAGEMENT EDUCATION AND SKILLS TRAINING
OVERVIEW
With a chronic disease such as asthma, it is important for patients to be provided with education and skills in order to
effectively manage their asthma. This is most effectively achieved through a partnership between the patient and their
health care providers. The essential components for this include:
• Skills training to use inhaler devices effectively
• Encouraging adherence with medications, appointments and other advice, within an agreed management
strategy
• Asthma information
• Training in guided self-management, with self-monitoring of symptoms or peak flow; a written asthma action
plan to show how to recognize and respond to worsening asthma; and regular review by a health care provider
or trained health care worker.
TE
In developing, customizing and evaluating self-management interventions for different cultures, sociocultural factors
U
should be taken into account.360
IB
TR
SKILLS TRAINING FOR EFFECTIVE USE OF INHALER DEVICES
IS
D
Delivery of respiratory medications by inhalation achieves a high concentration in the airways, more rapid onset of
R
O
action, and fewer systemic adverse effects than systemic delivery. However, using an inhaler is a skill that must be
PY
learnt and maintained in order for the medication to be delivered effectively.
O
C
Poor inhaler technique leads to poor asthma control, increased risk of exacerbations and increased adverse effects.86
T
Most patients (up to 70–80%) are unable to use their inhaler correctly. Unfortunately, many health care providers are
O
N
unable to correctly demonstrate how to use the inhalers they prescribe.361 Most people with incorrect technique are
O
unaware that they have a problem. There is no ‘perfect’ inhaler – patients can have problems using any inhaler device.
D
L-
Strategies for ensuring effective use of inhaler devices are summarized in Box 3-12, p.80.362
IA
ER
These principles apply to all types of inhaler devices. For patients prescribed pressurized metered dose inhalers
AT
(pMDIs), use of a spacer improves delivery and (for ICS) reduces the potential for local side-effects such as dysphonia
M
and oral candidiasis.363 With ICS, the risk of candidiasis can also be reduced by rinsing and spitting out after use.
D
TE
Checking and correcting inhaler technique using a standardized checklist takes only 2–3 minutes and leads to improved
H
asthma control in adults364,365 and older children362 (Evidence A). A physical demonstration is essential to improve
IG
inhaler technique.366 This is easiest if the health care provider has placebo inhalers and a spacer. After training, inhaler
R
PY
technique falls off with time, so checking and re-training must be repeated regularly. This is particularly important for
O
patients with poor symptom control or a history of exacerbations. Attaching a pictogram367 or a list of inhaler technique
C
steps368 to the inhaler substantially increases the proportion of patients with correct technique at 3 months. Pharmacists,
nurses and trained lay health workers can provide highly effective inhaler skills training.362,369-371
Some inhaler devices and techniques for their use are illustrated on the GINA website (www.ginasthma.org) and the
ADMIT website (www.inhalers4u.org).

Box 3-12. Strategies to ensure effective use of inhaler devices
CHOOSE
• Choose the most appropriate inhaler device for the patient before prescribing. Consider the medication options
(Box 3-5, p.54), the available devices, patient skills and cost.
• If different options are available, encourage the patient to participate in the choice
• For pMDIs, use of a spacer improves delivery and (with ICS) reduces the potential for side-effects
• Ensure that there are no physical barriers, e.g. arthritis, that limit use of the inhaler
• Avoid use of multiple different inhaler types where possible, to avoid confusion
CHECK
• Check inhaler technique at every opportunity
TE
• Ask the patient to show you how they use their inhaler (don’t just ask if they know how to use it)
U
• Identify any errors using a device-specific checklist
IB
R
CORRECT
T
IS
D
• Show the patient how to use the device correctly with a physical demonstration, e.g. using a placebo inhaler
R
O
• Check technique again, paying attention to problematic steps. You may need to repeat this process 2–3 times.364
PY
• Only consider an alternative device if the patient cannot use the inhaler correctly after several repeats of training
O
C
• Re-check inhaler technique frequently. After initial training, errors often recur within 4–6 weeks.372
T
O
CONFIRM
N
O
• Clinicians should be able to demonstrate correct technique for each of the inhalers they prescribe
D
L-
• Pharmacists and nurses can provide highly effective inhaler skills training369,370
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AT
ADHERENCE WITH MEDICATIONS AND OTHER ADVICE

M
D
Identifying poor adherence

TE
H
Poor adherence is defined as the failure of treatment to be taken as agreed upon by the patient and the health care
IG
R
provider. There is increasing awareness of the importance of poor adherence in chronic diseases, and of the potential to
PY
develop interventions to improve adherence.373 Approximately 50% of adults and children on long-term therapy for
O
asthma fail to take medications as directed at least part of the time.140

C
In clinical practice, poor adherence may be identified by an empathic question that acknowledges the likelihood of
incomplete adherence and encourages an open discussion. See Box 3-13, p.81 for examples.
Checking the date of the last prescription or the date on the inhaler may assist in identifying poor adherence. In some
health systems, pharmacists can assist in identifying poorly adherent patients by monitoring dispensing records. In
clinical studies, poor adherence may be identified by short adherence behavior questionnaires, or from dispensing
records; dose or pill counting; electronic inhaler monitoring;374 and drug assay such as for prednisolone.375
Factors contributing to poor adherence

It is important to elicit patients’ beliefs and concerns about asthma and asthma medications in order to understand the
reasons behind their medication-taking behavior. Specific drug and non-drug factors involved in poor adherence are
listed in Box 3-13, p.81. They include both intentional and unintentional factors. Issues such as ethnicity,376 health
literacy,377,378 and numeracy150 are often overlooked. Patients’ concerns about side-effects may be either real or
perceived.270,379

Interventions that improve adherence in asthma
Few adherence interventions have been studied comprehensively in asthma. Some examples of successful
interventions are:
• Shared decision-making for medication/dose choice improved adherence and asthma outcomes.141,144
• Inhaler reminders, either proactively or for missed doses, improved adherence and reduced exacerbations and
oral corticosteroid use.380-382
• In a difficult inner-city environment, home visits for a comprehensive asthma program by an asthma nurse led to
improved adherence and reduced prednisone courses over the following several months.383
• Providing adherence information to clinicians did not improve ICS use among patients with asthma unless
clinicians chose to view the details of their patients’ medication use.384
• In a health maintenance organization, an automated voice recognition program with messages triggered when
refills were due or overdue led to improved ICS adherence relative to usual care, but no difference in urgent
care visits.385
• In one study, directly observed controller medication administration at school, combined with telemedicine
TE
oversight, was associated with more symptom-free days and fewer urgent visits than usual care.386
U
IB
R
Improving adherence to controller medications may not necessarily translate to improved clinical outcomes.387 Further
T
IS
studies are needed of adherence strategies that are feasible for implementation in primary care.
D
R
O
Box 3-13. Poor medication adherence in asthma
PY
O
Factors contributing to poor adherence How to identify poor adherence in clinical practice
C
T
Medication/regimen factors Ask an empathic question

O
N
• Difficulties using inhaler device (e.g. arthritis) • Acknowledge the likelihood of incomplete adherence and
O
D
• Burdensome regimen (e.g. multiple times per encourage an open non-judgmental discussion.
L-
day) Examples are:

IA
• Multiple different inhalers o ‘Many patients don’t use their inhaler as prescribed.
ER
In the last 4 weeks, how many days a week have you

Unintentional poor adherence
AT
been taking it – not at all, 1, 2, 3 or more days a

• Misunderstanding about instructions
M
week?’388
D
• Forgetfulness o ‘Do you find it easier to remember your inhaler in the

TE
• Absence of a daily routine morning or the evening?’

H
• Cost
IG
Check medication usage

R
Intentional poor adherence • Check the date of the last controller prescription
PY
• Perception that treatment is not necessary • Check the date and dose counter on the inhaler
O
C
• Denial or anger about asthma or its treatment • In some health systems, prescribing and dispensing
• Inappropriate expectations frequency can be monitored electronically by clinicians
• Concerns about side-effects (real or perceived) and/or pharmacists
• Dissatisfaction with health care providers • See review articles for more detail.140,389
• Stigmatization
• Cultural or religious issues
• Cost
Examples of successful adherence interventions

• Shared decision-making for medication/dose choice141,144
• Inhaler reminders, either proactively or for missed doses380-382
• Prescribing low dose ICS once-daily versus twice-daily390
• Home visits for a comprehensive asthma program by an asthma nurse383

ASTHMA INFORMATION
While education is relevant to asthma patients of all ages, the information and skills training required by each person
may vary, as will their ability or willingness to take responsibility. All individuals will require certain core information and
skills but most education must be personalized and provided in a number of steps.
For young children, the focus of asthma education will be on the parent/carer, but young children can be taught simple
asthma management skills. Adolescents may have unique difficulties regarding adherence, and peer support group
education may help in addition to education provided by the health care provider.391 These are complex interventions,
and there have been few studies. Regional issues and the adolescent’s developmental stage may affect the outcomes
of such programs.392
The key features and components of an asthma education program are provided in Box 3-14. Information alone
improves knowledge but does not improve asthma outcomes.393 Social and psychological support may also be required
to maintain positive behavioral change, and skills are required for effective medication delivery. At the initial consultation,
verbal information should be supplemented with written or pictorial394,395 information about asthma and its treatment. The
TE
GINA website (www.ginasthma.org) contains patient educational materials as well as links to several asthma websites.
U
Patients and their families should be encouraged to make a note of any questions that arise from reading this
IB
R
information or as a result of the consultation, and should be given time to address these during the next consultation.
T
IS
Asthma education and training can be delivered effectively by a range of health care providers including pharmacists
D
R
and nurses369,370,396 (Evidence A). Trained lay health workers (also known as community health workers) can deliver
O
discrete areas of respiratory care such as asthma self-management education. In one study, this was associated with
PY
increased symptom-free days and reduced healthcare utilization compared with usual care,397 in another study, with
O
C
improved adherence, inhaler technique, symptom control and quality of life and reduced emergency department visits
T
compared with usual care,371 and in a third study, comparable outcomes to those achieved by practice nurses based in
O
N
primary care398 (Evidence B). These findings suggest the need for additional studies to assess applicability in other
O
settings and populations.

D
L-
IA
ER
Box 3-14. Asthma information

AT
Goal: To provide the person with asthma, their family and other carers with suitable information and training to manage
M
their asthma in partnership with their health care providers

D
TE
H
Approach Content
IG
R
• Focus on the development of the partnership. • Asthma diagnosis

PY
O
• Accept that this is a continuing process. • Rationale for treatment, and differences between
C
‘relievers’ and ‘controllers’

• Share information.
• Potential side-effects of medications
• Adapt the approach to the patient’s level of health
literacy (Box 3-1, p.43). • Prevention of symptoms and flare-ups
• Fully discuss expectations, fears and concerns. • How to recognize worsening asthma and what actions
to take; how and when to seek medical attention
• Develop shared goals.
• Management of comorbidities

TRAINING IN GUIDED ASTHMA SELF-MANAGEMENT
Guided self-management may involve varying degrees of independence, ranging broadly from patient-directed self-
management to doctor-directed self-management. With patient-directed self-management patients make changes in
accordance with a prior written action plan without needing to first contact their health care provider. With doctor-
directed self-management, patients still have a written action plan, but refer most major treatment decisions to their
physician at the time of a planned or unplanned consultation.
The essential components of effective guided asthma self-management education are:142
• Self-monitoring of symptoms and/or peak flow
• A written asthma action plan to show how to recognize and respond to worsening asthma; and
• Regular review of asthma control, treatment and skills by a health care provider.
Self-management education that includes these components dramatically reduces asthma morbidity in both
adults142,371,399 (Evidence A) and children143,399 (Evidence A). Benefits include reduction of one-third to two-thirds in
asthma-related hospitalizations, emergency department visits and unscheduled doctor or clinic visits, missed
TE
work/school days, and nocturnal wakening.142 It has been estimated that the implementation of a self-management
U
IB
program in 20 patients prevents one hospitalization, and successful completion of such a program by 8 patients
TR
prevents one emergency department visit.142,400 Less intensive interventions that involve self-management education but
IS
not a written action plan are less effective,401 and information alone is ineffective.393 A systematic meta-review of 270
D
R
RCTs on supported self-management for asthma confirmed that it reduces unscheduled healthcare use, improves
O
asthma control, is applicable to a wide range of target groups and clinical settings, and does not increase health care
costs (Evidence A).399 PY
O
C
T
Self-monitoring of symptoms and/or peak flow

O
N
Patients should be trained to keep track of their symptoms (with or without a diary), and notice and take action if
O
D
necessary when symptoms start to worsen. Peak expiratory flow (PEF) monitoring may sometimes be useful:
L-
• Short-term monitoring
IA
o Following an exacerbation, to monitor recovery

ER
o Following a change in treatment, to help in assessing whether the patient has responded
AT
o If symptoms appear excessive (for objective evidence of degree of lung function impairment)
M
o To assist in identification of occupational or domestic triggers for worsening asthma control

D
TE
• Long-term monitoring
H
o For earlier detection of exacerbations, mainly in patients with poor perception of airflow limitation126
IG
o For patients with a history of sudden severe exacerbations

R
PY
o For patients who have difficult-to-control or severe asthma

O
C
For patients carrying out PEF monitoring, use of a laterally compressed PEF chart (showing 2 months on a landscape
format page) allows more accurate identification of worsening asthma than other charts.137 One such chart is available
for download from www.woolcock.org.au/moreinfo/. There is increasing interest in internet or phone-based monitoring of
asthma. Based on existing studies, the main benefit is likely to be for more severe asthma402 (Evidence B).
Written asthma action plans

Personal written asthma action plans show patients how to make short-term changes to their treatment in response to
changes in their symptoms and/or PEF. They also describe how and when to access medical care.403,404
The benefits of self-management education for asthma morbidity are greater in adults when the action plans include
both a step up in ICS and the addition of OCS, and for PEF-based plans, when they are based on personal best rather
than percent predicted PEF404 (Evidence A).
The efficacy of self-management education is similar regardless of whether patients self-adjust their medications
according to an individual written plan or whether the medication adjustments are made by a doctor401 (Evidence A).

Thus, patients who are unable to undertake guided self-management can still achieve benefit from a structured program
of regular medical review.
Examples of written asthma action plan templates, including for adult and pediatric patients with low literacy, can be
found on several websites (e.g. Asthma UK, www.asthma.org.uk; Asthma Society of Canada, www.asthma.ca; Family
Physician Airways Group of Canada, www.fpagc.com; National Asthma Council Australia, www.nationalasthma.org.au)
and in research publications.405,406 Health care providers should become familiar with action plans that are relevant to
their local health care system, treatment options, and cultural and literacy context. Details of the specific treatment
adjustments that can be recommended for written asthma action plans are described in the next chapter (Box 4-2,
p.117).
Regular review by a healthcare provider or trained healthcare worker

The third component of effective asthma self-management education is regular review by a healthcare provider or
trained healthcare worker. Follow-up consultations should take place at regular intervals. Regular review should include
TE
the following:
U
• Ask the patient if they have any questions and concerns.
IB
Discuss issues, and provide additional educational messages as necessary; if available, refer the patient to
R
T
someone trained in asthma education.
IS
D
• Assess asthma control.
R
Review the patient’s level of symptom control and risk factors (Box 2-2, p.35).
O
PY
Ask about flare-ups to identify contributory factors and whether the patient’s response was appropriate (e.g.
was an action plan used?).
O
C
Review the patient’s symptom or PEF diary, if they keep one.
T
O
Assess comorbidities.
N
• Assess treatment issues.

O
D
Watch the patient use their inhaler, and correct and re-check technique if necessary (Box 3-12 p.80).
L-
Assess medication adherence and ask about adherence barriers (Box 3-13, p.81).
IA
ER
Ask about adherence with other interventions (e.g. smoking cessation).

AT
Review the asthma action plan and update it if level of asthma control or treatment have changed.407
M
A single page prompt to clinicians has been shown to improve the provision of preventive care to children with asthma
D
TE
during office visits.408 Follow-up by tele-healthcare is unlikely to benefit in mild asthma but may be of benefit in those
H
with severe disease at risk of hospital admission.402

IG
R
School-based programs for children

PY
O
A systematic review found that school-based studies (most conducted in the US and Canada) that included self-
C
management skills for children aged 5–18 years may be associated with a 30% decrease in emergency department
visits, and a significant decrease in hospitalizations and in days of reduced activity.409

PART D. MANAGING ASTHMA WITH COMORBIDITIES AND IN SPECIFIC POPULATIONS
KEY POINTS
• Identify and manage comorbidities such as rhinosinusitis, obesity and gastro-esophageal reflux disease.
Comorbidities may contribute to respiratory symptoms and impaired quality of life, and some contribute to poor
asthma control.
• For patients with dyspnea or wheezing on exertion:
o Distinguish between exercise-induced bronchoconstriction (EIB) and symptoms that result from obesity or a
lack of fitness, or are the result of alternative conditions such as inducible laryngeal obstruction.
o Provide advice about preventing and managing EIB.
• All adolescents and adults with asthma should receive ICS-containing controller medication to reduce their risk of
severe exacerbations. It should be taken every day or, as an alternative in mild asthma, by as-needed ICS-
formoterol for symptom relief.
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• Refer patients with difficult-to-treat or severe asthma to a specialist or severe asthma service, after addressing
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common problems such as incorrect diagnosis, incorrect inhaler technique, ongoing environmental exposures, and
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poor adherence (see Section 3E, p.94).
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MANAGING COMORBIDITIES
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Several comorbidities are commonly present in patients with asthma, particularly those with difficult-to-treat or severe
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asthma.88 Active management of comorbidities is recommended because they may contribute to symptom burden,
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impair quality of life, and lead to medication interactions. Some comorbidities also contribute to poor asthma control.410
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Obesity
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Clinical features
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Being overweight or obese is a risk factor for childhood asthma and wheeze, particularly in girls.411 Asthma is more
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difficult to control in obese patients.335-338 This may be due to a different type of airway inflammation, contributory
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comorbidities such as obstructive sleep apnea and gastroesophageal reflux disease (GERD), mechanical factors, or
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other as yet undefined factors. In addition, lack of fitness and reduction in lung volume due to abdominal fat may
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contribute to dyspnea.
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Diagnosis
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Document body mass index (BMI) for all patients with asthma. Because of other potential contributors to dyspnea and
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wheeze in obese patients, it is important to confirm the diagnosis of asthma with objective measurement of variable
airflow limitation (Box 1-2, p.23). Asthma is more common in obese than non-obese patients,50 but both over- and under-
diagnosis of asthma occur in obesity.31,51
Management
As for other patients with asthma, ICS are the mainstay of treatment in obese patients (Evidence B), although their
response may be reduced.338 Weight reduction should be included in the treatment plan for obese patients with asthma
(Evidence B). Increased exercise alone appears to be insufficient (Evidence B).344 Weight loss can improve asthma
control, lung function, health status and reduces medication needs in obese patients,340,341 but the studies have
generally been small, quality of some studies is poor, and the interventions and results have been variable.339 The most
striking results have been observed after bariatric surgery,342,343,412 but even 5–10% weight loss can lead to improved
asthma control and quality of life.344 For patients with comorbid obstructive sleep apnea, one study showed a significant
reduction in moderate exacerbations with 6 months of continuous positive airway pressure (CPAP) therapy.413

Gastroesophageal reflux disease (GERD)
Clinical features
GERD can cause symptoms such as heartburn, and epigastric or chest pain, and is also a common cause of dry cough.
Symptoms and/or diagnosis of GERD are more common in people with asthma than in the general population,410 but
this may be in part due to cough being attributed to asthma; in addition, some asthma medications such as beta2-
agonists and theophylline cause relaxation of the lower esophageal sphincter. Asymptomatic gastroesophageal reflux is
not a likely cause of poorly controlled asthma.410
Diagnosis
In patients with confirmed asthma, GERD should be considered as a possible cause of a dry cough; however, there is
no value in screening patients with uncontrolled asthma for GERD (Evidence A). For patients with asthma and
symptoms suggestive of reflux, an empirical trial of anti-reflux medication, such as a proton pump inhibitor or motility
agent, may be considered, as in the general population. If the symptoms do not resolve, specific investigations such as
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24-hour pH monitoring or endoscopy may be considered.
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Management
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A review of proton pump inhibitors in patients with confirmed asthma, most of whom had a diagnosis of GERD, showed
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a significant but small benefit for morning PEF, but no significant benefit for other asthma outcomes.414 In a study of
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adult patients with symptomatic asthma but without symptoms of GERD, treatment with high-dose proton pump
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inhibitors did not reduce asthma symptoms or exacerbations.415 In general, benefits of proton pump inhibitors in asthma
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appear to be limited to patients with both symptomatic reflux and night-time respiratory symptoms.416 Other treatment
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options include motility agents, lifestyle changes and fundoplication. In summary, symptomatic reflux should be treated,
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but patients with poorly controlled asthma should not be treated with anti-reflux therapy unless they also have
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symptomatic reflux (Evidence A). Few data are available for children with asthma symptoms and symptoms of
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GERD.417,418
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Anxiety and depression

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Clinical features
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Psychiatric disorders, particularly depressive and anxiety disorders, are more prevalent among people with asthma.419
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Psychiatric comorbidity is also associated with worse asthma symptom control and medication adherence, and worse
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asthma-related quality of life.420 Anxious and depressive symptoms have been associated with increased asthma-related
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exacerbations and emergency visits.421 Panic attacks may be mistaken for asthma.
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Diagnosis
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Although several tools are available for screening for anxious and depressive symptomatology in primary care, the
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majority have not been validated in asthma populations. Difficulties in distinguishing anxiety or depression from asthma
symptoms may therefore lead to misdiagnosis. It is important to be alert to possible depression and/or anxiety in people
with asthma, particularly when there is a previous history of these conditions. Where appropriate, patients should be
referred to psychiatrists or evaluated with a disease-specific psychiatric diagnostic tool to identify potential cases of
depression and/or anxiety.
Management
There have been few good quality pharmacological and non-pharmacological treatment trials for anxiety or depression
in patients with asthma, and results are inconsistent. A Cochrane review of 15 randomized controlled trials of
psychological interventions for adults with asthma included cognitive behavior therapy, psychoeducation, relaxation, and
biofeedback.422 Results for anxiety were conflicting, and none of the studies found significant treatment differences for
depression. Drug treatments and cognitive behavior therapy423 have been described as having some potential in
patients with asthma; however, current evidence is limited, with a small number of studies and methodological
shortcomings.

Food allergy and anaphylaxis
Clinical features
Rarely, food allergy is a trigger for asthma symptoms (<2% of people with asthma). In patients with confirmed food-
induced allergic reactions (anaphylaxis), co-existing asthma is a strong risk factor for more severe and even fatal
reactions. Food-induced anaphylaxis often presents as life-threatening asthma.90 An analysis of 63 anaphylaxis-related
deaths in the United States noted that almost all had a past history of asthma; peanuts and tree nuts were the foods
most commonly responsible.424 A UK study of 48 anaphylaxis-related deaths found that most were regularly treated for
asthma, and that in most of these, asthma was poorly controlled.425
Diagnosis
In patients with confirmed food allergy, it is important to assess for asthma. Children with food allergy have a four-fold
increased likelihood of having asthma compared with children without food allergy.426 Refer patients with suspected food
allergy or intolerance for specialist allergy assessment. This may include appropriate allergy testing such as skin prick
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testing and/or blood testing for specific IgE. On occasion, carefully supervised food challenges may be needed.
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Management
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Patients who have a confirmed food allergy that puts them at risk for anaphylaxis must have an epinephrine auto-injector
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available at all times, and be trained how to use it. They, and their family, must be educated in appropriate food
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avoidance strategies, and in the medical notes, they should be flagged as being at high risk. It is especially important to
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ensure that their asthma is well controlled, they have a written action plan, understand the difference between asthma
and anaphylaxis, and are reviewed on a regular basis.
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Rhinitis, sinusitis and nasal polyps

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Clinical features
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Evidence clearly supports a link between diseases of the upper and lower airways.427 Most patients with asthma, either
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allergic or non-allergic, have concurrent rhinitis, and 10–40% of patients with allergic rhinitis have asthma.428 Depending
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on sensitization and exposure, allergic rhinitis may be seasonal (e.g. ragweed or grass pollen), perennial (e.g. mite
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allergens), or intermittent (e.g. furred pets).427

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Rhinitis is defined as irritation and inflammation of the mucous membranes of the nose. Allergic rhinitis may be
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accompanied by ocular symptoms (conjunctivitis). Rhinosinusitis is defined as inflammation of the nose and paranasal
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sinuses characterized by more than two symptoms including nasal blockage/obstruction and/or nasal discharge
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(anterior/posterior nasal drip).429 Other symptoms may include facial pain/pressure and/or a reduction or loss of smell.
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Sinusitis rarely occurs in the absence of rhinitis.

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Rhinosinusitis is defined as acute when symptoms last <12 weeks with complete resolution, and chronic when
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symptoms occur on most days for at least 12 weeks without complete resolution. Chronic rhinosinusitis is an
inflammatory condition of the paranasal sinuses that encompasses two clinically distinct entities: chronic rhinosinusitis
without nasal polyposis and chronic rhinosinusitis with nasal polyposis.430 The heterogeneity of chronic rhinosinusitis
may explain the wide variation in prevalence rates in the general population ranging from 1–10% without polyps and 4%
with polyps. Chronic rhinosinusitis is associated with more severe asthma, especially in patients with nasal polyps.431
Diagnosis
Rhinitis can be classified as either allergic or non-allergic depending on whether allergic sensitization is demonstrated.
Variation in symptoms by season or with environmental exposure (e.g. furred pets) suggests allergic rhinitis.
Examination of the upper airway should be arranged for patients with severe asthma.
Management
Evidence-based guidelines (Allergic Rhinitis in Asthma, ARIA)432 recommend intranasal corticosteroids for treatment of
allergic rhinitis. In a case-control study, treatment of rhinitis with intranasal corticosteroids was associated with less need

for asthma-related hospitalization and emergency department visits,433 but a meta-analysis found improvement in
asthma outcomes only in patients not also receiving ICS.434 However, few placebo-controlled studies have
systematically evaluated the effect of proper treatment and management of chronic rhinosinusitis on asthma control. A
recent placebo-controlled trial of nasal mometasone in adults and children with chronic rhinosinusitis and poorly
controlled asthma showed no benefit for asthma outcomes, suggesting that, while chronic rhinosinusitis can contribute
to respiratory symptoms, e.g. chronic cough, its treatment in patients with asthma should be targeted at the symptoms of
rhinosinusitis rather than to improve asthma control.435
MANAGING ASTHMA IN SPECIFIC POPULATIONS OR SETTINGS

This section includes brief advice about managing asthma in specific populations or settings in which the usual
treatment approach may need to be modified. Also refer to the Diagnosis of respiratory symptoms in special populations
section of Chapter 1 (p.28).
Settings with limited resources
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Communities with limited resources are found not only in low and middle income countries, but also in affluent nations.
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In these settings, in general, the GINA strategy may be followed for asthma management at the individual level (Box 3-
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3), as it offers options for low cost diagnostic procedures, and therapeutic interventions which have been shown to be
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effective and reduce costs among the underserved.436,437 In dealing with asthma control at the population level (Box 3-3),
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it is critical to prioritize the most cost-effective approach to asthma treatment in primary health care, which includes the
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use of ICS and SABA;438 these are listed as essential medications by the World Health Organization (WHO).
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Budesonide-formoterol is also listed as an essential medication by the WHO, but at present access is limited. For
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diagnosis of asthma and monitoring of treatment response, WHO also lists PEF meters as essential tools in the
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Package of Essential Non-communicable Diseases Interventions,53 with pulse oximeters also recommended when
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resources permit, for assessment of severity of acute asthma. It is possible to build capacity of primary health care
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teams, including nurses and other health professionals, for the development of an integrated approach to the most
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common diseases and symptoms, including asthma.439

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Adolescents
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Clinical features
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Care of teenagers with asthma should take into account the rapid physical, emotional, cognitive and social changes that
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occur during adolescence. Asthma control may improve or worsen, although remission of asthma is seen more
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commonly in males than females.440 Exploratory and risk-taking behaviors such as smoking occur at a higher rate in
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adolescents with chronic diseases than in healthy adolescents.

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Management
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General principles for managing chronic disease in adolescents have been published by WHO.441 Adolescents and their
parent/carers should be encouraged in the transition towards asthma self-management by the adolescent. This may
involve the transition from a pediatric to an adult health care facility. During consultations, the adolescent should be seen
separately from the parent/carer so that sensitive issues such as smoking, adherence and mental health can be
discussed privately, and confidentiality agreed. Information and self-management strategies should be tailored to the
patient’s stage of psychosocial development and desire for autonomy; adolescents are often focused on short-term
rather than long-term outcomes. An empathic approach should be used to identify beliefs and behaviors that may be
barriers to optimal treatment; for example, adolescents may be concerned about the impact of treatment on their
physical or sexual capabilities. Medication regimens should be tailored to the adolescent’s needs and lifestyle, and
reviews arranged regularly so that the medication regimen can be adjusted for changing needs. Information about local
youth-friendly resources and support services should be provided, where available.

Exercise-induced bronchoconstriction (EIB)
Clinical features
Physical activity is an important stimulus for asthma symptoms for many patients, with symptoms and
bronchoconstriction typically worsening after cessation of exercise. However, shortness of breath or wheezing during
exercise may also relate to obesity or a lack of fitness, or to comorbid or alternative conditions such as inducible
laryngeal obstruction.19,36
Management
Regular controller treatment with ICS significantly reduces EIB19 (Evidence A). Training and sufficient warm-up reduce
the incidence and severity of EIB19 (Evidence A). Taking SABAs, LABAs or chromones prior to exercise prevents EIB
(Evidence A), but tolerance to the protective effects of SABAs and LABAs against EIB develops with regular (more than
once-daily) use (Evidence A).19 However, in a 6-week study in patients with mild asthma, low dose budesonide-
formoterol, taken as needed for relief of symptoms and before exercise, was non-inferior for reducing EIB to regular
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daily ICS with as-needed SABA.183 More studies are needed, but this suggests that patients with mild asthma who are
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prescribed as-needed ICS-formoterol to prevent exacerbations and control symptoms can use the same medication
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prior to exercise, if needed, and do not need to be prescribed a SABA for pre-exercise use (Evidence B).
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Breakthrough EIB often indicates poorly controlled asthma, and stepping up controller treatment (after checking inhaler
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technique and adherence) generally results in the reduction of exercise-related symptoms.
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Athletes O
Clinical features
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Athletes, particularly those competing at a high level, have an increased prevalence of various respiratory conditions
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compared to non-athletes. They experience a higher prevalence of asthma, EIB, allergic or non-allergic rhinitis, chronic
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cough, inducible laryngeal obstruction, and recurrent respiratory infections. Airway hyperresponsiveness is common in
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elite athletes, often without reported symptoms. Asthma in elite athletes is commonly characterized by less correlation
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between symptoms and pulmonary function; higher lung volumes and expiratory flows; less eosinophilic airway
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inflammation; more difficulty in controlling symptoms; and some improvement in airway dysfunction after cessation of
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training.
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Management
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Preventative measures to avoid high exposure to air pollutants, allergens (if sensitized) and chlorine levels in pools,
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particularly during training periods, should be discussed with the athlete. They should avoid training in extreme cold or
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pollution (Evidence C), and the effects of any therapeutic trials of asthma medications should be documented. Adequate
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anti-inflammatory therapy, especially ICS, is advised; minimization of use of beta2-agonists will help to avoid the
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development of tolerance.19 Information on treatment of exercise-induced asthma in athletes can be found in a Joint
Task Force Report prepared by the European Respiratory Society, the European Academy of Allergy and Clinical
Immunology, and GA(2)LEN442 and the World Anti-Doping Agency website (www.wada-ama.org).
Pregnancy
Clinical features
Asthma control often changes during pregnancy; in approximately one-third of women asthma symptoms worsen, in
one-third they improve, and in the remaining one-third they remain unchanged.443 Exacerbations are common in
pregnancy, particularly in the second trimester.91 Exacerbations and poor asthma control during pregnancy may be due
to mechanical or hormonal changes, or to cessation or reduction of asthma medications due to concerns by the mother
and/or the health care provider. Pregnant women appear to be particularly susceptible to the effects of viral respiratory
infections,444 including influenza. Exacerbations and poor symptom control are associated with worse outcomes for both

the baby (pre-term delivery, low birth weight, increased perinatal mortality) and the mother (pre-eclampsia).91 If asthma
is well controlled throughout pregnancy there is little or no increased risk of adverse maternal or fetal complications.42
Management
Although there is a general concern about any medication use in pregnancy, the advantages of actively treating
asthma in pregnancy markedly outweigh any potential risks of usual controller and reliever medications42
(Evidence A). For this reason, using medications to achieve good symptom control and prevent exacerbations is justified
even when their safety in pregnancy has not been unequivocally proven. Use of ICS, beta2-agonists, montelukast or
theophylline is not associated with an increased incidence of fetal abnormalities.445
Importantly, ICS reduce the risk of exacerbations of asthma during pregnancy42,446,447 (Evidence A), and cessation of
ICS during pregnancy is a significant risk factor for exacerbations91 (Evidence A). A study using administrative data
reported that uncontrolled maternal asthma increased the risk of early-onset asthma in the offspring.448 One study
reported that a treatment algorithm in non-smoking pregnant women based on monthly FeNO and ACQ was associated
with significantly fewer exacerbations and better fetal outcomes than an algorithm based only on ACQ.449 However, the
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ACQ-only algorithm did not reflect current clinical recommendations, as LABA was introduced only after ICS had been
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increased to medium dose, and ICS could be stopped; 58% of women in the ACQ-only group were being treated without
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ICS by the end of pregnancy. In a follow-up study after 4-6 years, the prevalence of asthma was over 50% lower both in
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children of women in the FeNO group and in children of women receiving ICS in the ACQ group, compared with women
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in the clinical group who did not receive ICS.450 Use of ICS in early pregnancy (before randomization at weeks 12-20)
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also appeared to be protective for asthma in the child.450
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On balance, given the evidence in pregnancy and infancy for adverse outcomes from exacerbations during pregnancy42
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(Evidence A), including due to lack of ICS or poor adherence,91 and evidence for safety of usual doses of ICS and
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LABA445 (Evidence A), a low priority should be placed on stepping down treatment (however guided) until after
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delivery (Evidence D), and ICS should not be stopped in preparation for pregnancy or during pregnancy
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(Evidence C).
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Despite lack of evidence for adverse effects of asthma treatment in pregnancy, many women and doctors remain
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concerned.451 Pregnant patients with asthma should be advised that poorly controlled asthma, and exacerbations,
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provide a much greater risk to their baby than do current asthma treatments. Educational resources about asthma
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management during pregnancy may provide additional reassurance.452 During pregnancy, monthly monitoring of asthma
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is recommended.452 It is feasible for this to be achieved by pharmacist-clinician collaboration, with monthly telephone
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monitoring of asthma symptom control.453 One observational study found that pregnant women whose asthma was well-
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controlled without controller therapy and who have no history of previous exacerbations were at low risk for
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exacerbations during pregnancy.454 However, they should still be closely monitored.

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Respiratory infections should be monitored and managed appropriately during pregnancy.444 During acute asthma
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exacerbations, pregnant women may be less likely to be treated appropriately than non-pregnant patients.91 To avoid
fetal hypoxia, it is important to aggressively treat acute exacerbations during pregnancy with SABA, oxygen and early
administration of systemic corticosteroids.
During labor and delivery, usual controller medications should be taken, with reliever if needed. Acute exacerbations
during labor and delivery are uncommon, but bronchoconstriction may be induced by hyperventilation during labor, and
should be managed with SABA. Neonatal hypoglycemia may be seen, especially in preterm babies, when high doses of
beta-agonists have been given within the last 48 hours prior to delivery. If high doses of SABA have been given during
labor and delivery, blood glucose levels should be monitored in the baby (especially if preterm) for the first 24 hours.455
A recent review of asthma guidelines for the management of asthma during pregnancy highlighted the need for greater
clarity in current recommendations and the need for more RCTs among pregnant asthma patients.456

Women – perimenstrual asthma (catamenial asthma)
Clinical features
In approximately 20% of women, asthma is worse in the premenstrual phase. These women tend to be older, have more
severe asthma, a higher body mass index, a longer duration of asthma, and a greater likelihood of aspirin exacerbated
respiratory disease. They more often have dysmenorrhea, premenstrual syndrome, shorter menstrual cycles, and longer
menstrual bleeding. The role of hormone levels and systemic inflammation remains unclear.457
Management
In addition to the usual strategies for management of asthma, oral contraceptives and/or leukotriene receptor
antagonists may be helpful457 (Evidence D). Further research is needed.
Occupational asthma
Clinical features
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In the occupational setting, rhinitis often precedes the development of asthma (see p.28 regarding diagnosis of
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occupational asthma). Once a patient has become sensitized to an occupational allergen, the level of exposure
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necessary to induce symptoms may be extremely low; resulting exacerbations become increasingly severe, and with
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continued exposure, persistent symptoms and irreversible airflow limitation may result.38
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Management
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Detailed information is available in evidence-based guidelines about management of occupational asthma.38 All patients
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with adult-onset asthma should be asked about their work history and other exposures (Evidence A). The early
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identification and elimination of occupational sensitizers and the removal of sensitized patients from any further
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exposure are important aspects of the management of occupational asthma (Evidence A). Attempts to reduce
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occupational exposure have been successful, especially in industrial settings.38 Cost-effective minimization of latex
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sensitization can be achieved by using non-powdered low-allergen gloves instead of powdered latex gloves.38 Patients
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with suspected or confirmed occupational asthma should be referred for expert assessment and advice, if this is
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available, because of the economic and legal implications of the diagnosis (Evidence A)
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The elderly
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Clinical features
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Lung function generally decreases with longer duration of asthma and increasing age, due to stiffness of the chest wall,
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reduced respiratory muscle function, loss of elastic recoil and airway wall remodeling. Older patients may not report
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asthma symptoms, and may attribute breathlessness to normal aging or comorbidities such as cardiovascular disease
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and obesity.458-460 Comorbid arthritis may contribute to reduced exercise capacity and lack of fitness, and make inhaler
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device use difficult. Asthma costs may be higher amongst older patients, because of higher hospitalization rates and
medication costs.459
Management
Decisions about management of asthma in older people with asthma need to take into account both the usual goals of
symptom control and risk minimization and the impact of comorbidities, concurrent treatments and lack of self-
management skills.458,459 Data on efficacy of asthma medications in the elderly are limited because these patients are
often excluded from major clinical trials. Side-effects of beta2-agonists such as cardiotoxicity, and corticosteroid side-
effects such as skin bruising, osteoporosis, and cataracts, are more common in the elderly than in younger adults.458
Clearance of theophylline is also reduced.458 Elderly patients should be asked about all of the other medications they are
taking, including eye-drops, and potential drug interactions should be considered. Factors such as arthritis, muscle
weakness, impaired vision and inspiratory flow should be considered when choosing inhaler devices for older
patients,459,461 and inhaler technique should be checked at each visit. Older patients may have difficulties with complex
medication regimens, and prescribing of multiple inhaler devices should be avoided if possible. Large print versions may

be needed for written information such as asthma action plans. Patients with cognitive impairment may require a carer to
help them use their asthma medications. For diagnosis and initial management of patients with asthma-COPD overlap,
see Chapter 5, p.129.
Surgery and asthma

Clinical features
There is no evidence of increased peri-operative risk for the general asthma population.462 However, there is an
increased risk for patients with COPD,462 and this may also apply to asthma patients with reduced FEV1. The incidence
of severe peri-operative bronchospasm in people with asthma is low, but it may be life threatening.463
Management
For elective surgery, meticulous attention should be paid pre-operatively to achieving good asthma control, as detailed
elsewhere in this chapter, especially for patients with more severe asthma, uncontrolled symptoms, exacerbation
history, or persistent airflow limitation463 (Evidence B). For patients requiring emergency surgery, the risks of proceeding
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without first achieving good asthma control should be weighed against the need for immediate surgery. Patients taking
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long-term high dose ICS or who have received OCS for more than 2 weeks during the previous 6 months should receive
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hydrocortisone peri-operatively as they are at risk of adrenal crisis in the context of surgery464 (Evidence B). More
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immediate intra-operative issues relating to asthma management are reviewed in detail elsewhere.463 For all patients,
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maintaining regular controller therapy throughout the peri-operative period is important.
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Aspirin-exacerbated respiratory disease
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Clinical features
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The clinical picture and course of aspirin-exacerbated respiratory disease (AERD, previously called aspirin-induced
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asthma) are well established.311 It starts with nasal congestion and anosmia, and progresses to chronic rhinosinusitis
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with nasal polyps that re-grow rapidly after surgery. Asthma and hypersensitivity to aspirin and non-steroidal anti-
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inflammatory drugs (NSAIDs) develop subsequently. Following ingestion of aspirin or NSAIDs, an acute asthma attack
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develops within minutes to 1–2 hours. It is usually accompanied by rhinorrhea, nasal obstruction, conjunctival irritation,
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and scarlet flush of the head and neck, and may sometimes progress to severe bronchospasm, shock, loss of
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consciousness, and respiratory arrest.465,466 AERD is more likely to be associated with low lung function and severe
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asthma,467,468 and with increased need for emergency care.468 The prevalence of AERD is 7% in general adult asthma
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populations, and 15% in severe asthma.468,469

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Diagnosis
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A history of exacerbation following ingestion of aspirin or other NSAIDs is highly suggestive of AERD. Aspirin challenge
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(oral, bronchial or nasal) is the gold standard for diagnosis470,471 as there are no reliable in vitro tests, but oral aspirin
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challenge tests must only be conducted in a specialized center with cardiopulmonary resuscitation capabilities because
of the high risk of severe reactions.470,471 Bronchial (inhalational) and nasal challenges with lysine aspirin are safer than
oral challenges and may be safely performed in allergy centers.471,472
Management
Patients with AERD should avoid aspirin or NSAID-containing products and other medications that inhibit
cyclooxygenase-1 (COX-1), but this does not prevent progression of the disease. Where an NSAID is indicated for other
medical conditions, a COX-2 inhibitor (e.g. celocoxib,or etoricoxib), or paracetamol (acetaminophen), may be
considered473,474 with appropriate health care provider supervision and observation for at least 2 hours after
administration475 (Evidence B). ICS are the mainstay of asthma therapy in AERD, but OCS are sometimes required;
LTRA may also be useful466,475 (Evidence B), but note the recent FDA warning about adverse effects with
montelukast.205. An additional option is desensitization, which may be conducted under specialist care in a clinic or
hospital.476 Desensitization to aspirin followed by daily aspirin treatment can significantly improve overall symptoms and

quality of life, decrease formation of nasal polyps and sinus infections, reduce the need for OCS and sinus surgery, and
improve nasal and asthma scores.471,477
Allergic bronchopulmonary aspergillosis (ABPA)

Clinical features
Allergic bronchopulmonary aspergillosis (ABPA) is a complex pulmonary disease characterized by repeated episodes of
wheezing, fleeting pulmonary opacities and development of bronchiectasis, sometimes with malaise, weight loss and
hemoptysis. Some patients expectorate brownish sputum plugs. ABPA is most commonly found in asthma or cystic
fibrosis, due to a hypersensitivity response to Aspergillus fumigatus, a common indoor and outdoor mold.
Diagnosis
Diagnosis of ABPA is based on composite criteria including immediate hypersensitivity reaction to A. fumigatus, total
serum IgE, specific IgG to A. fumigatus, radiological features and blood eosinophils.478 Sensitization to fungal allergens,
without the full picture of ABPA, is often found in asthma, particularly in severe asthma, where it is sometimes called
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‘severe asthma with fungal sensitization’.
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Management
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Current first-line therapy is with oral corticosteroids (e.g. 4 month tapering course), with itraconazole reserved for those
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with exacerbations or requiring long-term OCS.478,479 One open-label study comparing itraconazole and OCS found that
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patients treated with itraconazole had a slightly lower response rate at 6 weeks but similar long-term response rates,
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with substantially fewer side-effects than with OCS.480 A randomized double-blind placebo-controlled study in patients
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with severe asthma and ABPA found significantly fewer exacerbations with omalizumab (anti-IgE) than placebo.481 In
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ABPA patients with bronchiectasis, regular physiotherapy and daily drainage are recommended.
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Difficult-to-treat and severe asthma are covered in the next section, Chapter 3 Part E.
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PART E. DIFFICULT-TO-TREAT AND SEVERE ASTHMA IN ADULTS AND ADOLESCENTS
KEY POINTS
What are difficult to treat and severe asthma?

• Difficult-to-treat asthma is asthma that is uncontrolled despite GINA Step 4 or 5 treatment or that requires such
treatment to maintain good symptom control and reduce exacerbations. It does not mean a ‘difficult patient’.
• Severe asthma is asthma that is uncontrolled despite adherence with maximal optimized Step 4 or Step 5 therapy
and treatment of contributory factors, or that worsens when high dose treatment is decreased. Approximately 3–
10% of people with asthma have severe asthma.
• Severe asthma places a large physical, mental, emotional, social and economic burden on patients.
How should these patients be assessed?
• Assess all patients with difficult to treat asthma to confirm the diagnosis of asthma, and to identify and manage
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factors that may be contributing to symptoms, poor quality of life, or exacerbations.
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• Refer for expert advice at any stage, or if asthma does not improve in response to optimizing treatment.
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• For patients with persistent symptoms and/or exacerbations despite high dose ICS, the clinical or inflammatory
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phenotype should be assessed, as this may guide the selection of add-on treatment.
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Management of severe asthma
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• Add-on treatments for severe asthma include tiotropium, LTRA and low dose macrolides, and biologic agents for
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severe allergic or severe Type 2 asthma. Maintenance OCS should be avoided if other options are available,
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because of its serious side-effects.

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• Assess the response to any add-on treatment, stop ineffective treatments, and consider other options.
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• Utilize specialist multidisciplinary team care for severe asthma, if available.

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• For patients with severe asthma, continue to optimize patient care in collaboration with the primary care clinician,
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and taking into account the patient’s social and emotional needs.
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• Invite patients with severe asthma to enrol in a registry or clinical trial, if available and relevant, to help fill evidence
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gaps.
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Although the majority of patients can achieve the goal of well controlled asthma, some patients’ asthma will not be well
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controlled even with optimal therapy. The material that follows is from the GINA Pocket Guide for health professionals
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on Diagnosis and Management of Difficult-to-Treat and Severe Asthma in Adolescent and Adult Patients v2.0, published
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in April 2019. A copy of the Pocket Guide can be downloaded from the GINA website (www.ginasthma.org).
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Other resources about severe asthma include an online toolkit published by the Australian Centre of Excellence in
Severe Asthma (https: //toolkit.severeasthma.org.au).
DEFINITIONS: UNCONTROLLED, DIFFICULT-TO-TREAT AND SEVERE ASTHMA

Understanding the definitions of difficult-to-treat and severe asthma starts with the concept of uncontrolled asthma.
Uncontrolled asthma includes one or both of the following:
• Poor symptom control (frequent symptoms or reliever use, activity limited by asthma, night waking due to
asthma)
• Frequent exacerbations (≥2/year) requiring OCS, or serious exacerbations (≥1/year) requiring hospitalization
Difficult-to-treat asthma138 is asthma that is uncontrolled despite GINA Step 4 or 5 treatment (e.g. medium or high dose
inhaled corticosteroids (ICS) with a second controller; maintenance OCS), or that requires such treatment to maintain
good symptom control and reduce the risk of exacerbations. It does not mean a ‘difficult patient’. In many cases, asthma

may appear to be difficult-to-treat because of modifiable factors such as incorrect inhaler technique, poor adherence,
smoking or comorbidities, or because the diagnosis is incorrect.
Severe asthma138 is a subset of difficult-to-treat asthma (Box 3-15). It means asthma that is uncontrolled despite
adherence with maximal optimized therapy and treatment of contributory factors, or that worsens when high dose
treatment is decreased.138 At present, therefore, ‘severe asthma’ is a retrospective label. It is sometimes called ‘severe
refractory asthma’138 since it is defined by being relatively refractory to high dose inhaled therapy. However, with the
advent of biologic therapies, the word ‘refractory’ is no longer appropriate.
Asthma is not classified as severe if it markedly improves when contributory factors such as inhaler technique and
adherence are addressed.138
PREVALENCE: HOW MANY PEOPLE HAVE SEVERE ASTHMA?

A study in the Netherlands estimated that around 3.7% of asthma patients have severe asthma, based on the number of
patients prescribed Step 4 or 5 treatment, who had poor symptom control (by Asthma Control Questionnaire) and had
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good adherence and inhaler technique (Box 3-15).482
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Box 3-15. What proportion of adults have difficult-to-treat or severe asthma?
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IMPORTANCE: THE IMPACT OF SEVERE ASTHMA
The patient perspective

Patients with severe asthma experience a heavy burden of symptoms, exacerbations and medication side-effects.
Frequent shortness of breath, wheeze, chest tightness and cough interfere with day-to-day living, sleeping, and physical
activity, and patients often have frightening or unpredictable exacerbations (also called attacks or severe flare-ups).
Medication side-effects are particularly common and problematic with OCS,263 which in the past were a mainstay of
treatment for severe asthma. Adverse effects of long-term OCS include obesity, diabetes, osteoporosis, cataracts
diabetes, hypertension and adrenal suppression; psychological side-effects such as depression and anxiety are
particularly concerning for patients.483 Even short- term use of OCS is associated with sleep disturbance, and increased
risk of infection, fracture and thromboembolism.484 Strategies to minimize need for OCS are therefore a high priority.

Severe asthma often interferes with family, social and working life, limits career choices and vacation options, and
affects emotional and mental health. Patients with severe asthma often feel alone and misunderstood, as their
experience is so different from that of most people with asthma.483
Adolescents with severe asthma

The teenage years are a time of great psychological and physiological development which can impact on asthma
management. It is vital to ensure that the young person has a good understanding of their condition and treatment and
appropriate knowledge to enable supported self-management. The process of transition from pediatric to adult care
should help support the young person in gaining greater autonomy and responsibility for their own health and wellbeing.
Healthcare utilization and costs

Severe asthma has very high healthcare costs due to medications, physician visits, hospitalizations, and the costs of
OCS side-effects. In a UK study, healthcare costs per patient were higher than for type 2 diabetes, stroke, or COPD.485
In a Canadian study, severe uncontrolled asthma was estimated to account for more than 60% of asthma costs.486
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Patients with severe asthma and their families also bear a significant financial burden, not only for medical care and
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medications, but also through lost earnings and career choices.
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ASSESSMENT AND MANAGEMENT OF DIFFICULT-TO-TREAT AND SEVERE ASTHMA
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The clinical decision tree starting on page 97, provides brief information about what should be considered in each phase
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of diagnosis and management of difficult-to-treat and severe asthma. The decision tree is divided into three broad areas:
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• Sections 1-4 (green) are for use in primary care and/or specialist care.
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• Sections 5-7 (blue) are mainly relevant to respiratory specialists.

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• Section 8 (brown) is about maintaining ongoing collaborative care between the patient, GP, specialist and other
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health professionals.
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Development of the Pocket Guide and decision tree included extensive collaboration with experts in human-centered
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design to enhance the utility of these resources for end-users. This included translating existing high level flowcharts
and text-based information to a more detailed visual format, and applying information architecture and diagramming
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principles.
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Further information follows the decision tree.

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Box 3-16A. Decision tree – investigate and manage adult and adolescent patients with difficult-to-treat asthma
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Box 3-16B. Decision tree – assess and treat severe asthma phenotypes
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Box 3-16C. Decision tree – consider add-on biologic Type 2 targeted treatments
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Box 3-16D. Decision tree – monitor and manage severe asthma treatment
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INVESTIGATE AND MANAGE ADULT AND ADOLESCENT PATIENTS WITH DIFFICULT-TO-TREAT ASTHMA
1. CONFIRM THE DIAGNOSIS (ASTHMA OR DIFFERENTIAL DIAGNOSES)

Stages 1-5 can be carried out in primary or specialist care. Difficult-to-treat asthma is defined if the patient has persistent
symptoms and/or exacerbations despite prescribing of GINA Step 4-5 treatment (e.g. medium or high dose ICS with
another controller such as LABA, or maintenance oral corticosteroids (OCS)). It does not mean a ‘difficult patient’.
Consider referral to a specialist or severe asthma clinic at any stage, particularly if:
• There is difficulty confirming the diagnosis of asthma
• Patient has frequent urgent healthcare utilization
• Patient needs frequent or maintenance OCS
• Occupational asthma is suspected
• Food allergy or anaphylaxis, as this increases the risk of death
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• Symptoms are suggestive of infective or cardiac cause
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• Symptoms are suggestive of complications such as bronchiectasis
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• Presence of multiple comorbidities
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Are the symptoms due to asthma?
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Perform a careful history and physical examination to identify whether symptoms are typical of asthma, or are more
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likely due to an alternative diagnosis or comorbidity. Investigate according to clinical suspicion.
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• Dyspnea: COPD, obesity, cardiac disease, deconditioning

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Cough: inducible laryngeal obstruction (also called vocal cord dysfunction, VCD), upper airway cough syndrome
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(also called post-nasal drip), gastro-esophageal reflux disease (GERD), bronchiectasis, ACE inhibitors
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• Wheeze: obesity, COPD, tracheobronchomalacia, VCD

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How can the diagnosis of asthma be confirmed?

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Confirmation of the diagnosis is important, because in 12–50% of people assumed to have severe asthma, asthma is
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not found to be the correct diagnosis.487 Perform spirometry, before and after bronchodilator, to assess baseline lung
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function and seek objective evidence of variable expiratory airflow limitation. If initial reversibility testing is negative
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(<200mL or <12% increase in FEV1), consider repeating when symptomatic. Check full flow-volume curve to assess for
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upper airway obstruction. If spirometry is normal or is not available, provide the patient with a peak flow diary for
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assessing variability; consider bronchial provocation testing if patient is able to withhold bronchodilators (short-acting
beta2-agonist (SABA) for at least 6 hours, LABA for up to 2 days depending on duration of action)488. Strategies for
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confirming the diagnosis of asthma in patients already taking controller treatment are shown in Box 1-4 (p.27).
Airflow limitation may be persistent in patients with long-standing asthma, due to remodeling of the airway walls, or
limited lung development in childhood. It is important to document lung function when the diagnosis of asthma is first
made. Specialist advice should be obtained if the history is suggestive of asthma but the diagnosis cannot be confirmed
by spirometry.
2. LOOK FOR FACTORS CONTRIBUTING TO SYMPTOMS AND EXACERBATIONS

Systematically consider factors that may be contributing to uncontrolled symptoms or exacerbations, or poor quality of
life, and that can be treated. The most important modifiable factors include:
• Incorrect inhaler technique (seen in up to 80% patients): ask the patient to show you how they use their
inhaler; compare with a checklist or video
• Suboptimal adherence (up to 75% asthma patients): ask empathically about frequency of use (e.g. ‘Many
patients don’t use their inhaler as prescribed. In the last 4 weeks, how many days a week have you been taking

it – not at all, 1 day a week, 2, 3 or more?’ or, ‘Do you find it easier to remember your inhaler in the morning or
the evening?’ (see Box 3-13, p.81). Ask about barriers to medication use, including cost, and concerns about
necessity or side-effects. Check dates on inhalers and view dispensing data, if available.
• Comorbidities: review history and examination for comorbidities that can contribute to respiratory symptoms,
exacerbations, or poor quality of life. These include anxiety and depression, obesity, deconditioning, chronic
rhinosinusitis, inducible laryngeal obstruction (often referred to as VCD), GERD, COPD, obstructive sleep
apnea, bronchiectasis, cardiac disease, and kyphosis due to osteoporosis. Investigate according to clinical
suspicion.
• Modifiable risk factors and triggers: identify factors that increase the risk of exacerbations, e.g. smoking,
environmental tobacco exposure, other environmental exposures at home or work including allergens (if
sensitized), indoor and outdoor air pollution, molds and noxious chemicals, and medications such as beta-
blockers or non-steroid anti-inflammatory drugs (NSAIDs). For allergens, check for sensitization using skin prick
testing or specific IgE.
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• Regular or over-use of SABAs: this causes beta-receptor down-regulation and reduction in response,489
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leading in turn to greater use. Overuse may also be habitual. Dispensing of ≥3 SABA canisters per year
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(average 1.5 puffs per day, or more) is associated with increased risk of emergency department visit or
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hospitalization independent of severity,490 and dispensing of ≥12 canisters per year (one a month) increases the
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risk of death.84 Risks are higher with nebulized SABA.
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• Anxiety, depression and social and economic problems: these are very common in asthma, particularly in
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difficult asthma483 and contribute to symptoms, impaired quality of life, and poor adherence.
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• Medication side-effects: systemic effects, particularly with frequent or continuous OCS, or long-term high dose
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ICS may contribute to poor quality of life and increase the likelihood of poor adherence. Local side-effects of
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dysphonia or thrush may occur with high dose or potent ICS especially if inhaler technique is poor. Consider
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drug interactions including risk of adrenal suppression with use of P450 inhibitors such as itraconazole.
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3. REVIEW AND OPTIMIZE MANAGEMENT

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Review and optimize treatment for asthma, and for comorbidities and risk factors identified in Section 2. For more
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details, see Chapter 3D, p.85.

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• Provide asthma self-management education, and confirm that patient has (and knows how to use) a
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personalized written or electronic asthma action plan. Refer to an asthma educator if available.
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• Optimize inhaled controller medications: confirm that the inhaler is suitable for the patient; check and correct
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inhaler technique with a physical demonstration and teach-back method, check inhaler technique again at each
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visit.491 Address suboptimal adherence, both intentional and unintentional.387 For patients with a history of
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exacerbations, switch to ICS-formoterol maintenance and reliever regimen if available, to reduce the risk of
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exacerbations.181
• Treat comorbidities and modifiable risk factors identified in Section 2 of the decision tree, where there is
evidence for benefit; however, there is no evidence to support routine treatment of asymptomatic GERD (see
p.86). Avoid medications that make asthma worse (beta-blockers including eye-drops; aspirin and other NSAIDs
in patients with aspirin-exacerbated respiratory disease, p.92). Refer for management of mental health problems
if relevant.
• Consider non-pharmacologic add-on therapy, e.g. smoking cessation, physical exercise, healthy diet, weight
loss, mucus clearance strategies, influenza vaccination, breathing exercises, allergen avoidance, if feasible, for
patients who are sensitized and exposed. For details see Box 3-9, p.70.
• Consider trial of non-biologic medication added to medium/high dose ICS, e.g. LABA, tiotropium, leukotriene
modifier if not already tried
• Consider trial of high dose ICS, if not currently used.

4. REVIEW RESPONSE AFTER 3–6 MONTHS
Schedule a review visit to assess the response to the above interventions. Timing of the review visit depends on clinical
urgency and what changes to treatment have been made.
When assessing the response to treatment, specifically review:
• Symptom control (symptom frequency, SABA reliever use, night waking due to asthma, activity limitation)
• Exacerbations since previous visit, and how they were managed
• Medication side-effects
• Inhaler technique and adherence
• Lung function
• Patient satisfaction and concerns
Is asthma still uncontrolled, despite optimized therapy?
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YES: if asthma is still uncontrolled, the diagnosis of severe asthma has been confirmed. If not done by now, refer the
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patient to a specialist or severe asthma clinic if possible.
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NO: if asthma is now well-controlled, consider stepping down treatment. Start by decreasing/ceasing OCS first (if used),
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then remove other add-on therapy, then decrease ICS dose (do not stop ICS). See Box 3-7 (p.66) for how to gradually
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down-titrate treatment intensity.
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Does asthma become uncontrolled when treatment is stepped down? O
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YES: if asthma symptoms become uncontrolled or an exacerbation occurs when high dose treatment is stepped down,
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the diagnosis of severe asthma has been confirmed. Restore the patient's previous dose to regain good asthma control,
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and refer to a specialist or severe asthma clinic if possible, if not done already.
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NO: if symptoms and exacerbations remain well-controlled despite treatment being stepped down, the patient does not
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have severe asthma. Continue optimizing management.

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ASSESS AND TREAT SEVERE ASTHMA PHENOTYPES

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5. ASSESS THE SEVERE ASTHMA PHENOTYPE AND OTHER CONTRIBUTORS

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Further assessment and management should be by a specialist, preferably in a multidisciplinary severe asthma clinic if
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available. The team may include a certified asthma educator and health professionals from fields such as speech
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pathology, ENT, social work and mental health.

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Assessment includes:
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• Assessment of the patient’s inflammatory phenotype: Type 2 or non-Type 2?

• More detailed assessment of comorbidities and differential diagnoses
• Need for social/psychological support483
• Invite patient to enroll in a registry (if available) or clinical trial (if appropriate)
What is Type 2 inflammation?
Type 2 inflammation is found in ~50% of people with severe asthma. It is characterized by cytokines such as interleukin
(IL)-4, IL-5 and IL-13, which are often produced by the adaptive immune system on recognition of allergens. It may also
be activated by viruses, bacteria and irritants that stimulate the innate immune system via production of IL-33, IL-25 and
thymic stromal lymphopoietin (TSLP) by epithelial cells. Type 2 inflammation is often characterized by eosinophilia or
increased FeNO, and may be accompanied by atopy, whereas non- Type 2 inflammation is often characterized by
increased neutrophils.492 In many patients with asthma, Type 2 inflammation rapidly improves when ICS are taken
regularly and correctly; this is classified as mild or moderate asthma. In severe asthma, Type 2 inflammation may be

relatively refractory to high dose ICS. It may respond to OCS but their serious adverse effects263 mean that alternative
treatments should be sought.
Could the patient have refractory or underlying Type 2 inflammation?
The possibility of refractory Type 2 inflammation should be considered if any of the following are found while the patient
is taking high dose ICS or daily OCS:
• Blood eosinophils ≥150/μl, and/or
• FeNO ≥20 ppb, and/or
• Sputum eosinophils ≥2%, and/or
• Asthma is clinically allergen-driven
Patients requiring maintenance OCS may also have underlying Type 2 inflammation. However, biomarkers of Type 2
inflammation (blood eosinophils, sputum eosinophils and FeNO) are often suppressed by OCS. If possible, therefore,
these tests should be performed before starting OCS (a short course, or maintenance treatment), or on the lowest
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possible OCS dose.
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The above criteria are suggested for initial assessment; those for blood eosinophils and FeNO are based on lowest
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levels associated with response to some biologics. They are not the criteria for eligibility for Type 2-targeted biologic
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therapy, which may differ - see section 6b and local criteria. Consider repeating blood eosinophils and FeNO up to 3
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times (e.g. when asthma worsens, before giving OCS), before assuming asthma is non-Type 2.
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Why is the inflammatory phenotype assessed on high dose ICS? O
• Most RCT evidence about Type 2 targeted biologics is in such patients.
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• Currently, the high cost of biologic therapies generally precludes their widespread clinical use in patients whose
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symptoms or exacerbations and Type 2 biomarkers are found to respond to ICS when it is taken correctly.
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of uncontrolled Type 2 inflammation.

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What other tests may be considered at the specialist level?

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Additional investigations may be appropriate for identifying less-common comorbidities and differential diagnoses
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contributing to symptoms and/or exacerbations. Tests should be based on clinical suspicion, and may include:
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• Blood tests: CBC, CRP, IgG, IgA, IgM, IgE, fungal precipitins including Aspergillus
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• Allergy testing for clinically relevant allergens: skin prick test or specific IgE, if not already done
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• Other pulmonary investigations: DLCO; CXR or high resolution chest CT

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• Other directed testing, e.g. ANCA, CT sinuses, BNP, echocardiogram

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• Testing for parasitic infections. Consider this if Type 2 targeted biologic therapy is considered; this is because
parasitic infection may be the cause of the blood eosinophilia, and because Type 2 targeted treatment in a
patient with untreated parasitic infection could potentially lead to disseminated disease
Consider need for social/psychological support
Refer patients to support services, where available, to help them deal with the emotional, social and financial burden of
asthma and its treatment, including during and after severe exacerbations.483 Consider the need for psychological or
psychiatric referral, including for patients with anxiety and/or depression.
Involve multidisciplinary team care (if available)
Multidisciplinary assessment and treatment of patients with severe asthma increases the identification of comorbidities,
and improves outcomes.493

Invite patient to enroll in a registry (if available) or clinical trial (if appropriate)
Systematic collection of data will help in understanding the mechanisms and burden of severe asthma. There is a need
for pragmatic clinical trials in severe asthma, including studies comparing two or more active treatments. Participants in
randomized controlled trials designed for regulatory purposes may not necessarily be representative of patients seen in
clinical practice. For example, a registry study found that over 80% of patients with severe asthma would have been
excluded from recent studies evaluating biologic therapy.246
6A. IF THERE IS NO EVIDENCE OF TYPE 2 INFLAMMATION

If the patient has no evidence of persistent Type 2 inflammation (section 5):
• Review the basics for factors that may be contributing to symptoms or exacerbations: differential diagnosis,
inhaler technique, adherence, comorbidities, medication side-effects (Section 2).
• Recommend avoidance of relevant exposures (tobacco smoke, pollution, allergens if sensitized and there is
evidence of benefit from withdrawal, irritants, infections). Ask about exposures at home and at work.
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• Consider additional diagnostic investigations (if available and not already done): sputum induction to confirm
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inflammatory phenotype, high resolution chest CT, bronchoscopy to exclude unusual comorbidities or alternative
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diagnoses such as tracheobronchomalacia or sub-glottic stenosis; functional laryngoscopy for inducible
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laryngeal obstruction.
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• Consider a trial of non-biologic add-on treatment if not already tried, e.g. tiotropium, leukotriene modifier, low-
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dose macrolide,248,249 but consider potential for antibiotic resistance. Consider add-on low dose OCS, but
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implement strategies such as alternate-day treatment to minimize side-effects. Stop ineffective add-on
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therapies.
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• Consider bronchial thermoplasty, with registry enrollment. However, the evidence for efficacy and long-term
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safety is limited.115,298
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No biologic options are currently available for non-Type 2 severe asthma.

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6a Non-biologic options if there IS evidence of Type 2 inflammation

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For patients with elevated Type 2 biomarkers despite high dose ICS (see section 5), consider non-biologic options first,
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given the current high cost of biologic therapy:

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• Assess adherence objectively by monitoring of prescribing or dispensing records, blood prednisone levels,494
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or electronic inhaler monitoring.374 In one study, suppression of high FeNO after 5 days of directly-observed
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therapy was an indicator of past poor adherence.495

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• Consider clinical Type 2 phenotypes for which specific add-on treatment is available (see Chapter 3D, p.85).
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For example, for aspirin-exacerbated respiratory disease (AERD), consider add-on leukotriene modifier and
possibly aspirin desensitization (p.92). For allergic bronchopulmonary aspergillosis (ABPA), consider add-on
OCS ± anti-fungal agent (p.93). For chronic rhinosinusitis and/or nasal polyposis, consider intensive intranasal
corticosteroids; surgical advice may be needed (p.87). For patients with atopic dermatitis, topical steroidal or
non-steroidal therapy may be helpful.
• Consider increasing the ICS dose for 3-6 months, and review again.
6B CONSIDER ADD-ON BIOLOGIC TYPE 2 TARGETED TREATMENTS

If available and affordable, consider an add-on Type 2 targeted biologic for patients with exacerbations or poor
symptom control despite taking at least high dose ICS-LABA, and who have allergic or eosinophilic biomarkers or need
maintenance OCS. Where relevant, test for parasitic infection, and treat if present, before commencing Type 2 targeted
treatment (see section 5).
Always check local criteria for eligibility and funding.

Consider whether to start first with anti-IgE, anti-IL5/5R or anti-IL4R. When choosing between available therapies,
consider the following:
• Does the patient satisfy local payer eligibility criteria?
• Predictors of asthma response (see below)
• Cost
• Dosing frequency
• Delivery route (IV or SC; potential for self-administration)
• Patient preference
Local payer eligibility criteria for biologic therapy may vary substantially. For any biologic therapy, ensure that the
manufacturer’s and/or regulator’s instructions for storage, administration and the duration of monitoring post-
administration are followed. Provide the patient with advice about what to do if they experience any adverse effects,
including hypersensitivity reactions.
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one biologic.
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Add-on anti-IgE for severe allergic asthma
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Currently approved: omalizumab for ages ≥6 years, given by SC injection every 2-4 weeks, with dose based on weight
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and serum IgE. Self- administration may be an option.
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Mechanism: binds to Fc part of free IgE, preventing binding of IgE to FcƐR1 receptors, reducing free IgE and down-
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regulating receptor expression.
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Eligibility criteria vary between payers, but usually include:

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• Sensitization to inhaled allergen(s) on skin prick testing or specific IgE, and

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• Total serum IgE and body weight within local dosing range, and
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• More than a specified number of exacerbations within the last year

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Benefits: RCTs in severe asthma: 34% decrease in severe exacerbations,496 but no significant difference in symptoms
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or quality of life.250 In open-label studies in patients with severe allergic asthma and ≥1 severe exacerbation in last 12
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months, there was a 50-65% reduction in exacerbation rate,497,498 a significant improvement in quality of life,497 and 40-
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50% reduction in OCS dose.497,498

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Potential predictors of good asthma response to omalizumab:

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• Baseline IgE level does not predict likelihood of response497

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• In RCTs: a greater decrease in exacerbations was observed (cf. placebo) if blood eosinophils ≥260/μl499,500 or
FeNO ≥20 ppb,499 but in a large observational study, exacerbations were reduced with both low or high blood
eosinophils498,501
• Childhood-onset asthma
• Clinical history suggesting allergen-driven symptoms
Adverse effects: injection site reactions; anaphylaxis in ~0.2% patients250
Suggested initial trial: at least 4 months

Add-on anti-IL5 or anti-IL5R for severe eosinophilic asthma
Currently approved: For ages ≥12 years: mepolizumab (anti-IL5), 100mg by SC injection every 4 weeks, and
benralizumab (anti-IL5 receptor α), 30mg by SC injection every 4 weeks for 3 doses then every 8 weeks. For ages ≥18
years: reslizumab (anti-IL5), 3mg/kg by IV infusion every 4 weeks. For ages ≥6 years, mepolizumab (anti-IL5), 40mg by
SC injection every 4 weeks.
Mechanism: mepolizumab and reslizumab bind circulating IL-5; benralizumab binds to IL-5 receptor alpha subunit
leading to apoptosis (cell death) of eosinophils.
Eligibility criteria: these vary by product and between payers, but usually include:
• More than a specified number of severe exacerbations in the last year, and
• Blood eosinophils above specified level (e.g. ≥300/μl). In some cases there is a different eosinophil cutpoint for
patients taking OCS.
Outcomes: RCTs in severe asthma patients with exacerbations in the last year, with varying eosinophil criteria: anti-IL5
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and anti-IL5R led to ~55% reduction in severe exacerbations, and improved quality of life, lung function and symptom
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control.256 All reduced blood eosinophils; almost completely with benralizumab.256 In patients taking OCS, median OCS
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dose was able to be reduced by ~50% with mepolizumab or benralizumab compared with placebo. Mepolizumab may
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improve nasal polyposis.502 Efficacy data for mepolizumab in children are limited to one very small uncontrolled open
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label study.257
R
O
Potential predictors of good asthma response:
• Higher blood eosinophils (strongly predictive)503 PY
O
C
• Higher number of severe exacerbations in previous year (strongly predictive)503

T
O
Adult-onset asthma504
N
•
O
• Nasal polyposis505
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• Maintenance OCS at baseline505

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Adverse effects: injection site reactions; anaphylaxis is rare; adverse events generally similar between active and
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placebo groups
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Add-on anti-IL4R for severe eosinophilic/Type 2 asthma or patients requiring maintenance OCS
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Currently approved: For ages ≥12 years: dupilumab (anti-IL4 receptor α), 200mg or 300mg by SC injection every 2
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PY
weeks for severe eosinophilic/Type 2 asthma; 300mg by SC injection every 2 weeks for OCS-dependent severe asthma
O
or if there is concomitant moderate/severe atopic dermatitis. Self-administration may be an option.

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Mechanism: binds to interleukin-4 (IL-4) receptor alpha, blocking both IL-4 and IL-13 signaling
Eligibility criteria: these vary between payers, but usually include:
• More than a specified number of severe exacerbations in the last year, and
• Type 2 biomarkers above a specified level (e.g. blood eosinophils ≥300/μl or FeNO ≥25 ppb); OR
• Requirement for maintenance OCS
Dupilumab is also indicated for treatment of moderate-severe atopic dermatitis506 and may improve nasal polyposis.507
Outcomes: RCTs in uncontrolled (ACQ-5 ≥ 1.5) severe asthma patients with at least one exacerbation in the last year:
anti-IL4R led to ~50% reduction in severe exacerbations, and significantly improved quality of life, symptom control and
lung function.258,260 In patients with OCS-dependent severe asthma, without minimum requirements of blood eosinophil
count or FeNO, treatment with anti-IL4R reduced median OCS dose by 50% versus placebo.508

Potential predictors of good asthma response:
• Higher blood eosinophils (strongly predictive)258
• Higher FeNO258
Adverse effects: injection-site reactions; transient blood eosinophilia
Review response to an initial trial of add-on Type 2 targeted therapy
• At present, there are no well-defined criteria for a good response, but consider exacerbations, symptom control,
lung function, side-effects, treatment intensity (including OCS dose), and patient satisfaction
• If the response is unclear, consider extending the trial to 6–12 months
• If there is no response, stop the biologic therapy, and consider switching to a trial of a different Type 2 targeted
therapy, if available and the patient is eligible;498,509 review response as above
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MANAGE AND MONITOR SEVERE ASTHMA TREATMENT
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7. REVIEW RESPONSE AND IMPLICATIONS FOR TREATMENT
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IS
D
Review the patient’s response to add-on biologic therapy after 34‫ צ‬months, and every 3–6 months for ongoing care,
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including:
O
PY
• Asthma: symptom control, e.g. Asthma Control Test, Asthma Control Questionnaire; frequency and severity of
O
exacerbations (e.g. were OCS needed), lung function
C
T
• Type 2 comorbidities, e.g. nasal polyposis, atopic dermatitis

O
N
• Medications: treatment intensity, including dose of OCS, side-effects, affordability

O
D
• Patient satisfaction
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If the patient has had a good response to Type 2 targeted therapy:

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Re-evaluate the need for each asthma medication every 3–6 months, but do not completely stop inhaled therapy. Base
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the order of reduction or cessation of add-on treatments on the observed benefit when they were started, patient risk
M
factors, medication side-effects, cost, and patient satisfaction.

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For oral treatments, consider gradually decreasing or stopping OCS first, because of their significant adverse effects.
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IG
Tapering may be supported by internet-based monitoring of symptom control and FeNO.510 Monitor patients for risk of
R
adrenal suppression, and provide patient and GP with advice about the need for extra corticosteroid doses during injury,
PY
illness or surgery for up to 6 months after cessation of long-term OCS. Continue to assess for presence of osteoporosis,
O
and review need for preventative strategies including bisphosphonates.264

C
For inhaled treatments, consider reducing the ICS dose after 3–6 months, but do not completely stop inhaled therapy.
Current consensus advice is to continue at least medium dose ICS. Patients should be reminded of the importance of
continuing their inhaled controller.
For biologic treatments, current consensus advice is that, generally, for a patient with a good response, a trial of
withdrawal of the biologic should not be considered until after at least 12 months of treatment, and only if asthma
remains well-controlled on medium dose ICS therapy, and (for allergic asthma) there is no further exposure to a
previous well-documented allergic trigger. There are few studies of cessation of biologic therapy,511,512 in these studies,
symptom control worsened and/or exacerbations recurred for many (but not all) patients after cessation of the biologic.
If the patient has NOT had a good response to any Type 2 targeted therapy:
Review the basics for factors contributing to symptoms, exacerbations and poor quality of life (see Section 2):
diagnosis, inhaler technique, adherence, modifiable risk factors and triggers including smoking and other environmental

exposures at home or work, comorbidities including obesity, medication side-effects or drug interactions, socio-
economic and mental health issues.
Consider additional investigations (if not already done): high resolution chest CT; induced sputum to confirm
inflammatory phenotype, consider referral if available, including for diagnosis of alternative conditions.
Reassess treatment options (if not already done), such as add-on low-dose macrolide,248 but consider potential for
antibiotic resistance; consider add-on low-dose maintenance OCS, but implement strategies such as alternate- day
therapy and add-on bisphosphonates264 to minimize side-effects, and alert patient to the need for additional
corticosteroid therapy during illness or surgery. Consider bronchial thermoplasty (+ registry).
Stop ineffective add-on therapies, but do not completely stop ICS
8. CONTINUE TO COLLABORATIVELY OPTIMIZE PATIENT CARE

Ongoing management of a patient with severe asthma involves a collaboration between the patient, the GP,
specialist(s), and other health professionals, to optimize clinical outcomes and patient satisfaction.
TE
U
Continue to review the patient every 3–6 months including:
IB
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• Clinical asthma measures (symptom control; exacerbations; lung function)
T
IS
• Comorbidities
D
R
• The patient's risk factors for exacerbations
O
PY
• Treatments (check inhaler technique and adherence; review need for add- on treatments; assess side-effects
O
including of OCS; optimize comorbidity management and non-pharmacologic strategies)
C
T
• The patient’s social and emotional needs

O
N
The optimal frequency and location of review (GP or specialist) will depend on the patient’s asthma control, risk factors
O
and comorbidities, and their confidence in self-management, and may depend on local payer requirements and
D
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availability of specialist physicians.

IA
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Communicate regularly about:

AT
• Outcome of review visits (as above)

M
• Patient concerns
D
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• Action plan for worsening asthma or other risks

H
IG
• Changes to medications (asthma and non-asthma); potential side-effects

R
PY
• Indications and contact details for expedited review

O
C

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TR
IS
D
R
O
PY
O
C
T
O
N
O
D
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D
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H
IG
R
PY
O
C

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Chapter 4.
D
R
O
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O
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Management of
O
N
O
D
worsening asthma
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and exacerbations
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O
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KEY POINTS
Terminology
• Exacerbations represent an acute or sub-acute worsening in symptoms and lung function from the patient’s usual
status, or in some cases, a patient may present for the first time during an exacerbation.
• The terms ‘episodes’, ‘attacks’ and ‘acute severe asthma’ are also often used, but they have variable meanings.
The term ‘flare-up’ is preferable for use in discussions with most patients.
• Patients who are at increased risk of asthma-related death should be identified, and flagged for more frequent
review.
• All patients should be provided with a written asthma action plan appropriate for their level of asthma control and
health literacy, so they know how to recognize and respond to worsening asthma.
TE
• On the action plan, state when and how to change reliever and controller medications, use oral corticosteroids, and
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access medical care if symptoms fail to respond to treatment.
IB
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• Advise patients who have a history of rapid deterioration to go to an acute care facility or see their doctor
T
immediately their asthma starts to worsen.
IS
D
• Base the action plan on changes in symptoms or (only in adults) peak expiratory flow.
R
O
Management of exacerbations in a primary care or acute care facility
PY
O
• Assess exacerbation severity from the degree of dyspnea, respiratory rate, pulse rate, oxygen saturation and lung
C
function, while starting short-acting beta2-agonist (SABA) and oxygen therapy.

T
O
• Arrange immediate transfer to an acute care facility if there are signs of severe exacerbation, or to intensive care if
N
O
the patient is drowsy, confused, or has a silent chest. During transfer, give inhaled SABA and ipratropium bromide,
D
controlled oxygen and systemic corticosteroids.

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• Start treatment with repeated administration of SABA (in most patients, by pressurized metered dose inhaler and
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spacer), early introduction of oral corticosteroids, and controlled flow oxygen if available. Review response of
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symptoms, oxygen saturation and lung function after 1 hour. Give ipratropium bromide only for severe
M
exacerbations. Consider intravenous magnesium sulfate for patients with severe exacerbations not responding to
D
initial treatment.
TE
H
• Do not routinely request a chest X-ray, and do not routinely prescribe antibiotics for asthma exacerbations.
IG
R
• Decide about hospitalization based on the patient’s clinical status, lung function, response to treatment, recent and
PY
past history of exacerbations, and ability to manage at home.

O
C
Discharge management
• Arrange ongoing treatment before the patient goes home. This should include starting inhaled corticosteroid (ICS)-
containing controller treatment or stepping up the dose of existing controller treatment for 2–4 weeks, and reducing
reliever medication to as-needed use.
• Arrange early follow-up after any exacerbation, regardless of where it was managed.
o Review the patient’s symptom control and risk factors for further exacerbations.
o For most patients, prescribe regular controller therapy to reduce the risk of further exacerbations. Continue
increased controller doses for 2–4 weeks.
• Check inhaler technique and adherence.
For management of asthma exacerbations in children 5 years and younger, see Chapter 6, p.155.
112 4. Management of worsening asthma and exacerbations

OVERVIEW
Definition of asthma exacerbations

Exacerbations of asthma are episodes characterized by a progressive increase in symptoms of shortness of breath,
cough, wheezing or chest tightness and progressive decrease in lung function, i.e. they represent a change from the
patient’s usual status that is sufficient to require a change in treatment.17 Exacerbations may occur in patients with a pre-
existing diagnosis of asthma or, occasionally, as the first presentation of asthma.
What triggers asthma exacerbations?

Exacerbations usually occur in response to exposure to an external agent (e.g. viral upper respiratory tract infection,
pollen or pollution) and/or poor adherence with controller medication; however, a subset of patients present more
acutely and without exposure to known risk factors.513,514 Severe exacerbations can occur in patients with mild or well-
controlled asthma symptoms.11,188 Box 2-2B (p.35) lists factors that increase a patient’s risk of exacerbations,
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independent of their level of symptom control.
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Common exacerbation triggers include:
TR
• Viral respiratory infections515
IS
D
• Allergen exposure e.g. grass pollen,516 soy bean dust,517 fungal spores
R
• Food allergy90
O
PY
• Outdoor air pollution95,513 O
• Seasonal changes and/or returning to school in fall (autumn)518
C
• Poor adherence with ICS519

T
O
• Epidemics of severe asthma exacerbations may occur suddenly, putting high pressure on local health system
N
responses. Such epidemics have been reported in association with springtime thunderstorms and either rye
O
D
grass pollen or fungal spores,520 and with environmental exposure to soy bean dust.517
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Identifying patients at risk of asthma-related death

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In addition to factors known to increase the risk of asthma exacerbations (Box 2-2, p.35), some features are specifically
M
associated with an increase in the risk of asthma-related death (Box 4-1). The presence of one or more of these risk
D
factors should be quickly identifiable in the clinical notes, and these patients should be encouraged to seek urgent
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medical care early in the course of an exacerbation.

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Box 4-1. Factors that increase the risk of asthma-related death

O
C
• A history of near-fatal asthma requiring intubation and mechanical ventilation521

• Hospitalization521 or emergency care visit for asthma in the past year
• Currently using or having recently stopped using oral corticosteroids (a marker of event severity)521
• Not currently using inhaled corticosteroids85,521
• Over-use of SABAs, especially use of more than one canister of salbutamol (or equivalent) monthly102,522
• A history of psychiatric disease or psychosocial problems,96
• Poor adherence with asthma medications and/or poor adherence with (or lack of) a written asthma action plan96
• Food allergy in a patient with asthma425,523
4. Management of worsening asthma and exacerbations 113

Terminology about exacerbations
The academic term ‘exacerbation’ is commonly used in scientific and clinical literature, although hospital-based studies
more often refer to ‘acute severe asthma’. However, the term ‘exacerbation’ is not suitable for use in clinical practice, as
it is difficult for many patients to pronounce and remember.524,525 The term ‘flare-up’ is simpler, and conveys the sense
that asthma is present even when symptoms are absent. The term ‘attack’ is used by many patients and health care
providers but with widely varying meanings, and it may not be perceived as including gradual worsening.524,525 In
pediatric literature, the term ‘episode’ is commonly used, but understanding of this term by parent/carers is not known.
DIAGNOSIS OF EXACERBATIONS
Exacerbations represent a change in symptoms and lung function from the patient’s usual status.17 The decrease in
expiratory airflow can be quantified by lung function measurements such as peak expiratory flow (PEF) or forced
expiratory volume in 1 second (FEV1),526 compared with the patient’s previous lung function or predicted values. In the
acute setting, these measurements are more reliable indicators of the severity of the exacerbation than symptoms. The
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frequency of symptoms may, however, be a more sensitive measure of the onset of an exacerbation than PEF.527
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A minority of patients perceive airflow limitation poorly and can experience a significant decline in lung function without a
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change in symptoms.126,127,135 This especially affects patients with a history of near-fatal asthma and also appears to be
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more common in males.
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Severe exacerbations are potentially life threatening and their treatment requires careful assessment and close
O
monitoring. Patients with severe exacerbations should be advised to see their health care provider promptly or,
PY
depending on the organization of local health services, to proceed to the nearest facility that provides emergency access
O
for patients with acute asthma.
C
T
O
SELF-MANAGEMENT OF EXACERBATIONS WITH A WRITTEN ASTHMA ACTION PLAN

N
O
D
All patients with asthma should be provided with guided self-management education as described in Chapter 3 (p.79),
L-
including monitoring of symptoms and/or lung function, a written asthma action plan, and regular review by a health
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professional.399 (For children 5 years and younger, see Chapter 6, p.139) A sample written asthma action plan template
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is included in the GINA toolbox, available from the GINA website at www.ginasthma.org/gina-implementation-guide/.
AT
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Treatment options for written asthma action plans

D
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A written asthma action plan helps patients to recognize and respond appropriately to worsening asthma. It should
H
IG
include specific instructions for the patient about changes to reliever and controller medications, how to use oral
R
corticosteroids (OCS) if needed (Box 4-2) and when and how to access medical care.
PY
O
The criteria for initiating an increase in controller medication will vary from patient to patient. For patients taking
C
maintenance-only ICS-containing treatment, this should generally be increased when there is a clinically important
change from the patient’s usual level of asthma control, for example, if asthma symptoms are interfering with normal
activities, or PEF has fallen by >20% for more than 2 days.404
Inhaled reliever medication
For patients with mild asthma prescribed as-needed combination low dose ICS-formoterol (see Box 3-5A, p.54),
increasing the as-needed doses of ICS-formoterol when asthma worsens reduces the risk of severe exacerbations
requiring OCS by two-thirds compared with SABA-only treatment,177 and is non-inferior for progression to severe
exacerbation compared with daily ICS plus as-needed SABA. 177,180 Based on product information, the maximum
recommended dose of ICS-formoterol in a single day is a total of 48mcg formoterol for beclometasone-formoterol, and
72mcg formoterol for budesonide-formoterol.
For patients prescribed an inhaled short-acting beta2-agonist (SABA) bronchodilator as their reliever, repeated SABA
dosing provides temporary relief until the cause of the worsening symptoms passes or increased controller treatment
has had time to take effect. However, use of SABA reliever is less effective in preventing progression to severe

exacerbation requiring OCS than use of low dose ICS-formoterol reliever, either with181 or without177,180 daily
maintenance controller (see Chapter 3).
The need for repeated doses of SABA over more than 1–2 days signals the need to review, and possibly increase,
controller treatment if this has not already been done. This is particularly important if there has been a lack of response
to increased use of beta2-agonist therapy.
Combination low dose ICS (budesonide or beclometasone) with formoterol maintenance and reliever regimen
The combination of rapid-onset LABA (formoterol) and low dose ICS (budesonide or beclometasone) in a single inhaler
as both the controller and the reliever medication is effective in improving asthma symptom control,159 and it reduces
exacerbations requiring OCS, and hospitalizations181,219-222 compared with the same or higher dose of controller with as-
needed SABA reliever (Evidence A). The recommended maximum total dose of formoterol in 24 hours with this regimen
is 72 mcg. The benefit of this regimen in preventing exacerbations appears to be due to intervention at a very early
stage of worsening asthma.528,529 This regimen was also effective in reducing exacerbations in children aged 4–11
years,234 (Evidence B), but it is not approved for this age group in many countries. This approach should not be
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attempted with other combination ICS-LABA controller therapies with a slower-onset LABA, or that lack evidence of
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efficacy and safety with a maintenance and reliever regimen.
IB
TR
Other ICS and ICS-LABA maintenance controller regimens
IS
D
In a systematic review of self-management studies, action plans in which the ICS dose was at least doubled were
R
associated with improved asthma outcomes and reduced health care utilization404 (Evidence A). In placebo-controlled
O
PY
trials, temporarily doubling the dose of ICS was not effective530 (Evidence A); however, the delay before increasing the
O
ICS dose (mean 5–7 days531,532) may have contributed. Some studies in adults533 and young children534 have reported
C
that higher ICS doses might help prevent worsening asthma progressing to a severe exacerbation. In a randomized
T
O
controlled trial in primary care with patients aged ≥16 years, those who quadrupled their ICS dose (to average of
N
2000mcg/day BDP equivalent) after their PEF fell were significantly less likely to require OCS.535 In an open-label
O
D
primary care randomized controlled trial of adult and adolescent patients using ICS with or without LABA, early
L-
quadrupling of ICS dose (to average 3200mcg/day BDP equivalent) was associated with a modest reduction in
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prescribing of OCS.536 However, a double-blind placebo-controlled study in children 5-11 years with high adherence to
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low dose ICS found no difference in the rate of severe exacerbations requiring OCS if maintenance ICS was quintupled
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(to 1600mcg BDP equivalent) versus continuing maintenance low-dose therapy.537 Given the shape of the ICS dose-
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response curve, the effect of increasing maintenance ICS when asthma worsens may be greater when background
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adherence is lower. In adult patients with an acute deterioration, high dose ICS for 7–14 days (500–1600mcg BDP-HFA
H
equivalent) had an equivalent benefit to a short course of OCS533 (Evidence A).

IG
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For adults taking combination ICS-LABA as a maintenance controller medication, the ICS dose may be increased by
PY
adding a separate ICS inhaler533,536 (Evidence D). More research is needed to standardize this strategy.
O
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Leukotriene receptor antagonists

For patients using a leukotriene receptor antagonist (LTRA) as their controller, there are no specific studies about how to
manage worsening asthma. Clinician judgment should be used (Evidence D).
Oral corticosteroids
For most patients, the written asthma action plan should provide instructions for when and how to commence OCS.
Typically, a short course of OCS is used (e.g. 40–50 mg/day usually for 5–7 days,533 Evidence B) for patients who:
• Fail to respond to an increase in reliever and controller medication for 2–3 days
• Deteriorate rapidly or who have a PEF or FEV1 <60% of their personal best or predicted value
• Have a history of sudden severe exacerbations.
For children 6–11 years, the recommended dose of OCS is 1–2 mg/kg/day to a maximum of 40 mg/day (Evidence B),
usually for 3–5 days. Patients should be advised about common side-effects, including sleep disturbance, increased
appetite, reflux, and mood changes.538 Patients should contact their doctor if they start taking OCS (Evidence D).

Reviewing response
Patients should see their doctor immediately or present to an acute care unit if their asthma continues to deteriorate
despite following their written asthma action plan, or if their asthma suddenly worsens.
Follow up after a self-managed exacerbation

After a self-managed exacerbation, patients should see their primary care health care provider for a semi-urgent review
(e.g. within 1–2 weeks, ideally before ceasing oral corticosteroids if prescribed), for assessment of symptom control and
additional risk factors for exacerbations (Box 2-2, p.35), and to identify the potential cause of the exacerbation.
This visit provides an opportunity for additional asthma education by a trained asthma educator or trained lay health care
worker.
The written asthma action plan should be reviewed to see if it met the patient’s needs. Maintenance controller treatment
can generally be resumed at previous levels 2–4 weeks after the exacerbation (Evidence D), unless the history suggests
that the exacerbation occurred on a background of long-term poorly controlled asthma. In this situation, provided inhaler
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technique and adherence have been checked, a step up in treatment is indicated (Box 3-5, p.54).
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Adult and adolescent patients with more than 1–2 exacerbations per year despite Step 4-5 therapy should be referred to
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a specialist center for assessment (see decision tree in Chapter 3E, p.94).
D
R
O
PY
O
C
T
O
N
O
D
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D
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H
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O
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Box 4-2. Self-management of worsening asthma in adults and adolescents with a written asthma action plan
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TR
IS
D
Evidence
Medication Short-term change (1–2 weeks) for worsening asthma
R
level
O
PY
Increase usual reliever: O
Low dose ICS-formoterol † Increase frequency of as-needed ICS-formoterol † A
C
T
Short-acting beta2-agonist Increase frequency of SABA use A

O
N
(SABA) For pMDI, add spacer A

O
Increase usual controller:

D
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Maintenance and reliever Continue maintenance ICS-formoterol and increase reliever A

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ICS-formoterol † ICS--formoterol as needed †

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Maintenance ICS In adults and adolescents, quadruple ICS dose. In children with B
AT
with SABA as reliever high adherence, 5x increase in ICS dose is not effective
M
Maintenance ICS-formoterol Quadruple maintenance ICS-formoterol † B

D
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with SABA as reliever †

H
Maintenance ICS plus other Step up to higher dose formulation of ICS plus other LABA B
IG
LABA with SABA as In adults, consider adding a separate ICS inhaler to quadruple ICS D
R
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reliever dose
O
Add oral corticosteroids (OCS) and contact doctor; review before ceasing
C
OCS (prednisone or Add OCS for severe exacerbations (e.g. PEF or FEV1 <60% A
prednisolone) personal best or predicted), or patient not responding to treatment
over 48 hours. Once started, morning dosing is preferable.
Adults: prednisolone 40-50mg/day, usually for 5–7 days. Children D

6--11 years: 1–2 mg/kg/day (maximum 40 mg) usually for 3–5
days.
Tapering is not needed if OCS are prescribed for <2 weeks B
BDP: beclometasone dipropionate; FEV1: forced expiratory volume in 1 second; ICS: inhaled corticosteroid;
PEF: peak expiratory flow; SABA: short-acting beta2-agonist. Options in each section are listed in order of evidence.
* or equivalent dose of prednisone.

† ICS-formoterol as-needed for relief of symptoms in mild asthma, or as part of maintenance and reliever regimen with low
dose budesonide or beclometasone with formoterol. Based on product information, the maximum recommended dose of ICS-
formoterol in a single day is a total of 48mcg formoterol for beclometasone-formoterol, and 72mcg formoterol for budesonide-
formoterol.

MANAGEMENT OF ASTHMA EXACERBATIONS IN PRIMARY CARE
Assessing exacerbation severity

A brief focused history and relevant physical examination should be conducted concurrently with the prompt initiation of
therapy, and findings documented in the notes. If the patient shows signs of a severe or life-threatening exacerbation,
treatment with SABA, controlled oxygen and systemic corticosteroids should be initiated while arranging for the patient’s
urgent transfer to an acute care facility where monitoring and expertise are more readily available. Milder exacerbations
can usually be treated in a primary care setting, depending on resources and expertise.
History
The history should include:
• Timing of onset and cause (if known) of the present exacerbation
• Severity of asthma symptoms, including any limiting exercise or disturbing sleep
• Any symptoms of anaphylaxis
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• Any risk factors for asthma-related death (Box 4-1, p.113)
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• All current reliever and controller medications, including doses and devices prescribed, adherence pattern, any
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recent dose changes, and response to current therapy.
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D
R
O
The physical examination should assess:
•
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Signs of exacerbation severity (Box 4-3, p.119) and vital signs (e.g. level of consciousness, temperature, pulse
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rate, respiratory rate, blood pressure, ability to complete sentences, use of accessory muscles, wheeze).
C
T
• Complicating factors (e.g. anaphylaxis, pneumonia, pneumothorax)

O
N
• Signs of alternative conditions that could explain acute breathlessness (e.g. cardiac failure, inducible laryngeal
O
obstruction, inhaled foreign body or pulmonary embolism).

D
L-
Objective measurements
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• Pulse oximetry. Saturation levels <90% in children or adults signal the need for aggressive therapy.
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• PEF in patients older than 5 years (Box 4-3, p.119)

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D
Treating exacerbations in primary care

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The main initial therapies include repetitive administration of short-acting inhaled bronchodilators, early introduction of
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systemic corticosteroids, and controlled flow oxygen supplementation.526 The aim is to rapidly relieve airflow obstruction
R
PY
and hypoxemia, address the underlying inflammatory pathophysiology, and prevent relapse.
O
Inhaled short-acting beta2-agonists

C
For mild to moderate exacerbations, repeated administration of inhaled SABA (up to 4–10 puffs every 20 minutes for the
first hour) is an effective and efficient way to achieve rapid reversal of airflow limitation539 (Evidence A). After the first
hour, the dose of SABA required varies from 4–10 puffs every 3–4 hours up to 6–10 puffs every 1–2 hours, or more
often. No additional SABA is needed if there is a good response to initial treatment (e.g. PEF >60–80% of predicted or
personal best for 3–4 hours).
Delivery of SABA via a pMDI and spacer or a DPI leads to a similar improvement in lung function as delivery via
nebulizer539,540 (Evidence A); however, patients with acute severe asthma were not included in these studies. The most
cost-effective route of delivery is pMDI and spacer,541 provided the patient can use this device. Because of static charge,
some spacers require pre-washing with detergent before use. The manufacturer’s advice should be followed.

Box 4-3. Management of asthma exacerbations in primary care (adults, adolescents, children 6–11 years)
TE
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IB
T R
IS
D
R
O
PY
O
C
T
O
N
O
D
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AT
M
D
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O2: oxygen; PEF: peak expiratory flow; SABA: short-acting beta2-agonist (doses are for salbutamol).

Controlled oxygen therapy (if available)
Oxygen therapy should be titrated against pulse oximetry (if available) to maintain oxygen saturation at 93–95% (94–
98% for children 6–11 years). In hospitalized asthma patients, controlled or titrated oxygen therapy is associated with
lower mortality and better outcomes than high concentration (100%) oxygen therapy542-545 (Evidence A). Oxygen should
not be withheld if oximetry is not available, but the patient should be monitored for deterioration, somnolence or fatigue
because of the risk of hypercapnia and respiratory failure.542-545 If supplemental oxygen is administered, oxygen
saturation should be maintained no higher than 96% in adults.546
Systemic corticosteroids
OCS should be given promptly, especially if the patient is deteriorating, or had already increased their reliever and
controller medications before presenting (Evidence B). The recommended dose for adults is 1 mg prednisolone/kg/day
or equivalent up to a maximum of 50 mg/day, and 1–2 mg/kg/day for children 6–11 years up to a maximum of 40
mg/day). OCS should usually be continued for 5–7 days in adults547,548 and 3-5 days in children549 (Evidence B). Patients
should be advised about common side-effects, including sleep disturbance, increased appetite, reflux and mood
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changes.538
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Controller medication
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Patients already prescribed controller medication should be provided with advice about increasing the dose for the next
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2–4 weeks, as summarized in Box 4-2 (p.117). Patients not currently taking controller medication should be commenced
R
on regular ICS-containing therapy, as SABA-only treatment of asthma is no longer recommended. An exacerbation
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requiring medical care indicates that the patient is at increased risk of future exacerbations (Box 2-2, p.35).
O
Antibiotics (not recommended)
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T
O
Evidence does not support routine use of antibiotics in the treatment of acute asthma exacerbations unless there is
N
strong evidence of lung infection (e.g. fever and purulent sputum or radiographic evidence of pneumonia).550
O
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Reviewing response
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During treatment, patients should be closely monitored, and treatment titrated according to their response. Patients who
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present with signs of a severe or life-threatening exacerbation (Box 4-3, p.119), who fail to respond to treatment, or who
M
continue to deteriorate should be transferred immediately to an acute care facility. Patients with little or slow response to
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SABA treatment should be closely monitored.

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For many patients, lung function can be monitored after SABA therapy is initiated. Additional treatment should continue
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until PEF or FEV1 reaches a plateau or (ideally) returns to the patient’s previous best. A decision can then be made
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whether to send the patient home or transfer them to an acute care facility.
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Follow up
Discharge medications should include as-needed reliever medication, a short course of OCS and regular controller
treatment. SABA-only treatment is not recommended. Inhaler technique and adherence should be reviewed before
discharge. Patients should be advised to use their reliever inhaler only as-needed, rather than routinely. A follow-up
appointment should be arranged for about 2–7 days later, depending on the clinical and social context.
At the review visit the health care provider should assess whether the flare-up has resolved, and whether OCS can be
ceased. They should assess the patient’s level of symptom control and risk factors; explore the potential cause of the
exacerbation; and review the written asthma action plan (or provide one if the patient does not already have one).
Maintenance controller treatment can generally be stepped back to pre-exacerbation levels 2–4 weeks after the
exacerbation, unless the exacerbation was preceded by symptoms suggestive of chronically poorly controlled asthma. In
this situation, provided inhaler technique and adherence have been checked, a step up in treatment (Box 3-5, p.54) is
indicated.

MANAGEMENT OF ASTHMA EXACERBATIONS IN THE EMERGENCY DEPARTMENT
Severe exacerbations of asthma are life-threatening medical emergencies, which are most safely managed in an acute
care setting e.g. emergency department (Box 4-4). Management of asthma in the intensive care unit is beyond the
scope of this report and readers are referred to a comprehensive review.551
Assessment
History
A brief history and physical examination should be conducted concurrently with the prompt initiation of therapy. Include:
• Time of onset and cause (if known) of the present exacerbation
• Severity of asthma symptoms, including any limiting exercise or disturbing sleep
• Any symptoms of anaphylaxis
• Risk factors for asthma-related death (Box 4-1, p.113)
• All current reliever and controller medications, including doses and devices prescribed, adherence pattern, any
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recent dose changes, and response to current therapy.
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The physical examination should assess:
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• Signs of exacerbation severity (Box 4-4), including vital signs (e.g. level of consciousness, temperature, pulse
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rate, respiratory rate, blood pressure, ability to complete sentences, use of accessory muscles)
• PY
Complicating factors (e.g. anaphylaxis, pneumonia, atelectasis, pneumothorax or pneumomediastinum)
O
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• Signs of alternative conditions that could explain acute breathlessness (e.g. cardiac failure, inducible laryngeal
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obstruction, inhaled foreign body or pulmonary embolism).

O
N
O
Objective assessments
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Objective assessments are also needed as the physical examination alone may not indicate the severity of the
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exacerbation.552,553 However, patients, and not their laboratory values, should be the focus of treatment.
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• Measurement of lung function: this is strongly recommended. If possible, and without unduly delaying treatment,
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PEF or FEV1 should be recorded before treatment is initiated, although spirometry may not be possible in children
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with acute asthma. Lung function should be monitored at one hour and at intervals until a clear response to
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treatment has occurred or a plateau is reached.

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• Oxygen saturation: this should be closely monitored, preferably by pulse oximetry. This is especially useful in
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children if they are unable to perform PEF. In children, oxygen saturation is normally >95%, and saturation <92%
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is a predictor of the need for hospitalization554 (Evidence C). Saturation levels <90% in children or adults signal the
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need for aggressive therapy. Subject to clinical urgency, saturation should be assessed before oxygen is
commenced, or 5 minutes after oxygen is removed or when saturation stabilizes.
• Arterial blood gas measurements are not routinely required:555 They should be considered for patients with PEF or
FEV1 <50% predicted,556 or for those who do not respond to initial treatment or are deteriorating. Supplemental
controlled oxygen should be continued while blood gases are obtained. During an asthma exacerbation PaCO2 is
often below normal (<40 mmHg). Fatigue and somnolence suggest that pCO2 may be increasing and airway
intervention may be needed. PaO2<60 mmHg (8 kPa) and normal or increased PaCO2 (especially >45 mmHg, 6
kPa) indicate respiratory failure.
• Chest X-ray (CXR) is not routinely recommended: In adults, CXR should be considered if a complicating or
alternative cardiopulmonary process is suspected (especially in older patients), or for patients who are not
responding to treatment where a pneumothorax may be difficult to diagnose clinically.557 Similarly, in children,
routine CXR is not recommended unless there are physical signs suggestive of pneumothorax, parenchymal
disease or an inhaled foreign body. Features associated with positive CXR findings in children include fever, no
family history of asthma, and localized lung examination findings.558

Treatment in acute care settings such as the emergency department
The following treatments are usually administered concurrently to achieve rapid improvement.559
Oxygen
To achieve arterial oxygen saturation of 93–95% (94–98% for children 6–11 years), oxygen should be administered by
nasal cannulae or mask. In severe exacerbations, controlled low flow oxygen therapy using pulse oximetry to maintain
saturation at 93–95% is associated with better physiological outcomes than with high concentration (100%) oxygen
therapy542-544 (Evidence B). However, oxygen therapy should not be withheld if pulse oximetry is not available (Evidence
D). Once the patient has stabilized, consider weaning them off oxygen using oximetry to guide the need for ongoing
oxygen therapy.
Inhaled short-acting beta2-agonists
Inhaled SABA therapy should be administered frequently for patients presenting with acute asthma. The most cost-
effective and efficient delivery is by pMDI with a spacer539,541 (Evidence A). Evidence is less robust in severe and near-
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fatal asthma. Systematic reviews of intermittent versus continuous SABA in acute asthma, which mostly used nebulized
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SABA, provide conflicting results. Use of nebulizers can disseminate aerosols and potentially contribute to spread of
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respiratory viral infections.560
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Current evidence does not support the routine use of intravenous beta2-agonists in patients with severe asthma
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exacerbations561 (Evidence A).
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Epinephrine (for anaphylaxis) O
Intramuscular epinephrine (adrenaline) is indicated in addition to standard therapy for acute asthma associated with
C
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anaphylaxis and angioedema. It is not routinely indicated for other asthma exacerbations.
O
N
Systemic corticosteroids
O
D
Systemic corticosteroids speed resolution of exacerbations and prevent relapse, and in acute care settings should be
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utilized in all but the mildest exacerbations in adults, adolescents and children 6–11 years.562-564 (Evidence A). Where
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possible, systemic corticosteroids should be administered to the patient within 1 hour of presentation.563,565 Use of
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systemic corticosteroids is particularly important in the emergency department if:

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• Initial SABA treatment fails to achieve lasting improvement in symptoms

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• The exacerbation developed while the patient was taking OCS

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• The patient has a history of previous exacerbations requiring OCS

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Route of delivery: oral administration is as effective as intravenous. The oral route is preferred because it is quicker, less
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invasive and less expensive.566,567 For children, a liquid formulation is preferred to tablets. OCS require at least 4 hours
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to produce a clinical improvement. Intravenous corticosteroids can be administered when patients are too dyspneic to
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swallow; if the patient is vomiting; or when patients require non-invasive ventilation or intubation. In patients discharged
from the emergency department, an intramuscular corticosteroid may be an alternative to a course of OCS for
preventing relapse,568 especially if there are concerns about adherence with oral therapy.569 However, current evidence
does not demonstrate a benefit of intramuscular over oral corticosteroids.564
Dosage: daily doses of OCS equivalent to 50 mg prednisolone as a single morning dose, or 200 mg hydrocortisone in
divided doses, are typically used for adults. For children, an OCS dose of 1–2 mg/kg up to a maximum of 40 mg/day is
suggested.570
Duration: 5- and 7-day courses in adults have been found to be as effective as 10- and 14-day courses
respectively547,548 (Evidence B), and a 3–5-day course in children is usually considered sufficient for most. A small
number of studies examined oral dexamethasone 0.6mg/kg, given once daily for 1-2 days in children and adults; the
relapse rate was similar to that with prednisolone for 3-5 days, with a lower risk of vomiting, but there are concerns
about metabolic side-effects if dexamethasone is instead continued beyond 2 days.571-573 If there is a failure of

Box 4-4. Management of asthma exacerbations in acute care facility, e.g. emergency department
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R
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O
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T
O
N
O
D
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D
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H
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O
C
ICS: inhaled corticosteroids; ICU: intensive care unit; IV: intravenous; O2: oxygen; PEF: peak expiratory flow; FEV1: forced expiratory volume in 1 sec

resolution, or relapse of symptoms, consideration should be given to switching to prednisolone. Evidence from studies in
which all patients were taking maintenance ICS after discharge suggests that there is no benefit in tapering the dose of
OCS, either in the short term574 or over several weeks575 (Evidence B).
Inhaled corticosteroids
Within the emergency department: high dose ICS given within the first hour after presentation reduces the need for
hospitalization in patients not receiving systemic corticosteroids565 (Evidence A). When given in addition to systemic
corticosteroids, evidence is conflicting565 (Evidence B). Overall, ICS are well tolerated; however, cost is a significant
factor, and the agent, dose and duration of treatment with ICS in the management of asthma in the emergency
department remain unclear.
On discharge home: patients should be prescribed regular ongoing ICS-containing treatment since the occurrence of a
severe exacerbation is a risk factor for future exacerbations (Evidence B) (Box 2-2, p.35), and ICS-containing
medications significantly reduce the risk of asthma-related death or hospitalization190 (Evidence A). SABA-only treatment
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of asthma is no longer recommended. For short-term outcomes such as relapse requiring admission, symptoms, and
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quality of life, a systematic review found no significant differences when ICS were added to systemic corticosteroids
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after discharge.576 There was some evidence, however, that post-discharge ICS were as effective as systemic
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corticosteroids for milder exacerbations, but the confidence limits were wide.576 (Evidence B). Cost may be a significant
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factor for patients in the use of high dose ICS, and further studies are required to establish their role.576
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O
Other treatments
Ipratropium bromide
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O
C
For adults and children with moderate-severe exacerbations, treatment in the emergency department with both SABA
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O
and ipratropium, a short-acting anticholinergic, was associated with fewer hospitalizations and greater improvement in
N
PEF and FEV1 compared with SABA alone.577-579 For children hospitalized for acute asthma, no benefits were seen from
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adding ipratropium to SABA, including no reduction in length of stay.580

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Aminophylline and theophylline

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Intravenous aminophylline and theophylline should not be used in the management of asthma exacerbations, in view of
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their poor efficacy and safety profile, and the greater effectiveness and relative safety of SABA.581 The use of
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intravenous aminophylline is associated with severe and potentially fatal side-effects, particularly in patients already
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treated with sustained-release theophylline. In adults with severe asthma exacerbations, add-on treatment with
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aminophylline does not improve outcomes compared with SABA alone.581

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Magnesium
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O
Intravenous magnesium sulfate is not recommended for routine use in asthma exacerbations; however, when
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administered as a single 2 g infusion over 20 minutes, it reduces hospital admissions in some patients, including adults
with FEV1 <25–30% predicted at presentation; adults and children who fail to respond to initial treatment and have
persistent hypoxemia; and children whose FEV1 fails to reach 60% predicted after 1 hour of care582-584 (Evidence A).
Randomized, controlled trials that excluded patients with more severe asthma showed no benefit with the addition of
intravenous or nebulized magnesium compared with placebo in the routine care of asthma exacerbations in adults and
adolescents585-587 or children.586,588 (Evidence B).
Helium oxygen therapy
A systematic review of studies comparing helium-oxygen with air–oxygen suggests there is no role for this intervention
in routine care (Evidence B), but it may be considered for patients who do not respond to standard therapy; however,
availability, cost and technical issues should be considered.589

There is limited evidence to support a role for oral or intravenous LTRAs in acute asthma. Small studies have
demonstrated improvement in lung function590,591 but the clinical role and safety of these agents requires more study.
ICS-LABA combinations
The role of these medications in the emergency department or hospital is unclear. One study showed that high-dose
budesonide-formoterol in patients in the emergency department, all of whom received prednisolone, had similar efficacy
and safety profile to SABA,592 but more studies are needed. Another study examined addition of salmeterol to OCS for
hospitalized patients, but was not adequately powered to support a recommendation.593
Antibiotics (not recommended)
Evidence does not support the routine use of antibiotics in the treatment of acute asthma exacerbations unless there is
strong evidence of lung infection (e.g. fever or purulent sputum or radiographic evidence of pneumonia).550
Sedatives
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Sedation should be strictly avoided during exacerbations of asthma because of the respiratory depressant effect of
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anxiolytic and hypnotic drugs. An association between the use of these drugs and avoidable asthma deaths has been
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reported.594,595
D
Non-invasive ventilation (NIV)
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O
The evidence regarding the role of NIV in asthma is weak. A systematic review identified five studies involving 206
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participants with acute severe asthma treated with NIV or placebo.596 Two studies found no difference in need for
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endotracheal intubation but one study identified fewer admissions in the NIV group. No deaths were reported in either
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study. Given the small size of the studies, no recommendation is offered. If NIV is tried, the patient should be monitored
N
closely (Evidence D). It should not be attempted in agitated patients, and patients should not be sedated in order to
O
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receive NIV (Evidence D).

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Reviewing response
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Clinical status and oxygen saturation should be re-assessed frequently, with further treatment titrated according to the
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patient’s response (Box 4-4, p.123). Lung function should be measured after one hour, i.e. after the first three
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bronchodilator treatments, and patients who deteriorate despite intensive bronchodilator and corticosteroid treatment
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should be re-evaluated for transfer to the intensive care unit.

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Criteria for hospitalization versus discharge from the emergency department

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From retrospective analyses, clinical status (including the ability to lie flat) and lung function 1 hour after commencement
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of treatment are more reliable predictors of the need for hospitalization than the patient’s status on arrival.597,598
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Spirometric criteria proposed for consideration for discharge from the emergency department include:599
• If pre-treatment FEV1 or PEF is <25% predicted or personal best, or post-treatment FEV1 or PEF is <40%
predicted or personal best, hospitalization is recommended.
• If post-treatment lung function is 40–60% predicted, discharge may be possible after considering the patient’s risk
factors (Box 4-1, p.113) and availability of follow-up care.
• If post-treatment lung function is >60% predicted or personal best, discharge is recommended after considering
risk factors and availability of follow-up care.
Other factors associated with increased likelihood of need for admission include:600-602
• Female sex, older age and non-white race
• Use of more than eight beta2-agonist puffs in the previous 24 hours
• Severity of the exacerbation (e.g. need for resuscitation or rapid medical intervention on arrival, respiratory rate
>22 breaths/minute, oxygen saturation <95%, final PEF <50% predicted)

• Past history of severe exacerbations (e.g. intubations, asthma admissions)
• Previous unscheduled office and emergency department visits requiring use of OCS
Overall, these risk factors should be considered by clinicians when making decisions on admission/discharge for
patients with asthma managed in the acute care setting. The patient’s social circumstances should also be considered.
Discharge planning
Prior to discharge from the emergency department or hospital to home, arrangements should be made for a follow-up
appointment within 2–7 days, and strategies to improve asthma management including medications, inhaler skills and
written asthma action plan, should be addressed (Box 4-5).268
Follow up after emergency department presentation or hospitalization for asthma

Following discharge, the patient should be reviewed by their health care provider regularly over subsequent weeks until
good symptom control is achieved and personal best lung function is reached or surpassed. Incentives such as free
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transport and telephone reminders improve primary care follow up but have shown no effect on long-term outcomes.268
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Patients discharged following an emergency department presentation or hospitalization for asthma should be especially
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targeted for an asthma education program, if one is available. Patients who were hospitalized may be particularly
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receptive to information and advice about their illness. Health care providers should take the opportunity to review:
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• The patient’s understanding of the cause of their asthma exacerbation
O
• Modifiable risk factors for exacerbations (including, where relevant, smoking) (Box 3-8, p.67)
• PY
The patient’s understanding of the purposes and correct uses of medications
O
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• The actions the patient needs to take to respond to worsening symptoms or peak flows.
T
O
After emergency department presentation, comprehensive intervention programs that include optimal controller
N
O
management, inhaler technique, and elements of self-management education (self-monitoring, written action plan and
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regular review142) are cost effective and have shown significant improvement in asthma outcomes268 (Evidence B).
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Referral for expert advice should be considered for patients who have been hospitalized for asthma, or who repeatedly
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present to an acute care setting despite having a primary care provider. No recent studies are available, but earlier
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studies suggest that follow-up by a specialist is associated with fewer subsequent emergency department visits or
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hospitalizations and better asthma control.268

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Box 4-5. Discharge management after hospital or emergency department care for asthma
Medications
Inhaled corticosteroids (ICS)
Initiate ICS prior to discharge, if not previously prescribed (Box 3-4,A-D, p.50 – p.53). Patients currently prescribed
ICS-containing medication should generally have their treatment stepped up for 2–4 weeks (Box 4-2, p.117) and
should be reminded about the importance of adherence with daily use.
Oral corticosteroids (OCS)

To reduce the risk of relapse, prescribe at least a 5–7 day course of OCS for adults (prednisolone or equivalent 40-50
mg/day)576and 3–5 days for children (1–2 mg/kg/day to a maximum of 40 mg/day)603 (Evidence A). Review progress
before ceasing OCS. If the OCS is dexamethasone, treatment is only for total 1-2 days,571 but if there is failure of
resolution, or relapse of symptoms, consideration should be given to switching to prednisolone. For patients
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considered at risk of poor adherence, intramuscular corticosteroids may be considered564 (Evidence B).
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Reliever medication
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Transfer patients back to as-needed rather than regular reliever medication use, based on symptomatic and
D
objective improvement. If ipratropium bromide was used in the emergency department or hospital, it may be quickly
R
O
discontinued, as it is unlikely to provide ongoing benefit.
Risk factors that contributed to the exacerbation PY
O
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T
Identify factors that may have contributed to the exacerbation and implement strategies to reduce modifiable risk
O
N
factors (Box 3-8, p.67). An exacerbation severe enough to require hospitalization may follow irritant or allergen
O
exposure, inadequate long-term treatment, problems with adherence, and/or lack of a written asthma action plan, as
D
well as unavoidable factors such as viral respiratory infections.

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Self-management skills and written asthma action plan

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AT
• Review inhaler technique (Box 3-12, p.80).

M
• Review technique with PEF meter if used.

D
• Provide a written asthma action plan (Box 4-2, p.117) or review the patient’s existing plan, either at discharge or as
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soon as possible afterwards. Patients discharged from the emergency department with an action plan and PEF
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meter have better outcomes than patients discharged without these resources.604
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• Evaluate the patient’s response to the exacerbation. If it was inadequate, review the action plan and provide written
guidance to assist if asthma worsens again.604,605
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• Review the patient’s use of controller treatment before and during the exacerbation. Was it increased promptly and
by how much? Were OCS added and if not, why not? Consider providing a short-course of OCS to be on hand for
subsequent exacerbations.
Follow up appointment
A follow-up appointment within 2–7 days of discharge should be made with the patient’s usual health care provider, to
ensure that treatment is continued, that asthma symptoms are well controlled, and that the patient’s lung function
reaches their personal best (if known).
ICS: inhaled corticosteroids; OCS: oral corticosteroids; PEF: peak expiratory flow

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D
O
N
O
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O
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Chapter 5.
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Diagnosis and initial

N
O
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treatment of adults with

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features of asthma, COPD

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or both
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(‘asthma-COPD overlap’)
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KEY POINTS
Asthma and COPD are heterogeneous and overlapping conditions

• ‘Asthma’ and ‘COPD’ are umbrella labels for heterogeneous conditions characterized by chronic airway and/or lung
disease. Asthma and COPD each include several different clinical phenotypes, and are likely to have several
different underlying mechanisms, some of which may be common to both asthma and COPD.
• Symptoms of asthma and COPD may be similar, and the diagnostic criteria overlap.
Why are the labels ‘asthma’ and ‘COPD’ still important?
• There are extremely important differences in evidence-based treatment recommendations for asthma and COPD,
with treatment with long-acting bronchodilators alone (i.e. without inhaled corticosteroids (ICS)) recommended as
initial treatment in COPD but contraindicated in asthma due to the risk of severe exacerbations and death.
• These risks are also seen in patients who have diagnoses of both asthma and COPD, making it important to
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identify adult patients who, for safety, should not be treated with long-acting bronchodilators alone.
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• In COPD, high dose ICS should not be used because of the risk of pneumonia.
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Many patients have features of both asthma and COPD
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• Distinguishing asthma from COPD can be difficult, particularly in smokers and older adults, and some patients may
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have features of both asthma and COPD.
O
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• The terms ‘asthma-COPD overlap’ (ACO) or ‘asthma+COPD’ are simple descriptors for patients who have features
O
of both asthma and COPD.
C
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• These terms do not refer to a single disease entity. They include patients with several clinical phenotypes that are
O
likely caused by a range of different underlying mechanisms.

N
O
• More research is needed to better define these phenotypes and mechanisms, but in the meantime, safety of
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pharmacologic treatment is a high priority.

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Diagnosis
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• Diagnosis in patients with chronic respiratory symptoms involves a stepwise approach, first recognizing that the
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patient is likely to have chronic airways disease, then syndromic categorization as characteristic asthma,
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characteristic COPD, with features of both or having other conditions such as bronchiectasis.
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• Spirometry is essential for confirming persistent airflow limitation, but variable airflow obstruction can be detected
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with serial peak flow measurements and/or measurements before and after bronchodilator.
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Initial treatment for safety and clinical efficacy

O
C
• For asthma: inhaled corticosteroids (ICS) are essential either alone or in combination with a long-acting
bronchodilator (LABA), to reduce the risk of severe exacerbations and death. Do not treat with LABA and/or LAMA
alone without ICS.
• For patients with features of both asthma and COPD, treat as asthma. ICS-containing therapy is important to
reduce the risk of severe exacerbations and death. Do not give LABA and/or LAMA alone without ICS.
• For COPD: Treat according to current GOLD 2020 recommendations, i.e. initial treatment with LAMA and/or LABA,
with as-needed SABA; add ICS for patients with hospitalizations, ≥2 exacerbations/year requiring OCS, or blood
eosinophils ≥300/µl.
• All patients should be provided with structured education especially focusing on inhaler technique and adherence
as well as being assessed for, and receive appropriate treatment for, other clinical problems, including advice about
smoking cessation, immunizations, physical activity, and management of comorbidities.
• Specialist referral for additional investigations is encouraged, as patients with asthma +COPD often have worse
outcomes than those with asthma or COPD alone.
130 5. Diagnosis and initial treatment of asthma, COPD and asthma-COPD overlap
OBJECTIVES
The objectives of this section of the GINA report are:
o To assist primary care clinicians to identify typical asthma and typical COPD and to recognize when patients have
features of both. This is particularly relevant in older patients (40 years or above)
o To provide advice about safe and effective initial treatment
o To provide guidance on indications for referral for specialist assessment.
BACKGROUND TO DIAGNOSING ASTHMA AND/OR COPD IN ADULT PATIENTS

Why are the labels ‘asthma’ and ‘COPD’ still important?
Asthma and COPD are heterogeneous conditions characterized by airway obstruction. Each of these ‘umbrella’ labels
includes several different patterns of clinical features (phenotypes) that may overlap. Each may also include different
inflammatory patterns and different underlying mechanisms, some of which may be common to both asthma and
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COPD.606
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The most easily recognized phenotypes of asthma and COPD such as allergic asthma in children/young adults and
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emphysema in older smokers are clearly distinguishable. Regulatory studies of pharmacotherapy in asthma and COPD
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are largely restricted to patients with very clearly defined asthma or COPD. However, in the community, the features of
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asthma and COPD may overlap, especially in older adults.
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There are extremely important differences in treatment recommendations for asthma and COPD. In particular,
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treatment with long-acting bronchodilators alone (i.e. without ICS) is recommended for initial treatment in COPD47 but is
O
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contraindicated in asthma due to the risk of severe exacerbations and death. 116,198,607,608 Several studies have also
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shown that patients with diagnoses of both asthma and COPD are at increased risk of hospitalization or death if they are
O
N
treated with LABA compared with ICS-LABA.609-611

O
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Challenges in clinical diagnosis of asthma and COPD

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Although asthma is characterized by variable expiratory airflow limitation, at least initially (Box 1-2, p.23), and COPD is
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characterized by persistent airflow limitation,47 the definitions of asthma and COPD are not mutually exclusive (Box 5-1,
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p.132). This means that clinical features are also important in making a diagnosis.
M
In children and young adults with chronic or recurrent respiratory symptoms, the differential diagnosis is different from
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that in older adults. Once infectious disease and nonpulmonary conditions (e.g. congenital heart disease, inducible
H
laryngeal obstruction) have been excluded, the most likely chronic airway disease in children and young adults is
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asthma.
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However, in adults with a history of long-standing asthma,612,613 persistent airflow limitation may be found 614-618
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Distinguishing these from patients with COPD is problematic, especially if they are smokers or have other risk factors for
COPD.619-622 On the other hand, patients with COPD may show evidence of reversible airflow obstruction when a rapid-
acting bronchodilator is administered, a feature more strongly associated with asthma. In medical records, such patients
often are assigned both diagnoses.49,623
In keeping with common usage of the term “overlap” in other contexts, e.g. for the association between COPD with sleep
disorders, and in overlap syndromes of collagen vascular disease, the descriptive term ‘asthma-COPD overlap’ is often
used. Another common descriptor is ‘asthma+COPD’. However, to date there are no generally agreed more specific
terms or defining features for patients with this combination of diagnoses.
‘Asthma-COPD overlap’ is a descriptor for patients often seen in clinical practice, who comprise a heterogeneous group.
It does not mean a single disease entity.
5. Diagnosis and initial treatment of asthma, COPD and asthma-COPD overlap 131
Prevalence and morbidity of asthma-COPD overlap
In epidemiological studies, reported prevalence rates for asthma-COPD overlap have ranged between 9% and 55% of
those with either diagnosis, with variation by gender and age;617,624-626 the wide range reflects the different criteria that
have been used by different investigators. Concurrent doctor-diagnosed asthma and COPD has been reported in
between 15 and 32% of patients with one or other diagnosis.623,627,628
There is broad agreement that patients with features of both asthma and COPD experience frequent exacerbations,49,615
have poor quality of life,49,624 a more rapid decline in lung function, higher mortality,615,623 and greater use of healthcare
resources49,629 compared with patients with asthma or COPD alone.
Box 5-1. Current definitions of asthma and COPD, and clinical description of asthma-COPD overlap
Asthma
Asthma is a heterogeneous disease, usually characterized by chronic airway inflammation. It is defined by the history of
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respiratory symptoms such as wheeze, shortness of breath, chest tightness and cough that vary over time and in
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intensity, together with variable expiratory airflow limitation. [GINA 2020]
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COPD
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Chronic obstructive pulmonary disease (COPD) is a common, preventable and treatable disease that is characterized by
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persistent respiratory symptoms and airflow limitation that is due to airway and/or alveolar abnormalities usually caused
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by significant exposure to noxious particles or gases and influenced by host factors including abnormal lung
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development. [GOLD 2020]47
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Asthma-COPD overlap, also called asthma+COPD

N
O
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‘Asthma-COPD overlap’ and ‘asthma +COPD’ are terms used to collectively describe patients who have persistent
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airflow limitation together with clinical features that are consistent with both asthma and COPD.
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This is not a definition of a single disease entity, but a descriptive term for clinical use that includes several different
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clinical phenotypes reflecting different underlying mechanisms.

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ASSESSMENT AND MANAGEMENT OF PATIENTS WITH CHRONIC RESPIRATORY SYMPTOMS

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#1: History and clinical assessment to establish the following:

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• The nature and pattern of respiratory symptoms (variable and/or persistent)

• History of asthma diagnosis; childhood and/or current
• Exposure history: smoking and/or other exposures to risk factors for COPD
The features that are most helpful in identifying and distinguishing asthma from COPD, and the features that should
prompt a patient to be treated as asthma to reduce the risk of severe exacerbations and death, are shown in Box 5-2.
Caution: Consider alternative diagnoses: Other airways diseases, such as bronchiectasis and chronic bronchitis, and
other forms of lung disease such as interstitial lung disease may present with some of the above features. The approach
to diagnosis provided here does not replace the need for a full assessment of patients presenting with respiratory
symptoms, to first exclude non-respiratory diagnoses such as heart failure.9 Physical examination may provide
supportive information.
Box 5-2. Approach to initial treatment in patients with asthma and/or COPD
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GOLD: Global Initiative for Obstructive Lung Disease; ICS: inhaled corticosteroid; LABA: long-acting β2-agonist; LAMA: long-acting muscarinic antagonist
#2: Spirometry is essential to confirm the following:
• The presence of persistent expiratory airflow limitation
• Variable expiratory airflow limitation
Spirometry is preferably performed at the initial assessment. In cases of clinical urgency it may be delayed to a
subsequent visit, but confirmation of diagnosis may be more difficult once patients are started on ICS-containing therapy
(see Box 1-3, p.26). Early confirmation (or exclusion) of the presence of persistent expiratory airflow limitation may avoid
needless trials of therapy, or delays in initiating other investigations. Spirometry can confirm both persistent airflow
limitation and reversibility (Box 5-2, p.133, Box 5-3, p.134).
Measurement of peak expiratory flow (PEF), if performed repeatedly on the same meter over a period of 1–2 weeks,
may help to confirm reversible airflow limitation and the diagnosis of asthma by demonstrating excessive variability (Box
1-2, p.23). However, PEF is not as reliable as spirometry, and a normal PEF does not rule out either asthma or COPD.
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Box 5-3. Spirometric measures in asthma and COPD
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Spirometric variable Asthma COPD Asthma+COPD
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Normal FEV1/FVC Compatible with asthma Not compatible with COPD Not compatible
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pre- or post BD
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Reduced post-BD FEV1/FVC Indicates airflow limitation Required for diagnosis of
O Required for diagnosis of
(< lower limit of normal, or but may improve COPD asthma+COPD
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<0.7 (GOLD)) spontaneously or on

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treatment
N
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Post-BD FEV1 ≥80% Compatible with diagnosis of Compatible with mild Compatible with mild
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predicted asthma (good asthma persistent airflow limitation if persistent airflow limitation
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control or interval between post-BD FEV1/FVC is reduced if post-BD FEV1/FVC is

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symptoms) reduced
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Post-BD FEV1 <80% Compatible with diagnosis of An indicator of severity of As for COPD and asthma
predicted asthma. Risk factor for airflow limitation and risk of
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asthma exacerbations future events (e.g. mortality

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and COPD exacerbations)

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Post-BD increase in FEV1 Usual at some time in course Common and more likely Common and more likely
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>12% and 200 mL from of asthma, but may not be when FEV1 is low when FEV1 is low
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baseline (reversible airflow present when well-controlled

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limitation). or on controller therapy

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Post-BD increase in FEV1 High probability of asthma Unusual in COPD Compatible with
>12% and 400 mL from asthma+COPD
baseline (marked
reversibility)
BD: bronchodilator; FEV1: forced expiratory volume in 1 second; FVC: forced vital capacity; GOLD: Global Initiative for Obstructive Lung Disease.
#3: Selecting initial treatment (See Box 5-2, p.133)
For asthma
Commence treatment as described in Chapter 3 (Box 3-4,A-D, p.50 – p.53). Pharmacotherapy is based on ICS to
reduce the risk of severe exacerbations and death and to improve symptom control, with add-on treatment as required,
e.g. add-on LABA and/or LAMA. As-needed low dose ICS-formoterol may be used as the reliever, on its own in mild
asthma or in addition to maintenance ICS-formoterol in patients with moderate-severe asthma prescribed maintenance
and reliever therapy (see Box 3-5A, p.54). Inhaled therapy should be optimized to minimize the need for oral
corticosteroids (OCS).
For COPD
Commence treatment as in the current GOLD strategy report.47 Pharmacotherapy starts with symptomatic treatment
with long-acting bronchodilators (LABA and/or LAMA). ICS may be added as per GOLD for patients with
hospitalizations, ≥2 exacerbations/year requiring OCS, or blood eosinophils ≥300/µL, but is not used alone as
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monotherapy without LABA and/or LAMA. Inhaled therapy should be optimized to reduce the need for OCS. In patients
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with features of COPD, high dose ICS should be avoided because of the risk of pneumonia.630,631
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For patients with features of asthma and COPD
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Start treatment as for asthma (Box 3-4,A-D, p.50 – p.53) until further investigations have been performed.
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ICS play a pivotal role in preventing morbidity and even death in patients with uncontrolled asthma symptoms, for whom
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even seemingly ‘mild’ symptoms (compared to those of moderate or severe COPD) might indicate significant risk of a
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life-threatening attack.632 For patients with asthma+COPD, ICS should be used initially in a low or medium dose (see
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Box 3-6, p.56), depending on level of symptoms and risk of adverse effects, including pneumonia.
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Patients with features or diagnosis of both asthma and COPD will usually also require add-on treatment with LABA
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and/or LAMA to provide adequate symptom control.

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Patients with any features of asthma should not be treated with LABA and/or LAMA alone, without ICS. A large
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case-control study in community patients with newly-diagnosed COPD found that those who also had a diagnosis of
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asthma had a lower risk of COPD hospitalizations and death if treated with combination ICS-LABA than with LABA
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alone.609 In another large retrospective longitudinal population cohort study of patients aged ≥66 years, those recorded
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as having asthma with COPD had lower morbidity and hospitalizations if they received ICS treatment; a similar benefit
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was seen in those with COPD plus concurrent asthma.611

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All patients with chronic airflow limitation

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Provide advice, as described in the GINA and GOLD reports, about:

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• Treatment of modifiable risk factors including advice about smoking cessation

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• Treatment of comorbidities
• Non-pharmacological strategies including physical activity, and, for COPD or asthma-COPD overlap, pulmonary
rehabilitation and vaccinations
• Appropriate self-management strategies
• Regular follow-up
In a majority of patients, the initial management of asthma and COPD can be satisfactorily carried out at primary care
level. However, both the GINA and GOLD strategy reports recommend referral for further diagnostic procedures at
relevant points in patient management (see below). This may be particularly important for patients with features of both
asthma and COPD, given that this is associated with worse outcomes and greater health care utilization.
#4: Referral for specialized investigations (if necessary)
Referral for expert advice and further diagnostic evaluation is advised in the following contexts:
• Patients with persistent symptoms and/or exacerbations despite treatment.
• Diagnostic uncertainty, especially if an alternative diagnosis (e.g. bronchiectasis, post-tuberculous scarring,
bronchiolitis, pulmonary fibrosis, pulmonary hypertension, cardiovascular diseases and other causes of respiratory
symptoms) needs to be investigated.
• Patients with suspected asthma or COPD in whom atypical or additional symptoms or signs (e.g. haemoptysis,
significant weight loss, night sweats, fever, signs of bronchiectasis or other structural lung disease) suggest an
additional pulmonary diagnosis. This should prompt early referral, without waiting for a trial of treatment for
asthma or COPD.
• When chronic airways disease is suspected but syndromic features of both asthma and COPD are few.
• Patients with comorbidities that may interfere with the assessment and management of their airways disease.
• Referral may also be appropriate for issues arising during ongoing management of asthma, COPD or asthma-
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COPD overlap, as outlined in the GINA and GOLD strategy reports.
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Box 5-4 (p.136) summarizes specialized investigations that are sometimes used to distinguish asthma and COPD.
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Box 5-4. Specialized investigations sometimes used in distinguishing asthma and COPD
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Asthma COPD
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O
Lung function tests
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DLCO Normal (or slightly elevated). Often reduced.

O
N
Arterial blood gases Normal between exacerbations May be chronically abnormal between
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exacerbations in more severe forms of COPD

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Airway hyperresponsiveness Not useful on its own in distinguishing asthma from COPD, but higher levels
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(AHR) of AHR favor asthma

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Imaging
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High resolution CT Scan Usually normal but air trapping and Low attenuation areas denoting either air trapping
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increased bronchial wall thickness or emphysematous change can be quantitated;

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may be observed. bronchial wall thickening and features of pulmonary

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hypertension may be seen.

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Inflammatory biomarkers
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A positive test for atopy Increases probability of allergic Conforms to background prevalence; does not rule
(specific IgE and/or skin prick asthma; not essential for diagnosis out COPD
test to aeroallergens) of asthma
FeNO A high level (>50 ppb) in non- Usually normal.
smokers is moderately associated Low in current smokers.
with eosinophilic airway
inflammation
Blood eosinophilia Supports diagnosis of eosinophilic May be present in COPD including during
airway inflammation exacerbations
Sputum inflammatory cell Role in differential diagnosis is not established in large populations
analysis
DLCO: diffusing capacity of the lungs for carbon monoxide; FeNO: fractional concentration of exhaled nitric oxide; IgE: immunoglobulin E
FUTURE RESEARCH
There is an urgent need for more research on this topic, in order to guide better recognition and safe and effective
treatment. Patients who do not have ‘classical’ features of asthma or of COPD, or who have features of both, have
generally been excluded from randomized controlled trials of most therapeutic interventions for airways disease, and
from many mechanistic studies.
Future research should include study of clinical and physiological characteristics, biomarkers, outcomes and underlying
mechanisms, among broad populations of patients with respiratory symptoms or with chronic airflow limitation. In the
meantime, the present chapter provides interim advice about diagnosis and initial treatment, for the perspective of
clinicians, particularly those in primary care and nonpulmonary specialties. Further research is needed to inform
evidence-based definitions and a more detailed classification of patients who present overlapping features of asthma
and COPD, and to encourage the development of specific interventions for clinical use.
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SECTION 2. CHILDREN 5 YEARS AND
YOUNGER
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Chapter 6.
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Diagnosis and
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management of asthma
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in children
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5 years and younger

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PART A. DIAGNOSIS
KEY POINTS
• Recurrent wheezing occurs in a large proportion of children 5 years and younger, typically with viral upper
respiratory tract infections. Deciding when this is the initial presentation of asthma is difficult.
• Previous classifications of wheezing phenotypes (episodic wheeze and multiple-trigger wheeze; or transient
wheeze, persistent wheeze and late-onset wheeze) do not appear to identify stable phenotypes, and their clinical
usefulness is uncertain. However, emerging research suggest that more clinically relevant phenotypes will be
described and phenotype-directed therapy possible.
• A diagnosis of asthma in young children with a history of wheezing is more likely if they have:
o Wheezing or coughing that occurs with exercise, laughing or crying, or in the absence of an apparent
respiratory infection
o A history of other allergic disease (eczema or allergic rhinitis), allergen sensitization or asthma in first-degree
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relatives
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o Clinical improvement during 2–3 months of controller treatment, and worsening after cessation.
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ASTHMA AND WHEEZING IN YOUNG CHILDREN
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Asthma is the most common chronic disease of childhood and the leading cause of childhood morbidity from chronic
O
disease as measured by school absences, emergency department visits and hospitalizations.633 Asthma often begins in
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early childhood; in up to half of people with asthma, symptoms commence during childhood.634 Onset of asthma is
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earlier in males than females.635-637
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No intervention has yet been shown to prevent the development of asthma or modify its long-term natural course. Atopy
N
is present in the majority of children with asthma who are over 3 years old, and allergen-specific sensitization (and
O
D
particularly multiple early-life sensitizations) is one of the most important risk factors for the development of asthma.638
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Viral-induced wheezing
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AT
Recurrent wheezing occurs in a large proportion of children aged 5 years or younger. It is typically associated with upper
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respiratory tract infections (URTI), which occur in this age group around 6–8 times per year.639 Some viral infections
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(respiratory syncytial virus and rhinovirus) are associated with recurrent wheeze throughout childhood. Wheezing in this
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age group is a highly heterogeneous condition, and not all wheezing indicates asthma. A large proportion of wheezing
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episodes in young children is virally induced whether the child has asthma or not. Therefore, deciding when wheezing
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with a respiratory infection is truly an isolated event or represents a recurrent clinical presentation of childhood asthma
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may be difficult.637,640
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Wheezing phenotypes
In the past, two main classifications of wheezing (called ‘wheezing phenotypes’) were proposed:
• Symptom-based classification: 641 this was based on whether the child had only episodic wheeze (wheezing during
discrete time periods, often in association with URTI, with symptoms absent between episodes) or multiple-trigger
wheeze (episodic wheezing with symptoms also occurring between these episodes, e.g. during sleep or with
triggers such as activity, laughing, or crying).
• Time trend-based classification: this system was initially based on retrospective analysis of data from a cohort
study.637 It included transient wheeze (symptoms began and ended before the age of 3 years); persistent wheeze
(symptoms began before the age of 3 years and continued beyond the age of 6 years), and late-onset wheeze
(symptoms began after the age of 3 years). These general patterns have been confirmed in subsequent studies
using unsupervised statistical approaches.642,643
140 6. Diagnosis and management of asthma in children 5 years and younger

However, prospective allocation of individual children to these phenotypes has been challenging in ‘real-life’ clinical
situations, and the clinical usefulness of these, and other, classification and asthma prediction systems remain a subject
of active investigation.
CLINICAL DIAGNOSIS OF ASTHMA

It may be challenging to make a confident diagnosis of asthma in children 5 years and younger, because episodic
respiratory symptoms such as wheezing and cough are also common in children without asthma, particularly in those 0–
2 years old,644,645 and it is not possible to routinely assess airflow limitation or bronchodilator responsiveness in this age
group. A probability-based approach, based on the pattern of symptoms during and between viral respiratory
infections,646 may be helpful for discussion with parents/carers (Box 6-1 & 2). This allows individual decisions to be made
about whether to give a trial of controller treatment. It is important to make decisions for each child individually, to avoid
either over- or under-treatment.
Box 6-1. Probability of asthma diagnosis in children 5 years and younger
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Symptoms suggestive of asthma in children 5 years and younger

As shown in Box 6-1 and 2/2A an asthma diagnosis in children 5 years and younger can often be based on:
• Symptom patterns (recurrent episodes of wheeze, cough, breathlessness (typically manifested by activity
limitation), and nocturnal symptoms or awakenings)
• Presence of risk factors for development of asthma, such as family history of atopy, allergic sensitization, allergy
or asthma, or a personal history of food allergy or atopic dermatitis
• Therapeutic response to controller treatment.
• Exclusion of alternate diagnoses.
Box 6-1 is a schematic figure showing the estimated probability of an asthma diagnosis647,648 in children aged 5 years or
younger who have viral-induced cough, wheeze or heavy breathing, based on the pattern of symptoms. Many young
children wheeze with viral infections and deciding when a child should be given controller treatment may be difficult. The
frequency and severity of wheezing episodes and the temporal pattern of symptoms (only with viral colds or also in
6. Diagnosis and Management of asthma in children 5 years and younger 141

response to other triggers) should be taken into account. Any controller treatment should be viewed as a treatment trial,
with follow up scheduled after 2–3 months to review the response. Review is also important since the pattern of
symptoms tends to change over time in a large proportion of children.
A diagnosis of asthma in young children is therefore based largely on recurrent symptom patterns combined with a
careful clinical assessment of family history and physical findings with careful consideration of the differential diagnostic
possibilities. A positive family history of allergic disorders, or the presence of atopy or allergic sensitization provide
additional predictive support, as early allergic sensitization increases the likelihood that a wheezing child will develop
persistent asthma.638
Box 6-2. Features suggesting a diagnosis of asthma in children 5 years and younger
Feature Characteristics suggesting asthma

Cough Recurrent or persistent non-productive cough that may be worse at night or
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accompanied by wheezing and breathing difficulties
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Cough occurring with exercise, laughing, crying or exposure to tobacco
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smoke, particularly in the absence of an apparent respiratory infection
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Wheezing Recurrent wheezing, including during sleep or with triggers such as activity,
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laughing, crying or exposure to tobacco smoke or air pollution
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Difficult or heavy breathing or Occurring with exercise, laughing, or crying
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shortness of breath
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Reduced activity Not running, playing or laughing at the same intensity as other children; tires
O
N
earlier during walks (wants to be carried)

O
D
Past or family history Other allergic disease (atopic dermatitis or allergic rhinitis, food allergy).
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Asthma in first-degree relative(s)

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Therapeutic trial with low dose inhaled Clinical improvement during 2–3 months of controller treatment and worsening
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corticosteroid (ICS) (Box 6-5, p.152), when treatment is stopped

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and as-needed SABA

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SABA: short-acting beta2-agonist

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Box 6-2A. Questions that can be used to elicit features suggestive of asthma
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• Does your child have wheezing? Wheezing is a high pitched noise which comes from the chest and not the throat.
Use of a video questionnaire,649 or asking a parent to record an episode on a smartphone if available can help to
confirm the presence of wheeze and differentiate from upper airway abnormalities.
• Does your child wake up at night because of coughing, wheezing, or ‘difficult breathing’, ‘heavy breathing’, or
‘breathlessness?
• Does your child have to stop running, or play less hard, because of coughing, wheezing or ‘difficult breathing’,
‘heavy breathing’, or ‘shortness of breath’?
• Does your child cough, wheeze or get ‘difficult breathing’, ‘heavy breathing’, or ‘shortness of breath’ when laughing,
crying, playing with animals, or when exposed to strong smells or smoke?
• Has your child ever had eczema, or been diagnosed with allergy to foods?
• Has anyone in your family had asthma, hay fever, food allergy, eczema, or any other disease with breathing
problems?

Wheeze
Wheeze is the most common and specific symptom associated with asthma in children 5 years and younger. Wheezing
occurs in several different patterns, but a wheeze that occurs recurrently, during sleep, or with triggers such as activity,
laughing, or crying, is consistent with a diagnosis of asthma. Clinician confirmation is important, as parents may describe
any noisy breathing as ‘wheezing’.650 Some cultures do not have a word for wheeze.
Wheezing may be interpreted differently based on:
• Who observes it (e.g. parent/carer versus the health care provider)
• The environmental context (e.g. high income countries versus areas with a high prevalence of parasites that
involve the lung)
• The cultural context (e.g. the relative importance of certain symptoms can differ between cultures, as can the
diagnosis and treatment of respiratory tract diseases in general).
Cough
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Cough due to asthma is generally non-productive, recurrent and/or persistent, and is usually accompanied by wheezing
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episodes and breathing difficulties. Allergic rhinitis may be associated with cough in the absence of asthma. A nocturnal
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cough (when the child is asleep) or a cough that occurs with exercise, laughing or crying, in the absence of an apparent
respiratory infection, supports a diagnosis of asthma. The common cold and other respiratory illnesses are also
IS
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associated with coughing. Prolonged cough in infancy, and cough without cold symptoms, are associated with later
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parent-reported physician-diagnosed asthma, independent of infant wheeze. Characteristics of cough in infancy may be
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early markers of asthma susceptibility, particularly among children with maternal asthma.651
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Breathlessness
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Parents may also use terms such as ‘difficult breathing’, ‘heavy breathing’, or ‘shortness of breath’. Breathlessness that
O
N
occurs during exercise and is recurrent increases the likelihood of the diagnosis of asthma. In infants and toddlers,
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crying and laughing are equivalent to exercise in older children.

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Activity and social behavior

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Physical activity is an important trigger of asthma symptoms in young children. Young children with poorly controlled
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asthma often abstain from strenuous play or exercise to avoid symptoms, but many parents are unaware of such
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changes in their children’s lifestyle. Engaging in play is important for a child’s normal social and physical development.
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For this reason, careful review of the child’s daily activities, including their willingness to walk and play, is important when
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assessing a potential asthma diagnosis in a young child. Parents may report irritability, tiredness and mood changes in
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their child as the main problems when asthma is not well controlled.
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TESTS TO ASSIST IN DIAGNOSIS

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While no tests specifically and definitively diagnose asthma with certainty, in children 5 years and younger, the following
are useful adjuncts.
Therapeutic trial
A trial of treatment for at least 2–3 months with as-needed short-acting beta2-agonist (SABA) and regular low dose
inhaled corticosteroids (ICS) may provide some guidance about the diagnosis of asthma (Evidence D). Response should
be evaluated by symptom control (daytime and night-time), and the frequency of wheezing episodes and exacerbations.
Marked clinical improvement during treatment, and deterioration when treatment is stopped, support a diagnosis of
asthma. Due to the variable nature of asthma in young children, a therapeutic trial may need to be repeated in order to
be certain of the diagnosis.

Tests for allergic sensitization
Sensitization to allergens can be assessed using either skin prick testing or allergen-specific immunoglobulin E. Allergic
sensitization is present in the majority of children with asthma once they are over 3 years of age; however, absence of
sensitization to common aeroallergens does not rule out a diagnosis of asthma. Allergic sensitization is the best
predictor for development of persistent asthma.652
Chest X-ray
Radiographs are rarely indicated; however, if there is doubt about the diagnosis of asthma in a wheezing or coughing
child, a plain chest X-ray may help to exclude structural abnormalities (e.g. congenital lobar emphysema, vascular ring)
chronic infections such as tuberculosis, an inhaled foreign body, or other diagnoses. Other imaging investigations may
be appropriate, depending on the condition being considered.
Lung function testing
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Due to the inability of most children 5 years and younger to perform reproducible expiratory maneuvers, lung function
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testing, bronchial provocation testing, and other physiological tests do not have a major role in the diagnosis of asthma
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at this age. However, by 5 years of age, many children are capable of performing reproducible spirometry if coached by
an experienced technician and with visual incentives.
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Exhaled nitric oxide
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Measurement of fractional concentration of exhaled nitric oxide (FeNO) is not widely available for most children in this
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age group and currently remains primarily a research tool. FeNO can be measured in young children with tidal breathing,
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and normal reference values have been published for children aged 1–5 years.653 In pre-school children with recurrent
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coughing and wheezing, an elevated FeNO recorded 4 weeks from any URTI predicted physician-diagnosed asthma at
N
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school age,654 and increased the odds for wheezing, asthma and ICS use by school age, independent of clinical history
D
and presence of specific IgE.655

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Risk profiles
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A number of risk profile tools to identify wheezing children aged 5 years and younger who are at high risk of developing
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persistent asthma symptoms have been evaluated for use in clinical practice.643 The Asthma Predictive Index (API),
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based on the Tucson Children’s Respiratory Study, is designed for use in children with four or more wheezing episodes
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.
in a year.656 One study showed that children with a positive API have a 4- to 10-fold greater chance of developing
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asthma between the ages of 6–13 years than those with a negative API, and 95% of children with a negative API
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remained free of asthma.656 A modified API adding sensitization to an inhalant as a major criterion and to a food as a
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minor criterion and removing allergic rhinitis as a minor criterion657 has been validated in a separate cohort as predictive
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for development of persistent asthma.658 More research is needed to evaluate the applicability and validity of the API in
other contexts, and to develop prediction tools which can be used in a wider range of settings. The API includes
sensitization to aeroallergens measured by skin prick or blood tests and level of blood eosinophils; these tests may not
be available in all care settings. Furthermore, use of the API in regions where eosinophilia is commonly seen due to
helminth infections has not been assessed.
DIFFERENTIAL DIAGNOSIS
A definite diagnosis of asthma in this young age group is challenging but has important clinical consequences. It is
particularly important in this age group to consider and exclude alternative causes that can lead to symptoms of wheeze,
cough, and breathlessness before confirming an asthma diagnosis (Box 6-3).644

Key indications for referral of a child 5 years or younger for further diagnostic investigations or therapeutic
decisions
Any of the following features suggest an alternative diagnosis and indicate the need for further investigations:
• Failure to thrive
• Neonatal or very early onset of symptoms (especially if associated with failure to thrive)
• Vomiting associated with respiratory symptoms
• Continuous wheezing
• Failure to respond to asthma medications (inhaled ICS, oral steroids or SABA)
• No association of symptoms with typical triggers, such as viral URTI
• Focal lung or cardiovascular signs, or finger clubbing
• Hypoxemia outside context of viral illness.
Box 6-3. Common differential diagnoses of asthma in children 5 years and younger
TE
Condition
U
Typical features
IB
TR
Recurrent viral respiratory Mainly cough, runny congested nose for <10 days; no symptoms between infections
IS
tract infections
D
R
Gastroesophageal reflux Cough when feeding; recurrent chest infections; vomits easily especially after large
O
feeds; poor response to asthma medications
PY
O
Foreign body aspiration Episode of abrupt, severe cough and/or stridor during eating or play; recurrent chest
C
infections and cough; focal lung signs

T
O
N
Persistent bacterial Persistent wet cough; poor response to asthma medications

O
D
bronchitis
L-
IA
Tracheomalacia Noisy breathing when crying or eating, or during upper airway infections (noisy inspiration
ER
if extrathoracic or expiration if intrathoracic); harsh cough; inspiratory or expiratory

AT
retraction; symptoms often present since birth; poor response to asthma medications
M
Tuberculosis Persistent noisy respirations and cough; fever unresponsive to normal antibiotics;
D
TE
enlarged lymph nodes; poor response to bronchodilators or inhaled corticosteroids;

H
contact with someone who has tuberculosis

IG
R
Congenital heart disease Cardiac murmur; cyanosis when eating; failure to thrive; tachycardia; tachypnea or
PY
hepatomegaly; poor response to asthma medications

O
C
Cystic fibrosis Cough starting shortly after birth; recurrent chest infections; failure to thrive
(malabsorption); loose greasy bulky stools
Primary ciliary dyskinesia Cough and recurrent chest infections; neonatal respiratory distress, chronic ear infections
and persistent nasal discharge from birth; poor response to asthma medications; situs
inversus occurs in about 50% of children with this condition
Vascular ring Persistently noisy breathing; poor response to asthma medications
Bronchopulmonary Infant born prematurely; very low birth weight; needed prolonged mechanical ventilation
dysplasia or supplemental oxygen; difficulty with breathing present from birth
Immune deficiency Recurrent fever and infections (including non-respiratory); failure to thrive

PART B. ASSESSMENT AND MANAGEMENT
KEY POINTS
• The goals of asthma management in young children are similar to those in older patients:
o To achieve good control of symptoms and maintain normal activity levels
o To minimize the risk of asthma flare-ups, impaired lung development and medication side-effects.
• Wheezing episodes in young children should be treated initially with inhaled short-acting beta2-agonists, regardless
of whether the diagnosis of asthma has been made.
• A trial of controller therapy should be given if the symptom pattern suggests asthma, alternative diagnoses have
been excluded and respiratory symptoms are uncontrolled and/or wheezing episodes are frequent or severe.
• Response to treatment should be reviewed before deciding whether to continue it. If the response is absent or
incomplete, reconsider alternative diagnoses.
TE
• The choice of inhaler device should be based on the child’s age and capability. The preferred device is a
U
pressurized metered dose inhaler and spacer, with face mask for <3 years and mouthpiece for most 3–5 year-olds.
IB
Children should be switched from a face mask to mouthpiece as soon as they are able to demonstrate good
TR
technique.
IS
D
• Review the need for asthma treatment frequently, as asthma-like symptoms remit in many young children.
R
O
PY
GOALS OF ASTHMA MANAGEMENT
O
As with other age groups, the goals of asthma management in young children are:
C
T
• To achieve good control of symptoms and maintain normal activity levels

O
N
• To minimize future risk; that is to reduce the risk of flare-ups, maintain lung function and lung development as
O
close to normal as possible, and minimize medication side-effects.

D
L-
Maintaining normal activity levels is particularly important in young children because engaging in play is important for
IA
ER
their normal social and physical development. It is important to also elicit the goals of the parent/carer, as these may
differ from conventional medical goals.
AT
M
The goals of asthma management are achieved through a partnership between the parent/carer and the health
D
professional team, with a cycle of:

TE
H
• Assess (diagnosis, symptom control, risk factors, inhaler technique, adherence, parent preference)
IG
• Adjust treatment (medications, non-pharmacological strategies, and treatment of modifiable risk factors)
R
PY
• Review response including medication effectiveness and side-effects. This is carried out in combination with:
O
C
Education of parent/carer, and child (depending on the child’s age)

• Skills training for effective use of inhaler devices and encouragement of good adherence
• Monitoring of symptoms by parent/carer
• A written personalized asthma action plan.
ASSESSMENT OF ASTHMA
What does ‘asthma control’ mean?

Asthma control means the extent to which the manifestations of asthma are controlled, with or without treatment. 17,59 It
has two components (Box 6-4, p.147): the child’s asthma status over the previous four weeks (current symptom control),
and how asthma may affect them in the future (future risk). In young children, as in older patients, both symptom control
and future risk should be monitored (Evidence D). The rationale for this is described on p.37.

Assessing asthma symptom control
Defining satisfactory symptom control in children 5 years and younger depends on information derived from family
members and carers, who may be unaware either of how often the child has experienced asthma symptoms, or that their
respiratory symptoms represent uncontrolled asthma. Few objective measures to assess symptom control have been
validated for children <4 years. The Childhood Asthma Control Test has can be used for children aged 4–11 years.75 The
Test for Respiratory and Asthma Control in Kids (TRACK) is a validated questionnaire for caregiver completion for
preschool aged children with symptoms consistent with asthma; it includes both symptom control and courses of
systemic corticosteroids in the previous year.79
Box 6-4 shows a working schema for assessing asthma control in children ≤5 years, based on current expert opinion. It
incorporates assessment of symptoms; the child’s level of activity and their need for reliever/rescue treatment; and
assessment of risk factors for adverse outcomes (Evidence D).
Box 6-4. GINA assessment of asthma control in children 5 years and younger
TE
U
A. Symptom control Level of asthma symptom control
IB
TR
Well Partly
In the past 4 weeks, has the child had: Uncontrolled
IS
controlled controlled
D
Daytime asthma symptoms for more than a few minutes, Yes No
R
O
more than once a week?
PY
Any activity limitation due to asthma? (Runs/plays less Yes No
O None 1–2 3–4
than other children, tires easily during walks/playing?)
of these of these of these
C
Reliever medication needed* more than once a week? Yes No

T
O
N
Any night waking or night coughing due to asthma? Yes No

O
D
B. Future risk for poor asthma outcomes

L-
IA
Risk factors for asthma exacerbations within the next few months
ER
AT
• Uncontrolled asthma symptoms

M
• One or more severe exacerbations (ED attendance, hospitalization, or course of OCS) in previous year
D
• The start of the child’s usual ‘flare-up’ season (especially if autumn/fall)

TE
• Exposures: tobacco smoke; indoor or outdoor air pollution; indoor allergens (e.g. house dust mite, cockroach,
H
IG
pets, mold), especially in combination with viral infection659

R
• Major psychological or socio-economic problems for child or family

PY
• Poor adherence with controller medication, or incorrect inhaler technique

O
C
• Outdoor pollution (NO2 and particles)95

Risk factors for persistent airflow limitation
• Severe asthma with several hospitalizations
• History of bronchiolitis
• Systemic: Frequent courses of OCS, high-dose and/or potent ICS
• Local: moderate/high-dose or potent ICS; incorrect inhaler technique; failure to protect skin or eyes when using ICS
by nebulizer or spacer with face mask
ICS: inhaled corticosteroids; OCS: oral corticosteroids; * Excludes reliever taken before exercise
Before stepping up treatment, ensure that the child’s symptoms are due to asthma, and that the child has good inhaler technique and good adherence to
existing treatment.
6. Diagnosis and management of asthma in children 5 years and younger 147

Assessing future risk of adverse outcomes
The relationship between symptom control and future risk of adverse outcomes, such as exacerbations (Box 6-4, p.147),
has not been sufficiently studied in young children. Although exacerbations may occur in children after months of
apparently good symptom control, the risk is greater if current symptom control is poor. Preschool children at high risk of
asthma (based on modified API) who were treated with daily low dose ICS experienced fewer days with asthma
symptoms and a reduced risk of exacerbations than those receiving placebo.660
The future risk of harm due to excessive doses of inhaled or systemic corticosteroids must also be avoided. This can be
minimized by ensuring that the prescribed treatment is appropriate and reduced to the lowest dose that maintains
satisfactory symptom control and minimizes exacerbations. The child’s height should be measured and recorded at least
yearly, as growth velocity may be lower in the first 1–2 years of ICS treatment,113 and poorly controlled asthma can affect
growth.112 The minimum effective dose of ICS to maintain good asthma control should be used. If decreased growth
velocity is seen, other factors should be considered, including poorly controlled asthma, frequent use of oral
corticosteroids, and poor nutrition, and referral should be considered.
TE
If ICS is delivered through a face-mask or nebulizer, the skin on the nose and around the mouth should be cleaned
U
shortly after inhalation in order to avoid local side-effects such as steroid rash (reddening and atrophy).
IB
TR
IS
MEDICATIONS FOR SYMPTOM CONTROL AND RISK REDUCTION
D
R
Choosing medications for children 5 years and younger
O
PY
Good control of asthma can be achieved in the overwhelming majority of young children with a pharmacological
O
intervention strategy.661 This should be developed in a partnership between the family/carer and the health care provider.
C
T
As with older children and adults, medications comprise only one component of asthma management in young children;
O
other key components include education, skills training for inhaler devices and adherence, non-pharmacological
N
O
strategies including environmental control where appropriate, regular monitoring, and clinical review (see later sections in
D
this chapter).
L-
IA
When recommending treatment for a young child, both general and individual questions apply (Box 3-3, p.45).
ER
• What is the ‘preferred’ medication option at each treatment step to control asthma symptoms and minimize future
AT
risk? These decisions are based on data for efficacy, effectiveness and safety from clinical trials, and on
M
D
observational data. Recent studies suggest that consideration of factors such as allergic sensitization and/or
TE
peripheral blood count may help to better identify which children are more likely to have a short-term response to
H
ICS.662 However, further studies are needed to assess the applicability of these findings in a wider range of
IG
R
settings, particularly in areas where blood eosinophilia may reflect helminth infection rather than asthma or atopy.
PY
• How does this particular child differ from the ‘average’ child with asthma, in terms of:
O
C
o Response to previous treatment

o Parental preference (goals, beliefs and concerns about medications)
o Practical issues (cost, inhaler technique and adherence)?
The following treatment recommendations for children of 5 years of age or younger are based on the available evidence
and on expert opinion. Although the evidence is expanding it is still rather limited as most clinical trials in this age group
have not characterized participants with respect to their symptom pattern, and different studies have used different
outcomes and different definitions of exacerbations.
A stepwise treatment approach is recommended (Box 6-5, p.152), based on symptom patterns, risk of exacerbations and
side-effects, and response to initial treatment. Generally, treatment includes the daily, long-term use of controller
medications to keep asthma well-controlled, and reliever medications for as-needed symptom relief. The choice of
inhaler device is also an important consideration (Box 6-7, p.154).

Which children should be prescribed regular controller treatment?
Intermittent or episodic wheezing of any severity may represent an isolated viral-induced wheezing episode, an episode
of seasonal or allergen-induced asthma, or unrecognized uncontrolled asthma. The initial treatment of wheezing is
identical for all of these – a SABA every 4–6 hours as needed until symptoms disappear, usually within 1 to 7 days.
Further treatment of the acute wheezing episodes themselves is described below (see Acute asthma exacerbations in
children 5 years and younger, p.155). However, uncertainty surrounds the addition of other drugs in these children,
especially when the nature of the episode is unclear. In general, the following principles apply.
• If the history and symptom pattern suggest a diagnosis of asthma (Box 6-2, p.142; Box 6-2A, p.142) and
respiratory symptoms are uncontrolled (Box 6-4, p.147) and/or wheezing episodes are frequent (e.g. three or more
episodes in a season), regular controller treatment should be initiated (Step 2, Box 6-5, p.152) and the response
evaluated (Evidence D). Regular controller treatment may also be indicated in a child with less frequent, but more
severe episodes of viral- induced wheeze (Evidence D).
• If the diagnosis of asthma is in doubt, and inhaled SABA therapy or courses of antibiotics need to be repeated
frequently, e.g. more than every 6–8 weeks, a trial of regular controller treatment should be considered to confirm
TE
whether the symptoms are due to asthma (Evidence D). Referral for specialist opinion should also be considered
U
IB
at this stage.
TR
IS
It is important to discuss the decision to prescribe controller treatment and the choice of treatment with the child’s
D
parents or carers. They should be aware of both the relative benefits and risks of the treatments, and the importance of
R
maintaining normal activity levels for their child’s normal physical and social development. Although effects of ICS on
O
PY
growth velocity are seen in pre-pubertal children in the first 1-2 years of treatment, this is not progressive or cumulative,
O
and the one study that examined long-term outcomes showed a difference of only 0.7% in adult height. 113,663 Poorly
C
controlled asthma itself adversely affects adult height.112 For more detail see Appendix Chapter 5B.
T
O
N
Treatment steps to control asthma symptoms and minimize future risk for children 5 years and younger
O
D
Asthma treatment in young children follows a stepwise approach (Box 6-5), with medication adjusted up or down to
L-
IA
achieve good symptom control and minimize future risk of exacerbations and medication side-effects. The need for
ER
controller treatment should be re-assessed regularly. More details about asthma medications for children 0–5 years are
AT
provided in Appendix Chapter 5, Part C.

M
Before considering a step-up of controller treatment

D
TE
If symptom control is poor and/or exacerbations persist despite 3 months of adequate controller therapy, check the
H
IG
following before any step up in treatment is considered.

R
• Confirm that the symptoms are due to asthma rather than a concomitant or alternative condition (Box 6-3, p.105).
PY
Refer for expert assessment if the diagnosis is in doubt.

O
C
• Check and correct inhaler technique.

• Confirm good adherence with the prescribed dose.
• Consider trial of one of the other treatment options for that step, as many children may respond to one of the
options.
• Enquire about risk factors such as allergen or tobacco smoke exposure (Box 6-4, p.147).

ASTHMA TREATMENT STEPS FOR CHILDREN AGED 5 YEARS AND YOUNGER
STEP 1: As-needed inhaled short-acting beta2-agonist (SABA)
Preferred option: as-needed inhaled short-acting beta2-agonist (SABA)

All children who experience wheezing episodes should be provided with inhaled SABA for relief of symptoms (Evidence
D), although it is not effective in all children. See Box 6-7 (p.154) for choice of inhaler device. Use of SABA for the relief
of symptoms on average more than twice a week over a one month period indicates the need for a trial of controller
medication.
Other options
Oral bronchodilator therapy is not recommended due to its slower onset of action and higher rate of side-effects
compared with inhaled SABA (Evidence D).
TE
For children with intermittent viral-induced wheeze and no interval symptoms, particularly those with underlying atopy
U
IB
(positive mAPI) in whom inhaled SABA medication is not sufficient, intermittent high dose ICS may be
TR
considered534,664,665 (see Management of worsening asthma and exacerbations, p.155), but because of the risk of side-
IS
effects, this should only be considered if the physician is confident that the treatment will be used appropriately.
D
R
O
STEP 2: Initial controller treatment plus as-needed SABA
PY
O
Preferred option: regular daily low dose ICS plus as-needed SABA
C
T
Regular daily, low dose ICS (Box 6-6, p.153) is recommended as the preferred initial treatment to control asthma in
O
N
children 5 years and younger (Evidence A).660,666-668 This initial treatment should be given for at least 3 months to
O
establish its effectiveness in achieving good asthma control.

D
L-
Other options
IA
ER
In young children with persistent asthma, regular treatment with a leukotriene receptor antagonist (LTRA) modestly
AT
reduces symptoms and need for oral corticosteroids compared with placebo.669 However, for young children with
M
recurrent viral- induced wheezing, a recent review concluded that neither regular nor intermittent LTRA reduces OCS-
D
requiring exacerbations (Evidence A).670 A further systematic review found that in pre-schoolers with asthma or recurrent
TE
wheezing, daily ICS was more effective in improving symptom control and reducing exacerbations than regular LRTA
H
IG
monotherapy.671 Parents should be counselled about the risk of the impact on sleep and behavior with montelukast and
R
health professionals should consider the benefits and risks of side effects before prescribing; the FDA has required a
PY
boxed warning about these problems.205

O
C
For pre-school children with frequent viral-induced wheezing and interval asthma symptoms, as-needed (prn)672 or
episodic ICS673 may be considered, but a trial of regular daily low dose ICS should be undertaken first. The effect on
exacerbation risk seems similar for regular daily low dose and episodic high dose ICS.668 See also Initial home
management of asthma exacerbations, p.156.
If good asthma control is not achieved with a given therapy, trials of the alternative Step 2 therapies are recommended
prior to moving to Step 3.
STEP 3: Additional controller treatment, plus as-needed SABA and consider specialist referral
If 3 months of initial therapy with a low dose ICS fails to control symptoms, or if exacerbations continue to occur, check
the following before any step up in treatment is considered.
• Confirm that the symptoms are due to asthma rather than a concomitant or alternative condition (Box 6-3,
p.145).

• Check and correct inhaler technique. Consider alternative delivery systems if indicated.
• Confirm good adherence with the prescribed dose.
• Enquire about risk factors such as allergen or tobacco smoke exposure (Box 6-4, p.147).
Preferred option: medium dose ICS (double the ‘low’ daily dose)
Doubling the initial low dose of ICS may be the best option (Evidence C). Assess response after 3 months.
The child should be referred for expert assessment if symptom control remains poor and/or flare-ups persist, or if side-
effects of treatment are observed or suspected.
Other options
Addition of a LTRA to low dose ICS may be considered, based on data from older children (Evidence D). The relative
cost of different treatment options in some countries may be relevant to controller choices for children. See note above
about the FDA warning for montelukast. 205
TE
Not recommended
U
There are insufficient data about the efficacy and safety of ICS-LABA in children <4 years old to recommend their use. A
IB
TR
short-term (8 week) placebo-controlled study did not show any significant difference in symptoms between combination
IS
fluticasone propionate-salmeterol vs fluticasone propionate alone; no additional safety signals were noted in the group
D
receiving LABA.674
R
O
PY
STEP 4: Continue controller treatment and refer for expert assessment
C
O
Preferred option: refer the child for expert advice and further investigation (Evidence D).
T
O
If doubling the initial dose of ICS fails to achieve and maintain good asthma control, carefully reassess inhaler technique
N
O
and medication adherence as these are common problems in this age group. In addition, reassess and address control
D
of environmental factors where relevant, and reconsider the asthma diagnosis.

L-
IA
Other options
ER
AT
The best treatment for this population has not been established. If the diagnosis of asthma has been confirmed, options
M
to consider, with specialist advice, are:

D
• Further increase the dose of ICS for a few weeks until the control of the child’s asthma improves (Evidence D).
TE
Monitor for side-effects.

H
IG
• Add LTRA (data based on studies in older children, Evidence D). Benefits, and risks of side effects, should be
R
PY
considered, as described previously.205

O
• Add long acting beta agonist (LABA) in combination with ICS; data based on studies in children ≥4 years of age
C
• Add a low dose of oral corticosteroid (for a few weeks only) until asthma control improves (Evidence D); monitor
for side-effects.
• Add intermittent high dose ICS at onset of respiratory illnesses to the regular daily ICS if exacerbations are the
main problem (Evidence D).
The need for additional controller treatment should be re-evaluated at each visit and maintained for as short a period as
possible, taking into account potential risks and benefits. Treatment goals and their feasibility should be re-considered
and discussed with the child’s family/carer.

Box 6-5. Personalized management of asthma in children 5 years and younger
TE
U
IB
TR
IS
D
R
O
PY
O
C
T
O
N
O
D
L-
IA
ER
AT
M
D
TE
H
IG
R
PY
O
C
ICS: inhaled corticosteroids; LTRA: leukotriene receptor antagonist; SABA: short-acting beta2-agonist

Box 6-6. Low daily doses of inhaled corticosteroids for children 5 years and younger
This is not a table of equivalence, but instead, suggestions for ‘low’ total daily doses for the ICS treatment
recommendations for children aged 5 years and younger in Box 6.5 (p.152), based on available studies and product
information. Data on comparative potency are not readily available, particularly for children, and this table does NOT
imply potency equivalence. The doses listed here are the lowest approved doses for which safety and effectiveness
have been adequately studied in this age group.
Low dose ICS provides most of the clinical benefit for most children with asthma. Higher doses are associated with an
increased risk of local and systemic side-effects, which must be balanced against potential benefits.
Low total daily dose (mcg)
Inhaled corticosteroid
(age-group with adequate safety and effectiveness data)
BDP (pMDI, standard particle, HFA) 100 (ages 5 years and older)
BDP (pMDI, extrafine particle, HFA) 50 (ages 5 years and older)
TE
Budesonide nebulized 500 (ages 1 year and older)
U
IB
Fluticasone propionate (pMDI, standard particle, HFA) 50 (ages 4 years and older)
TR
IS
Fluticasone furoate (DPI) Not sufficiently studied in children 5 years and younger)
D
Mometasone furoate (pMDI, standard particle, HFA) 100 (ages 5 years and older)
R
O
Ciclesonide (pMDI, extrafine particle, HFA) Not sufficiently studied in children 5 years and younger
PY
O
BDP: beclometasone dipropionate; DPI: dry powder inhaler; HFA: hydrofluoroalkane propellant; ICS: inhaled corticosteroid; pMDI: pressurized metered
C
dose inhaler (non-chlorofluorocarbon formulations); in children, pMDI should always be used with a spacer
T
O
N
REVIEWING RESPONSE AND ADJUSTING TREATMENT

O
D
Assessment at every visit should include asthma symptom control and risk factors (Box 6-4, p.147), and side-effects.
L-
The child’s height should be measured every year, or more often. Asthma-like symptoms remit in a substantial proportion
IA
ER
of children of 5 years or younger,675-677 so the need for continued controller treatment should be regularly assessed (e.g.
AT
every 3–6 months) (Evidence D). If therapy is stepped-down or discontinued, schedule a follow-up visit 3–6 weeks later
M
to check whether symptoms have recurred, as therapy may need to be stepped-up or reinstituted (Evidence D).
D
TE
Marked seasonal variations may be seen in symptoms and exacerbations in this age-group. For children with seasonal
H
symptoms whose daily long-term controller treatment is to be discontinued (e.g. 4 weeks after their season ends), the
IG
parent/carer should be provided with a written asthma action plan detailing specific signs of worsening asthma, the
R
PY
medications that should be initiated to treat it, and when and how to contact medical care.
O
C
CHOICE OF INHALER DEVICE

Inhaled therapy constitutes the cornerstone of asthma treatment in children 5 years and younger. A pressurized
metered-dose inhaler (pMDI) with a valved spacer (with or without a face mask, depending on the child’s age) is the
preferred delivery system 678 (Box 6-7, p.154) (Evidence A). This recommendation is based on studies with beta2-
agonists. The spacer device should have documented efficacy in young children. The dose delivered may vary
considerably between spacers, so consider this if changing from one spacer to another.
The only possible inhalation technique in young children is tidal breathing. The optimal number of breaths required to
empty the spacer depends on the child’s tidal volume, and the dead space and volume of the spacer. Generally, 5–10
breaths will be sufficient per actuation. The way a spacer is used can markedly affect the amount of drug delivered:
• Spacer size may affect the amount of drug available for inhalation in a complex way depending on the drug
prescribed and the pMDI used. Young children can use spacers of all sizes, but theoretically a lower volume
spacer (<350 mL) is advantageous in very young children.

• A single pMDI actuation should be delivered at a time, with the inhaler shaken in between. Multiple actuations into
the spacer before inhalation may markedly reduce the amount of drug inhaled.
• Delay between actuating the pMDI into the spacer and inhalation may reduce the amount of drug available. This
varies between spacers, but to maximize drug delivery, inhalation should start as soon as possible after actuation.
If a health care provider or a carer is giving the medication to the child, they should actuate the pMDI only when
the child is ready and the spacer is in the child’s mouth.
• If a face mask is used it must be fitted tightly around the child’s mouth and nose, to avoid loss of drug.
• Ensure that the valve is moving while the child is breathing through the spacer.
• Static charge may accumulate on some plastic spacers, attracting drug particles and reducing lung delivery. This
charge can be reduced by washing the spacer with detergent (without rinsing) and allowing it to air dry, but it may
re-accumulate over time. Spacers made of anti-static materials or metals are less subject to this problem. If a
patient or health care provider carries a new plastic spacer for emergency use, it should be regularly washed with
detergent (e.g. monthly) to reduce static charge.
• Nebulizers, the only viable alternative delivery systems in children, are reserved for the minority of children who
TE
cannot be taught effective use of a spacer device. If a nebulizer is used for delivery of ICS, it should be used with
U
a mouthpiece to avoid the medication reaching the eyes.
IB
TR
IS
Box 6-7. Choosing an inhaler device for children 5 years and younger
D
R
O
Age Preferred device Alternate device
0–3 years Pressurized metered dose inhaler plus PY
Nebulizer with face mask
O
C
dedicated spacer with face mask
T
O
4–5 years Pressurized metered dose inhaler plus Pressurized metered dose inhaler plus dedicated spacer
N
dedicated spacer with mouthpiece with face mask or nebulizer with mouthpiece or face mask
O
D
L-
ASTHMA SELF-MANAGEMENT EDUCATION FOR CARERS OF YOUNG CHILDREN

IA
ER
Asthma self-management education should be provided to family members and carers of wheezy children 5 years and
AT
younger when wheeze is suspected to be caused by asthma. An educational program should contain:
M
• A basic explanation about asthma and the factors that influence it

D
TE
• Training about correct inhalation technique

H
• Information on the importance of the child’s adherence to the prescribed medication regimen
IG
• A written asthma action plan.

R
PY
Crucial to a successful asthma education program are a partnership between patient/carer and health care providers,
O
C
with a high level of agreement regarding the goals of treatment for the child, and intensive follow-up (Evidence D).18

Asthma action plans should be provided for the family/carers of all children with asthma, including those aged 5 years
and younger (Evidence D). Action plans, developed through collaboration between an asthma educator, the health care
provider and the family, have been shown to be of value in older children,679 although they have not been extensively
studied in children of 5 years and younger. A written asthma action plan includes:
• A description of how the parent or carer can recognize when symptom control is deteriorating
• The medications to administer
• When and how to obtain medical care, including telephone numbers of services available for emergencies (e.g.
doctors’ offices, emergency departments and hospitals, ambulance services and emergency pharmacies). Details
of treatments that can be initiated at home are provided in the following section, Part C: Management of worsening
asthma and exacerbations in children 5 years and younger, p.155.

PART C. MANAGEMENT OF WORSENING ASTHMA AND EXACERBATIONS IN CHILDREN 5
YEARS AND YOUNGER
KEY POINTS
Symptoms of exacerbation in young children

• Early symptoms of exacerbations in young children may include increased symptoms; increased coughing,
especially at night; lethargy or reduced exercise tolerance; impaired daily activities including feeding; and a poor
response to reliever medication.
Home management in a written asthma action plan
• Give a written asthma action plan to parents/carers of young children with asthma so they can recognize an
impending severe attack, start treatment, and identify when urgent hospital treatment is required.
• Initial treatment at home is with inhaled short-acting beta2-agonist (SABA), with review after 1 hour or earlier.
TE
• Parents/carers should seek urgent medical care if the child is acutely distressed, lethargic, fails to respond to initial
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bronchodilator therapy, or is worsening, especially in children <1 year of age.
IB
R
• Medical attention should be sought on the same day if inhaled SABA is needed more often than 3-hourly or for
T
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more than 24 hours.
D
R
• There is no compelling evidence to support parent-initiated oral corticosteroids.
O
Management of exacerbations in primary care or acute care facility
PY
O
• Assess severity of the exacerbation while initiating treatment with SABA (2–6 puffs every 20 minutes for first hour)
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and oxygen (to maintain saturation 94–98%).

T
O
• Recommend immediate transfer to hospital if there is no response to inhaled SABA within 1–2 hours; if the child is
N
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unable to speak or drink, has a respiratory rate >40/minute or is cyanosed, if resources are lacking in the home, or
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if oxygen saturation is <92% on room air.

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• Consider oral prednisone/prednisolone 1–2 mg/kg/day for up to 5 days for children attending an Emergency
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Department or admitted to hospital, up to a maximum of 20 mg/day for 0–2 years, and 30 mg/day for 3–5 years; or
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dexamethasone 0.6 mg/kg/day for 2 days. If there is failure of resolution, or relapse of symptoms with
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dexamethasone, consideration should be given to switching to prednisolone.

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Arrange early follow-up after an exacerbation

H
• Children who have experienced an asthma exacerbation are at risk of further exacerbations. Arrange follow up
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within 1 week of an exacerbation to plan ongoing asthma management.

PY
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DIAGNOSIS OF EXACERBATIONS
A flare-up or exacerbation of asthma in children 5 years and younger is defined as an acute or sub-acute deterioration in
symptom control that is sufficient to cause distress or risk to health, and necessitates a visit to a health care provider or
requires treatment with systemic corticosteroids. In pediatric literature, the term ‘episode’ is commonly used, but
understanding of this term by parent/carers is not known
Early symptoms of an exacerbation may include any of the following:
• Onset of symptoms of respiratory tract infection
• An acute or sub-acute increase in wheeze and shortness of breath
• An increase in coughing, especially while the child is asleep
• Lethargy or reduced exercise tolerance
• Impairment of daily activities, including feeding
• A poor response to reliever medication.

In a study of children aged 2–5 years, the combination of increased daytime cough, daytime wheeze, and night-time
beta2-agonist use was a strong predictor at a group level of an imminent exacerbation (1 day later). This combination
predicted around 70% of exacerbations, with a low false positive rate of 14%. In contrast, no individual symptom was
predictive of an imminent asthma exacerbation.680
Upper respiratory symptoms frequently precede the onset of an asthma exacerbation, indicating the important role of
viral URTI in precipitating exacerbations in many, although not all, children with asthma. In a randomized controlled trial
of acetaminophen versus ibuprofen, given for pain or fever in children with mild persistent asthma, there was no
evidence of a difference in the subsequent risk of flare-ups or poor symptom control.662
INITIAL HOME MANAGEMENT OF ASTHMA EXACERBATIONS

Initial management includes an action plan to enable the child’s family members and carers to recognize worsening
asthma and initiate treatment, recognize when it is severe, identify when urgent hospital treatment is necessary, and
provide recommendations for follow up (Evidence D). The action plan should include specific information about
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medications and dosages and when and how to access medical care.
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Need for urgent medical attention
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IS
Parents/carers should know that immediate medical attention should be sought if:
D
• The child is acutely distressed
R
O
• The child’s symptoms are not relieved promptly by inhaled bronchodilator
•
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The period of relief after doses of SABA becomes progressively shorter
O
• A child younger than 1 year requires repeated inhaled SABA over several hours.
C
T
O
Initial treatment at home

N
O
Inhaled SABA via a mask or spacer, and review response

D
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The parent/carer should initiate treatment with two puffs of inhaled SABA (200 mcg salbutamol or equivalent), given one
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puff at a time via a spacer device with or without a facemask (Evidence D). This may be repeated a further two times at
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20 minute intervals, if needed. The child should be observed by the family/carer and, if improving, maintained in a restful
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and reassuring atmosphere for an hour or more. Medical attention should be sought urgently if any of the features listed
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above apply; or on the same day if more than 6 puffs of inhaled SABA are required for symptom relief within the first 2
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hours, or if the child has not recovered after 24 hours.

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Family/carer-initiated corticosteroids
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Although practiced in some parts of the world, the evidence to support the initiation of oral corticosteroid (OCS)
O
treatment by family/carers in the home management of asthma exacerbations in children is weak.681-685 Preemptive
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episodic high-dose nebulized ICS may reduce exacerbations in children with intermittent viral triggered wheezing.668
However, because of the high potential for side-effects, especially if the treatment is continued inappropriately or is
given frequently, family-administered high dose ICS should be considered only where the health care provider is
confident that the medications will be used appropriately, and the child is closely monitored for side-effects (see p.159.
Emergency treatment and initial pharmacotherapy).
In children aged 2–5 years with intermittent viral wheezing, one study found that a short course of an oral LTRA (for 7–
20 days, commenced at the start of an URTI or the first sign of asthma symptoms) reduced symptoms, health care
utilization and time off work for the carer.686 In contrast another study found no significant effect with LTRA vs placebo
on episode-free days (primary outcome), OCS use, health care utilization, quality of life or hospitalization in children with
or without a positive Asthma Predictive Index (API). However, activity limitation and a symptom trouble score were
significantly improved, particularly in children with a positive API.687 Parents should be counseled about the risk of an
impact on sleep and behavior with montelukast.205

Box 6-8. Primary care management of acute asthma or wheezing in children 5 years and younger
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O
N
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IG
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PRIMARY CARE OR HOSPITAL MANAGEMENT OF ACUTE ASTHMA EXACERBATIONS
Assessment of exacerbation severity

Conduct a brief history and examination concurrently with the initiation of therapy (Box 6-8, Box 6-9). The presence of
any of the features of a severe exacerbation listed in Box 6-9 are an indication of the need for urgent treatment and
immediate transfer to hospital (Evidence D). Oxygen saturation from pulse oximetry of <92% on presentation (before
oxygen or bronchodilator treatment) is associated with high morbidity and likely need for hospitalization; saturation of
92–95% is also associated with higher risk.554 Agitation, drowsiness and confusion are features of cerebral hypoxemia.
A quiet chest on auscultation indicates minimal ventilation, insufficient to produce a wheeze.
Several clinical scoring systems such as PRAM (Preschool Respiratory Assessment Measure) and PASS (Pediatric
Asthma Severity Score) have been developed for assessing the severity of acute asthma exacerbations in children.688
Box 6-9. Initial assessment of acute asthma exacerbations in children 5 years and younger
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Symptoms Mild Severe*
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Altered consciousness No Agitated, confused or drowsy
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IS
D
Oximetry on presentation (SaO2)** >95% <92%
R
O
Speech† Sentences Words
Pulse rate <100 beats/minute PY >180 beats/minute (0–3 years)
O
C
>150 beats/minute (4–5 years)

T
O
N
Respiratory rate ≤ 40/minute >40/minute

O
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Central cyanosis Absent Likely to be present

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Wheeze intensity Variable Chest may be quiet

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*Any of these features indicates a severe asthma exacerbation. **Oximetry before treatment with oxygen or bronchodilator.
†
The normal developmental capability of the child must be taken into account.
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Indications for immediate transfer to hospital

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Children with features of a severe exacerbation that fail to resolve within 1–2 hours despite repeated dosing with inhaled
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SABA must be referred to hospital for observation and further treatment (Evidence D). Other indications are respiratory
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arrest or impending arrest; lack of supervision in the home or doctor’s office; and recurrence of signs of a severe
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exacerbation within 48 hours (particularly if treatment with OCS has already been given). In addition, early medical
attention should be sought for children with a history of severe life-threatening exacerbations, and those less than 2
years of age as the risk of dehydration and respiratory fatigue is increased (Box 6-10, p.159).
Emergency treatment and initial pharmacotherapy

Oxygen
Treat hypoxemia urgently with oxygen by face mask to achieve and maintain percutaneous oxygen saturation 94–98%
(Evidence A). To avoid hypoxemia during changes in treatment, children who are acutely distressed should be treated
immediately with oxygen and SABA (2.5 mg of salbutamol or equivalent diluted in 3 mL of sterile normal saline)
delivered by an oxygen-driven nebulizer (if available). This treatment should not be delayed, and may be given before
the full assessment is completed. Transient hypoxemia due to ventilation/perfusion mismatch may occur during
treatment with SABAs.

Box 6-10.Indications for immediate transfer to hospital for children 5 years and younger
Immediate transfer to hospital is indicated if a child ≤5 years with asthma has ANY of the following:
• At initial or subsequent assessment
o Child is unable to speak or drink
o Cyanosis
o Respiratory rate >40 per minute
o Oxygen saturation <92% when breathing room air
o Silent chest on auscultation
• Lack of response to initial bronchodilator treatment
o Lack of response to 6 puffs of inhaled SABA (2 separate puffs, repeated 3 times) over 1–2 hours
o Persisting tachypnea* despite three administrations of inhaled SABA, even if the child shows other clinical
signs of improvement
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• Social environment that limits delivery of acute treatment, or parent/carer unable to manage acute asthma at home
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IB
During transfer to hospital, continue to give inhaled SABA, oxygen (if available) to maintain saturation 94-98%, and
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give systemic corticosteroids (see Box 6-8, p.157)
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D
*Normal respiratory rates: <60 breaths/minute in children 0–2 months; <50 breaths/minute in children 2–12 months;
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<40 breaths/minute in children 1–5 years.
O
PY
O
Bronchodilator therapy
C
T
The initial dose of SABA may be given by a pMDI with spacer and mask or mouthpiece or an air-driven nebulizer; or, if
O
N
oxygen saturation is low, by an oxygen-driven nebulizer (as described above). For most children, pMDI plus spacer is
O
favored as it is more efficient than a nebulizer for bronchodilator delivery689 (Evidence A). The initial dose of SABA is two
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puffs of salbutamol (100 mcg per puff) or equivalent, except in acute, severe asthma when six puffs should be given.
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When a nebulizer is used, a dose of 2.5 mg salbutamol solution is recommended. The frequency of dosing depends on
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the response observed over 1–2 hours (see below).

AT
For children with moderate-severe exacerbations and a poor response to initial SABA, ipratropium bromide may be
M
D
added, as 2 puffs of 80 mcg (or 250 mcg by nebulizer) every 20 minutes for 1 hour only.689
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H
Magnesium sulfate
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R
The role of magnesium sulfate is not established for children 5 years and younger, because there are few studies in this
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age group. Nebulized isotonic magnesium sulfate may be considered as an adjuvant to standard treatment with
O
C
nebulized salbutamol and ipratropium in the first hour of treatment for children ≥2 years old with acute severe asthma
(e.g. oxygen saturation <92%, Box 6-9, p.158), particularly those with symptoms lasting <6 hours.690 Intravenous
magnesium sulfate in a single dose of 40–50 mg/kg (maximum 2 g) by slow infusion (20–60 minutes) has also been
used.691
Assessment of response and additional bronchodilator treatment

Children with a severe asthma exacerbation must be observed for at least 1 hour after initiation of treatment, at which
time further treatment can be planned.
• If symptoms persist after initial bronchodilator: a further 2–6 puffs of salbutamol (depending on severity) may be
given 20 minutes after the first dose and repeated at 20-minute intervals for an hour. Failure to respond at 1 hour,
or earlier deterioration, should prompt urgent admission to hospital and a short-course of oral corticosteroids
(Evidence D).
• If symptoms have improved by 1 hour but recur within 3–4 hours: the child may be given more frequent doses of
bronchodilator (2–3 puffs each hour), and oral corticosteroids should be given. The child may need to remain in

the emergency department, or, if at home, should be observed by the family/carer and have ready access to
emergency care. Children who fail to respond to 10 puffs of inhaled SABA within a 3–4 hour period should be
referred to hospital (Evidence D).
• If symptoms resolve rapidly after initial bronchodilator and do not recur for 1–2 hours: no further treatment may be
required. Further SABA may be given every 3–4 hours (up to a total of 10 puffs/24 hours) and, if symptoms persist
beyond 1 day, other treatments including inhaled or oral corticosteroids are indicated (Evidence D), as outlined
below.
Box 6-11.Initial emergency department management of asthma exacerbations in children 5 years and younger
Therapy Dose and administration
Supplemental oxygen Delivered by face mask (usually 1 L/minute) to maintain oxygen saturation 94–98%
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Short-acting beta2- 2–6 puffs of salbutamol by spacer, or 2.5 mg of salbutamol by nebulizer, every 20 minutes
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agonist (SABA) for first hour*, then reassess severity. If symptoms persist or recur, give an additional 2–3
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puffs per hour. Admit to hospital if >10 puffs required in 3–4 hours.
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IS
Systemic Give initial dose of oral prednisolone (1–2 mg/kg up to a maximum 20 mg for children <2
D
R
corticosteroids years old; 30 mg for children 2–5 years)
O
PY
OR, intravenous methylprednisolone 1 mg/kg 6-hourly on day 1
O
Additional options in the first hour of treatment
C
T
O
N
Ipratropium bromide For children with moderate-severe exacerbations, 2 puffs of ipratropium bromide
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80mcg (or 250mcg by nebulizer) every 20 minutes for 1 hour only

D
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Magnesium sulfate Consider nebulized isotonic magnesium sulfate (150mg) 3 doses in the first hour of
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treatment for children aged ≥2 years with severe exacerbation (Box 6-9, p.158)
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*If inhalation is not possible an intravenous bolus of terbutaline 2 mcg/kg may be given over 5 minutes, followed by continuous infusion of 5
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mcg/kg/hour692 (Evidence C). The child should be closely monitored, and the dose should be adjusted according to clinical improvement and side-
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effects. See below for additional and ongoing treatment, including controller therapy.
H
IG
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Additional treatment
PY
O
When treatment in addition to SABA is required for an exacerbation, the options available for children in this age group
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include ICS; a short course of oral corticosteroid; and/or LTRA (see p.156). However, the clinical benefit of these
interventions – particularly on endpoints such as hospitalizations and longer-term outcomes – has not been impressive.
Maintain current controller treatment (if prescribed)
Children who have been prescribed maintenance therapy with ICS, LTRA or both should continue to take the prescribed
dose during and after an exacerbation (Evidence D).
Inhaled corticosteroids
For children not previously on ICS, an initial dose of ICS twice the low daily dose indicated in Box 6-6 (p.153) may be
given and continued for a few weeks or months (Evidence D). Some studies have used high dose ICS (1600 mcg/day,
preferably divided into four doses over the day and given for 5–10 days) as this may reduce the need for
OCS.534,664,665,693,694 In one study of hospitalized pre-school children, adding nebulized budesonide to existing treatment
(including OCS) reduced length of stay.695 However, the potential for side-effects with high dose ICS should be taken
into account, especially if used repeatedly, and the child should be monitored closely. For those children already on ICS,

doubling the dose was not effective in a small study of mild-moderate exacerbations in children aged 6–14 years,696 nor
was quintupling the dose in children aged 5–11 years with good adherence. This approach should be reserved mainly
for individual cases, and should always involve regular follow up and monitoring of adverse effects (Evidence D).
Oral corticosteroids
For children with severe exacerbations, a dose of OCS equivalent to prednisolone 1–2 mg/kg/day, with a maximum of
20 mg/day for children under 2 years of age and 30 mg/day for children aged 2–5 years, is currently recommended
(Evidence A),697 although several studies have failed to show any benefits when given earlier (e.g. by parents) during
periods of worsening wheeze managed in an outpatient setting (Evidence D).681-684,698,699 A recent meta-analysis
demonstrated a reduced risk of hospitalization when oral corticosteroids were administered in the emergency
department, but no clear benefit in risk of hospitalization when given in the outpatient setting.700 A course of 3–5 days is
sufficient in most children of this age, and can be stopped without tapering (Evidence D), but the child must be reviewed
after discharge (as below) to confirm they are recovering.
In children discharged from the emergency department, an intramuscular corticosteroid may be an alternative to a
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course of OCS for preventing relapse.564 There is insufficient evidence to recommend intramuscular over oral
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corticosteroids.564
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Regardless of treatment, the severity of the child’s symptoms must be carefully monitored. The sooner therapy is started
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in relation to the onset of symptoms, the more likely it is that the impending exacerbation may be clinically attenuated or
D
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prevented.
O
Discharge and follow up after an exacerbation
PY
O
C
Before discharge, the condition of the child should be stable (e.g. he/she should be out of bed and able to eat and drink
T
O
without problems).
N
O
Children who have recently had an asthma exacerbation are at risk of further exacerbations and require follow up. The
D
purpose is to ensure complete recovery, to establish the cause of the exacerbation, and, when necessary, to establish
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appropriate maintenance treatment and adherence (Evidence D).

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Prior to discharge from the emergency department or hospital, family/carers should receive the following advice and
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information (all are Evidence D).

M
D
• Instruction on recognition of signs of recurrence and worsening of asthma. The factors that precipitated the
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exacerbation should be identified, and strategies for future avoidance of these factors implemented.
H
A written, individualized action plan, including details of accessible emergency services

IG
•
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• Careful review of inhaler technique

PY
• Further treatment advice explaining that:

O
C
o SABAs should be used on an as-needed basis, but the daily requirement should be recorded to ensure it is
being decreased over time to pre-exacerbation levels.
o ICS has been initiated where appropriate (at twice the low initial dose in Box 6-6 (p.153) for the first month
after discharge, then adjusted as needed) or continued, for those previously prescribed controller medication.
• A supply of SABA and, where applicable, the remainder of the course of oral corticosteroid, ICS or LTRA
• A follow-up appointment within 1–2 days and another within 1–2 months, depending on the clinical, social and
practical context of the exacerbation

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D
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O
N
O
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SECTION 2. CHILDREN 5 YEARS AND YOUNGER
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Chapter 7.
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O
Primary prevention
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O
N
of asthma
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KEY POINTS
• The development and persistence of asthma are driven by gene–environment interactions. For children, a ‘window
of opportunity’ to prevent asthma exists in utero and in early life, but intervention studies are limited.
• With regard to allergen avoidance strategies aimed at preventing asthma in children:
o Strategies directed at a single allergen have not been effective in reducing the incidence of asthma
o Multifaceted strategies may be effective, but the essential components have not been identified.
• Current recommendations for preventing asthma in children, based on high quality evidence or consensus, include:
o Avoid exposure to environmental tobacco smoke during pregnancy and the first year of life
o Encourage vaginal delivery
o Advise breast-feeding for its general health benefits (not necessarily for asthma prevention)
o Where possible, avoid use of paracetamol (acetaminophen) and broad-spectrum antibiotics during the first
year of life.
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FACTORS CONTRIBUTING TO THE DEVELOPMENT OF ASTHMA IN CHILDREN
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Asthma is generally believed to be a heterogeneous disease whose inception and persistence is driven by gene–
D
environment interactions. The most important of these interactions may occur in early life and even in utero. There is
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consensus that a ‘window of opportunity’ exists during pregnancy and early in life when environmental factors may
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influence asthma development. Multiple environmental factors, both biological and sociological, may be important in the
O
development of asthma. Data supporting the role of environmental risk factors for the development of asthma include a
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focus on: nutrition, allergens (both inhaled and ingested), pollutants (particularly environmental tobacco smoke),
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microbes, and psychosocial factors. Additional information about factors contributing to the development of asthma,
N
including occupational asthma, is found in Appendix Chapter 2.

O
D
‘Primary prevention’ refers to preventing the onset of disease. This chapter focuses on primary prevention in children.
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See p.91 and review articles38 for strategies for preventing occupational asthma.
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FACTORS ASSOCIATED WITH INCREASED OR DECREASED RISK OF ASTHMA IN CHILDREN

M
D
Nutrition of mother and baby

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Maternal diet
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For some time, the mother’s diet during pregnancy has been a focus of concern relating to the development of allergy
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and asthma in the child. There is no firm evidence that ingestion of any specific foods during pregnancy increases the
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risk for asthma. However, a recent study of a pre-birth cohort observed that maternal intake of foods commonly
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considered allergenic (peanut and milk) was associated with a decrease in allergy and asthma in the offspring.701 Similar
data have been shown in a very large Danish National birth cohort, with an association between ingestion of peanuts,
tree nuts and/or fish during pregnancy and a decreased risk of asthma in the offspring.702,703 Epidemiological studies and
randomized controlled trials on maternal dietary intake of fish or long-chain polyunsaturated fatty acids during pregnancy
showed no consistent effects on the risk of wheeze, asthma or atopy in the child.704-707 Dietary changes during
pregnancy are therefore not recommended for prevention of allergies or asthma.
Maternal obesity and weight gain during pregnancy
Data suggest that maternal obesity and weight gain during pregnancy pose an increased risk for asthma in children. A
meta-analysis708 showed that maternal obesity in pregnancy was associated with higher odds of ever asthma or wheeze
or current asthma or wheeze; each 1 kg/m2 increase in maternal BMI was associated with a 2% to 3% increase in the
odd of childhood asthma. High gestational weight gain was associated with higher odds of ever asthma or wheeze.
However, no recommendations can be made at present, as unguided weight loss in pregnancy should not be
encouraged.
164 7. Primary prevention of asthma

Breastfeeding
Despite the existence of many studies reporting a beneficial effect of breastfeeding on asthma prevention, results are
conflicting,432 and caution should be taken in advising families that breastfeeding will prevent asthma.709 Breastfeeding
decreases wheezing episodes in early life; however, it may not prevent development of persistent asthma (Evidence D).
Regardless of its effect on development of asthma, breastfeeding should be encouraged for all of its other positive
benefits (Evidence A).
Timing of introduction of solids
Beginning in the 1990s, many national pediatric agencies and societies recommended delay of introduction of solid food,
especially for children at a high risk for developing allergy. However, meta-analyses have found no evidence that this
practice reduces the risk of allergic disease (including asthma).710 In the case of peanuts, early introduction may prevent
peanut allergy in high risk infants.710
Dietary supplements for mothers and/or babies
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Vitamin D
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Intake of vitamin D may be through diet, dietary supplementation or sunlight. A systematic review of cohort, case control
T
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and cross-sectional studies concluded that maternal dietary intake of vitamin D, and of vitamin E, was associated with
D
lower risk of wheezing illnesses in children.711 This was not confirmed in two randomized controlled trials of vitamin D
R
supplementation in pregnancy comparing standard dose with high dose vitamin D, although a significant effect was not
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ruled out.712,713 When the results from these two trials were combined, there was a 25% reduction of risk of
O
asthma/recurrent wheeze at ages 0–3 years.714 The effect was greatest among women who maintained 25(OH)vitamin
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D levels of at least 30ng/ml from the time of study entry through delivery, suggesting that sufficient levels of Vitamin D
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during early pregnancy may be important in decreasing risk for early life wheezing episodes.714
N
O
Fish oil and long-chain polyunsaturated fatty acids

D
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Systematic reviews of cohort studies about maternal dietary intake of fish or seafood during pregnancy704,715 and of
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randomized controlled trials on maternal dietary intake of fish or long-chained polyunsaturated fatty acids during
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pregnancy704 showed no consistent effects on the risk of wheeze, asthma or atopy in the child. One recent study
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demonstrated decreased wheeze/asthma in pre-school children at high risk for asthma when mothers were given a high
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dose fish oil supplement in the third trimester;716 however ‘fish oil’ is not well defined, and the optimal dosing regimen
D
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has not been established.

H
IG
Probiotics
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A meta-analysis provided insufficient evidence to recommend probiotics for the prevention of allergic disease (asthma,
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rhinitis, eczema or food allergy).717

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Inhalant allergens
Sensitization to indoor, inhaled aero-allergens is generally more important than sensitization to outdoor allergens for the
presence of, and/or development of, asthma. While there appears to be a linear relationship between exposure and
sensitization to house dust mite,718,719 the relationship for animal allergen appears to be more complex.432 Some studies
have found that exposure to pet allergens is associated with increased risk of sensitization to these allergens,720,721 and
of asthma and wheezing.722,723 By contrast, other studies have demonstrated a decreased risk of developing allergy with
exposure to pets.724,725 A review of over 22,000 school-age children from 11 birth cohorts in Europe found no correlation
between pets in the homes early in life and higher or lower prevalence of asthma in children.726 For children at risk of
asthma, dampness, visible mold and mold odor in the home environment are associated with increased risk of
developing asthma.727 Overall, there are insufficient data to recommend efforts to either reduce or increase pre-natal or
early-life exposure to common sensitizing allergens, including pets, for the prevention of allergies and asthma.
7. Primary prevention of asthma 165

Birth cohort studies provide some evidence for consideration. A meta-analysis found that studies of interventions
focused on reducing exposure to a single allergen did not significantly affect asthma development, but that multifaceted
interventions such as in the Isle of Wight study,728 the Canadian Asthma Primary Prevention Study,729 and the
Prevention of Asthma in Children study730 were associated with lower risk of asthma diagnosis in children younger than
5 years.731 Two multifaceted studies that followed children beyond 5 years of age demonstrated a significant protective
effect both before and after the age of 5 years.728,732 The Isle of Wight study has shown a continuing positive benefit for
early-life intervention through to 18 years of age;733 however, exactly which components of the intervention were
important and which specific mechanistic changes were induced remain elusive.
Treatment with grass SLIT for 3 years did not reduce the incidence of asthma diagnosis (primary outcome) in a large
randomized double-blind placebo-controlled trial in children 5-12 years with grass-allergic rhinoconjunctivitis, but asthma
symptoms and asthma medication use were reduced. At present, SLIT for children with grass allergic rhinoconjunctivitis
is not recommended for asthma prevention.734 Additional studies are needed.
Pollutants
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Maternal smoking during pregnancy is the most direct route of pre-natal environmental tobacco smoke exposure.735 A
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meta-analysis concluded that pre-natal smoking had its strongest effect on young children, whereas post-natal maternal
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smoking seemed relevant only to asthma development in older children.736 Exposure to outdoor pollutants, such as
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living near a main road, is associated with increased risk of asthma.737,738 A recent study suggested that up to 4 million
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new pediatric asthma cases (13% of the global incidence) may be attributable to exposure to traffic-related air pollution
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(TRAP).739 Prenatal NO2, SO2, and PM10 exposures are associated with an increased risk of asthma in childhood,740 but
it is difficult to separate pre- and post-natal exposure. PY
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Microbial effects
O
N
The ‘hygiene hypothesis’, and the more recently coined ‘microflora hypothesis’ and ‘biodiversity hypothesis’,741 suggest
O
D
that human interaction with microbiota may be beneficial in preventing asthma. For example, there is a lower risk of
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asthma among children raised on farms with exposure to stables and consumption of raw farm milk than among children
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of non-farmers.742 The risk of asthma is also reduced in children whose bedrooms have high levels of bacterial-derived
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lipopolysaccharide endotoxin.743,744 Similarly, children in homes with ≥2 dogs or cats are less likely to be allergic than
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those in homes without dogs or cats.725 Exposure of an infant to the mother’s vaginal microflora through vaginal delivery
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may also be beneficial; the prevalence of asthma is higher in children born by cesarean section than those born
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vaginally.745,746 This may relate to differences in the infant gut microbiota according to their mode of delivery.747
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Respiratory syncytial virus infection is associated with subsequent recurrent wheeze, and preventative treatment of
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premature infants with monthly injections of the monoclonal antibody, palivizumab, (prescribed for prophylaxis of
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respiratory syncytial virus) is associated with a reduction in recurrent wheezing in the first year of life.748 However, there
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is little evidence to suggest that this effect is sustained. Although the risk of parent-reported asthma with infrequent
wheeze was reduced at 6 years, there was no impact on doctor-diagnosed asthma or lung function.749 Thus, the long-
term effect of palivizumab in the prevention of asthma remains uncertain.
Medications and other factors

Antibiotic use during pregnancy and in infants and toddlers has been associated with the development of asthma later in
life,750-752 although not all studies have shown this association.753 Intake of the analgesic, paracetamol (acetaminophen),
may be associated with asthma in both children and adults,754 although exposure during infancy may be confounded by
use of paracetamol for respiratory tract infections.754 Frequent use of paracetamol by pregnant women has been
associated with asthma in their children.755 There is no evidence that vaccinations increase the risk of a child developing
asthma.
166 7. Primary prevention of asthma

Psychosocial factors
The social environment to which children are exposed may also contribute to the development and severity of asthma.
Maternal distress during pregnancy756 or during the child’s early years750 has been associated with an increased risk of
the child developing asthma.
Obesity
A meta-analysis of 18 studies found that being either overweight or obese was a risk factor for childhood asthma and
wheeze, particularly in girls.411 In adults, there is evidence suggesting that obesity affects the risk of asthma, but that
asthma does not affect the risk of obesity.757
ADVICE ABOUT PRIMARY PREVENTION OF ASTHMA

Based on the results of cohort and observational studies,758 and a GRADE-based analysis for the Allergic Rhinitis and
its Impact on Asthma (ARIA) guidelines,432 parents enquiring about how to reduce the risk of their children developing
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asthma can be provided with the advice summarized in Box 7-1.
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Possibly the most important factor is the need to provide a positive, supportive environment for discussion that
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decreases stress, and which encourages families to make choices with which they feel comfortable.
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Box 7-1. Advice about primary prevention of asthma in children 5 years and younger
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Parents enquiring about how to reduce the risk of their child developing asthma can be provided with the following
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advice:
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• Children should not be exposed to environmental tobacco smoke during pregnancy or after birth.
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• Vaginal delivery should be encouraged where possible.

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• Breastfeeding is advised, for reasons other than prevention of allergy and asthma.
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• The use of broad-spectrum antibiotics during the first year of life should be discouraged.
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7. Primary prevention of asthma 167

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SECTION 3. TRANSLATION INTO CLINICAL
PRACTICE
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Chapter 8.
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Implementing asthma
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management strategies
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into health systems

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KEY POINTS
• In order to improve asthma care and patient outcomes, evidence-based recommendations must not only be
developed, but also disseminated and implemented at a national and local level, and integrated into clinical
practice.
• Recommendations for implementing asthma care strategies are based on many successful programs worldwide.
• Implementation requires an evidence-based strategy involving professional groups and stakeholders, and should
take into account local cultural and socioeconomic conditions.
• Cost-effectiveness of implementation programs should be assessed so a decision can be made to pursue or
modify them.
• Local adaptation and implementation of asthma care strategies is aided by the use of tools developed for this
purpose.
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INTRODUCTION
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Due to the exponential increase in medical research publications, practical syntheses are needed to guide policy makers
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and health care professionals in delivering evidence-based care. When asthma care is consistent with evidence-based
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recommendations, outcomes improve.153,759,760 The Global Strategy for Asthma Management and Prevention is a
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resource document for health care professionals to establish the main goals of asthma treatment and the actions
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required to ensure their fulfilment, as well as to facilitate the achievement of standards for quality asthma care.
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The recent adoption of rigorous methodologies such as GRADE2 for the development of clinical practice
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recommendations, and the ADAPTE761 and similar approaches for assisting the adaptation of recommendations for local
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country and regional conditions, has assisted in reducing biased opinion as the basis for asthma programs worldwide.
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Adaptation of clinical practice recommendations to local conditions using the GRADE method is costly and often
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requires expertise that is not available locally; in addition, regular revision is required to remain abreast of developments,
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including drug availability and new evidence, and this is not easily achieved.762 Further, there is generally very limited
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high quality evidence addressing the many decision nodes in comprehensive clinical practice guidelines, particularly in
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developing countries.
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ADAPTING AND IMPLEMENTING ASTHMA CLINICAL PRACTICE GUIDELINES

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Implementation of asthma management strategies may be carried out at a national, regional or local level.763 Ideally,
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implementation should be a multidisciplinary effort involving many stakeholders, and using cost-effective methods of
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knowledge translation.763-765 Each implementation initiative needs to consider the nature of the local health system and
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its resources (e.g. human, infrastructure, available treatments) (Box 8-1). Moreover, goals and implementation strategies
will need to vary from country to country and within countries, based on economics, culture and the physical and social
environment. Priority should be given to high-impact interventions.
Specific steps need to be followed before clinical practice recommendations can be embedded into local clinical practice
and become the standard of care, particularly in low resource settings. The individual steps are summarized in Box 8-2,
and a detailed description of the processes involved in each step can be found in the GINA Appendix Chapter 6,
available online at www.ginasthma.org.
170 8. Implementing asthma management strategies in health systems

Box 8-1. Approach to implementation of the Global Strategy for Asthma Management and Prevention
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Box 8-2. Essential elements required to implement a health-related strategy

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Steps in implementing an asthma strategy into a health system

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1. Develop a multidisciplinary working group.

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2. Assess the current status of asthma care delivery, care gaps and current needs.
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3. Select the material to be implemented, agree on main goals, identify key recommendations for diagnosis and
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treatment, and adapt them to the local context or environment.

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4. Identify barriers to, and facilitators of, implementation.

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5. Select an implementation framework and its component strategies

6. Develop a step-by-step implementation plan:
o Select target populations and evaluable outcomes.
o Identify local resources to support implementation.
o Set timelines.
o Distribute tasks to members.
o Evaluate outcomes.
7. Continuously review progress and results to determine if the strategy requires modification.
8. Implementing asthma management strategies in health systems 171

BARRIERS AND FACILITATORS
Many barriers to, and facilitators of, implementation procedures have been described.765-768 Some of the barriers to
implementation of evidence-based asthma management relate to the delivery of care, while others relate to patients’
attitudes (see Box 8-3, and examples in Appendix Chapter 6, Box 6-1). Cultural and economic barriers can particularly
affect the application of recommendations.
Box 8-3. Examples of barriers to the implementation of evidence-based recommendations
Health care providers Patients
Insufficient knowledge of recommendations Low health literacy

Lack of agreement with recommendations or Insufficient understanding of asthma and its
expectation that they will be effective management
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Resistance to change Lack of agreement with recommendations
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External barriers (organizational, health policies, Cultural and economic barriers
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financial constraints)
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Peer influence
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Lack of time and resources
Attitudes, beliefs, preferences, fears and
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Medico-legal issues misconceptions
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EXAMPLES OF HIGH IMPACT IMPLEMENTATION INTERVENTIONS

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Ideally, interventions should be applied at the level of both the patient and the health care provider and, where relevant,
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the health system. Studies of the most effective means of medical education show that it may be difficult to induce
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changes in clinical practice. Examples of highly effective interventions are shown in Box 8-4.
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Box 8-4. Examples of high-impact interventions in asthma management

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• Free ICS for patients with a recent hospital admission and/or severe asthma769
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• Early treatment with ICS, guided self-management, reduction in exposure to tobacco smoke, improved access to
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asthma education153
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• Self-inking stamp prompting assessment of asthma control and treatment strategies770

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• Use of individualized written asthma action plans as part of self-management education404

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• An evidence-based care process model for acute and chronic pediatric asthma management, implemented at
multiple hospitals771
ICS: inhaled corticosteroids
EVALUATION OF THE IMPLEMENTATION PROCESS

An important part of the implementation process is to establish a means of evaluating the effectiveness of the program
and any improvements in quality of care (see Appendix Chapter 6, Box A6-3). The Cochrane Effective Practice and
Organization of Care Group (EPOC) offers suggestions on how to assess the effectiveness of interventions.772
Evaluation involves surveillance of traditional epidemiological parameters, such as morbidity and mortality, as well as
specific audits of both process and outcome within different sectors of the health care system. Each country should
determine its own minimum sets of data to audit health outcomes.
172 8. Implementing asthma management strategies in health systems

HOW CAN GINA HELP WITH IMPLEMENTATION?
GINA, through the work of its Dissemination and Implementation Committee, assists in the processes of adaptation and
implementation of the recommendations in the Global Strategy for Asthma Management and Prevention report. The
GINA report provides an annually-updated summary of evidence relevant to asthma diagnosis, management and
prevention that may be used in the formulation and adaptation of local guidelines; where evidence is lacking, the GINA
report provides approaches for consideration. A web-based implementation ‘toolkit’ will provide a template and guide to
local adaptation and implementation of these recommendations, together with materials and advice from successful
examples of asthma clinical practice guideline development and implementation in different settings.
Educational materials and tools based on the Global Strategy for Asthma Management and Prevention are available in
several forms and can be found on the GINA Website (www.ginasthma.org).
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8. Implementing asthma management strategies in health systems 173

REFERENCES
1. National Heart Lung and Blood Institute N. Global initiative for asthma. Global strategy for asthma management
and prevention. NHBLI/WHO workshop. 1995:NIH Publication no. 95-3659.
2. Schunemann HJ, Jaeschke R, Cook DJ, Bria WF, El-Solh AA, Ernst A, Fahy BF, et al. An official ATS statement:
grading the quality of evidence and strength of recommendations in ATS guidelines and recommendations. Am J
Respir Crit Care Med 2006;174:605-14.
3. Asher I, Bissell K, Chiang CY, El Sony A, Ellwood P, Garcia-Marcos L, Marks GB, et al. Calling time on asthma
deaths in tropical regions-how much longer must people wait for essential medicines? Lancet Respir Med
2019;7:13-5.
4. Chiang CY, Ait-Khaled N, Bissell K, Enarson DA. Management of asthma in resource-limited settings: role of low-
cost corticosteroid/beta-agonist combination inhaler. Int J Tuberc Lung Dis 2015;19:129-36.
5. Bel EH. Clinical phenotypes of asthma. Curr Opin Pulm Med 2004;10:44-50.
TE
6. Moore WC, Meyers DA, Wenzel SE, Teague WG, Li H, Li X, D'Agostino R, Jr., et al. Identification of asthma
U
phenotypes using cluster analysis in the Severe Asthma Research Program. Am J Respir Crit Care Med
IB
R
2010;181:315-23.
T
7. Wenzel SE. Asthma phenotypes: the evolution from clinical to molecular approaches. Nat Med 2012;18:716-25.
IS
D
8. Westerhof GA, Coumou H, de Nijs SB, Weersink EJ, Bel EH. Clinical predictors of remission and persistence of
R
adult-onset asthma. J Allergy Clin Immunol 2018;141:104-9.e3.
O
PY
9. Levy ML, Fletcher M, Price DB, Hausen T, Halbert RJ, Yawn BP. International Primary Care Respiratory Group
(IPCRG) Guidelines: diagnosis of respiratory diseases in primary care. Prim Care Respir J 2006;15:20-34.
O
C
10. Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, Enright PL, et al. Multi-ethnic reference values for
T
O
spirometry for the 3-95-yr age range: the global lung function 2012 equations. Eur Respir J 2012;40:1324-43.
N
11. Reddel H, Ware S, Marks G, Salome C, Jenkins C, Woolcock A. Differences between asthma exacerbations and
O
D
poor asthma control [erratum in Lancet 1999;353:758]. Lancet 1999;353:364-9.

L-
12. Aaron SD, Vandemheen KL, FitzGerald JM, Ainslie M, Gupta S, Lemiere C, Field SK, et al. Reevaluation of
IA
diagnosis in adults with physician-diagnosed asthma. JAMA 2017;317:269-79.

ER
13. Graham BL, Steenbruggen I, Miller MR, Barjaktarevic IZ, Cooper BG, Hall GL, Hallstrand TS, et al. Standardization
AT
of spirometry 2019 update. An official American Thoracic Society and European Respiratory Society technical
M
statement. Am J Respir Crit Care Med 2019;200:e70-e88.

D
TE
14. Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, Crapo R, et al. Standardisation of
H
spirometry. Eur Respir J 2005;26:319-38.

IG
15. Pellegrino R, Viegi G, Brusasco V, Crapo RO, Burgos F, Casaburi R, Coates A, et al. Interpretative strategies for
R
PY
lung function tests. Eur Respir J 2005;26:948-68.

O
16. Tan WC, Vollmer WM, Lamprecht B, Mannino DM, Jithoo A, Nizankowska-Mogilnicka E, Mejza F, et al. Worldwide
C
patterns of bronchodilator responsiveness: results from the Burden of Obstructive Lung Disease study. Thorax
2012;67:718-26.
17. Reddel HK, Taylor DR, Bateman ED, Boulet LP, Boushey HA, Busse WW, Casale TB, et al. An official American
Thoracic Society/European Respiratory Society statement: asthma control and exacerbations: standardizing
endpoints for clinical asthma trials and clinical practice. Am J Respir Crit Care Med 2009;180:59-99.
18. Brouwer AF, Brand PL. Asthma education and monitoring: what has been shown to work. Paediatr Respir Rev
2008;9:193-9.
19. Parsons JP, Hallstrand TS, Mastronarde JG, Kaminsky DA, Rundell KW, Hull JH, Storms WW, et al. An official
American Thoracic Society clinical practice guideline: exercise-induced bronchoconstriction. Am J Respir Crit Care
Med 2013;187:1016-27.
20. Crapo RO, Casaburi R, Coates AL, Enright PL, Hankinson JL, Irvin CG, MacIntyre NR, et al. Guidelines for
methacholine and exercise challenge testing-1999. Am J Respir Crit Care Med 2000;161:309-29.
21. Joos GF, O'Connor B, Anderson SD, Chung F, Cockcroft DW, Dahlen B, DiMaria G, et al. Indirect airway
challenges. Eur Respir J 2003;21:1050-68.
174 References
22. Ramsdale EH, Morris MM, Roberts RS, Hargreave FE. Asymptomatic bronchial hyperresponsiveness in rhinitis. J
Allergy Clin Immunol 1985;75:573-7.
23. van Haren EH, Lammers JW, Festen J, Heijerman HG, Groot CA, van Herwaarden CL. The effects of the inhaled
corticosteroid budesonide on lung function and bronchial hyperresponsiveness in adult patients with cystic fibrosis.
Respir Med 1995;89:209-14.
24. Joshi S, Powell T, Watkins WJ, Drayton M, Williams EM, Kotecha S. Exercise-induced bronchoconstriction in
school-aged children who had chronic lung disease in infancy.[Erratum in J Pediatr. 2013 Jun;162(6):1298]. J
Pediatr 2013;162:813-8.e1.
25. Ramsdale EH, Morris MM, Roberts RS, Hargreave FE. Bronchial responsiveness to methacholine in chronic
bronchitis: relationship to airflow obstruction and cold air responsiveness. Thorax 1984;39:912-8.
26. Ahlstedt S, Murray CS. In vitro diagnosis of allergy: how to interpret IgE antibody results in clinical practice. Prim
Care Respir J 2006;15:228-36.
27. Korevaar DA, Westerhof GA, Wang J, Cohen JF, Spijker R, Sterk PJ, Bel EH, et al. Diagnostic accuracy of
minimally invasive markers for detection of airway eosinophilia in asthma: a systematic review and meta-analysis.
TE
Lancet Respir Med 2015;3:290-300.
U
28. Fahy JV. Type 2 inflammation in asthma--present in most, absent in many. Nature Reviews Immunology
IB
2015;15:57-65.
R
T
29. American Thoracic Society, European Respiratory Society. ATS/ERS Recommendations for Standardized
IS
D
Procedures for the Online and Offline Measurement of Exhaled Lower Respiratory Nitric Oxide and Nasal Nitric
R
Oxide, 2005. Am J Respir Crit Care Med 2005;171:912-30.
O
30. Haccuria A, Michils A, Michiels S, Van Muylem A. Exhaled nitric oxide: a biomarker integrating both lung function
PY
and airway inflammation changes. J Allergy Clin Immunol 2014;134:554-9.
O
C
31. Aaron SD, Vandemheen KL, Boulet LP, McIvor RA, Fitzgerald JM, Hernandez P, Lemiere C, et al. Overdiagnosis of
T
asthma in obese and nonobese adults. CMAJ 2008;179:1121-31.

O
N
32. Lucas AE, Smeenk FW, Smeele IJ, van Schayck CP. Overtreatment with inhaled corticosteroids and diagnostic
O
problems in primary care patients, an exploratory study. Fam Pract 2008;25:86-91.

D
L-
33. Marklund B, Tunsater A, Bengtsson C. How often is the diagnosis bronchial asthma correct? Fam Pract
IA
1999;16:112-6.
ER
34. Montnemery P, Hansson L, Lanke J, Lindholm LH, Nyberg P, Lofdahl CG, Adelroth E. Accuracy of a first diagnosis
AT
of asthma in primary health care. Fam Pract 2002;19:365-8.

M
35. Gibson PG, Chang AB, Glasgow NJ, Holmes PW, Katelaris P, Kemp AS, Landau LI, et al. CICADA: Cough in
D
TE
Children and Adults: Diagnosis and Assessment. Australian cough guidelines summary statement. Med J Aust
H
2010;192:265-71.
IG
36. Halvorsen T, Walsted ES, Bucca C, Bush A, Cantarella G, Friedrich G, Herth FJF, et al. Inducible laryngeal
R
PY
obstruction: an official joint European Respiratory Society and European Laryngological Society statement. Eur
O
Respir J 2017;50.
C
37. Desai D, Brightling C. Cough due to asthma, cough-variant asthma and non-asthmatic eosinophilic bronchitis.
Otolaryngol Clin North Am 2010;43:123-30.
38. Baur X, Sigsgaard T, Aasen TB, Burge PS, Heederik D, Henneberger P, Maestrelli P, et al. Guidelines for the
management of work-related asthma.[Erratum appears in Eur Respir J. 2012 Jun;39(6):1553]. Eur Respir J
2012;39:529-45.
39. Tarlo SM, Malo JL. An official ATS proceedings: asthma in the workplace: the Third Jack Pepys Workshop on
Asthma in the Workplace: answered and unanswered questions. Proc Am Thorac Soc 2009;6:339-49.
40. Levy ML, Nicholson PJ. Occupational asthma case finding: a role for primary care. Br J Gen Pract 2004;54:731-3.
41. Carlsen KH, Anderson SD, Bjermer L, Bonini S, Brusasco V, Canonica W, Cummiskey J, et al. Exercise-induced
asthma, respiratory and allergic disorders in elite athletes: epidemiology, mechanisms and diagnosis: Part I of the
report from the Joint Task Force of the European Respiratory Society (ERS) and the European Academy of Allergy
and Clinical Immunology (EAACI) in cooperation with GA2LEN. Allergy 2008;63:387-403.
42. Murphy VE, Gibson PG. Asthma in pregnancy. Clin Chest Med 2011;32:93-110, ix.
References 175
43. Adams RJ, Wilson DH, Appleton S, Taylor A, Dal Grande E, Chittleborough CR, Ruffin RE. Underdiagnosed
asthma in South Australia. Thorax 2003;58:846-50.
44. Hsu J, Chen J, Mirabelli MC. Asthma Morbidity, Comorbidities, and Modifiable Factors Among Older Adults. J
Allergy Clin Immunol Pract 2018;6:236-43.e7.
45. Parshall MB, Schwartzstein RM, Adams L, Banzett RB, Manning HL, Bourbeau J, Calverley PM, et al. An Official
American Thoracic Society Statement: Update on the Mechanisms, Assessment, and Management of Dyspnea. Am
J Respir Crit Care Med 2012;185:435-52.
46. Januzzi JL, Jr., Camargo CA, Anwaruddin S, Baggish AL, Chen AA, Krauser DG, Tung R, et al. The N-terminal Pro-
BNP investigation of dyspnea in the emergency department (PRIDE) study. Am J Cardiol 2005;95:948-54.
47. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for Diagnosis, Management and
Prevention of COPD Fontana, WI, USA 2020.
48. Hanania NA, Celli BR, Donohue JF, Martin UJ. Bronchodilator reversibility in COPD. Chest 2011;140:1055-63.
49. Alshabanat A, Zafari Z, Albanyan O, Dairi M, FitzGerald JM. Asthma and COPD overlap syndrome (ACOS): A
systematic review and meta analysis. PLoS One 2015;10:e0136065.
TE
50. Boulet LP. Asthma and obesity. Clin Exp Allergy 2013;43:8-21.
U
51. van Huisstede A, Castro Cabezas M, van de Geijn GJ, Mannaerts GH, Njo TL, Taube C, Hiemstra PS, et al.
IB
Underdiagnosis and overdiagnosis of asthma in the morbidly obese. Respir Med 2013;107:1356-64.
TR
52. English RG, Bachmann MO, Bateman ED, Zwarenstein MF, Fairall LR, Bheekie A, Majara BP, et al. Diagnostic
IS
D
accuracy of an integrated respiratory guideline in identifying patients with respiratory symptoms requiring screening
R
for pulmonary tuberculosis: a cross-sectional study. BMC Pulm Med 2006;6:22.
O
53. Package of essential noncommunicable (PEN) disease interventions for primary health care in low-resource
PY
settings. WHO, 2010. at www.who.int/cardiovascular_diseases/publications/pen2010/en/.)
O
C
54. Ait-Khaled N, Enarson DA, Chiang C-Y, Marks G, K B. Management of asthma: a guide to the essentials of good
T
clinical practice. Paris, France: International Union Against Tuberculosis and Lung Disease; 2008.
O
N
55. Barreto ML, Ribeiro-Silva Rde C, Malta DC, Oliveira-Campos M, Andreazzi MA, Cruz AA. Prevalence of asthma
O
symptoms among adolescents in Brazil: National Adolescent School-based Health Survey (PeNSE 2012). Revista
D
L-
Brasileira de Epidemiologia 2014;17 Suppl 1:106-15.

IA
56. To T, Stanojevic S, Moores G, Gershon AS, Bateman ED, Cruz AA, Boulet LP. Global asthma prevalence in adults:
ER
findings from the cross-sectional world health survey. BMC Public Health 2012;12:204.
AT
57. Jose BP, Camargos PA, Cruz Filho AA, Correa Rde A. Diagnostic accuracy of respiratory diseases in primary
M
health units. Rev Assoc Med Bras 2014;60:599-612.

D
TE
58. Burney P, Jithoo A, Kato B, Janson C, Mannino D, Nizankowska-Mogilnicka E, Studnicka M, et al. Chronic
H
obstructive pulmonary disease mortality and prevalence: the associations with smoking and poverty--a BOLD
IG
analysis. Thorax 2014;69:465-73.

R
PY
59. Taylor DR, Bateman ED, Boulet LP, Boushey HA, Busse WW, Casale TB, Chanez P, et al. A new perspective on
O
concepts of asthma severity and control. Eur Respir J 2008;32:545-54.

C
60. Aroni R, Goeman D, Stewart K, Thien F, Sawyer S, Abramson M, Douglass J. Enhancing validity: what counts as
an asthma attack? J Asthma 2004;41:729-37.
61. McCoy K, Shade DM, Irvin CG, Mastronarde JG, Hanania NA, Castro M, Anthonisen NR. Predicting episodes of
poor asthma control in treated patients with asthma. J Allergy Clin Immunol 2006;118:1226-33.
62. Meltzer EO, Busse WW, Wenzel SE, Belozeroff V, Weng HH, Feng J, Chon Y, et al. Use of the Asthma Control
Questionnaire to predict future risk of asthma exacerbation. J Allergy Clin Immunol 2011;127:167-72.
63. Schatz M, Zeiger RS, Yang SJ, Chen W, Crawford W, Sajjan S, Allen-Ramey F. The relationship of asthma
impairment determined by psychometric tools to future asthma exacerbations. Chest 2012;141:66-72.
64. O'Byrne PM, Reddel HK, Eriksson G, Ostlund O, Peterson S, Sears MR, Jenkins C, et al. Measuring asthma
control: a comparison of three classification systems. Eur Respir J 2010;36:269-76.
65. Thomas M, Kay S, Pike J, Williams A, Rosenzweig JR, Hillyer EV, Price D. The Asthma Control Test (ACT) as a
predictor of GINA guideline-defined asthma control: analysis of a multinational cross-sectional survey. Prim Care
Respir J 2009;18:41-9.
176 References
66. LeMay KS, Armour CL, Reddel HK. Performance of a brief asthma control screening tool in community pharmacy: a
cross-sectional and prospective longitudinal analysis. Prim Care Respir J 2014;23:79-84.
67. Ahmed S, Ernst P, Tamblyn R, Colman N. Validation of The 30 Second Asthma Test as a measure of asthma
control. Can Respir J 2007;14:105-9.
68. Pinnock H, Burton C, Campbell S, Gruffydd-Jones K, Hannon K, Hoskins G, Lester H, et al. Clinical implications of
the Royal College of Physicians three questions in routine asthma care: a real-life validation study. Prim Care
Respir J 2012;21:288-94.
69. Svedsater H, Jones R, Bosanquet N, Jacques L, Lay-Flurrie J, Leather DA, Vestbo J, et al. Patient-reported
outcomes with initiation of fluticasone furoate/vilanterol versus continuing usual care in the Asthma Salford Lung
Study. Respir Med 2018;141:198-206.
70. Juniper EF, O'Byrne PM, Guyatt GH, Ferrie PJ, King DR. Development and validation of a questionnaire to
measure asthma control. Eur Respir J 1999;14:902-7.
71. Juniper EF, Svensson K, Mork AC, Stahl E. Measurement properties and interpretation of three shortened versions
of the asthma control questionnaire. Respir Med 2005;99:553-8.
TE
72. Juniper EF, Bousquet J, Abetz L, Bateman ED, The GOAL Committee. Identifying 'well-controlled' and 'not well-
U
controlled' asthma using the Asthma Control Questionnaire. Respir Med 2006;100:616-21.
IB
73. Nathan RA, Sorkness CA, Kosinski M, Schatz M, Li JT, Marcus P, Murray JJ, et al. Development of the asthma
TR
control test: a survey for assessing asthma control. J Allergy Clin Immunol 2004;113:59-65.
IS
D
74. Schatz M, Kosinski M, Yarlas AS, Hanlon J, Watson ME, Jhingran P. The minimally important difference of the
R
Asthma Control Test. J Allergy Clin Immunol 2009;124:719-23 e1.
O
75. Liu AH, Zeiger R, Sorkness C, Mahr T, Ostrom N, Burgess S, Rosenzweig JC, et al. Development and cross-
PY
sectional validation of the Childhood Asthma Control Test. J Allergy Clin Immunol 2007;119:817-25.
O
C
76. Juniper EF, Gruffydd-Jones K, Ward S, Svensson K. Asthma Control Questionnaire in children: validation,
T
measurement properties, interpretation. Eur Respir J 2010;36:1410-6.

O
N
77. Nguyen JM, Holbrook JT, Wei CY, Gerald LB, Teague WG, Wise RA, American Lung Association Asthma Clinical
O
Research C. Validation and psychometric properties of the Asthma Control Questionnaire among children. J Allergy
D
L-
Clin Immunol 2014;133:91-7.e1-6.

IA
78. Chipps B, Zeiger RS, Murphy K, Mellon M, Schatz M, Kosinski M, Lampl K, et al. Longitudinal validation of the Test
ER
for Respiratory and Asthma Control in Kids in pediatric practices. Pediatrics 2011;127:e737-47.
AT
79. Murphy KR, Zeiger RS, Kosinski M, Chipps B, Mellon M, Schatz M, Lampl K, et al. Test for respiratory and asthma
M
control in kids (TRACK): a caregiver-completed questionnaire for preschool-aged children. J Allergy Clin Immunol
D
TE
2009;123:833-9 e9.
H
80. Zeiger RS, Mellon M, Chipps B, Murphy KR, Schatz M, Kosinski M, Lampl K, et al. Test for Respiratory and Asthma
IG
Control in Kids (TRACK): clinically meaningful changes in score. J Allergy Clin Immunol 2011;128:983-8.
R
PY
81. Wildfire JJ, Gergen PJ, Sorkness CA, Mitchell HE, Calatroni A, Kattan M, Szefler SJ, et al. Development and
O
validation of the Composite Asthma Severity Index--an outcome measure for use in children and adolescents. J
C

82. Haselkorn T, Fish JE, Zeiger RS, Szefler SJ, Miller DP, Chipps BE, Simons FER, et al. Consistently very poorly
controlled asthma, as defined by the impairment domain of the Expert Panel Report 3 guidelines, increases risk for
future severe asthma exacerbations in The Epidemiology and Natural History of Asthma: Outcomes and Treatment
Regimens (TENOR) study. J Allergy Clin Immunol 2009;124:895-902.e1-4.
83. Patel M, Pilcher J, Reddel HK, Pritchard A, Corin A, Helm C, Tofield C, et al. Metrics of salbutamol use as
predictors of future adverse outcomes in asthma. Clin Exp Allergy 2013;43:1144-51.
84. Suissa S, Ernst P, Boivin JF, Horwitz RI, Habbick B, Cockroft D, Blais L, et al. A cohort analysis of excess mortality
in asthma and the use of inhaled beta-agonists. Am J Respir Crit Care Med 1994;149:604-10.
85. Ernst P, Spitzer WO, Suissa S, Cockcroft D, Habbick B, Horwitz RI, Boivin JF, et al. Risk of fatal and near-fatal
asthma in relation to inhaled corticosteroid use. JAMA 1992;268:3462-4.
86. Melani AS, Bonavia M, Cilenti V, Cinti C, Lodi M, Martucci P, Serra M, et al. Inhaler mishandling remains common
in real life and is associated with reduced disease control. Respir Med 2011;105:930-8.
References 177
87. Fitzpatrick S, Joks R, Silverberg JI. Obesity is associated with increased asthma severity and exacerbations, and
increased serum immunoglobulin E in inner-city adults. Clin Exp Allergy 2012;42:747-59.
88. Denlinger LC, Phillips BR, Ramratnam S, Ross K, Bhakta NR, Cardet JC, Castro M, et al. Inflammatory and
Comorbid Features of Patients with Severe Asthma and Frequent Exacerbations. Am J Respir Crit Care Med
2017;195:302-13.
89. Bousquet J, Khaltaev N, Cruz AA, Denburg J, Fokkens WJ, Togias A, Zuberbier T, et al. Allergic Rhinitis and its
Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and
AllerGen). Allergy 2008;63 Suppl 86:8-160.
90. Burks AW, Tang M, Sicherer S, Muraro A, Eigenmann PA, Ebisawa M, Fiocchi A, et al. ICON: food allergy. J Allergy
Clin Immunol 2012;129:906-20.
91. Murphy VE, Clifton VL, Gibson PG. Asthma exacerbations during pregnancy: incidence and association with
adverse pregnancy outcomes. Thorax 2006;61:169-76.
92. Osborne ML, Pedula KL, O'Hollaren M, Ettinger KM, Stibolt T, Buist AS, Vollmer WM. Assessing future need for
acute care in adult asthmatics: the Profile of Asthma Risk Study: a prospective health maintenance organization-
TE
based study. Chest 2007;132:1151-61.
U
93. Lim H, Kwon HJ, Lim JA, Choi JH, Ha M, Hwang SS, Choi WJ. Short-term Effect of Fine Particulate Matter on
IB
Children's Hospital Admissions and Emergency Department Visits for Asthma: A Systematic Review and Meta-
TR
analysis. J Prev Med Public Health 2016;49:205-19.
IS
D
94. Zheng XY, Ding H, Jiang LN, Chen SW, Zheng JP, Qiu M, Zhou YX, et al. Association between air pollutants and
R
asthma emergency room visits and hospital admissions in time series studies: A systematic review and meta-
O
analysis. PLoS One 2015;10:e0138146.
95. PY
Mazenq J, Dubus JC, Gaudart J, Charpin D, Viudes G, Noel G. City housing atmospheric pollutant impact on
O
C
emergency visit for asthma: A classification and regression tree approach. Respir Med 2017;132:1-8.
T
96. Sturdy PM, Victor CR, Anderson HR, Bland JM, Butland BK, Harrison BD, Peckitt C, et al. Psychological, social and
O
N
health behaviour risk factors for deaths certified as asthma: a national case-control study. Thorax 2002;57:1034-9.
O
97. Fuhlbrigge AL, Kitch BT, Paltiel AD, Kuntz KM, Neumann PJ, Dockery DW, Weiss ST. FEV1 is associated with risk
D
L-
of asthma attacks in a pediatric population. J Allergy Clin Immunol 2001;107:61-7.

IA
98. Ulrik CS. Peripheral eosinophil counts as a marker of disease activity in intrinsic and extrinsic asthma. Clin Exp
ER
Allergy 1995;25:820-7.
AT
99. Pongracic JA, Krouse RZ, Babineau DC, Zoratti EM, Cohen RT, Wood RA, Khurana Hershey GK, et al.
M
Distinguishing characteristics of difficult-to-control asthma in inner-city children and adolescents. J Allergy Clin
D
TE
Immunol 2016;138:1030-41.
H
100. Belda J, Giner J, Casan P, Sanchis J. Mild exacerbations and eosinophilic inflammation in patients with stable, well-
IG
controlled asthma after 1 year of follow-up. Chest 2001;119:1011-7.

R
PY
101. Zeiger RS, Schatz M, Zhang F, Crawford WW, Kaplan MS, Roth RM, Chen W. Elevated exhaled nitric oxide is a
O
clinical indicator of future uncontrolled asthma in asthmatic patients on inhaled corticosteroids. J Allergy Clin
C
Immunol 2011;128:412-4.
102. Turner MO, Noertjojo K, Vedal S, Bai T, Crump S, FitzGerald JM. Risk factors for near-fatal asthma. A case-control
study in hospitalized patients with asthma. Am J Respir Crit Care Med 1998;157:1804-9.
103. Miller MK, Lee JH, Miller DP, Wenzel SE. Recent asthma exacerbations: a key predictor of future exacerbations.
Respir Med 2007;101:481-9.
104. Buelo A, McLean S, Julious S, Flores-Kim J, Bush A, Henderson J, Paton JY, et al. At-risk children with asthma
(ARC): a systematic review. Thorax 2018;73:813-24.
105. den Dekker HT, Sonnenschein-van der Voort AMM, de Jongste JC, Anessi-Maesano I, Arshad SH, Barros H,
Beardsmore CS, et al. Early growth characteristics and the risk of reduced lung function and asthma: A meta-
analysis of 25,000 children. J Allergy Clin Immunol 2016;137:1026-35.
106. Lange P, Parner J, Vestbo J, Schnohr P, Jensen G. A 15-year follow-up study of ventilatory function in adults with
asthma. N Engl J Med 1998;339:1194-200.
107. Ulrik CS. Outcome of asthma: longitudinal changes in lung function. Eur Respir J 1999;13:904-18.
178 References
108. O'Byrne PM, Pedersen S, Lamm CJ, Tan WC, Busse WW. Severe exacerbations and decline in lung function in
asthma. Am J Respir Crit Care Med 2009;179:19-24.
109. Raissy HH, Kelly HW, Harkins M, Szefler SJ. Inhaled corticosteroids in lung diseases. Am J Respir Crit Care Med
2013;187:798-803.
110. Foster JM, Aucott L, van der Werf RH, van der Meijden MJ, Schraa G, Postma DS, van der Molen T. Higher patient
perceived side effects related to higher daily doses of inhaled corticosteroids in the community: a cross-sectional
analysis. Respir Med 2006;100:1318-36.
111. Roland NJ, Bhalla RK, Earis J. The local side effects of inhaled corticosteroids: current understanding and review of
the literature. Chest 2004;126:213-9.
112. Pedersen S. Do inhaled corticosteroids inhibit growth in children? Am J Respir Crit Care Med 2001;164:521-35.
113. Loke YK, Blanco P, Thavarajah M, Wilson AM. Impact of inhaled corticosteroids on growth in children with asthma:
Systematic review and meta-analysis. PLoS One 2015;10:e0133428.
114. Wechsler ME, Kelley JM, Boyd IO, Dutile S, Marigowda G, Kirsch I, Israel E, et al. Active albuterol or placebo, sham
acupuncture, or no intervention in asthma. N Engl J Med 2011;365:119-26.
TE
115. Castro M, Rubin AS, Laviolette M, Fiterman J, De Andrade Lima M, Shah PL, Fiss E, et al. Effectiveness and safety
U
of bronchial thermoplasty in the treatment of severe asthma: a multicenter, randomized, double-blind, sham-
IB
controlled clinical trial. Am J Respir Crit Care Med 2010;181:116-24.
TR
116. Lazarus SC, Boushey HA, Fahy JV, Chinchilli VM, Lemanske RF, Jr., Sorkness CA, Kraft M, et al. Long-acting
IS
D
beta2-agonist monotherapy vs continued therapy with inhaled corticosteroids in patients with persistent asthma: a
R
randomized controlled trial. JAMA 2001;285:2583-93.
O
117. Loymans RJ, Honkoop PJ, Termeer EH, Snoeck-Stroband JB, Assendelft WJ, Schermer TR, Chung KF, et al.
PY
Identifying patients at risk for severe exacerbations of asthma: development and external validation of a
O
C
multivariable prediction model. Thorax 2016;71:838-46.
T
118. Kohansal R, Martinez-Camblor P, Agusti A, Buist AS, Mannino DM, Soriano JB. The natural history of chronic
O
N
airflow obstruction revisited: an analysis of the Framingham offspring cohort. Am J Respir Crit Care Med
O
2009;180:3-10.
D
L-
119. McGeachie MJ, Yates KP, Zhou X, Guo F, Sternberg AL, Van Natta ML, Wise RA, et al. Patterns of growth and
IA
decline in lung function in persistent childhood asthma. N Engl J Med 2016;374:1842-52.

ER
120. Kerstjens HA, Brand PL, de Jong PM, Koeter GH, Postma DS. Influence of treatment on peak expiratory flow and
AT
its relation to airway hyperresponsiveness and symptoms. The Dutch CNSLD Study Group. Thorax 1994;49:1109-
M
15.
D
TE
121. Brand PL, Duiverman EJ, Waalkens HJ, van Essen-Zandvliet EE, Kerrebijn KF. Peak flow variation in childhood
H
asthma: correlation with symptoms, airways obstruction, and hyperresponsiveness during long-term treatment with
IG
inhaled corticosteroids. Dutch CNSLD Study Group. Thorax 1999;54:103-7.

R
PY
122. Bateman ED, Boushey HA, Bousquet J, Busse WW, Clark TJ, Pauwels RA, Pedersen SE. Can guideline-defined
O
asthma control be achieved? The Gaining Optimal Asthma ControL study. Am J Respir Crit Care Med
C
2004;170:836-44.
123. Jenkins CR, Thien FC, Wheatley JR, Reddel HK. Traditional and patient-centred outcomes with three classes of
asthma medication. Eur Respir J 2005;26:36-44.
124. Li D, German D, Lulla S, Thomas RG, Wilson SR. Prospective study of hospitalization for asthma. A preliminary risk
factor model. Am J Respir Crit Care Med 1995;151:647-55.
125. Kitch BT, Paltiel AD, Kuntz KM, Dockery DW, Schouten JP, Weiss ST, Fuhlbrigge AL. A single measure of FEV1 is
associated with risk of asthma attacks in long-term follow-up. Chest 2004;126:1875-82.
126. Killian KJ, Watson R, Otis J, St Amand TA, O'Byrne PM. Symptom perception during acute bronchoconstriction. Am
J Respir Crit Care Med 2000;162:490-6.
127. Rosi E, Stendardi L, Binazzi B, Scano G. Perception of airway obstruction and airway inflammation in asthma: a
review. Lung 2006;184:251-8.
128. Reddel HK, Jenkins CR, Marks GB, Ware SI, Xuan W, Salome CM, Badcock CA, et al. Optimal asthma control,
starting with high doses of inhaled budesonide. Eur Respir J 2000;16:226-35.
References 179
129. Santanello NC, Davies G, Galant SP, Pedinoff A, Sveum R, Seltzer J, Seidenberg BC, et al. Validation of an
asthma symptom diary for interventional studies. Arch Dis Child 1999;80:414-20.
130. Szefler SJ, Martin RJ, King TS, Boushey HA, Cherniack RM, Chinchilli VM, Craig TJ, et al. Significant variability in
response to inhaled corticosteroids for persistent asthma. J Allergy Clin Immunol 2002;109:410-8.
131. Reddel HK, Marks GB, Jenkins CR. When can personal best peak flow be determined for asthma action plans?
Thorax 2004;59:922-4.
132. Frey U, Brodbeck T, Majumdar A, Taylor DR, Town GI, Silverman M, Suki B. Risk of severe asthma episodes
predicted from fluctuation analysis of airway function. Nature 2005;438:667-70.
133. Julius SM, Davenport KL, Davenport PW. Perception of intrinsic and extrinsic respiratory loads in children with life-
threatening asthma. Pediatr Pulmonol 2002;34:425-33.
134. Kikuchi Y, Okabe S, Tamura G, Hida W, Homma M, Shirato K, Takishima T. Chemosensitivity and perception of
dyspnea in patients with a history of near-fatal asthma. N Engl J Med 1994;330:1329-34.
135. Magadle R, Berar-Yanay N, Weiner P. The risk of hospitalization and near-fatal and fatal asthma in relation to the
perception of dyspnea. Chest 2002;121:329-33.
TE
136. Nuijsink M, Hop WC, Jongste JC, Sterk PJ, Duiverman AE, Cato Study G. Perception of bronchoconstriction: a
U
complementary disease marker in children with asthma. J Asthma 2013;50:560-4.
IB
137. Jansen J, McCaffery KJ, Hayen A, Ma D, Reddel HK. Impact of graphic format on perception of change in biological
R
T
data: implications for health monitoring in conditions such as asthma. Prim Care Respir J 2012;21:94-100.
IS
D
138. Chung KF, Wenzel SE, Brozek JL, Bush A, Castro M, Sterk PJ, Adcock IM, et al. International ERS/ATS Guidelines
R
on Definition, Evaluation and Treatment of Severe Asthma. Eur Respir J 2014;43:343-73.
O
139. Bousquet J, Mantzouranis E, Cruz AA, Ait-Khaled N, Baena-Cagnani CE, Bleecker ER, Brightling CE, et al. Uniform
PY
definition of asthma severity, control, and exacerbations: document presented for the World Health Organization
O
C
Consultation on Severe Asthma. J Allergy Clin Immunol 2010;126:926-38.
T
140. Boulet L-P, Vervloet D, Magar Y, Foster JM. Adherence: the goal to control asthma. Clin Chest Med 2012;33:405-
O
N
17.
O
141. Taylor YJ, Tapp H, Shade LE, Liu TL, Mowrer JL, Dulin MF. Impact of shared decision making on asthma quality of
D
L-
life and asthma control among children. J Asthma 2018;55:675-83.

IA
142. Gibson PG, Powell H, Coughlan J, Wilson AJ, Abramson M, Haywood P, Bauman A, et al. Self-management
ER
education and regular practitioner review for adults with asthma. Cochrane Database Syst Rev 2003:CD001117.
AT
143. Guevara JP, Wolf FM, Grum CM, Clark NM. Effects of educational interventions for self management of asthma in
M
children and adolescents: systematic review and meta-analysis. BMJ 2003;326:1308-9.

D
TE
144. Wilson SR, Strub P, Buist AS, Knowles SB, Lavori PW, Lapidus J, Vollmer WM. Shared treatment decision making
H
improves adherence and outcomes in poorly controlled asthma. Am J Respir Crit Care Med 2010;181:566-77.
IG
145. Cabana MD, Slish KK, Evans D, Mellins RB, Brown RW, Lin X, Kaciroti N, et al. Impact of physician asthma care
R
PY
education on patient outcomes. Pediatrics 2006;117:2149-57.

O
146. Partridge MR, Hill SR. Enhancing care for people with asthma: the role of communication, education, training and
C
self-management. 1998 World Asthma Meeting Education and Delivery of Care Working Group. Eur Respir J
2000;16:333-48.
147. Maguire P, Pitceathly C. Key communication skills and how to acquire them. BMJ 2002;325:697-700.
148. Clark NM, Cabana MD, Nan B, Gong ZM, Slish KK, Birk NA, Kaciroti N. The clinician-patient partnership paradigm:
outcomes associated with physician communication behavior. Clin Pediatr (Phila) 2008;47:49-57.
149. Rosas-Salazar C, Apter AJ, Canino G, Celedon JC. Health literacy and asthma. J Allergy Clin Immunol
2012;129:935-42.
150. Rosas-Salazar C, Ramratnam SK, Brehm JM, Han YY, Acosta-Perez E, Alvarez M, Colon-Semidey A, et al.
Parental numeracy and asthma exacerbations in Puerto Rican children. Chest 2013;144:92-8.
151. Apter AJ, Wan F, Reisine S, Bender B, Rand C, Bogen DK, Bennett IM, et al. The association of health literacy with
adherence and outcomes in moderate-severe asthma. J Allergy Clin Immunol 2013;132:321-7.
152. Poureslami I, Nimmon L, Doyle-Waters M, Rootman I, Schulzer M, Kuramoto L, FitzGerald JM. Effectiveness of
educational interventions on asthma self-management in Punjabi and Chinese asthma patients: a randomized
controlled trial. J Asthma 2012;49:542-51.
180 References
153. Haahtela T, Tuomisto LE, Pietinalho A, Klaukka T, Erhola M, Kaila M, Nieminen MM, et al. A 10 year asthma
programme in Finland: major change for the better. Thorax 2006;61:663-70.
154. Ait-Khaled N, Enarson DA, Bencharif N, Boulahdib F, Camara LM, Dagli E, Djankine TK, et al. Implementation of
asthma guidelines in health centres of several developing countries. Int J Tuberc Lung Dis 2006;10:104-9.
155. Plaza V, Cobos A, Ignacio-Garcia JM, Molina J, Bergonon S, Garcia-Alonso F, Espinosa C. [Cost-effectiveness of
an intervention based on the Global INitiative for Asthma (GINA) recommendations using a computerized clinical
decision support system: a physicians randomized trial]. Med Clin (Barc) 2005;124:201-6.
156. Haldar P, Pavord ID, Shaw DE, Berry MA, Thomas M, Brightling CE, Wardlaw AJ, et al. Cluster analysis and clinical
asthma phenotypes. Am J Respir Crit Care Med 2008;178:218-24.
157. Gibson PG, Powell H, Ducharme FM. Differential effects of maintenance long-acting beta-agonist and inhaled
corticosteroid on asthma control and asthma exacerbations. J Allergy Clin Immunol 2007;119:344-50.
158. O'Byrne PM, Naya IP, Kallen A, Postma DS, Barnes PJ. Increasing doses of inhaled corticosteroids compared to
adding long-acting inhaled beta2-agonists in achieving asthma control. Chest 2008;134:1192-9.
159. Bateman ED, Reddel HK, Eriksson G, Peterson S, Ostlund O, Sears MR, Jenkins C, et al. Overall asthma control:
TE
the relationship between current control and future risk. J Allergy Clin Immunol 2010;125:600-8.
U
160. Reddel HK, Busse WW, Pedersen S, Tan WC, Chen YZ, Jorup C, Lythgoe D, et al. Should recommendations about
IB
starting inhaled corticosteroid treatment for mild asthma be based on symptom frequency: a post-hoc efficacy
TR
analysis of the START study. Lancet 2017;389:157-66.
IS
D
161. Petsky HL, Li A, Chang AB. Tailored interventions based on sputum eosinophils versus clinical symptoms for
R
asthma in children and adults. Cochrane Database Syst Rev 2017;8:Cd005603.
O
162. Gibson PG. Using fractional exhaled nitric oxide to guide asthma therapy: design and methodological issues for
PY
ASthma TReatment ALgorithm studies. Clin Exp Allergy 2009;39:478-90.
O
C
163. Dweik RA, Boggs PB, Erzurum SC, Irvin CG, Leigh MW, Lundberg JO, Olin A-C, et al. An official ATS clinical
T
practice guideline: interpretation of exhaled nitric oxide levels (FENO) for clinical applications. Am J Respir Crit Care
O
N
Med 2011;184:602-15.
O
164. Petsky HL, Kew KM, Chang AB. Exhaled nitric oxide levels to guide treatment for children with asthma. Cochrane
D
L-
Database Syst Rev 2016;11:Cd011439.

IA
165. Petsky HL, Kew KM, Turner C, Chang AB. Exhaled nitric oxide levels to guide treatment for adults with asthma.
ER
Cochrane Database Syst Rev 2016;9:Cd011440.

AT
166. Roche N, Reddel HK, Agusti A, Bateman ED, Krishnan JA, Martin RJ, Papi A, et al. Integrating real-life studies in
M
the global therapeutic research framework. Lancet Respir Med 2013;1:e29-e30.

D
TE
167. Chung KF. New treatments for severe treatment-resistant asthma: targeting the right patient. Lancet Respir Med
H
2013;1:639-52.
IG
168. Drazen JM. Asthma: the paradox of heterogeneity. J Allergy Clin Immunol 2012;129:1200-1.
R
PY
169. Busse WW, Pedersen S, Pauwels RA, Tan WC, Chen YZ, Lamm CJ, O'Byrne PM. The Inhaled Steroid Treatment
O
As Regular Therapy in Early Asthma (START) study 5-year follow-up: effectiveness of early intervention with
C
budesonide in mild persistent asthma. J Allergy Clin Immunol 2008;121:1167-74.

170. Selroos O, Pietinalho A, Lofroos AB, Riska H. Effect of early vs late intervention with inhaled corticosteroids in
asthma. Chest 1995;108:1228-34.
171. Selroos O. Effect of disease duration on dose-response of inhaled budesonide in asthma. Respir Med
2008;102:1065-72.
172. Price DB, Buhl R, Chan A, Freeman D, Gardener E, Godley C, Gruffydd-Jones K, et al. Fractional exhaled nitric
oxide as a predictor of response to inhaled corticosteroids in patients with non-specific respiratory symptoms and
insignificant bronchodilator reversibility: a randomised controlled trial. Lancet Respir Med 2018;6:29-39.
173. Beasley R, Holliday M, Reddel HK, Braithwaite I, Ebmeier S, Hancox RJ, Harrison T, et al. Controlled trial of
budesonide-formoterol as needed for mild asthma. N Engl J Med 2019;380:2020-30.
174. Hardy J, Baggott C, Fingleton J, Reddel HK, Hancox RJ, Harwood M, Corin A, et al. Budesonide-formoterol reliever
therapy versus maintenance budesonide plus terbutaline reliever therapy in adults with mild to moderate asthma
(PRACTICAL): a 52-week, open-label, multicentre, superiority, randomised controlled trial. The Lancet
2019;394:919-28.
References 181
175. Reddel HK, FitzGerald JM, Bateman ED, Bacharier LB, Becker A, Brusselle G, Buhl R, et al. GINA 2019: a
fundamental change in asthma management: Treatment of asthma with short-acting bronchodilators alone is no
longer recommended for adults and adolescents. Eur Respir J 2019;53:1901046.
176. El Baou C, Di Santostefano RL, Alfonso-Cristancho R, Suarez EA, Stempel D, Everard ML, Barnes N. Effect of
inhaled corticosteroid particle size on asthma efficacy and safety outcomes: a systematic literature review and
meta-analysis. BMC Pulm Med 2017;17:31.
177. O'Byrne PM, FitzGerald JM, Bateman ED, Barnes PJ, Zhong N, Keen C, Jorup C, et al. Inhaled combined
budesonide-formoterol as needed in mild asthma. N Engl J Med 2018;378:1865-76.
178. Dusser D, Montani D, Chanez P, de Blic J, Delacourt C, Deschildre A, Devillier P, et al. Mild asthma: an expert
review on epidemiology, clinical characteristics and treatment recommendations. Allergy 2007;62:591-604.
179. Barnes CB, Ulrik CS. Asthma and adherence to inhaled corticosteroids: current status and future perspectives.
Respir Care 2015;60.
180. Bateman ED, Reddel HK, O'Byrne PM, Barnes PJ, Zhong N, Keen C, Jorup C, et al. As-needed budesonide-
formoterol versus maintenance budesonide in mild asthma. N Engl J Med 2018;378:1877-87.
TE
181. Sobieraj DM, Weeda ER, Nguyen E, Coleman CI, White CM, Lazarus SC, Blake KV, et al. Association of inhaled
U
corticosteroids and long-acting beta-agonists as controller and quick relief therapy with exacerbations and symptom
IB
control in persistent asthma: A systematic review and meta-analysis. JAMA 2018;319:1485-96.
R
T
182. O'Byrne PM, Barnes PJ, Rodriguez-Roisin R, Runnerstrom E, Sandstrom T, Svensson K, Tattersfield A. Low dose
IS
D
inhaled budesonide and formoterol in mild persistent asthma: the OPTIMA randomized trial. Am J Respir Crit Care
R
Med 2001;164(8 Pt 1):1392-7.
O
183. Lazarinis N, Jørgensen L, Ekström T, Bjermer L, Dahlén B, Pullerits T, Hedlin G, et al. Combination of
PY
budesonide/formoterol on demand improves asthma control by reducing exercise-induced bronchoconstriction.
O
C
Thorax 2014;69:130-6.
T
184. Papi A, Canonica GW, Maestrelli P, Paggiaro PL, Olivieri D, Pozzi E, Crimi N, et al. Rescue use of beclomethasone
O
N
and albuterol in a single inhaler for mild asthma. N Engl J Med 2007;356:2040-52.
O
185. Martinez FD, Chinchilli VM, Morgan WJ, Boehmer SJ, Lemanske RF, Jr., Mauger DT, Strunk RC, et al. Use of
D
L-
beclomethasone dipropionate as rescue treatment for children with mild persistent asthma (TREXA): a randomised,
IA
double-blind, placebo-controlled trial. Lancet 2011;377:650-7.

ER
186. Calhoun WJ, Ameredes BT, King TS, Icitovic N, Bleecker ER, Castro M, Cherniack RM, et al. Comparison of
AT
physician-, biomarker-, and symptom-based strategies for adjustment of inhaled corticosteroid therapy in adults with
M
asthma: the BASALT randomized controlled trial. JAMA 2012;308:987-97.

D
TE
187. Sumino K, Bacharier LB, Taylor J, Chadwick-Mansker K, Curtis V, Nash A, Jackson-Triggs S, et al. A pragmatic trial
H
of symptom-based inhaled corticosteroid use in African-American children with mild asthma. The journal of allergy
IG
and clinical immunology In practice 2019.

R
PY
188. Pauwels RA, Pedersen S, Busse WW, Tan WC, Chen YZ, Ohlsson SV, Ullman A, et al. Early intervention with
O
budesonide in mild persistent asthma: a randomised, double-blind trial. Lancet 2003;361:1071-6.

C
189. Crompton G. A brief history of inhaled asthma therapy over the last fifty years. Prim Care Respir J 2006;15:326-31.
190. Suissa S, Ernst P, Benayoun S, Baltzan M, Cai B. Low-dose inhaled corticosteroids and the prevention of death
from asthma. N Engl J Med 2000;343:332-6.
191. Suissa S, Ernst P, Kezouh A. Regular use of inhaled corticosteroids and the long term prevention of hospitalisation
for asthma. Thorax 2002;57:880-4.
192. Reddel HK, Ampon RD, Sawyer SM, Peters MJ. Risks associated with managing asthma without a preventer:
urgent healthcare, poor asthma control and over-the-counter reliever use in a cross-sectional population survey.
BMJ open 2017;7:e016688.
193. Haahtela T, Jarvinen M, Kava T, Kiviranta K, Koskinen S, Selroos O, Sovijarvi A, et al. Comparison of a b2-agonist,
terbutaline, with an inhaled corticosteroid, budesonide, in newly detected asthma. N Engl J Med 1991;325:388-92.
194. Welsh EJ, Cates CJ. Formoterol versus short-acting beta-agonists as relief medication for adults and children with
asthma. Cochrane Database Syst Rev 2010:CD008418.
195. Tattersfield AE, Lofdahl CG, Postma DS, Eivindson A, Schreurs AG, Rasidakis A, Ekstrom T. Comparison of
formoterol and terbutaline for as-needed treatment of asthma: a randomised trial. Lancet 2001;357:257-61.
182 References
196. Pauwels RA, Sears MR, Campbell M, Villasante C, Huang S, Lindh A, Petermann W, et al. Formoterol as relief
medication in asthma: a worldwide safety and effectiveness trial. Eur Respir J 2003;22:787-94.
197. Rabe KF, Atienza T, Magyar P, Larsson P, Jorup C, Lalloo UG. Effect of budesonide in combination with formoterol
for reliever therapy in asthma exacerbations: a randomised controlled, double-blind study. Lancet 2006;368:744-53.
198. Rodrigo GJ, Castro-Rodriguez JA. Safety of long-acting beta agonists for the treatment of asthma: clearing the air.
Thorax 2012;67:342-9.
199. Adams NP, Bestall JB, Malouf R, Lasserson TJ, Jones PW. Inhaled beclomethasone versus placebo for chronic
asthma. Cochrane Database Syst Rev 2005:CD002738.
200. Adams NP, Bestall JC, Lasserson TJ, Jones P, Cates CJ. Fluticasone versus placebo for chronic asthma in adults
and children. Cochrane Database Syst Rev 2008:CD003135.
201. Sumino K, Bacharier LB, Taylor J, Chadwick-Mansker K, Curtis V, Nash A, Jackson-Triggs S, et al. A pragmatic trial
of symptom-based inhaled corticosteroid use in African-American children with mild asthma. J Allergy Clin Immunol
Pract 2020;8:176-85.e2.
202. Chauhan BF, Ducharme FM. Anti-leukotriene agents compared to inhaled corticosteroids in the management of
TE
recurrent and/or chronic asthma in adults and children. Cochrane Database Syst Rev 2012;5:CD002314.
U
203. Philip G, Nayak AS, Berger WE, Leynadier F, Vrijens F, Dass SB, Reiss TF. The effect of montelukast on rhinitis
IB
symptoms in patients with asthma and seasonal allergic rhinitis. Curr Med Res Opin 2004;20:1549-58.
TR
204. Wilson AM, Dempsey OJ, Sims EJ, Lipworth BJ. A comparison of topical budesonide and oral montelukast in
IS
D
seasonal allergic rhinitis and asthma. Clin Exp Allergy 2001;31:616-24.
R
205. FDA requires Boxed Warning about serious mental health side effects for asthma and allergy drug montelukast
O
(Singulair); advises restricting use for allergic rhinitis. FDA, 2020. (Accessed 04 March 2020, 2020, at
PY
https://www.fda.gov/drugs/drug-safety-and-availability/fda-requires-boxed-warning-about-serious-mental-health-
O
C
side-effects-asthma-and-allergy-drug.)
T
206. Ni Chroinin M, Greenstone I, Lasserson TJ, Ducharme FM. Addition of inhaled long-acting beta2-agonists to inhaled
O
N
steroids as first line therapy for persistent asthma in steroid-naive adults and children. Cochrane Database Syst Rev
O
2009:CD005307.
D
L-
207. Dahl R, Larsen BB, Venge P. Effect of long-term treatment with inhaled budesonide or theophylline on lung
IA
function, airway reactivity and asthma symptoms. Respir Med 2002;96:432-8.

ER
208. Rivington RN, Boulet LP, Cote J, Kreisman H, Small DI, Alexander M, Day A, et al. Efficacy of Uniphyl, salbutamol,
AT
and their combination in asthmatic patients on high-dose inhaled steroids. Am J Respir Crit Care Med
M
1995;151:325-32.
D
TE
209. American Lung Association Asthma Clinical Research Centers. Clinical trial of low-dose theophylline and
H
montelukast in patients with poorly controlled asthma. Am J Respir Crit Care Med 2007;175:235-42.
IG
210. Tsiu SJ, Self TH, Burns R. Theophylline toxicity: update. Ann Allergy 1990;64:241-57.
R
PY
211. Guevara JP, Ducharme FM, Keren R, Nihtianova S, Zorc J. Inhaled corticosteroids versus sodium cromoglycate in
O
children and adults with asthma. Cochrane Database Syst Rev 2006:CD003558.
C
212. Sridhar AV, McKean M. Nedocromil sodium for chronic asthma in children. Cochrane Database Syst Rev
2006:CD004108.
213. van der Wouden JC, Uijen JH, Bernsen RM, Tasche MJ, de Jongste JC, Ducharme F. Inhaled sodium
cromoglycate for asthma in children. Cochrane Database Syst Rev 2008:CD002173.
214. Cates CJ, Schmidt S, Ferrer M, Sayer B, Waterson S. Inhaled steroids with and without regular salmeterol for
asthma: serious adverse events. Cochrane Database Syst Rev 2018;12:Cd006922.
215. Busse WW, Bateman ED, Caplan AL, Kelly HW, O'Byrne PM, Rabe KF, Chinchilli VM. Combined analysis of
asthma safety trials of long-acting beta2-agonists. N Engl J Med 2018;378:2497-505.
216. Peters SP, Bleecker ER, Canonica GW, Park YB, Ramirez R, Hollis S, Fjallbrant H, et al. Serious Asthma Events
with Budesonide plus Formoterol vs. Budesonide Alone. N Engl J Med 2016;375:850-60.
217. Stempel DA, Raphiou IH, Kral KM, Yeakey AM, Emmett AH, Prazma CM, Buaron KS, et al. Serious asthma events
with fluticasone plus salmeterol versus fluticasone alone. N Engl J Med 2016;374:1822-30.
References 183
218. Woodcock A, Vestbo J, Bakerly ND, New J, Gibson JM, McCorkindale S, Jones R, et al. Effectiveness of
fluticasone furoate plus vilanterol on asthma control in clinical practice: an open-label, parallel group, randomised
controlled trial. Lancet 2017;390:2247-55.
219. Cates CJ, Karner C. Combination formoterol and budesonide as maintenance and reliever therapy versus current
best practice (including inhaled steroid maintenance), for chronic asthma in adults and children. Cochrane
Database Syst Rev 2013;4:CD007313.
220. Kew KM, Karner C, Mindus SM, Ferrara G. Combination formoterol and budesonide as maintenance and reliever
therapy versus combination inhaler maintenance for chronic asthma in adults and children. Cochrane Database
Syst Rev 2013;12:CD009019.
221. Papi A, Corradi M, Pigeon-Francisco C, Baronio R, Siergiejko Z, Petruzzelli S, Fabbri LM, et al. Beclometasone–
formoterol as maintenance and reliever treatment in patients with asthma: a double-blind, randomised controlled
trial. Lancet Respir Med 2013;1:23-31.
222. Patel M, Pilcher J, Pritchard A, Perrin K, Travers J, Shaw D, Holt S, et al. Efficacy and safety of maintenance and
reliever combination budesonide/formoterol inhaler in patients with asthma at risk of severe exacerbations: a
TE
randomised controlled trial. Lancet Respir Med 2013;1:32-42.
U
223. Bateman ED, Harrison TW, Quirce S, Reddel HK, Buhl R, Humbert M, Jenkins CR, et al. Overall asthma control
IB
achieved with budesonide/formoterol maintenance and reliever therapy for patients on different treatment steps.
TR
Respir Res 2011;12:38.
IS
D
224. Jorup C, Lythgoe D, Bisgaard H. Budesonide/formoterol maintenance and reliever therapy in adolescent patients
R
with asthma. Eur Respir J 2018;51.
O
225. Virchow JC, Backer V, Kuna P, Prieto L, Nolte H, Villesen HH, Ljorring C, et al. Efficacy of a house dust mite
PY
sublingual allergen immunotherapy tablet in adults with allergic asthma: A randomized clinical trial. Jama
O
C
2016;315:1715-25.
T
226. Mosbech H, Deckelmann R, de Blay F, Pastorello EA, Trebas-Pietras E, Andres LP, Malcus I, et al. Standardized
O
N
quality (SQ) house dust mite sublingual immunotherapy tablet (ALK) reduces inhaled corticosteroid use while
O
maintaining asthma control: a randomized, double-blind, placebo-controlled trial. J Allergy Clin Immunol
D
L-
2014;134:568-75.e7.
IA
227. Ducharme FM, Ni Chroinin M, Greenstone I, Lasserson TJ. Addition of long-acting beta2-agonists to inhaled
ER
steroids versus higher dose inhaled steroids in adults and children with persistent asthma. Cochrane Database Syst
AT
Rev 2010:CD005533.
M
228. Powell H, Gibson PG. Inhaled corticosteroid doses in asthma: an evidence-based approach. Med J Aust
D
TE
2003;178:223-5.
H
229. Chauhan BF, Ducharme FM. Addition to inhaled corticosteroids of long-acting beta2-agonists versus anti-
IG
leukotrienes for chronic asthma. Cochrane Database Syst Rev 2014;1:CD003137.

R
PY
230. Evans DJ, Taylor DA, Zetterstrom O, Chung KF, O'Connor BJ, Barnes PJ. A comparison of low-dose inhaled
O
budesonide plus theophylline and high- dose inhaled budesonide for moderate asthma. N Engl J Med
C
1997;337:1412-8.
231. Adams NP, Jones PW. The dose-response characteristics of inhaled corticosteroids when used to treat asthma: an
overview of Cochrane systematic reviews. Respir Med 2006;100:1297-306.
232. Vaessen-Verberne AA, van den Berg NJ, van Nierop JC, Brackel HJ, Gerrits GP, Hop WC, Duiverman EJ.
Combination therapy salmeterol/fluticasone versus doubling dose of fluticasone in children with asthma. Am J
233. Stempel DA, Szefler SJ, Pedersen S, Zeiger RS, Yeakey AM, Lee LA, Liu AH, et al. Safety of adding salmeterol to
fluticasone propionate in children with asthma. N Engl J Med 2016;375:840-9.
234. Bisgaard H, Le Roux P, Bjamer D, Dymek A, Vermeulen JH, Hultquist C. Budesonide/formoterol maintenance plus
reliever therapy: a new strategy in pediatric asthma. Chest 2006;130:1733-43.
235. Rodrigo GJ, Neffen H. Efficacy and safety of tiotropium in school-age children with moderate-to-severe symptomatic
asthma: A systematic review. Pediatr Allergy Immunol 2017;28:573-8.
184 References
236. Kew KM, Dahri K. Long-acting muscarinic antagonists (LAMA) added to combination long-acting beta2-agonists
and inhaled corticosteroids (LABA/ICS) versus LABA/ICS for adults with asthma. Cochrane Database Syst Rev
2016:Cd011721.
237. Sobieraj DM, Baker WL, Nguyen E, Weeda ER, Coleman CI, White CM, Lazarus SC, et al. Association of inhaled
corticosteroids and long-acting muscarinic antagonists with asthma control in patients with uncontrolled, persistent
asthma: A systematic review and meta-analysis. JAMA 2018;319:1473-84.
238. Malo JL, Cartier A, Ghezzo H, Trudeau C, Morris J, Jennings B. Comparison of four-times-a-day and twice-a-day
dosing regimens in subjects requiring 1200 micrograms or less of budesonide to control mild to moderate asthma.
Respir Med 1995;89:537-43.
239. Toogood JH, Baskerville JC, Jennings B, Lefcoe NM, Johansson SA. Influence of dosing frequency and schedule
on the response of chronic asthmatics to the aerosol steroid, budesonide. J Allergy Clin Immunol 1982;70:288-98.
240. Lofdahl CG, Reiss TF, Leff JA, Israel E, Noonan MJ, Finn AF, Seidenberg BC, et al. Randomised, placebo
controlled trial of effect of a leukotriene receptor antagonist, montelukast, on tapering inhaled corticosteroids in
asthmatic patients. BMJ 1999;319:87-90.
TE
241. Price DB, Hernandez D, Magyar P, Fiterman J, Beeh KM, James IG, Konstantopoulos S, et al. Randomised
U
controlled trial of montelukast plus inhaled budesonide versus double dose inhaled budesonide in adult patients
IB
with asthma. Thorax 2003;58:211-6.
TR
242. Vaquerizo MJ, Casan P, Castillo J, Perpina M, Sanchis J, Sobradillo V, Valencia A, et al. Effect of montelukast
IS
D
added to inhaled budesonide on control of mild to moderate asthma. Thorax 2003;58:204-10.
R
243. Virchow JC, Prasse A, Naya I, Summerton L, Harris A. Zafirlukast improves asthma control in patients receiving
O
high-dose inhaled corticosteroids. Am J Respir Crit Care Med 2000;162:578-85.
PY
244. Tamaoki J, Kondo M, Sakai N, Nakata J, Takemura H, Nagai A, Takizawa T, et al. Leukotriene antagonist prevents
O
C
exacerbation of asthma during reduction of high-dose inhaled corticosteroid. The Tokyo Joshi-Idai Asthma
T
Research Group. Am J Respir Crit Care Med 1997;155:1235-40.

O
N
245. Travers J, Marsh S, Williams M, Weatherall M, Caldwell B, Shirtcliffe P, Aldington S, et al. External validity of
O
randomised controlled trials in asthma: to whom do the results of the trials apply? Thorax 2007;62:219-23.
D
L-
246. Brown T, Jones T, Gove K, Barber C, Elliott S, Chauhan A, Howarth P. Randomised controlled trials in severe
IA
asthma: selection by phenotype or stereotype. Eur Respir J 2018;52.

ER
247. Broersen LH, Pereira AM, Jorgensen JO, Dekkers OM. Adrenal insufficiency in corticosteroids use: Systematic
AT
review and meta-analysis. J Clin Endocrinol Metab 2015;100:2171-80.

M
248. Gibson PG, Yang IA, Upham JW, Reynolds PN, Hodge S, James AL, Jenkins C, et al. Effect of azithromycin on
D
TE
asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised,
H
double-blind, placebo-controlled trial. Lancet 2017;390:659-68.

IG
249. Brusselle GG, Vanderstichele C, Jordens P, Deman R, Slabbynck H, Ringoet V, Verleden G, et al. Azithromycin for
R
PY
prevention of exacerbations in severe asthma (AZISAST): a multicentre randomised double-blind placebo-controlled

O
trial. Thorax 2013;68:322-9.

C
250. Normansell R, Walker S, Milan SJ, Walters EH, Nair P. Omalizumab for asthma in adults and children. Cochrane
251. Rodrigo GJ, Neffen H. Systematic review on the use of omalizumab for the treatment of asthmatic children and
adolescents. Pediatr Allergy Immunol 2015;26:551-6.
252. Haldar P, Brightling CE, Hargadon B, Gupta S, Monteiro W, Sousa A, Marshall RP, et al. Mepolizumab and
exacerbations of refractory eosinophilic asthma. N Engl J Med 2009;360:973-84.
253. Pavord ID, Korn S, Howarth P, Bleecker ER, Buhl R, Keene ON, Ortega H, et al. Mepolizumab for severe
eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet 2012;380:651-9.
254. Castro M, Zangrilli J, Wechsler ME, Bateman ED, Brusselle GG, Bardin P, Murphy K, et al. Reslizumab for
inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-
blind, randomised, placebo-controlled, phase 3 trials. Lancet Respir Med 2015;3:355-66.
255. Nair P, Wenzel S, Rabe KF, Bourdin A, Lugogo NL, Kuna P, Barker P, et al. Oral glucocorticoid-sparing effect of
benralizumab in severe asthma. N Engl J Med 2017;376:2448-58.
References 185
256. Farne HA, Wilson A, Powell C, Bax L, Milan SJ. Anti-IL5 therapies for asthma. Cochrane Database Syst Rev
2017;9:Cd010834.
257. Gupta A, Ikeda M, Geng B, Azmi J, Price RG, Bradford ES, Yancey SW, et al. Long-term safety and
pharmacodynamics of mepolizumab in children with severe asthma with an eosinophilic phenotype. J Allergy Clin
Immunol 2019;144:1336-42.e7.
258. Castro M, Corren J, Pavord ID, Maspero J, Wenzel S, Rabe KF, Busse WW, et al. Dupilumab efficacy and safety in
moderate-to-severe uncontrolled asthma. The New England journal of medicine 2018;378:2486-96.
259. Wenzel S, Castro M, Corren J, Maspero J, Wang L, Zhang B, Pirozzi G, et al. Dupilumab efficacy and safety in
adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-
acting b2agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial. The Lancet
2016;388:31-44.
260. Zayed Y, Kheiri B, Banifadel M, Hicks M, Aburahma A, Hamid K, Bachuwa G, et al. Dupilumab safety and efficacy
in uncontrolled asthma: a systematic review and meta-analysis of randomized clinical trials. J Asthma 2018:1-10.
261. Chupp G, Laviolette M, Cohn L, McEvoy C, Bansal S, Shifren A, Khatri S, et al. Long-term outcomes of bronchial
TE
thermoplasty in subjects with severe asthma: a comparison of 3-year follow-up results from two prospective
U
multicentre studies. Eur Respir J 2017;50.
IB
262. Walsh LJ, Wong CA, Oborne J, Cooper S, Lewis SA, Pringle M, Hubbard R, et al. Adverse effects of oral
TR
corticosteroids in relation to dose in patients with lung disease. Thorax 2001;56:279-84.
IS
D
263. Lefebvre P, Duh MS, Lafeuille M-H, Gozalo L, Desai U, Robitaille M-N, Albers F, et al. Acute and chronic systemic
R
corticosteroid–related complications in patients with severe asthma. J Allergy Clin Immunol 2015;136:1488-95.
O
264. Grossman JM, Gordon R, Ranganath VK, Deal C, Caplan L, Chen W, Curtis JR, et al. American College of
PY
Rheumatology 2010 recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis.
O
C
Arthritis Care Res 2010;62:1515-26.
T
265. Bateman ED, Bousquet J, Keech ML, Busse WW, Clark TJ, Pedersen SE. The correlation between asthma control
O
N
and health status: the GOAL study. Eur Respir J 2007;29:56-62.

O
266. Sont JK. How do we monitor asthma control? Allergy 1999;54 Suppl 49:68-73.
D
L-
267. Mintz M, Gilsenan AW, Bui CL, Ziemiecki R, Stanford RH, Lincourt W, Ortega H. Assessment of asthma control in
IA
primary care. Curr Med Res Opin 2009;25:2523-31.

ER
268. Schatz M, Rachelefsky G, Krishnan JA. Follow-up after acute asthma episodes: what improves future outcomes?
AT
Proc Am Thorac Soc 2009;6:386-93.

M
269. Thomas A, Lemanske RF, Jr., Jackson DJ. Approaches to stepping up and stepping down care in asthmatic
D
TE
patients. J Allergy Clin Immunol 2011;128:915-24.

H
270. Boulet LP. Perception of the role and potential side effects of inhaled corticosteroids among asthmatic patients.
IG
Chest 1998;113:587-92.
R
PY
271. Usmani OS, Kemppinen A, Gardener E, Thomas V, Konduru PR, Callan C, McLoughlin A, et al. A Randomized
O
Pragmatic Trial of Changing to and Stepping Down Fluticasone/Formoterol in Asthma. J Allergy Clin Immunol Pract
C
2017;5:1378-87.e5.
272. DiMango E, Rogers L, Reibman J, Gerald LB, Brown M, Sugar EA, Henderson R, et al. Risk factors for asthma
exacerbation and treatment failure in adults and adolescents with well-controlled asthma during continuation and
step-down therapy. Annals of the American Thoracic Society 2018;15:955-61.
273. Leuppi JD, Salome CM, Jenkins CR, Anderson SD, Xuan W, Marks GB, Koskela H, et al. Predictive markers of
asthma exacerbation during stepwise dose reduction of inhaled corticosteroids. Am J Respir Crit Care Med
2001;163:406-12.
274. Rogers L, Sugar EA, Blake K, Castro M, Dimango E, Hanania NA, Happel KI, et al. Step-Down Therapy for Asthma
Well Controlled on Inhaled Corticosteroid and Long-Acting Beta-Agonist: A Randomized Clinical Trial. J Allergy Clin
Immunol Pract 2018;6:633-43.e1.
275. FitzGerald JM, Boulet LP, Follows RM. The CONCEPT trial: a 1-year, multicenter, randomized,double-blind,
double-dummy comparison of a stable dosing regimen of salmeterol/fluticasone propionate with an adjustable
maintenance dosing regimen of formoterol/budesonide in adults with persistent asthma. Clin Ther 2005;27:393-406.
186 References
276. Rank MA, Hagan JB, Park MA, Podjasek JC, Samant SA, Volcheck GW, Erwin PJ, et al. The risk of asthma
exacerbation after stopping low-dose inhaled corticosteroids: a systematic review and meta-analysis of randomized
controlled trials. J Allergy Clin Immunol 2013;131:724-9.
277. Hagan JB, Samant SA, Volcheck GW, Li JT, Hagan CR, Erwin PJ, Rank MA. The risk of asthma exacerbation after
reducing inhaled corticosteroids: a systematic review and meta-analysis of randomized controlled trials. Allergy
2014;69:510-6.
278. Ahmad S, Kew KM, Normansell R. Stopping long-acting beta2-agonists (LABA) for adults with asthma well
controlled by LABA and inhaled corticosteroids. Cochrane Database Syst Rev 2015:Cd011306.
279. Rank MA, Gionfriddo MR, Pongdee T, Volcheck GW, Li JT, Hagan CR, Erwin PJ, et al. Stepping down from inhaled
corticosteroids with leukotriene inhibitors in asthma: a systematic review and meta-analysis. Allergy Asthma Proc
2015;36:200-5.
280. Masoli M, Weatherall M, Holt S, Beasley R. Budesonide once versus twice-daily administration: meta-analysis.
Respirology 2004;9:528-34.
281. Boulet LP, Drollmann A, Magyar P, Timar M, Knight A, Engelstatter R, Fabbri L. Comparative efficacy of once-daily
TE
ciclesonide and budesonide in the treatment of persistent asthma. Respir Med 2006;100:785-94.
U
282. Rice JL, Diette GB, Suarez-Cuervo C, Brigham EP, Lin SY, Ramanathan M, Jr., Robinson KA, et al. Allergen-
IB
specific immunotherapy in the treatment of pediatric asthma: A systematic review. Pediatrics 2018;141.
TR
283. Lin SY, Erekosima N, Kim JM, Ramanathan M, Suarez-Cuervo C, Chelladurai Y, Ward D, et al. Sublingual
IS
D
immunotherapy for the treatment of allergic rhinoconjunctivitis and asthma: a systematic review. JAMA
R
2013;309:1278-88.
O
284. Di Bona D, Frisenda F, Albanesi M, Di Lorenzo G, Caiaffa MF, Macchia L. Efficacy and safety of allergen
PY
immunotherapy in patients with allergy to molds: A systematic review. Clin Exp Allergy 2018;48:1391-401.
O
C
285. Abramson MJ, Puy RM, Weiner JM. Injection allergen immunotherapy for asthma. Cochrane Database Syst Rev
T
2010:CD001186.
O
N
286. Klimek L, Fox GC, Thum-Oltmer S. SCIT with a high-dose house dust mite allergoid is well tolerated: safety data
O
from pooled clinical trials and more than 10 years of daily practice analyzed in different subgroups. Allergo journal
D
L-
international 2018;27:131-9.
IA
287. Xu K, Deng Z, Li D, Yuan H, Liu C, Chen Z, Zhu L. Efficacy of add-on sublingual immunotherapy for adults with
ER
asthma: A meta-analysis and systematic review. Ann Allergy Asthma Immunol 2018;121:186-94.
AT
288. Calamita Z, Saconato H, Pela AB, Atallah AN. Efficacy of sublingual immunotherapy in asthma: systematic review
M
of randomized-clinical trials using the Cochrane Collaboration method. Allergy 2006;61:1162-72.

D
TE
289. Normansell R, Kew KM, Bridgman A. Sublingual immunotherapy for asthma. Cochrane Database Syst Rev 2015.
H
290. Marogna M, Spadolini I, Massolo A, Berra D, Zanon P, Chiodini E, Canonica GW, et al. Long-term comparison of
IG
sublingual immunotherapy vs inhaled budesonide in patients with mild persistent asthma due to grass pollen. Ann
R
PY
Allergy Asthma Immunol 2009;102:69-75.

O
291. Baena-Cagnani CE, Larenas-Linnemann D, Teijeiro A, Canonica GW, Passalacqua G. Will sublingual
C
immunotherapy offer benefit for asthma? Curr Allergy Asthma Rep 2013.
292. Burks AW, Calderon MA, Casale T, Cox L, Demoly P, Jutel M, Nelson H, et al. Update on allergy immunotherapy:
American Academy of Allergy, Asthma & Immunology/European Academy of Allergy and Clinical
Immunology/PRACTALL consensus report. J Allergy Clin Immunol 2013;131:1288-96.e3.
293. Dretzke J, Meadows A, Novielli N, Huissoon A, Fry-Smith A, Meads C. Subcutaneous and sublingual
immunotherapy for seasonal allergic rhinitis: a systematic review and indirect comparison. J Allergy Clin Immunol
2013;131:1361-6.
294. Cates CJ, Rowe BH. Vaccines for preventing influenza in people with asthma. Cochrane Database Syst Rev
2013;2:CD000364.
295. Vasileiou E, Sheikh A, Butler C, El Ferkh K, von Wissmann B, McMenamin J, Ritchie L, et al. Effectiveness of
Influenza Vaccines in Asthma: A Systematic Review and Meta-Analysis. Clin Infect Dis 2017;65:1388-95.
296. Talbot TR, Hartert TV, Mitchel E, Halasa NB, Arbogast PG, Poehling KA, Schaffner W, et al. Asthma as a risk factor
for invasive pneumococcal disease. N Engl J Med 2005;352:2082-90.
297. Sheikh A, Alves B, Dhami S. Pneumococcal vaccine for asthma. Cochrane Database Syst Rev 2002:CD002165.
References 187
298. Wechsler ME, Laviolette M, Rubin AS, Fiterman J, Lapa ESJR, Shah PL, Fiss E, et al. Bronchial thermoplasty:
Long-term safety and effectiveness in patients with severe persistent asthma. J Allergy Clin Immunol
2013;132:1295-302.e3.
299. Cassim R, Russell MA, Lodge CJ, Lowe AJ, Koplin JJ, Dharmage SC. The role of circulating 25 hydroxyvitamin D in
asthma: a systematic review. Allergy 2015;70:339-54.
300. Jolliffe DA, Greenberg L, Hooper RL, Griffiths CJ, Camargo CA, Jr., Kerley CP, Jensen ME, et al. Vitamin D
supplementation to prevent asthma exacerbations: a systematic review and meta-analysis of individual participant
data. Lancet Respir Med 2017;5:881-90.
301. Riverin BD, Maguire JL, Li P. Vitamin D supplementation for childhood asthma: A systematic review and meta-
analysis. PLoS One 2015;10:e0136841.
302. Pojsupap S, Iliriani K, Sampaio TZ, O'Hearn K, Kovesi T, Menon K, McNally JD. Efficacy of high-dose vitamin D in
pediatric asthma: a systematic review and meta-analysis. J Asthma 2015;52:382-90.
303. Castro M, King TS, Kunselman SJ, Cabana MD, Denlinger L, Holguin F, Kazani SD, et al. Effect of vitamin D3 on
asthma treatment failures in adults with symptomatic asthma and lower vitamin D levels: the VIDA randomized
TE
clinical trial. Jama 2014;311:2083-91.
U
304. Lazarus SC, Chinchilli VM, Rollings NJ, Boushey HA, Cherniack R, Craig TJ, Deykin A, et al. Smoking affects
IB
response to inhaled corticosteroids or leukotriene receptor antagonists in asthma. Am J Respir Crit Care Med
R
T
2007;175:783-90.
IS
D
305. Chaudhuri R, Livingston E, McMahon AD, Lafferty J, Fraser I, Spears M, McSharry CP, et al. Effects of smoking
R
cessation on lung function and airway inflammation in smokers with asthma. Am J Respir Crit Care Med
O
2006;174:127-33.
PY
306. Rayens MK, Burkhart PV, Zhang M, Lee S, Moser DK, Mannino D, Hahn EJ. Reduction in asthma-related
O
C
emergency department visits after implementation of a smoke-free law. J Allergy Clin Immunol 2008;122:537-41.
T
307. Carson KV, Chandratilleke MG, Picot J, Brinn MP, Esterman AJ, Smith BJ. Physical training for asthma. Cochrane
O
N

O
308. Toennesen LL, Meteran H, Hostrup M, Wium Geiker NR, Jensen CB, Porsbjerg C, Astrup A, et al. Effects of
D
L-
Exercise and Diet in Nonobese Asthma Patients-A Randomized Controlled Trial. J Allergy Clin Immunol Pract
IA
2018;6:803-11.
ER
309. Beggs S, Foong YC, Le HC, Noor D, Wood-Baker R, Walters JA. Swimming training for asthma in children and
AT
adolescents aged 18 years and under. Cochrane Database Syst Rev 2013;4:CD009607.
M
310. Kogevinas M, Zock JP, Jarvis D, Kromhout H, Lillienberg L, Plana E, Radon K, et al. Exposure to substances in the
D
TE
workplace and new-onset asthma: an international prospective population-based study (ECRHS-II). Lancet
H
2007;370:336-41.
IG
311. Szczeklik A, Nizankowska E, Duplaga M. Natural history of aspirin-induced asthma. AIANE Investigators. European
R
PY
Network on Aspirin-Induced Asthma. Eur Respir J 2000;16:432-6.

O
312. Covar RA, Macomber BA, Szefler SJ. Medications as asthma triggers. Immunol Allergy Clin North Am 2005;25:169-
C
90.
313. Olenchock BA, Fonarow GG, Pan W, Hernandez A, Cannon CP. Current use of beta blockers in patients with
reactive airway disease who are hospitalized with acute coronary syndromes. Am J Cardiol 2009;103:295-300.
314. Morales DR, Jackson C, Lipworth BJ, Donnan PT, Guthrie B. Adverse respiratory effect of acute beta-blocker
exposure in asthma: a systematic review and meta-analysis of randomized controlled trials. Chest 2014;145:779-
86.
315. Gotzsche PC, Johansen HK. House dust mite control measures for asthma. Cochrane Database Syst Rev
2008:CD001187.
316. Leas BF, D'Anci KE, Apter AJ, Bryant-Stephens T, Lynch MP, Kaczmarek JL, Umscheid CA. Effectiveness of indoor
allergen reduction in asthma management: A systematic review. J Allergy Clin Immunol 2018;141:1854-69.
317. Sheffer AL. Allergen avoidance to reduce asthma-related morbidity. N Engl J Med 2004;351:1134-6.
318. Platts-Mills TA. Allergen avoidance in the treatment of asthma and rhinitis. N Engl J Med 2003;349:207-8.
319. Rabito FA, Carlson JC, He H, Werthmann D, Schal C. A single intervention for cockroach control reduces
cockroach exposure and asthma morbidity in children. J Allergy Clin Immunol 2017;140:565-70.
188 References
320. Crocker DD, Kinyota S, Dumitru GG, Ligon CB, Herman EJ, Ferdinands JM, Hopkins DP, et al. Effectiveness of
home-based, multi-trigger, multicomponent interventions with an environmental focus for reducing asthma
morbidity: a community guide systematic review. Am J Prev Med 2011;41:S5-32.
321. Morgan WJ, Crain EF, Gruchalla RS, O'Connor GT, Kattan M, Evans R, 3rd, Stout J, et al. Results of a home-based
environmental intervention among urban children with asthma. N Engl J Med 2004;351:1068-80.
322. Murray CS, Foden P, Sumner H, Shepley E, Custovic A, Simpson A. Preventing Severe Asthma Exacerbations in
Children. A Randomized Trial of Mite-Impermeable Bedcovers. Am J Respir Crit Care Med 2017;196:150-8.
323. Custovic A, Green R, Taggart SC, Smith A, Pickering CA, Chapman MD, Woodcock A. Domestic allergens in public
places. II: Dog (Can f1) and cockroach (Bla g 2) allergens in dust and mite, cat, dog and cockroach allergens in the
air in public buildings. Clin Exp Allergy 1996;26:1246-52.
324. Almqvist C, Larsson PH, Egmar AC, Hedren M, Malmberg P, Wickman M. School as a risk environment for children
allergic to cats and a site for transfer of cat allergen to homes. J Allergy Clin Immunol 1999;103:1012-7.
325. Shirai T, Matsui T, Suzuki K, Chida K. Effect of pet removal on pet allergic asthma. Chest 2005;127:1565-71.
326. Wood RA, Chapman MD, Adkinson NF, Jr., Eggleston PA. The effect of cat removal on allergen content in
TE
household-dust samples. J Allergy Clin Immunol 1989;83:730-4.
U
327. Erwin EA, Woodfolk JA, Custis N, Platts-Mills TA. Animal danders. Immunol Allergy Clin North Am 2003;23:469-81.
IB
328. Phipatanakul W, Matsui E, Portnoy J, Williams PB, Barnes C, Kennedy K, Bernstein D, et al. Environmental
TR
assessment and exposure reduction of rodents: a practice parameter. Ann Allergy Asthma Immunol 2012;109:375-
IS
D
87.
R
329. Matsui EC, Perzanowski M, Peng RD, Wise RA, Balcer-Whaley S, Newman M, Cunningham A, et al. Effect of an
O
Integrated Pest Management Intervention on Asthma Symptoms Among Mouse-Sensitized Children and
PY
Adolescents With Asthma: A Randomized Clinical Trial. Jama 2017;317:1027-36.
O
C
330. Custovic A, Wijk RG. The effectiveness of measures to change the indoor environment in the treatment of allergic
T
rhinitis and asthma: ARIA update (in collaboration with GA(2)LEN). Allergy 2005;60:1112-5.
O
N
331. Eggleston PA, Wood RA, Rand C, Nixon WJ, Chen PH, Lukk P. Removal of cockroach allergen from inner-city
O
homes. J Allergy Clin Immunol 1999;104:842-6.

D
L-
332. Denning DW, O'Driscoll B R, Hogaboam CM, Bowyer P, Niven RM. The link between fungi and severe asthma: a
IA
summary of the evidence. Eur Respir J 2006;27:615-26.

ER
333. Hirsch T, Hering M, Burkner K, Hirsch D, Leupold W, Kerkmann ML, Kuhlisch E, et al. House-dust-mite allergen
AT
concentrations (Der f 1) and mold spores in apartment bedrooms before and after installation of insulated windows
M
and central heating systems. Allergy 2000;55:79-83.

D
TE
334. Wood LG, Garg ML, Smart JM, Scott HA, Barker D, Gibson PG. Manipulating antioxidant intake in asthma: a
H
randomized controlled trial. Am J Clin Nutr 2012;96:534-43.

IG
335. Boulet LP, Franssen E. Influence of obesity on response to fluticasone with or without salmeterol in moderate
R
PY
asthma. Respir Med 2007;101:2240-7.

O
336. Lavoie KL, Bacon SL, Labrecque M, Cartier A, Ditto B. Higher BMI is associated with worse asthma control and
C
quality of life but not asthma severity. Respir Med 2006;100:648-57.

337. Saint-Pierre P, Bourdin A, Chanez P, Daures JP, Godard P. Are overweight asthmatics more difficult to control?
Allergy 2006;61:79-84.
338. Sutherland ER, Goleva E, Strand M, Beuther DA, Leung DY. Body mass and glucocorticoid response in asthma.
Am J Respir Crit Care Med 2008;178:682-7.
339. Okoniewski W, Lu KD, Forno E. Weight loss for children and adults with obesity and asthma. A systematic review of
randomized controlled trials. Annals of the American Thoracic Society 2019;16:613-25.
340. Adeniyi FB, Young T. Weight loss interventions for chronic asthma. Cochrane Database Syst Rev
2012;7:CD009339.
341. Moreira A, Bonini M, Garcia-Larsen V, Bonini S, Del Giacco SR, Agache I, Fonseca J, et al. Weight loss
interventions in asthma: EAACI Evidence-Based Clinical Practice Guideline (Part I). Allergy 2013;68:425-39.
342. Boulet LP, Turcotte H, Martin J, Poirier P. Effect of bariatric surgery on airway response and lung function in obese
subjects with asthma. Respir Med 2012;106:651-60.
References 189
343. Dixon AE, Pratley RE, Forgione PM, Kaminsky DA, Whittaker-Leclair LA, Griffes LA, Garudathri J, et al. Effects of
obesity and bariatric surgery on airway hyperresponsiveness, asthma control, and inflammation. J Allergy Clin
Immunol 2011;128:508-15 e1-2.
344. Scott HA, Gibson PG, Garg ML, Pretto JJ, Morgan PJ, Callister R, Wood LG. Dietary restriction and exercise
improve airway inflammation and clinical outcomes in overweight and obese asthma: a randomized trial. Clin Exp
Allergy 2013;43:36-49.
345. Freitas DA, Holloway EA, Bruno SS, Chaves GS, Fregonezi GA, Mendonca KP. Breathing exercises for adults with
asthma. Cochrane Database Syst Rev 2013;10:CD001277.
346. Bruton A, Lee A, Yardley L, Raftery J, Arden-Close E, Kirby S, Zhu S, et al. Physiotherapy breathing retraining for
asthma: a randomised controlled trial. Lancet Respir Med 2018;6:19-28.
347. Slader CA, Reddel HK, Spencer LM, Belousova EG, Armour CL, Bosnic-Anticevich SZ, Thien FC, et al. Double
blind randomised controlled trial of two different breathing techniques in the management of asthma. Thorax
2006;61:651-6.
348. Upham JW, Holt PG. Environment and development of atopy. Curr Opin Allergy Clin Immunol 2005;5:167-72.
TE
349. Belanger K, Holford TR, Gent JF, Hill ME, Kezik JM, Leaderer BP. Household levels of nitrogen dioxide and
U
pediatric asthma severity. Epidemiology 2013;24:320-30.
IB
350. Howden-Chapman P, Pierse N, Nicholls S, Gillespie-Bennett J, Viggers H, Cunningham M, Phipps R, et al. Effects
TR
of improved home heating on asthma in community dwelling children: randomised controlled trial. BMJ
IS
D
2008;337:a1411.
R
351. Tibosch MM, Verhaak CM, Merkus PJ. Psychological characteristics associated with the onset and course of
O
asthma in children and adolescents: a systematic review of longitudinal effects. Patient Educ Couns 2011;82:11-9.
PY
352. Rietveld S, van Beest I, Everaerd W. Stress-induced breathlessness in asthma. Psychol Med 1999;29:1359-66.
O
C
353. Sandberg S, Paton JY, Ahola S, McCann DC, McGuinness D, Hillary CR, Oja H. The role of acute and chronic
T
stress in asthma attacks in children. Lancet 2000;356:982-7.

O
N
354. Lehrer PM, Isenberg S, Hochron SM. Asthma and emotion: a review. J Asthma 1993;30:5-21.
O
355. Nouwen A, Freeston MH, Labbe R, Boulet LP. Psychological factors associated with emergency room visits among
D
L-
asthmatic patients. Behav Modif 1999;23:217-33.

IA
356. Newson R, Strachan D, Archibald E, Emberlin J, Hardaker P, Collier C. Acute asthma epidemics, weather and
ER
pollen in England, 1987-1994. Eur Respir J 1998;11:694-701.

AT
357. Thien F, Beggs PJ, Csutoros D, Darvall J, Hew M, Davies JM, Bardin PG, et al. The Melbourne epidemic
M
thunderstorm asthma event 2016: an investigation of environmental triggers, effect on health services, and patient
D
TE
risk factors. The Lancet Planetary Health 2018;2:e255-e63.

H
358. Li Y, Wang W, Wang J, Zhang X, Lin W, Yang Y. Impact of air pollution control measures and weather conditions
IG
on asthma during the 2008 Summer Olympic Games in Beijing. Int J Biometeorol 2011;55:547-54.
R
PY
359. Taylor SL, Bush RK, Selner JC, Nordlee JA, Wiener MB, Holden K, Koepke JW, et al. Sensitivity to sulfited foods
O
among sulfite-sensitive subjects with asthma. J Allergy Clin Immunol 1988;81:1159-67.

C
360. Ahmed S, Steed L, Harris K, Taylor SJC, Pinnock H. Interventions to enhance the adoption of asthma self-
management behaviour in the South Asian and African American population: a systematic review. NPJ primary care
respiratory medicine 2018;28:5.
361. Fink JB, Rubin BK. Problems with inhaler use: a call for improved clinician and patient education. Respir Care
2005;50:1360-74; discussion 74-5.
362. Klijn SL, Hiligsmann M, Evers S, Roman-Rodriguez M, van der Molen T, van Boven JFM. Effectiveness and
success factors of educational inhaler technique interventions in asthma & COPD patients: a systematic review.
NPJ primary care respiratory medicine 2017;27:24.
363. Newman SP. Spacer devices for metered dose inhalers. Clin Pharmacokinet 2004;43:349-60.
364. Basheti IA, Reddel HK, Armour CL, Bosnic-Anticevich SZ. Improved asthma outcomes with a simple inhaler
technique intervention by community pharmacists. J Allergy Clin Immunol 2007;119:1537-8.
365. Giraud V, Allaert FA, Roche N. Inhaler technique and asthma: feasability and acceptability of training by
pharmacists. Respir Med 2011;105:1815-22.
190 References
366. van der Palen J, Klein JJ, Kerkhoff AH, van Herwaarden CL, Seydel ER. Evaluation of the long-term effectiveness
of three instruction modes for inhaling medicines. Patient Educ Couns 1997;32:S87-95.
367. Almomani BA, Mokhemer E, Al-Sawalha NA, Momany SM. A novel approach of using educational pharmaceutical
pictogram for improving inhaler techniques in patients with asthma. Respir Med 2018;143:103-8.
368. Basheti IA, Obeidat NM, Reddel HK. Effect of novel inhaler technique reminder labels on the retention of inhaler
technique skills in asthma: a single-blind randomized controlled trial. NPJ primary care respiratory medicine
2017;27:9.
369. Armour CL, Reddel HK, LeMay KS, Saini B, Smith LD, Bosnic-Anticevich SZ, Song YJC, et al. Feasibility and
effectiveness of an evidence-based asthma service in Australian community pharmacies: a pragmatic cluster
randomized trial. J Asthma 2013;50:302-9.
370. Kuethe MC, Vaessen-Verberne AA, Elbers RG, Van Aalderen WM. Nurse versus physician-led care for the
management of asthma. Cochrane Database Syst Rev 2013;2:Cd009296.
371. Federman AD, O'Conor R, Mindlis I, Hoy-Rosas J, Hauser D, Lurio J, Shroff N, et al. Effect of a self-management
support intervention on asthma outcomes in older adults: The SAMBA study randomized clinical trial. JAMA Intern
TE
Med 2019.
U
372. Crompton GK, Barnes PJ, Broeders M, Corrigan C, Corbetta L, Dekhuijzen R, Dubus JC, et al. The need to improve
IB
inhalation technique in Europe: a report from the Aerosol Drug Management Improvement Team. Respir Med
TR
2006;100:1479-94.
IS
D
373. Viswanathan M, Golin CE, Jones CD, Ashok M, Blalock SJ, Wines RC, Coker-Schwimmer EJ, et al. Interventions to
R
improve adherence to self-administered medications for chronic diseases in the United States: a systematic review.
O
Ann Intern Med 2012;157:785-95.
PY
374. Chan AH, Harrison J, Black PN, Mitchell EA, Foster JM. Using electronic monitoring devices to measure inhaler
O
C
adherence: a practical guide for clinicians. J Allergy Clin Immunol Pract 2015;3:335-49.e1-5.
T
375. Cohen JL, Mann DM, Wisnivesky JP, Home R, Leventhal H, Musumeci-Szabo TJ, Halm EA. Assessing the validity
O
N
of self-reported medication adherence among inner-city asthmatic adults: the Medication Adherence Report Scale
O
for Asthma. Ann Allergy Asthma Immunol 2009;103:325-31.

D
L-
376. Poureslami IM, Rootman I, Balka E, Devarakonda R, Hatch J, FitzGerald JM. A systematic review of asthma and
IA
health literacy: a cultural-ethnic perspective in Canada. MedGenMed 2007;9:40.

ER
377. Berkman ND, Sheridan SL, Donahue KE, Halpern DJ, Crotty K. Low health literacy and health outcomes: an
AT
updated systematic review. Ann Intern Med 2011;155:97-107.

M
378. Zeni MB. Systematic review of health literacy in Cochrane database studies on paediatric asthma educational
D
TE
interventions: searching beyond rigorous design. Int J Evid Based Healthc 2012;10:3-8.
H
379. Partridge MR, Dal Negro RW, Olivieri D. Understanding patients with asthma and COPD: insights from a European
IG
study. Prim Care Respir J 2011;20:315-23, 17 p following 23.

R
PY
380. Foster JM, Usherwood T, Smith L, Sawyer SM, Xuan W, Rand CS, Reddel HK. Inhaler reminders improve
O
adherence with controller treatment in primary care patients with asthma. J Allergy Clin Immunol 2014;134:1260-8.
C
381. Chan AH, Stewart AW, Harrison J, Camargo CA, Jr., Black PN, Mitchell EA. The effect of an electronic monitoring
device with audiovisual reminder function on adherence to inhaled corticosteroids and school attendance in children
with asthma: a randomised controlled trial. Lancet Respir Med 2015;3:210-9.
382. Morton RW, Elphick HE, Rigby AS, Daw WJ, King DA, Smith LJ, Everard ML. STAAR: a randomised controlled trial
of electronic adherence monitoring with reminder alarms and feedback to improve clinical outcomes for children
with asthma. Thorax 2017;72:347-54.
383. Otsuki M, Eakin MN, Rand CS, Butz AM, Hsu VD, Zuckerman IH, Ogborn J, et al. Adherence feedback to improve
asthma outcomes among inner-city children: a randomized trial. Pediatrics 2009;124:1513-21.
384. Williams LK, Peterson EL, Wells K, Campbell J, Wang M, Chowdhry VK, Walsh M, et al. A cluster-randomized trial
to provide clinicians inhaled corticosteroid adherence information for their patients with asthma. J Allergy Clin
Immunol 2010;126:225-31, 31 e1-4.
385. Bender BG, Cvietusa PJ, Goodrich GK, Lowe R, Nuanes HA, Rand C, Shetterly S, et al. Pragmatic trial of health
care technologies to improve adherence to pediatric asthma treatment: a randomized clinical trial. JAMA pediatrics
2015;169:317-23.
References 191
386. Halterman JS, Fagnano M, Tajon RS, Tremblay P, Wang H, Butz A, Perry TT, et al. Effect of the School-Based
Telemedicine Enhanced Asthma Management (SB-TEAM) program on asthma morbidity: A randomized clinical
trial. JAMA pediatrics 2018;172:e174938.
387. Normansell R, Kew KM, Stovold E. Interventions to improve adherence to inhaled steroids for asthma. Cochrane
388. Foster JM, Smith L, Bosnic-Anticevich SZ, Usherwood T, Sawyer SM, Rand CS, Reddel HK. Identifying patient-
specific beliefs and behaviours for conversations about adherence in asthma. Intern Med J 2012;42:e136-44.
389. Ulrik CS, Backer V, Soes-Petersen U, Lange P, Harving H, Plaschke PP. The patient's perspective: adherence or
non-adherence to asthma controller therapy? J Asthma 2006;43:701-4.
390. Price D, Robertson A, Bullen K, Rand C, Horne R, Staudinger H. Improved adherence with once-daily versus twice-
daily dosing of mometasone furoate administered via a dry powder inhaler: a randomized open-label study. BMC
Pulm Med 2010;10:1.
391. Kew KM, Carr R, Crossingham I. Lay-led and peer support interventions for adolescents with asthma. Cochrane
TE
392. Clark NM, Shah S, Dodge JA, Thomas LJ, Andridge RR, Little RJ. An evaluation of asthma interventions for preteen
U
students. J Sch Health 2010;80:80-7.
IB
393. Gibson PG, Powell H, Coughlan J, Wilson AJ, Hensley MJ, Abramson M, Bauman A, et al. Limited (information
TR
only) patient education programs for adults with asthma. Cochrane Database Syst Rev 2002:CD001005.
IS
D
394. Houts PS, Bachrach R, Witmer JT, Tringali CA, Bucher JA, Localio RA. Using pictographs to enhance recall of
R
spoken medical instructions. Patient Educ Couns 1998;35:83-8.
O
395. Meade CD, McKinney WP, Barnas GP. Educating patients with limited literacy skills: the effectiveness of printed
PY
and videotaped materials about colon cancer. Am J Public Health 1994;84:119-21.
O
C
396. Manfrin A, Tinelli M, Thomas T, Krska J. A cluster randomised control trial to evaluate the effectiveness and cost-
T
effectiveness of the Italian medicines use review (I-MUR) for asthma patients. BMC Health Serv Res 2017;17:300.
O
N
397. Campbell JD, Brooks M, Hosokawa P, Robinson J, Song L, Krieger J. Community health worker home visits for
O
medicaid-enrolled children with asthma: Effects on asthma outcomes and costs. Am J Public Health
D
L-
2015;105:2366-72.
IA
398. Partridge MR, Caress AL, Brown C, Hennings J, Luker K, Woodcock A, Campbell M. Can lay people deliver asthma
ER
self-management education as effectively as primary care based practice nurses? Thorax 2008;63:778-83.
AT
399. Pinnock H, Parke HL, Panagioti M, Daines L, Pearce G, Epiphaniou E, Bower P, et al. Systematic meta-review of
M
supported self-management for asthma: a healthcare perspective. BMC Med 2017;15:64.

D
TE
400. Boyd M, Lasserson TJ, McKean MC, Gibson PG, Ducharme FM, Haby M. Interventions for educating children who
H
are at risk of asthma-related emergency department attendance. Cochrane Database Syst Rev 2009:CD001290.
IG
401. Powell H, Gibson PG. Options for self-management education for adults with asthma. Cochrane Database Syst Rev
R
PY
2003:CD004107.
O
402. McLean S, Chandler D, Nurmatov U, Liu J, Pagliari C, Car J, Sheikh A. Telehealthcare for asthma. Cochrane
C
Database Syst Rev 2010:CD007717.

403. Fishwick D, D'Souza W, Beasley R. The asthma self-management plan system of care: what does it mean, how is it
done, does it work, what models are available, what do patients want and who needs it? Patient Educ Couns
1997;32:S21-33.
404. Gibson PG, Powell H. Written action plans for asthma: an evidence-based review of the key components. Thorax
2004;59:94-9.
405. Holt S, Masoli M, Beasley R. The use of the self-management plan system of care in adult asthma. Primary care
respiratory journal : journal of the General Practice Airways Group 2004;13:19-27.
406. Roberts NJ, Evans G, Blenkhorn P, Partridge MR. Development of an electronic pictorial asthma action plan and its
use in primary care. Patient Educ Couns 2010;80:141-6.
407. Ring N, Malcolm C, Wyke S, Macgillivray S, Dixon D, Hoskins G, Pinnock H, et al. Promoting the use of Personal
Asthma Action Plans: a systematic review. Prim Care Respir J 2007;16:271-83.
408. Halterman JS, Fisher S, Conn KM, Fagnano M, Lynch K, Marky A, Szilagyi PG. Improved preventive care for
asthma: a randomized trial of clinician prompting in pediatric offices. Arch Pediatr Adolesc Med 2006;160:1018-25.
192 References
409. Kneale D, Harris K, McDonald VM, Thomas J, Grigg J. Effectiveness of school-based self-management
interventions for asthma among children and adolescents: findings from a Cochrane systematic review and meta-
analysis. Thorax 2019.
410. Boulet LP. Influence of comorbid conditions on asthma. Eur Respir J 2009;33:897-906.
411. Deng X, Ma J, Yuan Y, Zhang Z, Niu W. Association between overweight or obesity and the risk for childhood
asthma and wheeze: An updated meta-analysis on 18 articles and 73 252 children. Pediatr Obes 2019;14:e12532.
412. Upala S, Thavaraputta S, Sanguankeo A. Improvement in pulmonary function in asthmatic patients after bariatric
surgery: a systematic review and meta-analysis. Surg Obes Relat Dis 2018.
413. Serrano-Pariente J, Plaza V, Soriano JB, Mayos M, Lopez-Vina A, Picado C, Vigil L. Asthma outcomes improve
with continuous positive airway pressure for obstructive sleep apnea. Allergy 2017;72:802-12.
414. Chan WW, Chiou E, Obstein KL, Tignor AS, Whitlock TL. The efficacy of proton pump inhibitors for the treatment of
asthma in adults: a meta-analysis. Arch Intern Med 2011;171:620-9.
415. Mastronarde JG, Anthonisen NR, Castro M, Holbrook JT, Leone FT, Teague WG, Wise RA. Efficacy of
esomeprazole for treatment of poorly controlled asthma. N Engl J Med 2009;360:1487-99.
TE
416. Kiljander TO, Harding SM, Field SK, Stein MR, Nelson HS, Ekelund J, Illueca M, et al. Effects of esomeprazole 40
U
mg twice daily on asthma: a randomized placebo-controlled trial. Am J Respir Crit Care Med 2006;173:1091-7.
IB
417. Sopo SM, Radzik D, Calvani M. Does treatment with proton pump inhibitors for gastroesophageal reflux disease
TR
(GERD) improve asthma symptoms in children with asthma and GERD? A systematic review. J Investig Allergol
IS
D
Clin Immunol 2009;19:1-5.
R
418. Holbrook JT, Wise RA, Gold BD, Blake K, Brown ED, Castro M, Dozor AJ, et al. Lansoprazole for children with
O
poorly controlled asthma: a randomized controlled trial. JAMA 2012;307:373-81.
PY
419. Goodwin RD, Jacobi F, Thefeld W. Mental disorders and asthma in the community. Arch Gen Psychiatry
O
C
2003;60:1125-30.
T
420. Lavoie KL, Cartier A, Labrecque M, Bacon SL, Lemiere C, Malo JL, Lacoste G, et al. Are psychiatric disorders
O
N
associated with worse asthma control and quality of life in asthma patients? Respir Med 2005;99:1249-57.
O
421. Ahmedani BK, Peterson EL, Wells KE, Williams LK. Examining the relationship between depression and asthma
D
L-
exacerbations in a prospective follow-up study. Psychosom Med 2013;75:305-10.

IA
422. Yorke J, Fleming SL, Shuldham C. Psychological interventions for adults with asthma. Cochrane Database Syst
ER
Rev 2009.
AT
423. Parry GD, Cooper CL, Moore JM, Yadegarfar G, Campbell MJ, Esmonde L, Morice AH, et al. Cognitive behavioural
M
intervention for adults with anxiety complications of asthma: prospective randomised trial. Respir Med
D
TE
2012;106:802-10.
H
424. Bock SA, Munoz-Furlong A, Sampson HA. Further fatalities caused by anaphylactic reactions to food, 2001-2006. J
IG

R
PY
425. Pumphrey RSH, Gowland MH. Further fatal allergic reactions to food in the United Kingdom, 1999-2006. J Allergy
O
Clin Immunol 2007;119:1018-9.

C
426. Liu AH, Jaramillo R, Sicherer SH, Wood RA, Bock SA, Burks AW, Massing M, et al. National prevalence and risk
factors for food allergy and relationship to asthma: results from the National Health and Nutrition Examination
Survey 2005-2006. J Allergy Clin Immunol 2010;126:798-806.e13.
427. Bousquet J, Schunemann HJ, Samolinski B, Demoly P, Baena-Cagnani CE, Bachert C, Bonini S, et al. Allergic
Rhinitis and its Impact on Asthma (ARIA): achievements in 10 years and future needs. J Allergy Clin Immunol
2012;130:1049-62.
428. Cruz AA, Popov T, Pawankar R, Annesi-Maesano I, Fokkens W, Kemp J, Ohta K, et al. Common characteristics of
upper and lower airways in rhinitis and asthma: ARIA update, in collaboration with GA(2)LEN. Allergy 2007;62
Suppl 84:1-41.
429. Fokkens WJ, Lund VJ, Mullol J, Bachert C, Alobid I, Baroody F, Cohen N, et al. EPOS 2012: European position
paper on rhinosinusitis and nasal polyps 2012. A summary for otorhinolaryngologists. Rhinol 2012;50:1-12.
430. Tan BK, Chandra RK, Pollak J, Kato A, Conley DB, Peters AT, Grammer LC, et al. Incidence and associated
premorbid diagnoses of patients with chronic rhinosinusitis. J Allergy Clin Immunol 2013;131:1350-60.
References 193
431. Hamilos DL. Chronic rhinosinusitis: epidemiology and medical management. J Allergy Clin Immunol 2011;128:693-
707.
432. Brozek JL, Bousquet J, Baena-Cagnani CE, Bonini S, Canonica GW, Casale TB, van Wijk RG, et al. Allergic
Rhinitis and its Impact on Asthma (ARIA) guidelines: 2010 revision. J Allergy Clin Immunol 2010;126:466-76.
433. Corren J, Manning BE, Thompson SF, Hennessy S, Strom BL. Rhinitis therapy and the prevention of hospital care
for asthma: a case-control study. J Allergy Clin Immunol 2004;113:415-9.
434. Lohia S, Schlosser RJ, Soler ZM. Impact of intranasal corticosteroids on asthma outcomes in allergic rhinitis: a
meta-analysis. Allergy 2013;68:569-79.
435. Dixon AE, Castro M, Cohen RI, Gerald LB, Holbrook JT, Irvin CG, Mohapatra S, et al. Efficacy of nasal
mometasone for the treatment of chronic sinonasal disease in patients with inadequately controlled asthma. J
Allergy Clin Immunol 2015;135:701-9.e5.
436. Souza-Machado C, Souza-Machado A, Franco R, Ponte EV, Barreto ML, Rodrigues LC, Bousquet J, et al. Rapid
reduction in hospitalisations after an intervention to manage severe asthma. Eur Respir J 2010;35:515-21.
437. Franco R, Nascimento HF, Cruz AA, Santos AC, Souza-Machado C, Ponte EV, Souza-Machado A, et al. The
TE
economic impact of severe asthma to low-income families. Allergy 2009;64:478-83.
U
438. Bahadori K, Quon BS, Doyle-Waters MM, Marra C, Fitzgerald JM. A systematic review of economic evaluations of
IB
therapy in asthma. J Asthma Allergy 2010;3:33-42.
TR
439. Fairall L, Bateman E, Cornick R, Faris G, Timmerman V, Folb N, Bachmann M, et al. Innovating to improve primary
IS
D
care in less developed countries: towards a global model. BMJ Innovations 2015.
R
440. Patton GC, Viner R. Pubertal transitions in health. Lancet 2007;369:1130-9.
O
441. Michaud P-A, Suris JC, Viner R. The adolescent with a chronic condition : epidemiology, developmental issues and
health care provision. Geneva: WHO; 2007. PY
O
C
442. Carlsen KH, Anderson SD, Bjermer L, Bonini S, Brusasco V, Canonica W, Cummiskey J, et al. Treatment of
T
exercise-induced asthma, respiratory and allergic disorders in sports and the relationship to doping: Part II of the
O
N
report from the Joint Task Force of European Respiratory Society (ERS) and European Academy of Allergy and
O
Clinical Immunology (EAACI) in cooperation with GA(2)LEN. Allergy 2008;63:492-505.

D
L-
443. Gluck JC, Gluck PA. The effect of pregnancy on the course of asthma. Immunol Allergy Clin North Am 2006;26:63-
IA
80.
ER
444. Murphy VE, Powell H, Wark PA, Gibson PG. A prospective study of respiratory viral infection in pregnant women
AT
with and without asthma. Chest 2013;144:420-7.

M
445. Lim A, Stewart K, Konig K, George J. Systematic review of the safety of regular preventive asthma medications
D
TE
during pregnancy. Ann Pharmacother 2011;45:931-45.

H
446. Wendel PJ, Ramin SM, Barnett-Hamm C, Rowe TF, Cunningham FG. Asthma treatment in pregnancy: a
IG
randomized controlled study. Am J Obstet Gynecol 1996;175:150-4.

R
PY
447. Schatz M, Leibman C. Inhaled corticosteroid use and outcomes in pregnancy. Annals of Allergy, Asthma &
O
Immunology 2005;95:234-8.
C
448. Liu X, Agerbo E, Schlunssen V, Wright RJ, Li J, Munk-Olsen T. Maternal asthma severity and control during
pregnancy and risk of offspring asthma. J Allergy Clin Immunol 2018;141:886-92 e3.
449. Powell H, Murphy VE, Taylor DR, Hensley MJ, McCaffery K, Giles W, Clifton VL, et al. Management of asthma in
pregnancy guided by measurement of fraction of exhaled nitric oxide: a double-blind, randomised controlled trial.
Lancet 2011;378:983-90.
450. Morten M, Collison A, Murphy VE, Barker D, Oldmeadow C, Attia J, Meredith J, et al. Managing Asthma in
Pregnancy (MAP) trial: FENO levels and childhood asthma. J Allergy Clin Immunol 2018;142:1765-72.e4.
451. Lim AS, Stewart K, Abramson MJ, Ryan K, George J. Asthma during pregnancy: the experiences, concerns and
views of pregnant women with asthma. J Asthma 2012;49:474-9.
452. National Heart Lung and Blood Institute, National Asthma Education and Prevention Program Asthma and
Pregnancy Working Group. NAEPP expert panel report. Managing asthma during pregnancy: recommendations for
pharmacologic treatment-2004 update. J Allergy Clin Immunol 2005;115:34-46.
453. Lim AS, Stewart K, Abramson MJ, Walker SP, Smith CL, George J. Multidisciplinary Approach to Management of
Maternal Asthma (MAMMA): a randomized controlled trial. Chest 2014;145:1046-54.
194 References
454. Ali Z, Nilas L, Ulrik CS. Determinants of low risk of asthma exacerbation during pregnancy. Clin Exp Allergy
2018;48:23-8.
455. Nelson-Piercy C. Asthma in pregnancy. Thorax 2001;56:325-8.
456. McLaughlin K, Foureur M, Jensen ME, Murphy VE. Review and appraisal of guidelines for the management of
asthma during pregnancy. Women and birth : journal of the Australian College of Midwives 2018;31:e349-e57.
457. Sanchez-Ramos JL, Pereira-Vega AR, Alvarado-Gomez F, Maldonado-Perez JA, Svanes C, Gomez-Real F. Risk
factors for premenstrual asthma: a systematic review and meta-analysis. Expert Rev Respir Med 2017;11:57-72.
458. Reed CE. Asthma in the elderly: diagnosis and management. J Allergy Clin Immunol 2010;126:681-7.
459. Gibson PG, McDonald VM, Marks GB. Asthma in older adults. Lancet 2010;376:803-13.
460. Slavin RG, Haselkorn T, Lee JH, Zheng B, Deniz Y, Wenzel SE, Group TS. Asthma in older adults: observations
from the epidemiology and natural history of asthma: outcomes and treatment regimens (TENOR) study. Ann
461. Vincken W, Dekhuijzen PR, Barnes P, on behalf of the ADMIT Working Group. The ADMIT series - Issues in
inhalation therapy. 4) How to choose inhaler devices for the treatment of COPD. Prim Care Respir J 2010;19:10-20.
TE
462. Smetana GW, Lawrence VA, Cornell JE. Preoperative pulmonary risk stratification for noncardiothoracic surgery:
U
systematic review for the American College of Physicians. Ann Intern Med 2006;144:581-95.
IB
463. Woods BD, Sladen RN. Perioperative considerations for the patient with asthma and bronchospasm. Br J Anaesth
TR
2009;103 Suppl 1:i57-65.
IS
D
464. Wakim JH, Sledge KC. Anesthetic implications for patients receiving exogenous corticosteroids. AANA Journal
R
2006;74:133-9.
O
465. Stevenson DD. Diagnosis, prevention, and treatment of adverse reactions to aspirin and nonsteroidal anti-
inflammatory drugs. J Allergy Clin Immunol 1984;74:617-22. PY
O
C
466. Szczeklik A, Sanak M, Nizankowska-Mogilnicka E, Kielbasa B. Aspirin intolerance and the cyclooxygenase-
T
leukotriene pathways. Curr Opin Pulm Med 2004;10:51-6.

O
N
467. Mascia K, Haselkorn T, Deniz YM, Miller DP, Bleecker ER, Borish L, Group TS. Aspirin sensitivity and severity of
O
asthma: evidence for irreversible airway obstruction in patients with severe or difficult-to-treat asthma. J Allergy Clin
D
L-
Immunol 2005;116:970-5.
IA
468. Morales DR, Guthrie B, Lipworth BJ, Jackson C, Donnan PT, Santiago VH. NSAID-exacerbated respiratory
ER
disease: a meta-analysis evaluating prevalence, mean provocative dose of aspirin and increased asthma morbidity.
AT
Allergy 2015;70:828-35.
M
469. Rajan JP, Wineinger NE, Stevenson DD, White AA. Prevalence of aspirin-exacerbated respiratory disease among
D
TE
asthmatic patients: A meta-analysis of the literature. J Allergy Clin Immunol 2015;135:676-81.e1.

H
470. Nizankowska E, Bestynska-Krypel A, Cmiel A, Szczeklik A. Oral and bronchial provocation tests with aspirin for
IG
diagnosis of aspirin-induced asthma. Eur Respir J 2000;15:863-9.

R
PY
471. Szczeklik A, Stevenson DD. Aspirin-induced asthma: advances in pathogenesis and management. J Allergy Clin
O
Immunol 1999;104:5-13.
C
472. Milewski M, Mastalerz L, Nizankowska E, Szczeklik A. Nasal provocation test with lysine-aspirin for diagnosis of
aspirin- sensitive asthma. J Allergy Clin Immunol 1998;101:581-6.
473. El Miedany Y, Youssef S, Ahmed I, El Gaafary M. Safety of etoricoxib, a specific cyclooxygenase-2 inhibitor, in
asthmatic patients with aspirin-exacerbated respiratory disease. Annals of Allergy, Asthma & Immunology
2006;97:105-9.
474. Morales DR, Lipworth BJ, Guthrie B, Jackson C, Donnan PT, Santiago VH. Safety risks for patients with aspirin-
exacerbated respiratory disease after acute exposure to selective nonsteroidal anti-inflammatory drugs and COX-2
inhibitors: Meta-analysis of controlled clinical trials. J Allergy Clin Immunol 2014;134:40-5.
475. Dahlen SE, Malmstrom K, Nizankowska E, Dahlen B, Kuna P, Kowalski M, Lumry WR, et al. Improvement of
aspirin-intolerant asthma by montelukast, a leukotriene antagonist: a randomized, double-blind, placebo-controlled
trial. Am J Respir Crit Care Med 2002;165:9-14.
476. Pleskow WW, Stevenson DD, Mathison DA, Simon RA, Schatz M, Zeiger RS. Aspirin desensitization in aspirin-
sensitive asthmatic patients: clinical manifestations and characterization of the refractory period. J Allergy Clin
Immunol 1982;69:11-9.
References 195
477. Swierczynska-Krepa M, Sanak M, Bochenek G, Strek P, Cmiel A, Gielicz A, Plutecka H, et al. Aspirin
desensitization in patients with aspirin-induced and aspirin-tolerant asthma: a double-blind study. J Allergy Clin
Immunol 2014;134:883-90.
478. Agarwal R, Chakrabarti A, Shah A, Gupta D, Meis JF, Guleria R, Moss R, et al. Allergic bronchopulmonary
aspergillosis: review of literature and proposal of new diagnostic and classification criteria. Clin Exp Allergy
2013;43:850-73.
479. Agarwal R, Sehgal IS, Dhooria S, Aggarwal AN. Developments in the diagnosis and treatment of allergic
bronchopulmonary aspergillosis. Expert Rev Respir Med 2016;10:1317-34.
480. Agarwal R, Dhooria S, Singh Sehgal I, Aggarwal AN, Garg M, Saikia B, Behera D, et al. A Randomized Trial of
Itraconazole vs Prednisolone in Acute-Stage Allergic Bronchopulmonary Aspergillosis Complicating Asthma. Chest
2018;153:656-64.
481. Voskamp AL, Gillman A, Symons K, Sandrini A, Rolland JM, O'Hehir RE, Douglass JA. Clinical efficacy and
immunologic effects of omalizumab in allergic bronchopulmonary aspergillosis. J Allergy Clin Immunol Pract
2015;3:192-9.
TE
482. Hekking PP, Wener RR, Amelink M, Zwinderman AH, Bouvy ML, Bel EH. The prevalence of severe refractory
U
asthma. J Allergy Clin Immunol 2015;135:896-902.
IB
483. Foster JM, McDonald VM, Guo M, Reddel Helen K. “I have lost in every facet of my life”: the hidden burden of
TR
severe asthma. Eur Respir J 2017;50:1700765.
IS
D
484. Waljee AK, Rogers MA, Lin P, Singal AG, Stein JD, Marks RM, Ayanian JZ, et al. Short term use of oral
R
corticosteroids and related harms among adults in the United States: population based cohort study. BMJ
O
2017;357:j1415.
PY
485. O'Neill S, Sweeney J, Patterson CC, Menzies-Gow A, Niven R, Mansur AH, Bucknall C, et al. The cost of treating
O
C
severe refractory asthma in the UK: an economic analysis from the British Thoracic Society Difficult Asthma
T
Registry. Thorax 2015;70:376-8.

O
N
486. Sadatsafavi M, Lynd L, Marra C, Carleton B, Tan WC, Sullivan S, FitzGerald JM. Direct health care costs
O
associated with asthma in British Columbia. Can Respir J 2010;17:74-80.

D
L-
487. Hashimoto S, Bel EH. Current treatment of severe asthma. Clin Exp Allergy 2012;42:693-705.
IA
488. Hallstrand TS, Leuppi JD, Joos G, Hall GL, Carlsen KH, Kaminsky DA, Coates AL, et al. ERS technical standard on
ER
bronchial challenge testing: pathophysiology and methodology of indirect airway challenge testing. Eur Respir J
AT
2018;52.
M
489. Hancox RJ, Cowan JO, Flannery EM, Herbison GP, McLachlan CR, Taylor DR. Bronchodilator tolerance and
D
TE
rebound bronchoconstriction during regular inhaled beta-agonist treatment. Respir Med 2000;94:767-71.
H
490. Stanford RH, Shah MB, D’Souza AO, Dhamane AD, Schatz M. Short-acting β-agonist use and its ability to predict
IG
future asthma-related outcomes. Annals of Allergy, Asthma & Immunology 2012;109:403-7.

R
PY
491. Basheti IA, Armour CL, Bosnic-Anticevich SZ, Reddel HK. Evaluation of a novel educational strategy, including
O
inhaler-based reminder labels, to improve asthma inhaler technique Patient Educ Couns 2008;72:26-33.
C
492. Israel E, Reddel HK. Severe and difficult-to-treat asthma in adults. N Engl J Med 2017;377:965-76.
493. Clark VL, Gibson PG, Genn G, Hiles SA, Pavord ID, McDonald VM. Multidimensional assessment of severe
asthma: A systematic review and meta-analysis. Respirology 2017;22:1262-75.
494. Gamble J, Stevenson M, McClean E, Heaney LG. The prevalence of nonadherence in difficult asthma. Am J Respir
Crit Care Med 2009;180:817-22.
495. McNicholl DM, Stevenson M, McGarvey LP, Heaney LG. The utility of fractional exhaled nitric oxide suppression in
the identification of nonadherence in difficult asthma. Am J Respir Crit Care Med 2012;186:1102-8.
496. Hanania NA, Alpan O, Hamilos DL, Condemi JJ, Reyes-Rivera I, Zhu J, Rosen KE, et al. Omalizumab in severe
allergic asthma inadequately controlled with standard therapy: a randomized trial. Ann Intern Med 2011;154:573-82.
497. Brusselle G, Michils A, Louis R, Dupont L, Van de Maele B, Delobbe A, Pilette C, et al. "Real-life" effectiveness of
omalizumab in patients with severe persistent allergic asthma: The PERSIST study. Respir Med 2009;103:1633-42.
498. Humbert M, Taille C, Mala L, Le Gros V, Just J, Molimard M. Omalizumab effectiveness in patients with severe
allergic asthma according to blood eosinophil count: the STELLAIR study. Eur Respir J 2018;51.
196 References
499. Hanania NA, Wenzel S, Rosen K, Hsieh HJ, Mosesova S, Choy DF, Lal P, et al. Exploring the effects of
omalizumab in allergic asthma: an analysis of biomarkers in the EXTRA study. Am J Respir Crit Care Med
2013;187:804-11.
500. Casale TB, Chipps BE, Rosen K, Trzaskoma B, Haselkorn T, Omachi TA, Greenberg S, et al. Response to
omalizumab using patient enrichment criteria from trials of novel biologics in asthma. Allergy 2018;73:490-7.
501. Busse WW. Are peripheral blood eosinophil counts a guideline for omalizumab treatment? STELLAIR says no! Eur
Respir J 2018;51:1800730.
502. Gevaert P, Van Bruaene N, Cattaert T, Van Steen K, Van Zele T, Acke F, De Ruyck N, et al. Mepolizumab, a
humanized anti-IL-5 mAb, as a treatment option for severe nasal polyposis. J Allergy Clin Immunol 2011;128:989-
95.e8.
503. Ortega HG, Yancey SW, Mayer B, Gunsoy NB, Keene ON, Bleecker ER, Brightling CE, et al. Severe eosinophilic
asthma treated with mepolizumab stratified by baseline eosinophil thresholds: a secondary analysis of the DREAM
and MENSA studies. Lancet Respir Med 2016;4:549-56.
504. Brusselle G, Germinaro M, Weiss S, Zangrilli J. Reslizumab in patients with inadequately controlled late-onset
TE
asthma and elevated blood eosinophils. Pulm Pharmacol Ther 2017;43:39-45.
U
505. FitzGerald JM, Bleecker ER, Menzies-Gow A, Zangrilli JG, Hirsch I, Metcalfe P, Newbold P, et al. Predictors of
IB
enhanced response with benralizumab for patients with severe asthma: pooled analysis of the SIROCCO and
TR
CALIMA studies. Lancet Respir Med 2018;6:51-64.
IS
D
506. Simpson EL, Akinlade B, Ardeleanu M. Two Phase 3 trials of dupilumab versus placebo in atopic dermatitis. N Engl
R
J Med 2017;376:1090-1.
O
507. Bachert C, Mannent L, Naclerio RM, Mullol J, Ferguson BJ, Gevaert P, Hellings P, et al. Effect of subcutaneous
PY
dupilumab on nasal polyp burden in patients with chronic sinusitis and nasal polyposis: A randomized clinical trial.
O
C
Jama 2016;315:469-79.
T
508. Rabe KF, Nair P, Brusselle G, Maspero JF, Castro M, Sher L, Zhu H, et al. Efficacy and safety of dupilumab in
O
N
glucocorticoid-dependent severe asthma. N Engl J Med 2018;378:2475-85.

O
509. Chipps BE, Newbold P, Hirsch I, Trudo F, Goldman M. Benralizumab efficacy by atopy status and serum
D
L-
immunoglobulin E for patients with severe, uncontrolled asthma. Ann Allergy Asthma Immunol 2018;120:504-11.e4.
IA
510. Hashimoto S, Brinke AT, Roldaan AC, van Veen IH, Moller GM, Sont JK, Weersink EJ, et al. Internet-based
ER
tapering of oral corticosteroids in severe asthma: a pragmatic randomised controlled trial. Thorax 2011;66:514-20.
AT
511. Haldar P, Brightling CE, Singapuri A, Hargadon B, Gupta S, Monteiro W, Bradding P, et al. Outcomes after
M
cessation of mepolizumab therapy in severe eosinophilic asthma: a 12-month follow-up analysis. J Allergy Clin
D
TE
Immunol 2014;133:921-3.
H
512. Ledford D, Busse W, Trzaskoma B, Omachi TA, Rosen K, Chipps BE, Luskin AT, et al. A randomized multicenter
IG
study evaluating Xolair persistence of response after long-term therapy. J Allergy Clin Immunol 2017;140:162-9.e2.
R
PY
513. Orellano P, Quaranta N, Reynoso J, Balbi B, Vasquez J. Effect of outdoor air pollution on asthma exacerbations in
O
children and adults: Systematic review and multilevel meta-analysis. PLoS One 2017;12:e0174050.
C
514. Ramnath VR, Clark S, Camargo CA, Jr. Multicenter study of clinical features of sudden-onset versus slower-onset
asthma exacerbations requiring hospitalization. Respir Care 2007;52:1013-20.
515. Jackson DJ, Johnston SL. The role of viruses in acute exacerbations of asthma. J Allergy Clin Immunol
2010;125:1178-87.
516. Erbas B, Jazayeri M, Lambert KA, Katelaris CH, Prendergast LA, Tham R, Parrodi MJ, et al. Outdoor pollen is a
trigger of child and adolescent asthma emergency department presentations: A systematic review and meta-
analysis. Allergy 2018;73:1632-41.
517. Anto JM, Sunyer J, Reed CE, Sabria J, Martinez F, Morell F, Codina R, et al. Preventing asthma epidemics due to
soybeans by dust-control measures. N Engl J Med 1993;329:1760-3.
518. Pike KC, Akhbari M, Kneale D, Harris KM. Interventions for autumn exacerbations of asthma in children. Cochrane
519. Williams LK, Peterson EL, Wells K, Ahmedani BK, Kumar R, Burchard EG, Chowdhry VK, et al. Quantifying the
proportion of severe asthma exacerbations attributable to inhaled corticosteroid nonadherence. J Allergy Clin
Immunol 2011;128:1185-91.e2.
References 197
520. Andrew E, Nehme Z, Bernard S, Abramson MJ, Newbigin E, Piper B, Dunlop J, et al. Stormy weather: a
retrospective analysis of demand for emergency medical services during epidemic thunderstorm asthma. BMJ
2017;359:j5636.
521. Alvarez GG, Schulzer M, Jung D, Fitzgerald JM. A systematic review of risk factors associated with near-fatal and
fatal asthma. Can Respir J 2005;12:265-70.
522. Suissa S, Blais L, Ernst P. Patterns of increasing beta-agonist use and the risk of fatal or near- fatal asthma. Eur
Respir J 1994;7:1602-9.
523. Roberts G, Patel N, Levi-Schaffer F, Habibi P, Lack G. Food allergy as a risk factor for life-threatening asthma in
childhood: a case-controlled study. J Allergy Clin Immunol 2003;112:168-74.
524. Blaiss MS, Nathan RA, Stoloff SW, Meltzer EO, Murphy KR, Doherty DE. Patient and physician asthma
deterioration terminology: results from the 2009 Asthma Insight and Management survey. Allergy Asthma Proc
2012;33:47-53.
525. Vincent SD, Toelle BG, Aroni RA, Jenkins CR, Reddel HK. "Exasperations" of asthma. A qualitative study of patient
language about worsening asthma. Med J Aust 2006;184:451-4.
TE
526. FitzGerald JM, Grunfeld A. Status asthmaticus. In: Lichtenstein LM, Fauci AS, eds. Current therapy in allergy,
U
immunology, and rheumatology. 5th edition. St. Louis, MO: Mosby; 1996:p. 63-7.
IB
527. Chan-Yeung M, Chang JH, Manfreda J, Ferguson A, Becker A. Changes in peak flow, symptom score, and the use
R
T
of medications during acute exacerbations of asthma. Am J Respir Crit Care Med 1996;154:889-93.
IS
D
528. Bousquet J, Boulet LP, Peters MJ, Magnussen H, Quiralte J, Martinez-Aguilar NE, Carlsheimer A.
R
Budesonide/formoterol for maintenance and relief in uncontrolled asthma vs. high-dose salmeterol/fluticasone.
O
Respir Med 2007;101:2437-46.
PY
529. Buhl R, Kuna P, Peters MJ, Andersson TL, Naya IP, Peterson S, Rabe KF. The effect of budesonide/formoterol
O
C
maintenance and reliever therapy on the risk of severe asthma exacerbations following episodes of high reliever
T
use: an exploratory analysis of two randomised, controlled studies with comparisons to standard therapy. Respir
O
N
Res 2012;13:59.
O
530. Kew KM, Quinn M, Quon BS, Ducharme FM. Increased versus stable doses of inhaled corticosteroids for
D
L-
exacerbations of chronic asthma in adults and children. Cochrane Database Syst Rev 2016:Cd007524.
IA
531. FitzGerald JM, Becker A, Sears MR, Mink S, Chung K, Lee J, Canadian Asthma Exacerbation Study Group.
ER
Doubling the dose of budesonide versus maintenance treatment in asthma exacerbations. Thorax 2004;59:550-6.
AT
532. Harrison TW, Oborne J, Newton S, Tattersfield AE. Doubling the dose of inhaled corticosteroid to prevent asthma
M
exacerbations: randomised controlled trial. Lancet 2004;363:271-5.

D
TE
533. Reddel HK, Barnes DJ. Pharmacological strategies for self-management of asthma exacerbations. Eur Respir J
H
2006;28:182-99.
IG
534. Ducharme FM, Lemire C, Noya FJ, Davis GM, Alos N, Leblond H, Savdie C, et al. Preemptive use of high-dose
R
PY
fluticasone for virus-induced wheezing in young children. N Engl J Med 2009;360:339-53.

O
535. Oborne J, Mortimer K, Hubbard RB, Tattersfield AE, Harrison TW. Quadrupling the dose of inhaled corticosteroid to
C
prevent asthma exacerbations: a randomized, double-blind, placebo-controlled, parallel-group clinical trial. Am J

536. McKeever T, Mortimer K, Wilson A, Walker S, Brightling C, Skeggs A, Pavord I, et al. Quadrupling inhaled
glucocorticoid dose to abort asthma exacerbations. N Engl J Med 2018;378:902-10.
537. Jackson DJ, Bacharier LB, Mauger DT, Boehmer S, Beigelman A, Chmiel JF, Fitzpatrick AM, et al. Quintupling
inhaled glucocorticoids to prevent childhood asthma exacerbations. N Engl J Med 2018;378:891-901.
538. Richards RN. Side effects of short-term oral corticosteroids. J Cutan Med Surg 2008;12:77-81.
539. Cates CJ, Welsh EJ, Rowe BH. Holding chambers (spacers) versus nebulisers for beta-agonist treatment of acute
asthma. Cochrane Database Syst Rev 2013.
540. Selroos O. Dry-powder inhalers in acute asthma. Ther Deliv 2014;5:69-81.
541. Newman KB, Milne S, Hamilton C, Hall K. A comparison of albuterol administered by metered-dose inhaler and
spacer with albuterol by nebulizer in adults presenting to an urban emergency department with acute asthma. Chest
2002;121:1036-41.
198 References
542. Chien JW, Ciufo R, Novak R, Skowronski M, Nelson J, Coreno A, McFadden ER, Jr. Uncontrolled oxygen
administration and respiratory failure in acute asthma. Chest 2000;117:728-33.
543. Rodrigo GJ, Rodriquez Verde M, Peregalli V, Rodrigo C. Effects of short-term 28% and 100% oxygen on PaCO2
and peak expiratory flow rate in acute asthma: a randomized trial. Chest 2003;124:1312-7.
544. Perrin K, Wijesinghe M, Healy B, Wadsworth K, Bowditch R, Bibby S, Baker T, et al. Randomised controlled trial of
high concentration versus titrated oxygen therapy in severe exacerbations of asthma. Thorax 2011;66:937-41.
545. Patel B, Khine H, Shah A, Sung D, Medar S, Singer L. Randomized clinical trial of high concentration versus titrated
oxygen use in pediatric asthma. Pediatr Pulmonol 2019;54:970-6.
546. Siemieniuk RAC, Chu DK, Kim LH, Guell-Rous MR, Alhazzani W, Soccal PM, Karanicolas PJ, et al. Oxygen
therapy for acutely ill medical patients: a clinical practice guideline. BMJ 2018;363:k4169.
547. Hasegawa T, Ishihara K, Takakura S, Fujii H, Nishimura T, Okazaki M, Katakami N, et al. Duration of systemic
corticosteroids in the treatment of asthma exacerbation; a randomized study. Intern Med 2000;39:794-7.
548. Jones AM, Munavvar M, Vail A, Aldridge RE, Hopkinson L, Rayner C, O'Driscoll BR. Prospective, placebo-
controlled trial of 5 vs 10 days of oral prednisolone in acute adult asthma. Respir Med 2002;96:950-4.
TE
549. Chang AB, Clark R, Sloots TP, Stone DG, Petsky HL, Thearle D, Champion AA, et al. A 5- versus 3-day course of
U
oral corticosteroids for children with asthma exacerbations who are not hospitalised: a randomised controlled trial.
IB
Med J Aust 2008;189:306-10.
R
T
550. Normansell R, Sayer B, Waterson S, Dennett EJ, Del Forno M, Dunleavy A. Antibiotics for exacerbations of asthma.
IS
D
Cochrane Database Syst Rev 2018;6:Cd002741.
R
551. Leatherman J. Mechanical ventilation for severe asthma. Chest 2015;147:1671-80.
O
552. Shim CS, Williams MH, Jr. Evaluation of the severity of asthma: patients versus physicians. Am J Med 1980;68:11-
3. PY
O
C
553. Atta JA, Nunes MP, Fonseca-Guedes CH, Avena LA, Borgiani MT, Fiorenza RF, Martins MA. Patient and physician
T
evaluation of the severity of acute asthma exacerbations. Braz J Med Biol Res 2004;37:1321-30.
O
N
554. Geelhoed GC, Landau LI, Le Souef PN. Evaluation of SaO2 as a predictor of outcome in 280 children presenting
O
with acute asthma. Ann Emerg Med 1994;23:1236-41.

D
L-
555. Nowak RM, Tomlanovich MC, Sarkar DD, Kvale PA, Anderson JA. Arterial blood gases and pulmonary function
IA
testing in acute bronchial asthma. Predicting patient outcomes. JAMA 1983;249:2043-6.

ER
556. Carruthers DM, Harrison BD. Arterial blood gas analysis or oxygen saturation in the assessment of acute asthma?
AT
Thorax 1995;50:186-8.
M
557. White CS, Cole RP, Lubetsky HW, Austin JH. Acute asthma. Admission chest radiography in hospitalized adult
D
TE
patients. Chest 1991;100:14-6.

H
558. Roback MG, Dreitlein DA. Chest radiograph in the evaluation of first time wheezing episodes: review of current
IG
clinical practice and efficacy. Pediatr Emerg Care 1998;14:181-4.

R
PY
559. Cates C, FitzGerald JM, O'Byrne PM. Asthma. Clin Evidence 2000;3:686-700.
O
560. Hui DS, Chow BK, Chu LC, Ng SS, Hall SD, Gin T, Chan MT. Exhaled air and aerosolized droplet dispersion during
C
application of a jet nebulizer. Chest 2009;135:648-54.

561. Travers AH, Milan SJ, Jones AP, Camargo CA, Jr., Rowe BH. Addition of intravenous beta(2)-agonists to inhaled
beta(2)-agonists for acute asthma. Cochrane Database Syst Rev 2012;12:CD010179.
562. Manser R, Reid D, Abramson M. Corticosteroids for acute severe asthma in hospitalised patients. Cochrane
Database Syst Rev 2000;2.
563. Rowe BH, Spooner CH, Ducharme FM, Bretzlaff JA, Bota GW. Corticosteroids for preventing relapse following
acute exacerbations of asthma. Cochrane Database Syst Rev 2007:CD000195.
564. Kirkland SW, Cross E, Campbell S, Villa-Roel C, Rowe BH. Intramuscular versus oral corticosteroids to reduce
relapses following discharge from the emergency department for acute asthma. Cochrane Database Syst Rev
2018;6:Cd012629.
565. Edmonds ML, Milan SJ, Camargo CA, Jr., Pollack CV, Rowe BH. Early use of inhaled corticosteroids in the
emergency department treatment of acute asthma. Cochrane Database Syst Rev 2012;12:CD002308.
566. Ratto D, Alfaro C, Sipsey J, Glovsky MM, Sharma OP. Are intravenous corticosteroids required in status
asthmaticus? JAMA 1988;260:527-9.
References 199
567. Harrison BD, Stokes TC, Hart GJ, Vaughan DA, Ali NJ, Robinson AA. Need for intravenous hydrocortisone in
addition to oral prednisolone in patients admitted to hospital with severe asthma without ventilatory failure. Lancet
1986;1:181-4.
568. Gries DM, Moffitt DR, Pulos E, Carter ER. A single dose of intramuscularly administered dexamethasone acetate is
as effective as oral prednisone to treat asthma exacerbations in young children. J Pediatr 2000;136:298-303.
569. Krishnan JA, Riekert KA, McCoy JV, Stewart DY, Schmidt S, Chanmugam A, Hill P, et al. Corticosteroid use after
hospital discharge among high-risk adults with asthma. Am J Respir Crit Care Med 2004;170:1281-5.
570. Kayani S, Shannon DC. Adverse behavioral effects of treatment for acute exacerbation of asthma in children: a
comparison of two doses of oral steroids. Chest 2002;122:624-8.
571. Keeney GE, Gray MP, Morrison AK, Levas MN, Kessler EA, Hill GD, Gorelick MH, et al. Dexamethasone for acute
asthma exacerbations in children: a meta-analysis. Pediatrics 2014;133:493-9.
572. Kravitz J, Dominici P, Ufberg J, Fisher J, Giraldo P. Two days of dexamethasone versus 5 days of prednisone in the
treatment of acute asthma: a randomized controlled trial. Ann Emerg Med 2011;58:200-4.
573. Cronin JJ, McCoy S, Kennedy U, An Fhaili SN, Wakai A, Hayden J, Crispino G, et al. A randomized trial of single-
TE
dose oral dexamethasone versus multidose prednisolone for acute exacerbations of asthma in children who attend
U
the emergency department. Ann Emerg Med 2016;67:593-601.e3.
IB
574. O'Driscoll BR, Kalra S, Wilson M, Pickering CA, Carroll KB, Woodcock AA. Double-blind trial of steroid tapering in
R
T
acute asthma. Lancet 1993;341:324-7.
IS
D
575. Lederle FA, Pluhar RE, Joseph AM, Niewoehner DE. Tapering of corticosteroid therapy following exacerbation of
R
asthma. A randomized, double-blind, placebo-controlled trial. Arch Intern Med 1987;147:2201-3.
O
576. Edmonds ML, Milan SJ, Brenner BE, Camargo CA, Jr., Rowe BH. Inhaled steroids for acute asthma following
PY
emergency department discharge. Cochrane Database Syst Rev 2012;12:CD002316.
O
C
577. Rodrigo GJ, Castro-Rodriguez JA. Anticholinergics in the treatment of children and adults with acute asthma: a
T
systematic review with meta-analysis. Thorax 2005;60:740-6.

O
N
578. Griffiths B, Ducharme FM. Combined inhaled anticholinergics and short-acting beta2-agonists for initial treatment of
O
acute asthma in children. Cochrane Database Syst Rev 2013;8:CD000060.

D
L-
579. Kirkland SW, Vandenberghe C, Voaklander B, Nikel T, Campbell S, Rowe BH. Combined inhaled beta-agonist and
IA
anticholinergic agents for emergency management in adults with asthma. Cochrane Database Syst Rev
ER
2017;1:Cd001284.
AT
580. Vezina K, Chauhan BF, Ducharme FM. Inhaled anticholinergics and short-acting beta(2)-agonists versus short-
M
acting beta2-agonists alone for children with acute asthma in hospital. Cochrane Database Syst Rev
D
TE
2014;7:Cd010283.
H
581. Nair P, Milan SJ, Rowe BH. Addition of intravenous aminophylline to inhaled beta(2)-agonists in adults with acute
IG
asthma. Cochrane Database Syst Rev 2012;12:CD002742.

R
PY
582. Rowe BH, Bretzlaff JA, Bourdon C, Bota GW, Camargo CA, Jr. Magnesium sulfate for treating exacerbations of
O
acute asthma in the emergency department. Cochrane Database Syst Rev 2000;2.
C
583. FitzGerald JM. Magnesium sulfate is effective for severe acute asthma treated in the emergency department. West
J Med 2000;172:96.
584. Gallegos-Solorzano MC, Perez-Padilla R, Hernandez-Zenteno RJ. Usefulness of inhaled magnesium sulfate in the
coadjuvant management of severe asthma crisis in an emergency department. Pulm Pharmacol Ther 2010;23:432-
7.
585. Goodacre S, Cohen J, Bradburn M, Gray A, Benger J, Coats T. Intravenous or nebulised magnesium sulphate
versus standard therapy for severe acute asthma (3Mg trial): a double-blind, randomised controlled trial. Lancet
Respir Med 2013;1:293-300.
586. Griffiths B, Kew KM. Intravenous magnesium sulfate for treating children with acute asthma in the emergency
department. Cochrane Database Syst Rev 2016;4:Cd011050.
587. Knightly R, Milan SJ, Hughes R, Knopp-Sihota JA, Rowe BH, Normansell R, Powell C. Inhaled magnesium sulfate
in the treatment of acute asthma. Cochrane Database Syst Rev 2017;11:Cd003898.
588. Turker S, Dogru M, Yildiz F, Yilmaz SB. The effect of nebulised magnesium sulphate in the management of
childhood moderate asthma exacerbations as adjuvant treatment. Allergol Immunopathol (Madr) 2017;45:115-20.
200 References
589. Rodrigo GJ, Castro-Rodriguez JA. Heliox-driven beta2-agonists nebulization for children and adults with acute
asthma: a systematic review with meta-analysis. Ann Allergy Asthma Immunol 2014;112:29-34.
590. Ramsay CF, Pearson D, Mildenhall S, Wilson AM. Oral montelukast in acute asthma exacerbations: a randomised,
double-blind, placebo-controlled trial. Thorax 2011;66:7-11.
591. Watts K, Chavasse RJ. Leukotriene receptor antagonists in addition to usual care for acute asthma in adults and
children. Cochrane Database Syst Rev 2012;5:Cd006100.
592. Balanag VM, Yunus F, Yang PC, Jorup C. Efficacy and safety of budesonide/formoterol compared with salbutamol
in the treatment of acute asthma. Pulm Pharmacol Ther 2006;19:139-47.
593. Peters JI, Shelledy DC, Jones AP, Jr., Lawson RW, Davis CP, LeGrand TS. A randomized, placebo-controlled
study to evaluate the role of salmeterol in the in-hospital management of asthma. Chest 2000;118:313-20.
594. Joseph KS, Blais L, Ernst P, Suissa S. Increased morbidity and mortality related to asthma among asthmatic
patients who use major tranquillisers. BMJ 1996;312:79-82.
595. FitzGerald JM, Macklem P. Fatal asthma. Annu Rev Med 1996;47:161-8.
596. Lim WJ, Mohammed Akram R, Carson KV, Mysore S, Labiszewski NA, Wedzicha JA, Rowe BH, et al. Non-invasive
TE
positive pressure ventilation for treatment of respiratory failure due to severe acute exacerbations of asthma.
U
Cochrane Database Syst Rev 2012;12:CD004360.
IB
597. Kelly A-M, Kerr D, Powell C. Is severity assessment after one hour of treatment better for predicting the need for
TR
admission in acute asthma? Respir Med 2004;98:777-81.
IS
D
598. Wilson MM, Irwin RS, Connolly AE, Linden C, Manno MM. A prospective evaluation of the 1-hour decision point for
R
admission versus discharge in acute asthma. J Intensive Care Med 2003;18:275-85.
O
599. Grunfeld A, FitzGerald J. Discharge considerations for adult asthmatic patients treated in emergency departments.
Can Respir J 1996;3:322 - 7. PY
O
C
600. Pollack CV, Jr., Pollack ES, Baren JM, Smith SR, Woodruff PG, Clark S, Camargo CA, et al. A prospective
T
multicenter study of patient factors associated with hospital admission from the emergency department among
O
N
children with acute asthma. Arch Pediatr Adolesc Med 2002;156:934-40.

O
601. Rowe BH, Villa-Roel C, Abu-Laban RB, Stenstrom R, Mackey D, Stiell IG, Campbell S, et al. Admissions to
D
L-
Canadian hospitals for acute asthma: a prospective, multicentre study. Can Respir J 2010;17:25-30.
IA
602. Weber EJ, Silverman RA, Callaham ML, Pollack CV, Woodruff PG, Clark S, Camargo CA, Jr. A prospective
ER
multicenter study of factors associated with hospital admission among adults with acute asthma. Am J Med
AT
2002;113:371-8.
M
603. Kirkland SW, Vandermeer B, Campbell S, Villa-Roel C, Newton A, Ducharme FM, Rowe BH. Evaluating the
D
TE
effectiveness of systemic corticosteroids to mitigate relapse in children assessed and treated for acute asthma: A
H
network meta-analysis. J Asthma 2018:1-12.

IG
604. Cowie RL, Revitt SG, Underwood MF, Field SK. The effect of a peak flow-based action plan in the prevention of
R
PY
exacerbations of asthma. Chest 1997;112:1534-8.

O
605. Ducharme FM, Zemek RL, Chalut D, McGillivray D, Noya FJ, Resendes S, Khomenko L, et al. Written action plan in
C
pediatric emergency room improves asthma prescribing, adherence, and control. Am J Respir Crit Care Med
2011;183:195-203.
606. Postma DS, Rabe KF. The Asthma-COPD Overlap Syndrome. N Engl J Med 2015;373:1241-9.
607. Nelson HS, Weiss ST, Bleecker ER, Yancey SW, Dorinsky PM. The Salmeterol Multicenter Asthma Research Trial:
a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest 2006;129:15-
26.
608. McMahon AW, Levenson MS, McEvoy BW, Mosholder AD, Murphy D. Age and risks of FDA-approved long-acting
2-adrenergic receptor agonists. Pediatrics 2011;128:e1147-54.
609. Gershon AS, Campitelli MA, Croxford R, et al. Combination long-acting β-agonists and inhaled corticosteroids
compared with long-acting β-agonists alone in older adults with chronic obstructive pulmonary disease. JAMA
2014;312:1114-21.
610. Suissa S, Ernst P. Observational studies of inhaled corticosteroid effectiveness in COPD: Lessons learned. Chest
2018;154:257-65.
References 201
611. Kendzerska T, Aaron SD, To T, Licskai C, Stanbrook M, Vozoris NT, Hogan ME, et al. Effectiveness and safety of
inhaled corticosteroids in older individuals with chronic obstructive pulmonary disease and/or asthma. A population
study. Annals of the American Thoracic Society 2019;16:1252-62.
612. Vonk JM, Jongepier H, Panhuysen CIM, Schouten JP, Bleecker ER, Postma DS. Risk factors associated with the
presence of irreversible airflow limitation and reduced transfer coefficient in patients with asthma after 26 years of
follow up. Thorax 2003;58:322-7.
613. Lange P, Celli B, Agusti A, Boje Jensen G, Divo M, Faner R, Guerra S, et al. Lung-function trajectories leading to
chronic obstructive pulmonary disease. N Engl J Med 2015;373:111-22.
614. Abramson MJ, Schattner RL, Sulaiman ND, Del Colle EA, Aroni R, Thien F. Accuracy of asthma and COPD
diagnosis in Australian general practice: a mixed methods study. Prim Care Respir J 2012;21:167-73.
615. Gibson PG, Simpson JL. The overlap syndrome of asthma and COPD: what are its features and how important is
it? Thorax 2009;64:728-35.
616. Mannino DM, Gagnon RC, Petty TL, Lydick E. Obstructive lung disease and low lung function in adults in the United
States: data from the National Health and Nutrition Examination Survey, 1988-1994. Arch Intern Med
TE
2000;160:1683-9.
U
617. Marsh SE, Travers J, Weatherall M, Williams MV, Aldington S, Shirtcliffe PM, Hansell AL, et al. Proportional
IB
classifications of COPD phenotypes. Thorax 2008;63:761-7.
TR
618. Shirtcliffe P, Marsh S, Travers J, Weatherall M, Beasley R. Childhood asthma and GOLD-defined chronic
IS
D
obstructive pulmonary disease. Intern Med J 2012;42:83-8.
R
619. Guerra S, Sherrill DL, Kurzius-Spencer M, Venker C, Halonen M, Quan SF, Martinez FD. The course of persistent
O
airflow limitation in subjects with and without asthma. Respir Med 2008;102:1473-82.
PY
620. Silva GE, Sherrill DL, Guerra S, Barbee RA. Asthma as a risk factor for COPD in a longitudinal study. Chest
O
C
2004;126:59-65.
T
621. van Schayck CP, Levy ML, Chen JC, Isonaka S, Halbert RJ. Coordinated diagnostic approach for adult obstructive
O
N
lung disease in primary care. Prim Care Respir J 2004;13:218-21.

O
622. Zeki AA, Schivo M, Chan A, Albertson TE, Louie S. The asthma-COPD overlap syndrome: a common clinical
D
L-
problem in the elderly. J Allergy 2011;2011:861926.

IA
623. Kendzerska T, Sadatsafavi M, Aaron SD, To TM, Lougheed MD, FitzGerald JM, Gershon AS. Concurrent
ER
physician-diagnosed asthma and chronic obstructive pulmonary disease: A population study of prevalence,
AT
incidence and mortality. PLoS One 2017;12:e0173830.

M
624. Kauppi P, Kupiainen H, Lindqvist A, Tammilehto L, Kilpelainen M, Kinnula VL, Haahtela T, et al. Overlap syndrome
D
TE
of asthma and COPD predicts low quality of life. J Asthma 2011;48:279-85.

H
625. Weatherall M, Travers J, Shirtcliffe PM, Marsh SE, Williams MV, Nowitz MR, Aldington S, et al. Distinct clinical
IG
phenotypes of airways disease defined by cluster analysis. Eur Respir J 2009;34:812-8.

R
PY
626. Inoue H, Nagase T, Morita S, Yoshida A, Jinnai T, Ichinose M. Prevalence and characteristics of asthma-COPD
O
overlap syndrome identified by a stepwise approach. Int J Chron Obstruct Pulmon Dis 2017;12:1803-10.
C
627. Uchida A, Sakaue K, Inoue H. Epidemiology of asthma-chronic obstructive pulmonary disease overlap (ACO).
Allergol Int 2018;67:165-71.
628. Krishnan JA, Nibber A, Chisholm A, Price D, Bateman ED, Bjermer L, van Boven JFM, et al. Prevalence and
characteristics of Asthma-Chronic Obstructive Pulmonary Disease Overlap in routine primary care practices. Annals
of the American Thoracic Society 2019;16:1143-50.
629. Andersen H, Lampela P, Nevanlinna A, Saynajakangas O, Keistinen T. High hospital burden in overlap syndrome of
asthma and COPD. Clin Respir J 2013;7:342-6.
630. Kew KM, Seniukovich A. Inhaled steroids and risk of pneumonia for chronic obstructive pulmonary disease.
Cochrane Database Syst Rev 2014;3:CD010115.
631. Suissa S, Patenaude V, Lapi F, Ernst P. Inhaled corticosteroids in COPD and the risk of serious pneumonia. Thorax
2013;68:1029-36.
632. Louie S, Zeki AA, Schivo M, Chan AL, Yoneda KY, Avdalovic M, Morrissey BM, et al. The asthma-chronic
obstructive pulmonary disease overlap syndrome: pharmacotherapeutic considerations. Expert Rev Clin Pharmacol
2013;6:197-219.
202 References
633. Masoli M, Fabian D, Holt S, Beasley R. The global burden of asthma: executive summary of the GINA
Dissemination Committee report. Allergy 2004;59:469-78.
634. Simpson CR, Sheikh A. Trends in the epidemiology of asthma in England: a national study of 333,294 patients. J R
Soc Med 2010;103:98-106.
635. Bisgaard H, Szefler S. Prevalence of asthma-like symptoms in young children. Pediatr Pulmonol 2007;42:723-8.
636. Kuehni CE, Strippoli MP, Low N, Brooke AM, Silverman M. Wheeze and asthma prevalence and related health-
service use in white and south Asian pre-schoolchildren in the United Kingdom. Clin Exp Allergy 2007;37:1738-46.
637. Martinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen M, Morgan WJ. Asthma and wheezing in the first six
years of life. The Group Health Medical Associates. N Engl J Med 1995;332:133-8.
638. Sly PD, Boner AL, Bjorksten B, Bush A, Custovic A, Eigenmann PA, Gern JE, et al. Early identification of atopy in
the prediction of persistent asthma in children. Lancet 2008;372:1100-6.
639. Heikkinen T, Jarvinen A. The common cold. Lancet 2003;361:51-9.
640. Caudri D, Wijga A, CM AS, Hoekstra M, Postma DS, Koppelman GH, Brunekreef B, et al. Predicting the long-term
prognosis of children with symptoms suggestive of asthma at preschool age. J Allergy Clin Immunol 2009;124:903-
TE
10 e1-7.
U
641. Brand PL, Baraldi E, Bisgaard H, Boner AL, Castro-Rodriguez JA, Custovic A, de Blic J, et al. Definition,
IB
assessment and treatment of wheezing disorders in preschool children: an evidence-based approach. Eur Respir J
R
T
2008;32:1096-110.
IS
D
642. Belgrave DCM, Simpson A, Semic-Jusufagic A, Murray CS, Buchan I, Pickles A, Custovic A. Joint modeling of
R
parentally reported and physician-confirmed wheeze identifies children with persistent troublesome wheezing. J
O
PY
643. Savenije OE, Kerkhof M, Koppelman GH, Postma DS. Predicting who will have asthma at school age among
O
C
preschool children. J Allergy Clin Immunol 2012;130:325-31.
T
644. Doherty G, Bush A. Diagnosing respiratory problems in young children. Practitioner 2007;251:20, 2-5.
O
N
645. Pedersen S. Preschool asthma--not so easy to diagnose. Prim Care Respir J 2007;16:4-6.
O
646. Brand PL, Caudri D, Eber E, Gaillard EA, Garcia-Marcos L, Hedlin G, Henderson J, et al. Classification and
D
L-
pharmacological treatment of preschool wheezing: changes since 2008. Eur Respir J 2014;43:1172-7.
IA
647. Cano Garcinuno A, Mora Gandarillas I, Group SS. Early patterns of wheezing in asthmatic and nonasthmatic
ER
children. Eur Respir J 2013;42:1020-8.

AT
648. Just J, Saint-Pierre P, Gouvis-Echraghi R, Boutin B, Panayotopoulos V, Chebahi N, Ousidhoum-Zidi A, et al.

M
Wheeze phenotypes in young children have different courses during the preschool period. Ann Allergy Asthma
D
TE
Immunol 2013;111:256-61.e1.
H
649. Saglani S, McKenzie SA, Bush A, Payne DN. A video questionnaire identifies upper airway abnormalities in
IG
preschool children with reported wheeze. Arch Dis Child 2005;90:961-4.

R
PY
650. Mellis C. Respiratory noises: how useful are they clinically? Pediatr Clin North Am 2009;56:1-17, ix.
O
651. Oren E, Rothers J, Stern DA, Morgan WJ, Halonen M, Wright AL. Cough during infancy and subsequent childhood
C
asthma. Clin Exp Allergy 2015;45:1439-46.

652. Azad MB, Chan-Yeung M, Chan ES, Dytnerski AM, Kozyrskyj AL, Ramsey C, Becker AB. Wheezing Patterns in
Early Childhood and the Risk of Respiratory and Allergic Disease in Adolescence. JAMA pediatrics 2016;170:393-5.
653. Van Der Heijden HH, Brouwer ML, Hoekstra F, Van Der Pol P, Merkus PJ. Reference values of exhaled nitric oxide
in healthy children 1-5 years using off-line tidal breathing. Pediatr Pulmonol 2014;49:291-5.
654. Singer F, Luchsinger I, Inci D, Knauer N, Latzin P, Wildhaber JH, Moeller A. Exhaled nitric oxide in symptomatic
children at preschool age predicts later asthma. Allergy 2013;68:531-8.
655. Caudri D, Wijga AH, Hoekstra MO, Kerkhof M, Koppelman GH, Brunekreef B, Smit HA, et al. Prediction of asthma
in symptomatic preschool children using exhaled nitric oxide, Rint and specific IgE. Thorax 2010;65:801-7.
656. Castro-Rodriguez JA, Holberg CJ, Wright AL, Martinez FD. A clinical index to define risk of asthma in young
children with recurrent wheezing. Am J Respir Crit Care Med 2000;162:1403-6.
657. Guilbert TW, Morgan WJ, Krawiec M, Lemanske RF, Jr., Sorkness C, Szefler SJ, Larsen G, et al. The Prevention of
Early Asthma in Kids study: design, rationale and methods for the Childhood Asthma Research and Education
network. Control Clin Trials 2004;25:286-310.
References 203
658. Chang TS, Lemanske RF, Jr., Guilbert TW, Gern JE, Coen MH, Evans MD, Gangnon RE, et al. Evaluation of the
modified asthma predictive index in high-risk preschool children. J Allergy Clin Immunol Pract 2013;1.
659. Murray CS, Poletti G, Kebadze T, Morris J, Woodcock A, Johnston SL, Custovic A. Study of modifiable risk factors
for asthma exacerbations: virus infection and allergen exposure increase the risk of asthma hospital admissions in
children. Thorax 2006;61:376-82.
660. Guilbert TW, Morgan WJ, Zeiger RS, Mauger DT, Boehmer SJ, Szefler SJ, Bacharier LB, et al. Long-term inhaled
corticosteroids in preschool children at high risk for asthma. N Engl J Med 2006;354:1985-97.
661. Bisgaard H, Allen D, Milanowski J, Kalev I, Willits L, Davies P. Twelve-month safety and efficacy of inhaled
fluticasone propionate in children aged 1 to 3 years with recurrent wheezing. Pediatrics 2004;113:e87-94.
662. Fitzpatrick AM, Jackson DJ, Mauger DT, Boehmer SJ, Phipatanakul W, Sheehan WJ, Moy JN, et al. Individualized
therapy for persistent asthma in young children. J Allergy Clin Immunol 2016;138:1608-18.e12.
663. Kelly HW, Sternberg AL, Lescher R, Fuhlbrigge AL, Williams P, Zeiger RS, Raissy HH, et al. Effect of inhaled
glucocorticoids in childhood on adult height. N Engl J Med 2012;367:904-12.
664. Bisgaard H, Hermansen MN, Loland L, Halkjaer LB, Buchvald F. Intermittent inhaled corticosteroids in infants with
TE
episodic wheezing. N Engl J Med 2006;354:1998-2005.
U
665. Wilson NM, Silverman M. Treatment of acute, episodic asthma in preschool children using intermittent high dose
IB
inhaled steroids at home. Arch Dis Child 1990;65:407-10.
R
T
666. Nielsen KG, Bisgaard H. The effect of inhaled budesonide on symptoms, lung function, and cold air and
IS
D
methacholine responsiveness in 2- to 5-year-old asthmatic children. Am J Respir Crit Care Med 2000;162:1500-6.
R
667. Szefler SJ, Baker JW, Uryniak T, Goldman M, Silkoff PE. Comparative study of budesonide inhalation suspension
O
and montelukast in young children with mild persistent asthma. J Allergy Clin Immunol 2007;120:1043-50.
PY
668. Kaiser SV, Huynh T, Bacharier LB, Rosenthal JL, Bakel LA, Parkin PC, Cabana MD. Preventing exacerbations in
O
C
preschoolers with recurrent wheeze: A meta-analysis. Pediatrics 2016;137.
T
669. Knorr B, Franchi LM, Bisgaard H, Vermeulen JH, LeSouef P, Santanello N, Michele TM, et al. Montelukast, a
O
N
leukotriene receptor antagonist, for the treatment of persistent asthma in children aged 2 to 5 years. Pediatrics
O
2001;108:E48.
D
L-
670. Brodlie M, Gupta A, Rodriguez-Martinez CE, Castro-Rodriguez JA, Ducharme FM, McKean MC. Leukotriene
IA
receptor antagonists as maintenance and intermittent therapy for episodic viral wheeze in children. Cochrane
ER
Database Syst Rev 2015:Cd008202.

AT
671. Castro-Rodriguez JA, Rodriguez-Martinez CE, Ducharme FM. Daily inhaled corticosteroids or montelukast for
M
preschoolers with asthma or recurrent wheezing: A systematic review. Pediatr Pulmonol 2018;53:1670-7.
D
TE
672. Papi A, Nicolini G, Baraldi E, Boner AL, Cutrera R, Rossi GA, Fabbri LM, et al. Regular vs prn nebulized treatment
H
in wheeze preschool children. Allergy 2009;64:1463-71.

IG
673. Zeiger RS, Mauger D, Bacharier LB, Guilbert TW, Martinez FD, Lemanske RF, Jr., Strunk RC, et al. Daily or
R
PY
intermittent budesonide in preschool children with recurrent wheezing. N Engl J Med 2011;365:1990-2001.
O
674. Yoshihara S, Tsubaki T, Ikeda M, Lenney W, Tomiak R, Hattori T, Hashimoto K, et al. The efficacy and safety of
C
fluticasone/salmeterol compared to fluticasone in children younger than four years of age. Pediatr Allergy Immunol
2019;30:195-203.
675. Piippo-Savolainen E, Remes S, Kannisto S, Korhonen K, Korppi M. Asthma and lung function 20 years after
wheezing in infancy: results from a prospective follow-up study. Arch Pediatr Adolesc Med 2004;158:1070-6.
676. Wennergren G, Hansson S, Engstrom I, Jodal U, Amark M, Brolin I, Juto P. Characteristics and prognosis of
hospital-treated obstructive bronchitis in children aged less than two years. Acta Paediatr 1992;81:40-5.
677. Goksor E, Amark M, Alm B, Gustafsson PM, Wennergren G. Asthma symptoms in early childhood--what happens
then? Acta Paediatr 2006;95:471-8.
678. Castro-Rodriguez JA, Rodrigo GJ. Beta-agonists through metered-dose inhaler with valved holding chamber versus
nebulizer for acute exacerbation of wheezing or asthma in children under 5 years of age: a systematic review with
meta-analysis. J Pediatr 2004;145:172-7.
679. Zemek RL, Bhogal SK, Ducharme FM. Systematic review of randomized controlled trials examining written action
plans in children: what is the plan? Arch Pediatr Adolesc Med 2008;162:157-63.
204 References
680. Swern AS, Tozzi CA, Knorr B, Bisgaard H. Predicting an asthma exacerbation in children 2 to 5 years of age. Ann
681. Brunette MG, Lands L, Thibodeau LP. Childhood asthma: prevention of attacks with short-term corticosteroid
treatment of upper respiratory tract infection. Pediatrics 1988;81:624-9.
682. Fox GF, Marsh MJ, Milner AD. Treatment of recurrent acute wheezing episodes in infancy with oral salbutamol and
prednisolone. Eur J Pediatr 1996;155:512-6.
683. Grant CC, Duggan AK, DeAngelis C. Independent parental administration of prednisone in acute asthma: a double-
blind, placebo-controlled, crossover study. Pediatrics 1995;96:224-9.
684. Oommen A, Lambert PC, Grigg J. Efficacy of a short course of parent-initiated oral prednisolone for viral wheeze in
children aged 1-5 years: randomised controlled trial. Lancet 2003;362:1433-8.
685. Vuillermin P, South M, Robertson C. Parent-initiated oral corticosteroid therapy for intermittent wheezing illnesses in
children. Cochrane Database Syst Rev 2006:CD005311.
686. Robertson CF, Price D, Henry R, Mellis C, Glasgow N, Fitzgerald D, Lee AJ, et al. Short-course montelukast for
intermittent asthma in children: a randomized controlled trial. Am J Respir Crit Care Med 2007;175:323-9.
TE
687. Bacharier LB, Phillips BR, Zeiger RS, Szefler SJ, Martinez FD, Lemanske RF, Jr., Sorkness CA, et al. Episodic use
U
of an inhaled corticosteroid or leukotriene receptor antagonist in preschool children with moderate-to-severe
IB
intermittent wheezing. J Allergy Clin Immunol 2008;122:1127-35 e8.
R
T
688. Gouin S, Robidas I, Gravel J, Guimont C, Chalut D, Amre D. Prospective evaluation of two clinical scores for acute
IS
D
asthma in children 18 months to 7 years of age. Acad Emerg Med 2010;17:598-603.
R
689. Pollock M, Sinha IP, Hartling L, Rowe BH, Schreiber S, Fernandes RM. Inhaled short-acting bronchodilators for
O
managing emergency childhood asthma: an overview of reviews. Allergy 2017;72:183-200.
PY
690. Powell C, Kolamunnage-Dona R, Lowe J, Boland A, Petrou S, Doull I, Hood K, et al. Magnesium sulphate in acute
O
C
severe asthma in children (MAGNETIC): a randomised, placebo-controlled trial. Lancet Respir Med 2013;1:301-8.
T
691. Pruikkonen H, Tapiainen T, Kallio M, Dunder T, Pokka T, Uhari M, Renko M. Intravenous magnesium sulfate for
O
N
acute wheezing in young children: a randomised double-blind trial. Eur Respir J 2018;51.
O
692. Fuglsang G, Pedersen S, Borgstrom L. Dose-response relationships of intravenously administered terbutaline in

D
L-
children with asthma. J Pediatr 1989;114:315-20.

IA
693. Connett G, Lenney W. Prevention of viral induced asthma attacks using inhaled budesonide. Arch Dis Child
ER
1993;68:85-7.
AT
694. Svedmyr J, Nyberg E, Thunqvist P, Asbrink-Nilsson E, Hedlin G. Prophylactic intermittent treatment with inhaled
M
corticosteroids of asthma exacerbations due to airway infections in toddlers. Acta Paediatr 1999;88:42-7.
D
TE
695. Razi CH, Akelma AZ, Harmanci K, Kocak M, Kuras Can Y. The addition of inhaled budesonide to standard therapy
H
shortens the length of stay in hospital for asthmatic preschool children: A randomized, double-blind, placebo-
IG
controlled trial. Int Arch Allergy Immunol 2015;166:297-303.

R
PY
696. Garrett J, Williams S, Wong C, Holdaway D. Treatment of acute asthmatic exacerbations with an increased dose of
O
inhaled steroid. Arch Dis Child 1998;79:12-7.

C
697. Rowe BH, Spooner C, Ducharme FM, Bretzlaff JA, Bota GW. Early emergency department treatment of acute
asthma with systemic corticosteroids. Cochrane Database Syst Rev 2001:CD002178.
698. Panickar J, Lakhanpaul M, Lambert PC, Kenia P, Stephenson T, Smyth A, Grigg J. Oral prednisolone for preschool
children with acute virus-induced wheezing. N Engl J Med 2009;360:329-38.
699. Webb MS, Henry RL, Milner AD. Oral corticosteroids for wheezing attacks under 18 months. Arch Dis Child
1986;61:15-9.
700. Castro-Rodriguez JA, Beckhaus AA, Forno E. Efficacy of oral corticosteroids in the treatment of acute wheezing
episodes in asthmatic preschoolers: Systematic review with meta-analysis. Pediatr Pulmonol 2016;51:868-76.
701. Bunyavanich S, Rifas-Shiman SL, Platts-Mills TA, Workman L, Sordillo JE, Camargo CA, Jr., Gillman MW, et al.
Peanut, milk, and wheat intake during pregnancy is associated with reduced allergy and asthma in children. J
702. Maslova E, Granstrom C, Hansen S, Petersen SB, Strom M, Willett WC, Olsen SF. Peanut and tree nut
consumption during pregnancy and allergic disease in children-should mothers decrease their intake? Longitudinal
evidence from the Danish National Birth Cohort. J Allergy Clin Immunol 2012;130:724-32.
References 205
703. Maslova E, Strom M, Oken E, Campos H, Lange C, Gold D, Olsen SF. Fish intake during pregnancy and the risk of
child asthma and allergic rhinitis - longitudinal evidence from the Danish National Birth Cohort. Br J Nutr
2013;110:1313-25.
704. Best KP, Gold M, Kennedy D, Martin J, Makrides M. Omega-3 long-chain PUFA intake during pregnancy and
allergic disease outcomes in the offspring: a systematic review and meta-analysis of observational studies and
randomized controlled trials. Am J Clin Nutr 2016;103:128-43.
705. Best KP, Sullivan T, Palmer D, Gold M, Kennedy DJ, Martin J, Makrides M. Prenatal Fish Oil Supplementation and
Allergy: 6-Year Follow-up of a Randomized Controlled Trial. Pediatrics 2016;137.
706. Hansen S, Strom M, Maslova E, Dahl R, Hoffmann HJ, Rytter D, Bech BH, et al. Fish oil supplementation during
pregnancy and allergic respiratory disease in the adult offspring. J Allergy Clin Immunol 2017;139:104-11.e4.
707. Best KP, Sullivan TR, Palmer DJ, Gold M, Martin J, Kennedy D, Makrides M. Prenatal omega-3 LCPUFA and
symptoms of allergic disease and sensitization throughout early childhood - a longitudinal analysis of long-term
follow-up of a randomized controlled trial. The World Allergy Organization journal 2018;11:10.
708. Forno E, Young OM, Kumar R, Simhan H, Celedon JC. Maternal obesity in pregnancy, gestational weight gain, and
TE
risk of childhood asthma. Pediatrics 2014;134:e535-46.
U
709. Chan-Yeung M, Becker A. Primary prevention of childhood asthma and allergic disorders. Curr Opin Allergy Clin
IB
Immunol 2006;6:146-51.
TR
710. Greer FR, Sicherer SH, Burks AW. The effects of early nutritional interventions on the development of atopic
IS
D
disease in infants and children: The role of maternal dietary restriction, breastfeeding, hydrolyzed formulas, and
R
timing of introduction of allergenic complementary foods. Pediatrics 2019;143.
O
711. Nurmatov U, Devereux G, Sheikh A. Nutrients and foods for the primary prevention of asthma and allergy:
PY
systematic review and meta-analysis. J Allergy Clin Immunol 2011;127:724-33.e1-30.
O
C
712. Chawes BL, Bonnelykke K, Stokholm J, Vissing NH, Bjarnadottir E, Schoos AM, Wolsk HM, et al. Effect of vitamin
T
D3 supplementation during pregnancy on risk of persistent wheeze in the offspring: A randomized clinical trial.
O
N
Jama 2016;315:353-61.
O
713. Litonjua AA, Carey VJ, Laranjo N, Harshfield BJ, McElrath TF, O'Connor GT, Sandel M, et al. Effect of prenatal
D
L-
supplementation with Vitamin D on asthma or recurrent wheezing in offspring by age 3 years: The VDAART
IA
randomized clinical trial. Jama 2016;315:362-70.

ER
714. Wolsk HM, Harshfield BJ, Laranjo N, Carey VJ, O'Connor G, Sandel M, Strunk RC, et al. Vitamin D
AT
supplementation in pregnancy, prenatal 25(OH)D levels, race, and subsequent asthma or recurrent wheeze in
M
offspring: Secondary analyses from the Vitamin D Antenatal Asthma Reduction Trial. J Allergy Clin Immunol
D
TE
2017;140:1423-9.e5.
H
715. Stratakis N, Roumeliotaki T, Oken E, Ballester F, Barros H, Basterrechea M, Cordier S, et al. Fish and seafood
IG
consumption during pregnancy and the risk of asthma and allergic rhinitis in childhood: a pooled analysis of 18
R
PY
European and US birth cohorts. Int J Epidemiol 2017;46:1465-77.

O
716. Bisgaard H, Stokholm J, Chawes BL, Vissing NH, Bjarnadottir E, Schoos AM, Wolsk HM, et al. Fish Oil-Derived
C
Fatty Acids in Pregnancy and Wheeze and Asthma in Offspring. N Engl J Med 2016;375:2530-9.
717. Azad MB, Coneys JG, Kozyrskyj AL, Field CJ, Ramsey CD, Becker AB, Friesen C, et al. Probiotic supplementation
during pregnancy or infancy for the prevention of asthma and wheeze: systematic review and meta-analysis. BMJ
2013;347:f6471.
718. Celedon JC, Milton DK, Ramsey CD, Litonjua AA, Ryan L, Platts-Mills TAE, Gold DR. Exposure to dust mite
allergen and endotoxin in early life and asthma and atopy in childhood. J Allergy Clin Immunol 2007;120:144-9.
719. Lodge CJ, Lowe AJ, Gurrin LC, Hill DJ, Hosking CS, Khalafzai RU, Hopper JL, et al. House dust mite sensitization
in toddlers predicts current wheeze at age 12 years. J Allergy Clin Immunol 2011;128:782-8.e9.
720. Custovic A, Simpson BM, Simpson A, Kissen P, Woodcock A, NAC Manchester Asthma Allergy Study Group. Effect
of environmental manipulation in pregnancy and early life on respiratory symptoms and atopy during first year of
life: a randomised trial. Lancet 2001;358:188-93.
721. Perzanowski MS, Chew GL, Divjan A, Johnson A, Goldstein IF, Garfinkel RS, Hoepner LA, et al. Cat ownership is a
risk factor for the development of anti-cat IgE but not current wheeze at age 5 years in an inner-city cohort. J Allergy
Clin Immunol 2008;121:1047-52.
206 References
722. Melen E, Wickman M, Nordvall SL, van Hage-Hamsten M, Lindfors A. Influence of early and current environmental
exposure factors on sensitization and outcome of asthma in pre-school children. Allergy 2001;56:646-52.
723. Takkouche B, Gonzalez-Barcala FJ, Etminan M, Fitzgerald M. Exposure to furry pets and the risk of asthma and
allergic rhinitis: a meta-analysis. Allergy 2008;63:857-64.
724. Bufford JD, Gern JE. Early exposure to pets: good or bad? Current Allergy & Asthma Reports 2007;7:375-82.
725. Ownby DR, Johnson CC, Peterson EL. Exposure to dogs and cats in the first year of life and risk of allergic
sensitization at 6 to 7 years of age. JAMA 2002;288:963-72.
726. Lodrup Carlsen KC, Roll S, Carlsen KH, Mowinckel P, Wijga AH, Brunekreef B, Torrent M, et al. Does pet
ownership in infancy lead to asthma or allergy at school age? Pooled analysis of individual participant data from 11
European birth cohorts. PLoS One 2012;7:e43214.
727. Quansah R, Jaakkola MS, Hugg TT, Heikkinen SA, Jaakkola JJ. Residential dampness and molds and the risk of
developing asthma: a systematic review and meta-analysis. PLoS ONE [Electronic Resource] 2012;7:e47526.
728. Arshad SH, Bateman B, Matthews SM. Primary prevention of asthma and atopy during childhood by allergen
avoidance in infancy: a randomised controlled study. Thorax 2003;58:489-93.
TE
729. Becker A, Watson W, Ferguson A, Dimich-Ward H, Chan-Yeung M. The Canadian asthma primary prevention
U
study: outcomes at 2 years of age. J Allergy Clin Immunol 2004;113:650-6.
IB
730. Schonberger HJAM, Dompeling E, Knottnerus JA, Maas T, Muris JWM, van Weel C, van Schayck CP. The
TR
PREVASC study: the clinical effect of a multifaceted educational intervention to prevent childhood asthma. Eur
IS
D
Respir J 2005;25:660-70.
R
731. van Schayck OCP, Maas T, Kaper J, Knottnerus AJA, Sheikh A. Is there any role for allergen avoidance in the
O
primary prevention of childhood asthma? J Allergy Clin Immunol 2007;119:1323-8.
PY
732. Chan-Yeung M, Ferguson A, Watson W, Dimich-Ward H, Rousseau R, Lilley M, Dybuncio A, et al. The Canadian
O
C
Childhood Asthma Primary Prevention Study: outcomes at 7 years of age. J Allergy Clin Immunol 2005;116:49-55.
T
733. Scott M, Roberts G, Kurukulaaratchy RJ, Matthews S, Nove A, Arshad SH. Multifaceted allergen avoidance during
O
N
infancy reduces asthma during childhood with the effect persisting until age 18 years. Thorax 2012;67:1046-51.
O
734. Valovirta E, Petersen TH, Piotrowska T, Laursen MK, Andersen JS, Sorensen HF, Klink R. Results from the 5-year
D
L-
SQ grass sublingual immunotherapy tablet asthma prevention (GAP) trial in children with grass pollen allergy. J
IA

ER
735. Wongtrakool C, Wang N, Hyde DM, Roman J, Spindel ER. Prenatal nicotine exposure alters lung function and
AT
airway geometry through 7 nicotinic receptors. Am J Respir Cell Mol Biol 2012;46:695-702.
M
736. Burke H, Leonardi-Bee J, Hashim A, Pine-Abata H, Chen Y, Cook DG, Britton JR, et al. Prenatal and passive
D
TE
smoke exposure and incidence of asthma and wheeze: systematic review and meta-analysis. Pediatrics
H
2012;129:735-44.
IG
737. Bowatte G, Lodge C, Lowe AJ, Erbas B, Perret J, Abramson MJ, Matheson M, et al. The influence of childhood
R
PY
traffic-related air pollution exposure on asthma, allergy and sensitization: a systematic review and a meta-analysis
O
of birth cohort studies. Allergy 2015;70:245-56.

C
738. Khreis H, Kelly C, Tate J, Parslow R, Lucas K, Nieuwenhuijsen M. Exposure to traffic-related air pollution and risk of
development of childhood asthma: A systematic review and meta-analysis. Environ Int 2017;100:1-31.
739. Achakulwisut P, Brauer M, Hystad P, Anenberg SC. Global, national, and urban burdens of paediatric asthma
incidence attributable to ambient NO2 pollution: estimates from global datasets. Lancet Planet Health 2019;3:e166-
e78.
740. Hehua Z, Qing C, Shanyan G, Qijun W, Yuhong Z. The impact of prenatal exposure to air pollution on childhood
wheezing and asthma: A systematic review. Environ Res 2017;159:519-30.
741. Haahtela T, Holgate S, Pawankar R, Akdis CA, Benjaponpitak S, Caraballo L, Demain J, et al. The biodiversity
hypothesis and allergic disease: world allergy organization position statement. World Allergy Org J 2013;6:3.
742. Riedler J, Braun-Fahrlander C, Eder W, Schreuer M, Waser M, Maisch S, Carr D, et al. Exposure to farming in early
life and development of asthma and allergy: a cross-sectional survey. Lancet 2001;358:1129-33.
743. Braun-Fahrlander C, Riedler J, Herz U, Eder W, Waser M, Grize L, Maisch S, et al. Environmental exposure to
endotoxin and its relation to asthma in school-age children. N Engl J Med 2002;347:869-77.
References 207
744. Karvonen AM, Hyvarinen A, Gehring U, Korppi M, Doekes G, Riedler J, Braun-Fahrlander C, et al. Exposure to
microbial agents in house dust and wheezing, atopic dermatitis and atopic sensitization in early childhood: a birth
cohort study in rural areas. Clin Exp Allergy 2012;42:1246-56.
745. Huang L, Chen Q, Zhao Y, Wang W, Fang F, Bao Y. Is elective cesarean section associated with a higher risk of
asthma? A meta-analysis. J Asthma 2015;52:16-25.
746. Keag OE, Norman JE, Stock SJ. Long-term risks and benefits associated with cesarean delivery for mother, baby,
and subsequent pregnancies: Systematic review and meta-analysis. PLoS Med 2018;15:e1002494.
747. Azad MB, Konya T, Maughan H, Guttman DS, Field CJ, Chari RS, Sears MR, et al. Gut microbiota of healthy
Canadian infants: profiles by mode of delivery and infant diet at 4 months. CMAJ 2013;185:385-94.
748. Blanken MO, Rovers MM, Molenaar JM, Winkler-Seinstra PL, Meijer A, Kimpen JLL, Bont L, et al. Respiratory
syncytial virus and recurrent wheeze in healthy preterm infants. N Engl J Med 2013;368:1791-9.
749. Scheltema NM, Nibbelke EE, Pouw J, Blanken MO, Rovers MM, Naaktgeboren CA, Mazur NI, et al. Respiratory
syncytial virus prevention and asthma in healthy preterm infants: a randomised controlled trial. Lancet Respir Med
2018;6:257-64.
TE
750. Kozyrskyj AL, Mai XM, McGrath P, Hayglass KT, Becker AB, Macneil B. Continued exposure to maternal distress in
U
early life is associated with an increased risk of childhood asthma. Am J Respir Crit Care Med 2008;177:142-7.
IB
751. Marra F, Marra CA, Richardson K, Lynd LD, Kozyrskyj A, Patrick DM, Bowie WR, et al. Antibiotic use in children is
R
T
associated with increased risk of asthma. Pediatrics 2009;123:1003-10.
IS
D
752. Stensballe LG, Simonsen J, Jensen SM, Bonnelykke K, Bisgaard H. Use of antibiotics during pregnancy increases
R
the risk of asthma in early childhood. J Pediatr 2013;162:832-8.e3.
O
753. Celedon JC, Fuhlbrigge A, Rifas-Shiman S, Weiss ST, Finkelstein JA. Antibiotic use in the first year of life and
asthma in early childhood. Clin Exp Allergy 2004;34:1011-6. PY
O
C
754. Cheelo M, Lodge CJ, Dharmage SC, Simpson JA, Matheson M, Heinrich J, Lowe AJ. Paracetamol exposure in
T
pregnancy and early childhood and development of childhood asthma: a systematic review and meta-analysis. Arch
O
N
Dis Child 2015;100:81-9.

O
755. Eyers S, Weatherall M, Jefferies S, Beasley R. Paracetamol in pregnancy and the risk of wheezing in offspring: a
D
L-
systematic review and meta-analysis. Clin Exp Allergy 2011;41:482-9.

IA
756. Flanigan C, Sheikh A, DunnGalvin A, Brew BK, Almqvist C, Nwaru BI. Prenatal maternal psychosocial stress and
ER
offspring's asthma and allergic disease: A systematic review and meta-analysis. Clin Exp Allergy 2018;48:403-14.
AT
757. Xu S, Gilliland FD, Conti DV. Elucidation of causal direction between asthma and obesity: a bi-directional Mendelian
M
randomization study. Int J Epidemiol 2019.

D
TE
758. Beasley R, Semprini A, Mitchell EA. Risk factors for asthma: is prevention possible? Lancet 2015;386:1075-85.
H
759. Burgers J, Eccles M. Clinical guidelines as a tool for implementing change in patient care. Oxford: Butterworth-
IG
Heinemann; 2005.
R
PY
760. Woolf SH, Grol R, Hutchinson A, Eccles M, Grimshaw J. Clinical guidelines: potential benefits, limitations, and
O
harms of clinical guidelines. BMJ 1999;318:527-30.

C
761. ADAPTE Framework. Available from http://www.adapte.org. 2012.

762. Brouwers MC, Kho ME, Browman GP, Burgers JS, Cluzeau F, Feder G, Fervers B, et al. AGREE II: advancing
guideline development, reporting and evaluation in health care. CMAJ 2010;182:E839-42.
763. Boulet LP, FitzGerald JM, Levy ML, Cruz AA, Pedersen S, Haahtela T, Bateman ED. A guide to the translation of
the Global Initiative for Asthma (GINA) strategy into improved care. Eur Respir J 2012;39:1220-9.
764. Davis DA, Taylor-Vaisey A. Translating guidelines into practice. A systematic review of theoretic concepts, practical
experience and research evidence in the adoption of clinical practice guidelines. CMAJ 1997;157:408-16.
765. Harrison MB, Legare F, Graham ID, Fervers B. Adapting clinical practice guidelines to local context and assessing
barriers to their use. CMAJ 2010;182:E78-84.
766. Partridge MR. Translating research into practice: how are guidelines implemented? Eur Respir J Suppl
2003;39:23s-9s.
767. Baiardini I, Braido F, Bonini M, Compalati E, Canonica GW. Why do doctors and patients not follow guidelines?
Curr Opin Allergy Clin Immunol 2009;9:228-33.
208 References
768. Boulet LP, Becker A, Bowie D, Hernandez P, McIvor A, Rouleau M, Bourbeau J, et al. Implementing practice
guidelines: a workshop on guidelines dissemination and implementation with a focus on asthma and COPD. Can
Respir J 2006;13 Suppl A:5-47.
769. Franco R, Santos AC, do Nascimento HF, Souza-Machado C, Ponte E, Souza-Machado A, Loureiro S, et al. Cost-
effectiveness analysis of a state funded programme for control of severe asthma. BMC Public Health 2007;7:82.
770. Renzi PM, Ghezzo H, Goulet S, Dorval E, Thivierge RL. Paper stamp checklist tool enhances asthma guidelines
knowledge and implementation by primary care physicians. Can Respir J 2006;13:193-7.
771. Nkoy F, Fassl B, Stone B, Uchida DA, Johnson J, Reynolds C, Valentine K, et al. Improving pediatric asthma care
and outcomes across multiple hospitals. Pediatrics 2015;136:e1602-10.
772. Cochrane Effective Practice and Organisation of Care Group (EPOC). Available at http://epoc.cochrane.org. 2013.
TE
U
IB
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D
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O
C
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O
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O
D
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ER
AT
M
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PY
O
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References 209
TE
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IS
D
R
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PY
O
C
T
O
N
O
D
L-
IA
R
E
AT
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D
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GLOBAL STRATEGY FOR

© 2020 Global Initiative for Asthma

Chapter 2. Assessment of asthma ................................................................................................................................ 31

Assessing asthma symptom control .......................................................................................................................... 33

Assessing future risk of adverse outcomes ............................................................................................................... 37

Role of lung function in assessing asthma control..................................................................................................... 37

Assessing asthma severity ........................................................................................................................................ 39

Chapter 3. Treating asthma to control symptoms and minimize risk ....................................................................... 41

Part A. General principles of asthma management ....................................................................................................... 42

Long-term goals of asthma management .................................................................................................................. 42

The patient-health care provider partnership ............................................................................................................. 43

Personalized control-based asthma management .................................................................................................... 44

Diagnosis of exacerbations ...................................................................................................................................... 114

Self-management of exacerbations with a written asthma action plan ................................................................... 114

Management of asthma exacerbations in primary care........................................................................................... 118

Management of asthma exacerbations in the emergency department ................................................................... 121

overlap’) .......................................................................................................................................................................... 129

Objectives ................................................................................................................................................................ 131

Background to diagnosing asthma and/or COPD in adult patients ......................................................................... 131

Future research ........................................................................................................................................................ 137

SECTION 2. CHILDREN 5 YEARS AND YOUNGER ......................................................................................................... 139

Barriers and facilitators ............................................................................................................................................ 172

Examples of high impact implementation interventions ........................................................................................... 172

Evaluation of the implementation process ............................................................................................................... 172

How can GINA help with implementation? .............................................................................................................. 173

REFERENCES .................................................................................................................................................................... 174

Box 3-8. Treating modifiable risk factors to reduce exacerbations 67

Box 3-9. Non-pharmacological interventions - summary 70

Box 3-10. Effectiveness of avoidance measures for indoor allergens 74

Box 3-12. Strategies to ensure effective use of inhaler devices 80

Box 3-13. Poor medication adherence in asthma 81

Box 3-14. Asthma information 82

Difficult-to-treat and severe asthma

Box 3-15. What proportion of adults have difficult-to-treat or severe asthma? 95

Box 8-2. Essential elements required to implement a health-related strategy 171

Box 8-3. Examples of barriers to the implementation of evidence-based recommendations 172

Box 8-4 Examples of high-impact interventions in asthma management 172

management in the past 30 years.

Helen K Reddel, MBBS PhD Louis-Philippe Boulet, MD

GINA SCIENTIFIC COMMITTEE

Guy Brusselle, MD, PhD

Ghent University Hospital

Ghent University Hospital

Roland Buhl, MD PhD

Mainz University Hospital

University of British Columbia

Vancouver, BC, Canada

Royal Brompton Hospital

Salvador, BA, Brazil

Québec, QC, Canada

Guy Brusselle, MD, PhD

Ghent University Hospital

Jerry A. Krishnan, MD PhD

University of Illinois Hospital & Health Sciences System

PROCESSES FOR UPDATES AND REVISIONS OF THE GINA REPORT

submissions have rarely resulted in substantial changes to the report.

Screening and review

population of the recommendation, or the results are somewhat inconsistent.